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Brensocatib
Brensocatib
WeightAverage: 420.469
Monoisotopic: 420.179755269
Chemical FormulaC23H24N4O4
- AZD7986
- CAS 1802148-05-5
- INS1007
- AZD 7986
- WHO 11097
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide
- 1,4-Oxazepine-2-carboxamide, N-((1S)-1-cyano-2-(4-(2,3-dihydro-3-methyl-2-oxo-5-benzoxazolyl)phenyl)ethyl)hexahydro-, (2S)-
- (2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide
- (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
- Brensocatib [USAN]
- (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide
- UNII-25CG88L0BB
- (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide
FDA 8/12/2025. Brinsupri, To treat non-cystic fibrosis bronchiectasis
Brensocatib is an investigational new drug that is being evaluated to treat bronchiectasis.[1] It is a dipeptidyl-peptidase I (also known as cathepsin C) inhibitor.[2]
A phase 3 clinical trial, known as the ASPEN trial, was conducted to evaluate the safety and efficacy of brensocatib in patients with non-cystic fibrosis bronchiectasis.[3] Brensocatib tablets (Brinsupri) by Insmed Inc. was approved by the FDA in August 2025 after it received breakthrough therapy designation and was reviewed on a priority timeline.
Brensocatib is an orally bioavailable, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), with potential anti-inflammatory activity. Upon oral administration, brensocatib reversibly binds to and inhibits the activity of DPP1, thereby inhibiting the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibits the activity of NSPs, and may prevent lung inflammation and injury and improve lung function associated with NSPs-induced respiratory diseases. NSPs, serine proteases released by neutrophils during inflammation, is upregulated in a number of respiratory diseases.
SYN
J. Med. Chem. 2016, 59, 9457–9472, DOI: 10.1021/acs.jmedchem.6b01127
https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0040-1719365.pdf
SYN
Brensocatib is now a clinical candidate to impair proteasedriven tissue degradation in COVID-19 (B. Korkmaz,
A. Lesner, S. Marchand-Adam, C. Moss, D. E. Jenne
J. Med. Chem. 2020, 63, 13258).
PAT
https://patents.google.com/patent/US9522894B2/en
A compound according to claim 1
which is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
EXAMPLESExample 1(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide
i) tert-Butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate
2-Pyridinol-1-oxide (0.155 g, 1.4 mmol), TEA (0.36 g, 3.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.268 g, 1.4 mmol) were added to a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 0.294 g, 1.2 mmol) in DCM (15 mL). After 20 min
4′-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile (Intermediate 1, 0.296 g, 1.2 mmol) was added and the mixture was stirred for 3 h and allowed to stand at rt for 18 h. The mixture was heated at 40° C. for 4 h before water (15 mL) was added. After 10 min the DCM was dried (phase separating cartridge) and evaporated under reduced pressure. The resultant yellow oil was purified by silica gel column chromatography to give the subtitled compound (0.29 g, 52%). Used without further purification in the next step.ii) (2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide
Prepared according to procedure in Method A step ii) using tert-butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate to afford the title compound as a white solid (60 mg, 28%).
1H NMR (400 MHz, CDCl3): δ 7.77-7.65 (m, 4H), 7.62-7.57 (m, 2H), 7.40 (d, 2H), 7.11 (d, 1H), 5.18-5.11 (m, 1H), 4.19-4.14 (m, 1H), 4.06-3.96 (m, 2H), 3.75-3.69 (m, 1H), 3.56-3.48 (m, 2H), 3.18-3.05 (m, 3H), 2.95-2.90 (m, 1H), 2.70 (ddd, 1H) (1 exchangeable proton not observed).
LCMS (10 cm_ESCI_Formic_MeCN) tR 2.57 (min) m/z 375 (MH+).Example 2(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
i) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (468 mg, 2.44 mmol) and 2-pyridinol 1-oxide (271 mg, 2.44 mmol) were added to a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 490 mg, 2.0 mmol) in DCM (15 mL). The reaction was stirred at rt for 30 min before the addition of (2S)-2-amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile (Intermediate 2, 586 mg, 2.0 mmol) and DiPEA (1.79 mL, 10 mmol). The reaction was stirred at rt for 18 h before transferring to a separating funnel. The mixture was washed with 2 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic extract was run through a hydrophobic frit/phase separator and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-60% EtOAc in iso-hexane to afford the subtitled compound as an oil (457 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 7.63-7.52 (m, 2H), 7.38 (d, 2H), 7.36-7.24 (m, 2H), 7.35-6.98 (m, 2H), 5.18 (t, 1H), 4.22-3.97 (m, 2H), 3.76-3.67 (m, 0.5H), 4.10-2.94 (m, 4.5H), 3.35-3.26 (m, 1H), 3.24-3.04 (m, 3H), 2.06-1.82 (m, 2H), 1.47 (s, 10H).ii) (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (457 mg, 0.85 mmol) was dissolved in formic acid (3 mL) and heated at 50° C. for 10 min on a pre-heated stirrer hotplate. After this time the reaction was concentrated under reduced pressure, dissolved in DCM and washed with saturated sodium hydrogen carbonate solution. The organic extract was run through a hydrophobic frit/phase separator and concentrated under reduced pressure. The resultant foam was purified by silica gel column chromatography eluting with 0-5% methanolic ammonia (7 N) in DCM to afford the title compound as solid material (230 mg, 64%).
1H NMR (400 MHz, CDCl3): δ 7.59-7.51 (m, 2H), 7.39 (dd, 2H), 7.33-7.23 (m, 3H), 7.14 (d, 1H), 5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m, 1H), 3.46 (s, 3H), 3.34-3.26 (m, 1H), 3.19-3.00 (m, 3H), 2.99-2.82 (m, 2H), 1.92-1.77 (m, 2H) (one exchangeable proton not observed).
LCMS (10 cm_ESCI_Formic_MeCN) tR 2.48 (min) m/z 375 (MH+).Example 2Alternative Synthesis(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamidei) 5-Chloro-1,3-benzoxazol-2(3H)-one
To a solution of 2-amino-4-chlorophenol (400 g, 2.79 mol) in 2-MeTHF (6 L) was added CDI (497 g, 3.07 mol) under N2 (exotherm 11.0° C.-22.0° C.). The reaction mixture was heated at reflux for 1 h. The mixture was cooled to rt, washed with 2 M HCl(aq) (6 L), 8% NaHCO3(aq) (6 L) and brine (3 L). The organic layer was dried over MgSO4, filtered and evaporated. This gave the product as a pale brown solid (456.1 g, 97% yield, LC purity >99%).
1H NMR (270 MHz, DMSO-d6): δ 12.0-11.5 (br s, 1H), 7.31 (d, 1H), 7.12 (m, 2H).
LCMS (5 cm_ESCI, aq. formic acid_methanol) tR 3.87 (min) m/z 169.8 (MH+).ii) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one
To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (stage i) (1111.8 g, 6.56 mol) in DMF (4.12 L) was added Cs2CO3 (2136.4 g, 6.56 mol) maintaining the temperature between 0-5° C. MeI (450 ml, 7.21 mol) was then added slowly maintaining the temperature between 0-5° C. The reaction mixture was allowed to warm-up to rt and stirred overnight. The mixture was cooled to 0-5° C. and H2O (4.12 L) was added slowly. The reaction mixture was then warmed to rt and stirred for 15 min. The solids were filtered off and washed with water (4×980 ml). The filter cake was dried under vacuum at 55° C. overnight (1149.9 g, 96% yield, LC purity >99%, H2O: (Karl Fischer) 0.1%).
1H NMR (270 MHz, DMSO-d6): δ 7.45 (d, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 3.35 (s, 3H). LCMS (5 cm_ESCI_aq. formic acid_methanol) tR 4.13 (min) m/z 183.8 (M+).iii) 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one
A solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (stage ii)) (350 g, 1.91 mol), B2pin2 (581.0 g, 2.29 mol) and KOAc (561.3 g, 5.72 mol) was vacuum degassed and purged with N2 (×3). Pd(OAc)2 (12.9 g, 57.2 mmol) and XPhos (54.6 g, 114 mmol) were added and the mixture was vacuum degassed and purged with N2 (×3). The mixture was heated to 75° C. A large exotherm was observed at ˜70° C. which warmed-up the mixture to reflux (100° C.). The reaction mixture was stirred for 1 h with no heating. HPLC analysis indicated 2.5% of the starting material remaining therefore the mixture was heated at 85° C. for 1 h. At this stage, no further change was observed. Additional portions of B2pin2 (14.6 g, 57.2 mmol), KOAc (5.7 g, 57.2 mmol), Pd(OAc)2 (12.9 g, 57.2 mmol) and XPhos (27.3 g, 57.2 mmol) were added and the mixture was stirred for 1 h at 75° C. HPLC analysis showed no starting material remaining. The mixture was cooled to rt, filtered through a pad of Celite (501 g) and the cake was washed with EtOAc (2240 ml). The filtrate was combined with two other batches prepared in the same way (2×350 g) and evaporated. This gave 1865.1 g of the product as a grey solid (97% yield, 90.0% pure by LC, 82±2% pure by 1H NMR (DMSO-d6) assay vs TCNB).
1H NMR (270 MHz, DMSO-d6): δ 7.40-7.50 (m, 2H), 7.30 (d, 1H), 3.40 (s, 3H), 1.30 (s, 12H).
LCMS (5 cm_ESCI_aq. formic acid_methanol_) tR 4.91 (min) m/z 276.1 (MH+).iv) Nα-(tert-Butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide
To a suspension of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one (stage iii)) (859 g, 700 g active, 2.544 mol) and tert-butyl (S)-1-carbamoyl-2-(4-iodophenypethylcarbamate (prepared according to the procedure in WO 2009/074829 p. 47), (903 g, 2.313 mol) in dioxane (4.1 L) was added 2 M K2CO3 (2.3 L). The suspension was vacuum degassed and purged with N2 (×3). Pd(dppf)Cl2.DCM (28.33 g, 0.0347 mol) was added and the reaction mixture was heated at 75° C. for 3 h. The mixture was cooled to rt and diluted with water (6.4 L). The suspension was stirred at rt overnight; the solid was filtered off and washed with water (3×1 L). The product was dried at 45° C. for 3 days (1269.1 g, yield 133%—by 1H NMR contains pinacol related impurity and dioxane, LC 94.3% pure, H2O: (Karl Fischer) 3.35%).
1H NMR (270 MHz, DMSO-d6): δ 7.62-7.34 (m, 7H), 7.04 (brs, 2H), 6.86 (d, 1H) 4.12 (m, 1H), 3.40 (s, 3H), 3.00 (dd, 1H), 2.78 (dd, 1H), 1.30 (s, 9H).
LCMS (5 cm_ESI_Water_MeCN) tR 4.51 (min) m/z 312 (MH+).v) 4-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide
To a very thick suspension of Nα-(tert-butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (stage iv)) (1269 g, active 952 g assumed 100% conversion at stage iv), 2.3138 mol) in DCM (2.1 L) under N2 was added dropwise 4.1 M HCl in dioxane (2.7 L, 11.06 mol) over 1 h maintaining the temperature at 15° C. (suspension became more mobile after addition of approx. 0.5 L of 4.1 M HCl dioxane). After 2 h, the mixture was diluted with water (5.6 L) and stirred for 30 min at rt. The mixture was then filtered through a pad of Celite (500 g) to remove undissolved material—very slow filtration; the Celite was checked for product by LC. The pad was washed with water (400 ml). The layers DCM/dioxane-water were separated. The aqueous layer was cooled to ˜5° C. and 35% NH3 (aq) (700 ml) was added slowly to achieve pH=9-10. The suspension was stirred overnight then the product was filtered off and washed with water (3×400 ml). The product was dried at 45° C. in vacuo for 2 days (off white solid, 489.4 g, 68% yield over two stages, 99.4% pure by LC, >99% EP, 98±2% pure by 1H NMR assay vs TCNB in DMSO, H2O: (Karl Fischer) 0.92%).
1H NMR (270 MHz, DMSO-d6): δ 7.59-7.30 (m, 7H), 6.98 (brs, 1H), 3.36 (m, 4H), 2.95 (dd, 1H), 2.67 (dd, 1H) 1.86 (brs, 2H).
LCMS (5 cm_ESI_Water_MeCN) tR 2.76 (min) m/z 312 (MH+).vi) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate
To a solution of 4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (stage v)) (756 g, active 733 g, 2.354 mol) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (577 g, 2.354) (Intermediate 3) in DMF (3 L) was added DiPEA (1230 ml, 7.062 mol) under N2. T3P in DMF (50% w/w, 1924 ml, 3.296 mol) was added dropwise over 1.5 h maintaining the temperature<25° C. After 30 min, LC completion check indicated completion of the coupling reaction. DiPEA (1230 ml, 7.062 mol) was then added and the reaction mixture was heated to 50° C. T3P in DMF (50% w/w, 3986 ml, 6.827 mol) was added portionwise over 1 h (no exotherm observed). The reaction mixture was stirred at 50° C. for 4 h and then at rt overnight. The mixture was cooled to 10° C., diluted with 2-MeTHF (4 L) and water (5.6 L, exothermic). The layers were separated and the aqueous layer was extracted with 2-MeTHF (2×4 L). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. This delivered the product as a pale brown solid in 98% yield (1242 g (active 1205 g), corrected yield 98%, LC purity 98.4%, 1H NMR assay vs TCNB 97±2%, main impurities by 1H NMR: 2-MeTHF 1.9%, DMF 0.6%).vii) (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
A solution of tert-butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (stage vi)) (1776 g, active 1671 g, 3.210 mol) in formic acid/water (4.2 L/440 ml) was stirred on a buchi at 35-37° C. under reduced pressure (300-500 mbar). After 3 h, LCMS completion check indicated 93.95% of the product and 0.5% of the starting material. The mixture was concentrated (4 h) to give an oily residue. The residue was dissolved in water (4.4 L) and washed with TBME (2.2 L). The aqueous layer was vigorously stirred and treated with NH3(aq) (1.8 L) at <25° C. to achieve pH=9-10. The mixture was stirred at rt for 3 h. The solid was filtered off and washed with water (3×1 L). The filter cake was dried at 45° C. overnight. This gave the product as a pale brown solid (1498 g, active 1333 g, LC 91.5%, 1H NMR assay vs TCNB 89±2%, H2O: (Karl Fischer) 4.63%).
The crude product was re-crystallised from EtOH/H2O in two batches (2×747 g).
Batch A: The crude product (747 g) was dissolved in EtOH (8 L) at reflux under N2. Water (1.6 L) was added slowly. The mixture was hot filtered (65° C.) to remove black particles (filtrate temperature
50° C.) and then stirred at 40° C. overnight. The suspension was cooled to 10° C. over 4 h and held at that temperature for 3 h. The product was filtered off and washed with EtOH/H2O (8:2, 3×500 ml) then water (3×500 ml). The filter cake was dried at 45° C. overnight (473 g, 97.7% pure by LC, Pd level 71.4 ppm).
Batch B gave 436 g of the product (95.8% pure by LC, Pd level 65.8 ppm).
The liquors from both batches were combined and concentrated to ˜8 L. The liquors were left overnight at rt. The solids were filtered off and washed with EtOH/H2O (8:2, 3×400 ml) then water (3×400 ml). The product was dried at 45° C. overnight. This gave additional 88 g of the product (LC purity 95.0%).
The products (LC purity of the blend 95.69%) were re-crystallised from EtOH/H2O in two batches (Batch C: 520 g, Batch D: 520 g).
Batch C: The crude product (520 g) was dissolved in EtOH (6.24 L) at reflux under N2. Water (1248 ml) was added slowly. The mixture was allowed to cool down to 40° C. (3 h), seeded with 0.5 g of the title compound and stirred at 40° C. for 10 h. The mixture was then cooled to 26° C. over 7 h. The resulting suspension was cooled to 10° C. and stirred at that temperature for 6 h. The product was filtered off, washed with EtOH/water (8:2, 3×500 ml) and water (3×500 ml). The filter cake was dried at 45° C. for 2 d. The product was obtained as a grey solid (418 g, yield ˜56%, LCMS purity 97.5%, chiral LC
100%, 1H NMR (DMSO-d6) assay vs TCNB
100±2%).
Batch D: 418 g, yield 56%, LCMS purity 97.5%, chiral LC
100%, 1H NMR (DMSO-d6) assay vs TCNB
100±2%
The product was blended with the material from an intermediate scale reaction performed in the same way and re-analysed (968 g, LC purity 98.04%, chiral LC
100%, 1H NMR assay vs TCNB 99±2%, 0.35% EtOH by 1H NMR, H2O: (Karl Fischer) 4.58%, Pd 57.6 ppm, XRPD (X-ray powder diffraction) Form A.
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References
- “Brensocatib – Insmed”. AdisInsight. Springer Nature Switzerland AG.
- Chalmers JD, Usansky H, Rubino CM, Teper A, Fernandez C, Zou J, et al. (October 2022). “Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis”. Clinical Pharmacokinetics. 61 (10): 1457–1469. doi:10.1007/s40262-022-01147-w. PMC 9553789. PMID 35976570.
- Chalmers JD, Burgel PR, Daley CL, De Soyza A, Haworth CS, Mauger D, et al. (April 2025). “Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis”. The New England Journal of Medicine. 392 (16): 1569–1581. doi:10.1056/NEJMoa2411664. PMID 40267423.
| Clinical data | |
|---|---|
| Other names | AZD7986; INS1007 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1802148-05-5 |
| PubChem CID | 118253852 |
| IUPHAR/BPS | 9412 |
| DrugBank | DB15638 |
| ChemSpider | 67896269 |
| UNII | 25CG88L0BB |
| KEGG | D12120 |
| ChEMBL | ChEMBL3900409 |
| Chemical and physical data | |
| Formula | C23H24N4O4 |
| Molar mass | 420.469 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
////////Brensocatib, APPROVALS 2025, FDA 2025, Brinsupri, non-cystic fibrosis, AZD7986, 1802148-05-5, INS1007, AZD 7986, WHO 11097
Unecritinib
Unecritinib
- CAS 1418026-92-2
- 4T3Z98RR86
- TQ-B3101
492.4 g/mol, C23H24Cl2FN5O2
N-[3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-yl]acetamide
- Acetamide, N-[3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-2-pyridinyl]-
- N-{3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1- (piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-yl}acetamide
Chia Tai Tianqing Pharmaceutical Group
Unecritinib is an orally available, small molecule inhibitor of the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), C-ros oncogene 1 (ROS1) and Met (hepatocyte growth factor receptor; HGFR; c-Met), with potential antineoplastic activity. Upon oral administration,unecritinib targets, binds to and inhibits the activity of ALK, ROS1 and c-Met, which leads to the disruption of ALK-, ROS1- and c-Met-mediated signaling and the inhibition of cell growth in ALK-, ROS1- and c-Met-expressing tumor cells. ALK, ROS1 and c-Met, overexpressed or mutated in many tumor cell types, play key roles in tumor cell proliferation, survival, invasion and metastasis.
UNECRITINIB is a small molecule drug with a maximum clinical trial phase of II (across all indications) and has 3 investigational indications.
- OriginatorChia Tai Tianqing Pharmaceutical Group
- ClassAcetamides; Antineoplastics; Benzofurans; Chlorobenzenes; Esters; Ethers; Fluorobenzenes; Ketones; Morpholines; Piperidines; Pyrazoles; Pyridines; Small molecules
- Mechanism of ActionAnaplastic lymphoma kinase inhibitors; Proto-oncogene protein c-met inhibitors; ROS1 protein inhibitors
- RegisteredNon-small cell lung cancer
- No development reportedAnaplastic large cell lymphoma
- 07 Sep 2024Efficacy and adverse events data from a phase II trial in Non-small cell lung cancer presented at the 25th World Conference on Lung Cancer (WCLC-2024)
- 17 May 2024Chemical structure information added
- 17 May 2024No development reported – Phase-II for Anaplastic large cell lymphoma (In adolescents, In children, Late-stage disease, Refractory metastatic disease, Second-line therapy or greater, In adults) in China (PO)
PATENT
https://patentscope.wipo.int/search/en/WO2013041038
Example 11: Synthesis of
(R)-N-(3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)- 5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-yl)acetamide (Compound 18)
Step 1. To a solution of (R)-tert-butyl 4-(4-(6-amino-5-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylate ( 4g, 7.27 mmol, 1.0 eq) and pyridine ( 2.3g, 29.1 mmol, 4.0 eq) in 50 ml DCM was added acetyl chloride (0.86g, 10.9 mmol, 1.5 eq) in an ice bath. The reaction mixture was stirred at room temperature for overnight. The resulting mixture was washed with H20 (3×20 mL). The organic layer was dried and concentrated. The crude product was purified on silica gel column to give (R)-tert-butyl 4-(4-(6-acetamido-5-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylatel .66g (38.6% yield).
Step 2. To a solution of (R)-tert-butyl 4-(4-(6-acetamido-5-(l-(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylate (500 mg, 0.84 mmol, 1.0 eq) in DCM (5 mL) was added trifluoroacetic acid (2 ml) in an ice bath. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 9 by saturated bicarbonate sodium in an ice bath. The aqueous solution was extracted with ethyl acetate (3×20 mL), the combined organic layers were washed with brine, dried over (MgSC^), filtered, and concentrated. The crude product was purified by silica gel column to give (R)-N-(3 -( 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)-5-( 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl)pyridin-2-yl)acetamide 250 mg (60.2% yield).
^-NMR^DC , 400Hz): 51.88(d, J=6.4Hz, 3H), 51.90-1.94(m, 2H), 52.16-2.20(m, 2H), 52.48(s, 3H), 52.76-2.824(m, 2H), 53.25-3.28(m, 2H), 53.69-3.74(m, 1H), 54.22-4.26 (m, 1H), 56.10-6.15(m, 1H), 57.05-7.07 (m, 1H), 57.09(s, 1H), 57.30-7.33 (m, 1H), 57.59(s, 1H), 57.62(s, 1H), 58.06(s, 1H),
58.12(s, 1H). MS m/z 493 [M+l]
PATENT
CN102850328
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN85774618&_cid=P12-MECPSG-91316-1
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Unecritinib, developed by Chia Tai Tianqing Pharmaceutical Group, is a novel small-molecule tyrosine kinase inhibitor. It targets c-rosoncogene 1 (ROS1), anaplastic lymphoma kinase (ALK), and c-mesen
chymal-epithelial transition factor (c-MET) kinases, exhibiting potent antitumor activity against cancers harboring these genetic alterations. In 2024, the NMPA approved Unecritinib under the brand name Anbaini for the treatment of adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Unecritinib exerts its therapeutic effects through selective inhibition of the kinase activities of ROS1, ALK, and c-MET, which effectively disrupts the downstream signaling pathways that are crucial for the proliferation and survival of tumor cells. Consequently, this inhibition induces cell cycle arrest and apoptosis in cancer cells that express these specific targets [13]. The clinical efficacy of Unecritinib was established in a Phase II single-arm, multicenter clinical trial (NCT03750739) enrolling patients with ROS1-positive advanced NSCLC. Among 111 evaluable patients, an ORR of 80.2 % was achieved, along with a median PFS of 16.5 months. These findings underscore the robust antitumor activity of Unecritinib in this specific patient cohort. In terms of safety, Unecritinib exhibited a
favorable tolerability profile. The most frequently reported treatment-related adverse events were neutropenia, leukopenia, vomit ing, and nausea, which were predominantly of mild (Grade 1) or mod
erate (Grade 2) severity. Importantly, no dose-limiting toxicities were observed, and the maximum tolerated dose was not established, further supporting its favorable safety profile. The approval of Unecritinib represents a novel therapeutic strategy for patients with ROS1-positive NSCLC, effectively addressing a significant unmet medical need within this population [13].
The synthesis of Unecritinib, depicted in Scheme 3, initiates with acetylation of Unec-001 to yield Unec-002, which undergoes deprotection to afford Unecritinib [14]
[13] S. Lu, H. Pan, L. Wu, Y. Yao, J. He, Y. Wang, X. Wang, Y. Fang, Z. Zhou, X. Wang,
X. Cai, Y. Yu, Z. Ma, X. Min, Z. Yang, L. Cao, H. Yang, Y. Shu, W. Zhuang, S. Cang,
J. Fang, K. Li, Z. Yu, J. Cui, Y. Zhang, M. Li, X. Wen, J. Zhang, W. Li, J. Shi, X. Xu,
D. Zhong, T. Wang, J. Zhu, Efficacy, safety and pharmacokinetics of unecritinib
(TQ-B3101) for patients with ROS1 positive advanced non-small cell lung cancer: a
phase I/II trial, Signal Transduct Target Ther 8 (2023) 249.
[14] A. Zhang, M. Geng, Y. Wang, J. Ai, X. Peng, Preparation of Pyridine Compounds as
Inhibitors of c-Met And/Or ALK Kinases, Shanghai Institute of Materia Medica,
2013 CN102850328A.
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/////////Unecritinib, Chia Tai Tianqing Pharmaceutical Group, 1418026-92-2, 4T3Z98RR86, TQ B3101, APPROVALS 2024, CHINA 2024
Dordaviprone
Dordaviprone
WeightAverage: 386.499
Monoisotopic: 386.210661473
Chemical FormulaC24H26N4O
- TIC10
- CAS 1616632-77-9
- Dordaviprone
- ONC201
- ONC 201
- 9U35A31JAI
- NSC-350625
11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one
Product Ingredients
| Ingredient | UNII | CAS | InChI Key |
|---|---|---|---|
| Dordaviprone dihydrochloride | 53VG71J90J | 1638178-82-1 | Not applicable |
- 11-benzyl-7-(o-tolylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one
- 11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.0(2,6)]trideca-1(9),5-dien-8-one
- 7-Benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one
- 7-benzyl-4-[(2-methylphenyl)methyl]-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one
FDA 8/6/2025, Modeyso, To treat diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy
Dordaviprone, sold under the brand name Modeyso is an anti-cancer medication used for the treatment of diffuse midline glioma (a type of brain tumor).[1][2] Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P.[1] It is dopamine receptor D2 antagonist and an allosteric activator of the mitochondrial caseinolytic protease P.[3]
Dordaviprone was approved for medical use in the United States in August 2025.[2] It is the first approval of a systemic therapy for H3 K27M-mutant diffuse midline glioma by the US Food and Drug Administration.[2]
Dordaviprone is an organic heterotricyclic compound that is 2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one substituted by 2-methylbenzyl and benzyl groups at positions 4 and 7, respectively. It is a selective antagonist of the dopamine receptor D2 and an allosteric agonist of mitochondrial protease caseinolytic protease P. It has a role as an antineoplastic agent, a dopamine receptor D2 antagonist and an apoptosis inducer. It is a member of toluenes, a member of benzenes and an organic heterotricyclic compound.
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References
- https://pp.jazzpharma.com/pi/modeyso.en.USPI.pdf [bare URL PDF]
- “FDA grants accelerated approval to dordaviprone for diffuse midline glioma”. U.S. Food and Drug Administration (FDA). 6 August 2025. Retrieved 7 August 2025.
This article incorporates text from this source, which is in the public domain. - Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, et al. (December 2020). “ONC201 and imipridones: Anti-cancer compounds with clinical efficacy”. Neoplasia. 22 (12). New York, N.Y.: 725–744. doi:10.1016/j.neo.2020.09.005. PMC 7588802. PMID 33142238.
- “Jazz Pharmaceuticals Announces U.S. FDA Approval of Modeyso (dordaviprone) as the First and Only Treatment for Recurrent H3 K27M-mutant Diffuse Midline Glioma” (Press release). Jazz Pharmaceuticals. 6 August 2025. Retrieved 10 August 2025 – via PR Newswire.
- World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89”. WHO Drug Information. 37 (1). hdl:10665/366661.
External links
- Clinical trial number NCT02525692 for “Oral ONC201 in Adult Recurrent Glioblastoma” at ClinicalTrials.gov
- Clinical trial number NCT03295396 for “ONC201 in Adults With Recurrent H3 K27M-mutant Glioma” at ClinicalTrials.gov
- Clinical trial number NCT03416530 for “ONC201 in Pediatric H3 K27M Gliomas” at ClinicalTrials.gov
- Clinical trial number NCT05392374 for “Expanded Access Use of ONC201 in a Patient With Diffuse Intrinsic Pontine Gliomas” at ClinicalTrials.gov
- Clinical trial number NCT03134131 for “Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Modeyso |
| Other names | ONC201, ONC-201 |
| AHFS/Drugs.com | Modeyso |
| License data | US DailyMed: Dordaviprone |
| Routes of administration | By mouth |
| Drug class | Protease activator |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1616632-77-9as HCl: 1638178-82-1 |
| PubChem CID | 73777259 |
| DrugBank | DB14844as HCl: DBSALT003291 |
| ChemSpider | 30904994 |
| UNII | 9U35A31JAIas HCl: 53VG71J90J |
| KEGG | D12733as HCl: D12734 |
| ChEBI | CHEBI:232328 |
| ChEMBL | ChEMBL4297310 |
| Chemical and physical data | |
| Formula | C24H26N4O |
| Molar mass | 386.499 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////Dordaviprone, Modeyso, FDA 2025, APPROVALS 2025, TIC10, 1616632-77-9, Dordaviprone, ONC201, ONC 201, 9U35A31JAI, NSC 350625
Tunlametinib
Tunlametinib
- CAS 1801756-06-8
- IF25NR1PV3
- HL085
- C16H12F2IN3O3S
491.3 g/mol
4-fluoro-5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide
- 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-6-benzothiazolecarboxamide
- 4-fluoro-5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide
- 6-Benzothiazolecarboxamide, 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-
Tunlametinib, an oral selective inhibitor of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), was developed by Shanghai KeChow Pharmaceuticals Co., Ltd. Marketed under the brand name
Keluping,
Tunlametinib is a pharmaceutical drug for the treatment of cancer. It is an inhbitor of mitogen-activated protein kinase kinase.[1]
In China, tunlametinib was approved in 2024 for the treatment of patients with NRAS-mutated advanced melanoma who were previously treated with a PD-1/PD-L1 targeting agent.[2][3]
It is also being studied for use in combination with vemurafenib in patients with advanced BRAF V600-mutant solid tumors.[4]
PAT
US9937158
PAT
https://patents.google.com/patent/WO2013107283A1/en
Step 1:
[0435] To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) was added strong base (such as LDA, nBuLi,
LiHDMS) at low temperature (-50 °C 80 °C, prefer -78 °C) under nitrogen atmosphere. The reaction is kept stirring for some time (0.5-12 h, prefer 0.5-2 h) and is added dry ice. After several hours (3-12 h, prefer 5-10 h), 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Step 2:
[0436] 5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) in the presence of base (such as LDA, n-BuLi, LiHDMS) in appropriate solvent (include aliphatic and aromatic
hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2- methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) at low temperature (-50 °C— -80 °C, prefer -78 °C) for some time (such as 3-12 h, prefer 5-10 h). 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.
Step 3:
[0437] 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl2 in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile(such as acetonitrile, propiononitrile), amide(such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol and ethanol). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl) amino)benzoate is obtained after conventional workup.
Step 4:
[0438] To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl) amino)benzoate in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester(such as ethyl acetate, methyl acetate), nitrile(such as acetonitrile, propiononitrile), amide(such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dioxane) was added base (such as aliphatic and aromatic amine(such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2- dimethylpropanamine), inorganic base(such as Na2C03, K2C03, NaHC03, KHC03, t-BuONa, t- BuOK), prefer N-ethyl-N-isopropylpropan-2-amine) at ambient temperature under nitrogen atmosphere, followed by Pd catalyst (such as tris(dibenzylideneacetone)dipalladium,
bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate, prefer tris(dibenzylideneacetone) dipalladium) and phosphine ligand (such as
dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4- chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1, 1 ‘- bis(diphenylphosphino)ferrocene, prefer dimethylbisdiphenylphosphinoxanthene). The reaction is kept stirring at high temperature (80-130 °C, prefer 90-110 °C) for some time (8-24 h, prefer 12-18 h). Methyl 3,4-difluoro-2- ((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup. Step 5:
[0439] Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be reacted with azide (such as NaN3, KN3) at high temperature (60-120 °C, prefer 80-100 °C) in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Methyl 4-azido-3-fluoro-2-((2-fluorophenyl) amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Step 6:
[0440] Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy
benzyl)thio)benzoate can be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester(such as ethyl acetate, methyl acetate), amide (such as N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol, ethanol, propan-l-ol and water) for some time (1-12 h, prefer 3-10 h). Methyl 4- amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup. Step 7:
[0441] 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be deprotected in the presence of acid (such as CF3COOH, HCOOH, CH3COOH and n- C5H11COOH, prefer CF3COOH) at certain temperature (20-75 °C, prefer 25-75 °C) in
appropriate aromatic aliphatic ether (such as anisole and phenetole, prefer anisole) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5- mercaptobenzoate is obtained after conventional workup.
Step 8:
[0442] Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercapto benzoate can be cyclized in the presence of acid (such as ^-toluenesulfonic acid, pyridinium toluene-4- sulphonate, formic acid, acetic acid, sulfuric acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as
dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N- methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane) for some time (0.2-12 h, prefer 0.5-10 h). Methyl 4-fluoro-5-((2- fluorophenyl)amino) benzo[d]thiazole-6-carboxylate is obtained after conventional workup. Step 9:
[0443] Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6- carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, acetic acid) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N- dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1- 12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl) amino)benzo[d]thiazole-6- carboxylate is obtained after conventional workup.
Step 10:
[0444] 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent(such as HOBt, EDCI, HATU, TBTU) at ambient temperature in appropriate solvent(include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N- methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane, 1,2- dichloroethane and N,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5- ((2-fluoro-4-iodophenyl) amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup. Step 11:
[0445] 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole- 6-carboxamide can be reacted in the presence of acid (such as HCl, H2S04, trifluoroacetic acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester(such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer 3-10 h). 4-Fluoro- 5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.
Example 9: Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyDamino)-N-(2- hydroxyethoxy)benzo[d]thiazole-6-carboxamide (Compound 9)
Step 1: 5-bromo-2,3,4-trifluorobenzoic acid
[0510] To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added «-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at -78 °C under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of l-bromo-2,3,4- trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at -78 °C, the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1- 2. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.95 (s, 1H), 7.97 (m, 1H).
Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid
[0511] To a solution of 2-fluoroaniline (17.54 g, 157.80 mmol) and 5-bromo-2,3,4- trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120 mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at -78 °C under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 24.24 g, 88.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.01 (dd, J= 7.4, 2.1 Hz, 1H), 7.25 (m, 1H), 7.10 (m, 3H).
Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate
[0512] To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino) benzoic acid (24.24 g, 70.04 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). After stirring at 85 °C overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL χ 3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50: 1, v/v), the corresponding product was obtained as a white solid (22.33 g, 88.5% yield). 1H NMR (400 MHz, CDC13): δ 9.06 (s, 1H), 8.01 (dd, J= 7.1, 2.3 Hz, 1H), 7.04 (m, 4H), 3.92 (s, 3H).
Step 4: methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate
[0513] To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl) amino)benzoate (22.33 g, 62.01 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N- diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd2(dba)3 (2.84 g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and 4-methoxy-a-toluenethiol (10.27 g, 65.11 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100 °C under N2 atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50: 1, v/v) to give the desired product (pale yellow solid, 24.35 g, 90.6% yield). 1H NMR (400 MHz, CDC13): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.25 (m, 6H), 6.85 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H). Step 5: methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate
[0514] To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2- ((2- fluorophenyl)amino)benzoate (24.35 g, 56.18 mmol) in DMF (200 mL) was added NaN3 (4.38 g, 67.41 mmol) at ambient temperature. The mixture was stirred at 90 °C for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL χ 3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10: 1, v/v) and gave the desired product (white solid, 21.04 g, 82.1% yield). 1H NMR (400 MHz, CDC13): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.10 (m, 6H), 6.84 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H). Step 6: methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2- fluorophenyl)amino)benzoate (21.04 g, 46.09 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.46 g, 98.1% yield). 1H NMR (400 MHz, CDC13): δ 9.07 (s, 1H), 7.77 (s, 1H), 7.06 (m, 4H), 6.95 (m, 2H), 6.81 (d, J = 8.3 Hz, 2H), 4.68 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).
Step 7: dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)
[0515] To a solution of methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2- fluorophenyl)amino)benzoate (19.46 g, 45.21 mmol) in CH2C12 (180 mL) was added DDQ (11.29 g, 49.73 mmol) followed by water (20 mL). After stirring at ambient temperature for 10 h, the reaction was quenched by saturated sodium bicarbonate (aq., 100 mL). The aqueous layer was extracted by CH2C12 (100 mL χ 3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5: 1, v/v) to give the desired product (pale yellow solid, 9.81 g, 35.1% yield). 1H NMR (400 MHz, CDC13): δ 9.34 (s, 2H), 7.46 (s, 2H), 7.06 (m, 8H), 4.89 (br, 4H), 3.75 (s, 6H). Step 8: methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate
[0516] To a solution of dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2- fluorophenyl)amino)benzoate) (9.81 g, 15.86 mmol) in THF/MeOH (100 mL, 10: 1, v/v) was added NaBH4 (3.00 g, 79.29 mmol) portion-wise in 1 h. After stirring at ambient temperature for 1 h, the reaction was quenched with 10% HCl (aq.) and pH was adjusted to 1-2. The aqueous layer was extracted with CH2C12 (50 mL χ 3). The combined organic phase was washed with water (50 mL) and brine (50 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.
Step 9: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzofdJthiazole-6-carboxylate
[0517] To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5- mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOU (0.61 g, 3.17 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.64 g, 85.1% yield for two steps). 1H MR (400 MHz, CDC13): δ 9.13 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s, 3H).
Step 10: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzofdJthiazole-6-carboxylate
[0518] To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6- carboxylate (8.64 g, 26.97 mmol) in DMF (100 mL) was added NIS (6.68 g, 29.67 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was treated by water (150 mL). The precipitate was filtered off and the filter cake was washed with water. The desired product was obtained as a yellow solid (10.34 g, 86.0% yield). 1H NMR (400 MHz, CDC13): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 7.42 (d, J= 10.4 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.63 (dd, J= 15.0, 8.7 Hz, 1H), 3.97 (s, 3H).
Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid
[0519] To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino) benzo[d]thiazole-6- carboxylate (10.34 g, 23.17 mmol) in THF and MeOH (20 mL, 4: 1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated to give the desired product (9.51 g, 95.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.18 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 6.65 (m, 1H). Step 12: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)etho
carboxamide
[0520] To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6- carboxylic acid (519 mg, 1.20 mmol) in CH2C12 (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-
(vinyloxy)ethyl)hydroxyl -amine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated H4C1 (aq.). The resultant mixture was extracted with CH2C12 (30 mL χ 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2S04 filtered, and concentrated in vacuo. The crude product (492 mg) was used directly in the next step without further purification.
Step 13: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6- carboxamide
[0521] To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2- (vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (492 mg, 1.00 mmol) in CH2C12 (10 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHC03 (aq.). The aqueous layer was washed with CH2C12 (30 mL). The combined organic layer was washed with water (30 mL x 2) and brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50: 1, v/v) and gave the desired product as a white solid (446 mg, 75.9% yield for the two steps). 1H MR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 9.55 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.55 (d, J= 11.0 Hz, 1H), 7.31 (d, J= 8.5 Hz, 1H), 6.48 (d, J= 9.2 Hz, 1H), 4.72 (s, 1H), 3.84 (m, 2H), 3.57 (m, 2H). MS APCI(+)m/z: 491.8, [M+H].
Example 9A: Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2- hydroxyethoxy)benzo[d]thiazole-6-carboxamide (Compound 9)
Step 1: 5-bromo-2,3,4-trifluorobenzoic aci
[0522] To a solution of l-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) in THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL, 67.8 mmol) at -78 °C under nitrogen atmosphere. After stirring for 1 h at -78 °C, the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HC1 (300 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 and extracted with ethyl acetate (200 mL χ 3). The combined organic extract was dried over Na2S04, filtered and concentrated under reduced pressure to afford the desired product (white solid, 13.51 g, 82% yield). 1H MR (400 MHz, CDC13): δ 13.94 (s, 1H), 7.95 (m,
1H).
Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic
[0523] To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4- trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at -78 °C under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HC1 (aq., 100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with water (200 mL x 3) and brine (200 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). 1H MR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).
Step 3: methyl 5-bromo-3,4-difluoro-2- -fluorophenyl)amino)benzoate
[0524] To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl2 (60 mL). After stirring at 85 °C overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (300 mL χ 3). The combined organic extract was washed with water (200 mL x 3) and brine (200 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo to afford the corresponding product (gray solid, 12.58 g, 90% yield). 1H MR (400 MHz, CDC13): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).
Step 4: methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate
[0525] To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.6 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.2 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and 4-methoxy-a-toluenethiol (5.48 g, 35.6 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100 °C under N2 atmosphere and then allowed to cool to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (200 mL χ 3). The combined organic extract was washed with water (200 mL χ 3) and brine (200 mL) sequentially, dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50: 1, v/v) to give the desired product (pale yellow solid, 12.64 g, 82% yield). 1H NMR (400 MHz, CDC13): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.06-7.44 (m, 6H), 6.82-6.88 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).
Step 5: methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate
[0526] To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2- fluorophenyl)amino)benzoate (12.64 g, 29.2 mmol) in DMF (30 mL) was added NaN3 (2.28 g, 35.0 mmol) at ambient temperature. The mixture was stirred at 90 °C for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL χ 3). The combined organic extracts were washed with water (100 mL χ 3) and brine (100 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10: 1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). 1H NMR (400 MHz, CDC13): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.02-7.28 (m, 6H), 6.83- 6.85 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Step 6: methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate
[0527] To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2- fluorophenyl)amino)benzoate (10.38 g, 22.7 mmol) in MeOH (100 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred at ambient temperature for 6 h. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.79 g, 100% yield).1H MR (400 MHz, CDC13): δ 9.08 (s, 1H), 7.78 (s, 1H), 6.93-7.28 (m, 8H), 4.65 (s, 2H), 4.00 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H).
Step 7: methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate
[0528] To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4- methoxybenzyl)thio)benzoate (9.79 g, 22.7 mmol) in anisole (12 mL) was added CF3COOH (20 mL). After stirring at ambient temperature for 23 h, the solvent was removed in vacuo. To the residue was added water (30 mL). The mixture was neutralized with 25% aqueous ammonia and extracted with ethyl acetate (100 mL χ 3). The combined organic layer was washed with water (100 mL x 3) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated to give the desired product (white solid, 5.28 g, 75% yield). The product was used directly in the next step without further purification.
Step 8: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzofdJthiazole-6-carboxylate
[0529] To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5- mercaptobenzoate (2.07 g, 6.67 mmol) in trimethyl orthoformate (20 mL) was added p-TsOU (166 mg, 0.65 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (white solid, 1.963 g, 92% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.15-6.78 (m, 4H), 3.91 (s, 3H).
Step 9: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzofdJthiazole-6-carboxylate
[0530] To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6- carboxylate (1.963 g, 6.14 mmol) in DMF (10 mL) was added NIS (1.5 g, 6.5 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was treated by saturated H4C1 (aq.). The aqueous layer was extracted with ethyl acetate (150 mL χ 3). The combined organic layer was washed with water (100 mL x 3) and brine (100 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo. After purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10: 1, v/v), the desired product was obtained as white solid (1.889 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.18-6.72 (m, 3H), 3.91 (s, 3H).
Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy
carboxamide
[0531] To a solution of O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) in THF (6 mL) was added LiHMDS (2.5 mL, 1 M in THF, 2.5 mmol) at -78 °C. After stirring at this temperature for 10 min, a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d] thiazole-6-carboxylate (360 mg, 0.81 mmol) in THF was syringed dropwisely. Then the mixture was allowed to warm to ambient temperature, quenched with saturated NH4C1 (aq., 20 mL) and extracted with ethyl acetate (15 mL χ 3). The combined organic extract was washed with water (10 mL x 3) and brine (10 mL), dried over Na2S04, filtered and concentrated in vacuo. After purification by flash chromatography (petroleum ether/ethyl acetate, 10: 1, v/v), the desired product was obtained (410 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H),
8.98 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.55 (d, J= 10.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.53 (dd, J= 13.9, 6.6 Hz, 1H), 6.42 (d, J= 6.0 Hz, 1H), 4.21 (d, J= 14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).
Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzofdJthiazole-6- carboxamide
[0532] To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2- (vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (410 mg, 0.8 mmol) in CH2C12 (5 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol) dropwise. After stirring for 1 h, the reaction mixture was neutralized with saturated NaHC03 (aq.). The organic layer was separated, washed with water (30 mL x 2) and brine (30 mL) sequentially, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 15: 1, v/v) and the desired product was obtained as a white solid (290 mg, 52 % yield). 1H MR (400 MHz, DMSO-de): δ 11.83 (s, 1H), 8.92 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.56 (d, J= 9.4 Hz, 1H), 7.30 (d, J= 8.7 Hz, 1H), 6.41 (m, 1H), 4.72 (m, 1H), 3.85 (m, 2H), 3.59 (m, 2H). MS (ES+): m/z 492.35 [MH+].
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Tunlametinib, an oral selective inhibitor of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), was developed by Shanghai KeChow Pharmaceuticals Co., Ltd. Marketed under the brand name
Keluping, it received conditional approval from the NMP in 2024 for the treatment of patients with advanced melanoma harboring NRAS mutations, particularly those who have not responded to anti-PD-1/PD-L1therapies [1]. Tunlametinib exerts its antitumor effects by targeting the MEK1/2 kinases within the RAS-RAF-MEK-ERK signaling pathway, thereby disrupting downstream signaling cascades and inhibiting tumor cell growth and proliferation [2]. Its clinical efficacy was demonstrated in a Phase II pivotal registration study (NCT05217303) involving patients with advanced NRAS-mutant melanoma [3]. The study reported a confirmed objective response rate (ORR) of 34.8 % and a median progression-free survival (mPFS) of 4.2 months. These findings suggest that Tunlametinib holds promise as a treatment option for NRAS-mutant melanoma, including in patients who have failed immunotherapy. In terms of safety, Tunlametinib has been generally well-tolerated [4]. Adverse events frequently encountered during treatment primarily consist of increased blood creatine phosphokinase (CPK) levels, diarrhea, and edema. Additionally, warnings and precautions pertinent to Tunlametinib therapy encompass decreased left ventricular ejection fraction (LVEF), skin toxicity, ocular toxicity, interstitial lung disease,
gastrointestinal reactions, and elevated CPK levels [5].
The synthetic pathway of Tunlametinib, illustrated in Scheme 1, begins with carboxylation of Tunl-001 to yield Tunl-002 [6]. Nucleophilic substitution of Tunl-002 with Tunl-003 then produces Tunl-004,
which undergoes esterification to form Tunl-005. Subsequent nucleophilic substitution between Tunl-05 and Tunl-006 generates Tunl-007. This intermediate undergoes azidation to afford Tunl-008, followed by
reduction to Tunl-009. Treatment of Tunl-009 with DDQ converts it to Tunl-010, which is deprotected to yield Tunl-011. Cycloaddition of Tunl-011 with Tunl-012 forms Tunl-013. Iodination of Tunl-013 gives
Tunl-014, which is hydrolyzed to produce Tunl-015. Amidation of Tunl-015 with Tunl-016 yields Tunl-017, and its subsequent acidolysis completes the synthesis of Tunlametinib.
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tunlametinib, a novel, potent, and selective MEK inhibitor, Front. Pharmacol. 14
(2023) 1271268.
[2] S.J. Keam, Tunlametinib: first approval, Drugs 84 (2024) 1005–1010.
[3] X. Wei, Z. Zou, W. Zhang, M. Fang, X. Zhang, Z. Luo, J. Chen, G. Huang, P. Zhang,
Y. Cheng, J. Liu, J. Liu, J. Zhang, D. Wu, Y. Chen, X. Ma, H. Pan, R. Jiang, X. Liu,
X. Ren, H. Tian, Z. Jia, J. Guo, L. Si, A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-Mutant melanoma,
Eur. J. Cancer 202 (2024) 114008.
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Pharmacol. 13 (2022) 1039416.
[5] Y. Shi, X. Han, Q. Zhao, Y. Zheng, J. Chen, X. Yu, J. Fang, Y. Liu, D. Huang, T. Liu,
H. Shen, S. Luo, H. Yu, Y. Cao, X. Zhang, P. Hu, Tunlametinib (HL-085) plus
vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-
label, single-arm, multicenter, phase I study, Exp. Hematol. Oncol. 13 (2024) 60.
[6] H. Tian, C. Ji, C. Liu, L. Kong, Y. Cheng, G. Huang, Benzoheterocyclic Compounds
and Use Thereof, 2014. US9937158B2.
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References
- “Tunlametinib”. NCI Drug Dictionary. National Cancer Institute.
- “Tunlametinib Wins Approval in China for NRAS+ Advanced Melanoma After PD-1/PD-L1 Therapy”. 18 March 2024.
- Keam SJ (2024). “Tunlametinib: First Approval”. Drugs. 84 (8): 1005–1010. doi:10.1007/s40265-024-02072-x. PMID 39034326.
- Shi Y, Han X, Zhao Q, Zheng Y, Chen J, Yu X, et al. (2024). “Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: An open-label, single-arm, multicenter, phase I study”. Experimental Hematology & Oncology. 13 (1): 60. doi:10.1186/s40164-024-00528-0. PMC 11167782. PMID 38867257.
| Clinical data | |
|---|---|
| Other names | HL-085 |
| ATC code | None |
| Legal status | |
| Legal status | Rx in China |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1801756-06-8 |
| PubChem CID | 71621329 |
| ChemSpider | 115006753 |
| UNII | IF25NR1PV3 |
| ChEMBL | ChEMBL5095241 |
| Chemical and physical data | |
| Formula | C16H12F2IN3O3S |
| Molar mass | 491.25 g·mol−1 |
/////////Tunlametinib, CHINA 2024, APPROVALS 2024, Shanghai KeChow, Keluping,1801756-06-8, IF25NR1PV3, HL 085
Befotertinib
Befotertinib
D-0316, 0XT2CPR891
CAS No. : 1835667-63-4, MESYLATE CAS No. 2226167-02-6
- 2-propenamide, n-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-
- N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)prop-2-enamide
- N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-[1-(2,2,2-trifluoroethyl)indol-3-yl]pyrimidin-2-yl]amino]phenyl]prop-2-enamide
| Molecular Weight | 567.61 |
|---|---|
| Formula | C29H32F3N7O2 |
Befotertinib (D-0316) is an orally active EGFR tyrosine kinase inhibitor. Befotertinib can inhibit the proliferation of tumor cells. Befotertinib can be used in the research of EGFR T790M-positive non-small cell lung cancer (NSCLC).
Befotertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, befotertinib specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, befotertinib may have therapeutic benefits in tumors with T790M-mediated drug resistance. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
PAPER
J. Med. Chem. 2017, 60, 6480−6515.
PATENT
WO 2019218987
https://patentscope.wipo.int/search/en/WO2019218987
[0054]
U.S. Publication No. 2017/0355696 A1 describes a method of preparing Compound 4 and various pharmaceutically acceptable salts thereof. The exemplified synthetic process in U. S. Publication No. 2017/0355696 A1 includes a two-step conversion from the aniline compound, corresponding to Compound 1 of this disclosure, into the bismesylate of Compound 4, which has a low yield.
[0055]
As shown herein, representative methods of preparation of Compound 4, or a pharmaceutically acceptable salt, (or alternatively referred to as synthetic methods) , can provide the desired Compound 4, or a pharmaceutically acceptable salt, in improved yield and high purity and can be adapted for large-scale manufacture.
[0056]
In various embodiments, the present invention provides a novel method of preparing Compound 4, or a pharmaceutically acceptable salt thereof. The method typically includes converting a compound of Formula III, or a salt thereof, into compound 4, typically under an elimination reaction condition:
Syn
https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182
Befotertinib (Surmana). Befotertinib (17), an oral, highly selective, third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Betta Pharmaceuticals and InventisBio, was approved in China in May 2023 for the second-line treatment of patients
with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with positive EGFR T790 M mutation who have disease progression on previous EGFR TKI therapy. 140 139 NSCLC
has a high incidence and disease burden in China, which has spurred the development of multiple EGFR TKIs by Chinese companies.
Achromatography-free process route to befotertinib (17) has been reported in the patent literature by researchers at InventisBio (Scheme 29), although details about scale and yields were not provided.
141 142 The reaction sequence closely follows that of osimertinib, a third generation EGFR inhibitor
that was first approved in 2015 and was covered in our previous review.
Osimertinib and befotertinib share a common backbone, differing only in N-substitution on the indole ring.
Friedel−Crafts arylation of 1H-indole with 2,4-dichloropyrimidine (17.1) gave the 3-pyrimidinyl indole 17.2. The trifluoroethyl moiety in indole 17.4 was introduced via Nalkylation of 17.2 with triflate 17.3. This was followed by an SAr reaction with nitroaniline 17.5 to provide amino pyrimidine 17.6. Next, N,N,N′-trimethylethylenediamine (17.7) displaced the electrophilic aryl fluoride in an SNArreaction to generate intermediate 17.8. The acrylamide moiety was installed using a three-step sequence: hydrogenolytic
reduction of the nitro group to the corresponding aniline, acylation with 3-chloropropanoyl chloride, and immediate elimination to the acrylamide. Mesylate salt formation and crystallization furnished befotertinib mesylate (17) in eight steps from 17.1.
(139) Blair, H. A. Befotertinib: first approval. Drugs 2023, 83, 1433−
1437.
(140) Lau, S. C. M.; Ou, S.-H. I. And still they come over troubled
waters: can Asia’s third-generation EGFR tyrosine kinase inhibitors
(Furmonertinib, Aumolertinib, Rezivertinib, Limertinib, Befotertinib,
SH-1028, and Lazertinib) affect global treatment of EGFR+ NSCLC. J.
Thorac. Oncol. 2022, 17, 1144−1154.
(141) Dai, X.; Jiang, Y. Preparation of pyrimidine derivative and its
pharmaceutical salt as EGFR inhibitors for the treatment of cancer and
other diseases. WO 2019218987, 2019.
(142) Flick, A. C.; Ding, H. X.; Leverett, C. A.; Kyne, R. E.; Liu, K. K.
C.; Fink, S. J.; O’Donnell, C. J. Synthetic approaches to the new drugs
approved during 2015. J. Med. Chem. 2017, 60, 6480−6515.
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- [1]. Nagasaka M, et, al. Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC. J Thorac Oncol. 2021 May;16(5):740-763. [Content Brief][2]. Blair HA. Befotertinib: First Approval. Drugs. 2023 Oct;83(15):1433-1437. [Content Brief]
/////////Befotertinib, APPROVALS 2023, CHINA 2023, Betta Pharmaceuticals, InventisBio, CANCER, D-0316, D 0316, 0XT2CPR891
Iruplinalkib
Iruplinalkib
CAS No. : 1854943-32-0
| Molecular Weight | 569.08 |
|---|---|
| Formula | C29H38ClN6O2P |
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl]pyrimidine-2,4-diamine
Iruplinalkib (WX-0593) is an orally active and selective ALK/ROS1 inhibitor. Iruplinalkib can effectively inhibit tyrosine autophosphorylation of ALK and mutant ALK, EGFR, with the IC50 between 5.38 and 16.74 nM. Iruplinalkib is also a suppressive agent of the transporter MATE1, MATE2K, P-gp and BCRP. Iruplinalkib can be used in the study of non-small cell lung cancer.
Iruplinalkib is an orally available, small molecule inhibitor of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Upon oral administration, iruplinalkib binds to and inhibits ALK tyrosine kinase, ALK fusion proteins, ALK point mutation variants ALK L1196M, ALK C1156Y, and EGFR L858R/T790M. Inhibition of ALK leads to the disruption of ALK-mediated signaling and the inhibition of cell growth in ALK-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a series of tumors. Additionally, ALK mutations are associated with acquired resistance to small molecule tyrosine kinase inhibitors.
SYN
Bioorg. Chem. 2023, 140, No. 106807
Bioorg. Med. Chem. Lett. 2022, 66, No. 128730.
CN106928275, 2017.
EP 3165530 A1, 2017
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US196228122&_cid=P22-ME5G3V-88608-1
Example 9
(2-((5-Chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide
This Example was prepared according to the process as described in Example 7, take the place of (2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide was replaced with (2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide to give the title compound as yellow solid, yield 57%. 1H NMR (400 MHz, CD 3OD): δ, 8.28 (s, 1H), 8.12 (br. s., 1H), 7.81-7.68 (m, 3H), 7.65 (d, J=2.0 Hz, 1H), 7.56-7.49 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.02 (s, 3H), 3.74 (br. s., 4H), 3.47 (d, J=12.8 Hz, 2H), 3.24 (t, J=12.8 Hz, 2H), 2.93 (s, 3H), 2.42-1.97 (m, 5H), 1.93-1.75 (m, 9H). LCMS (ESI) (0-60AB): m/z: 569.2 [M+1].
PATENT
CN 110407877, 2019
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN276468167&_cid=P22-ME5FTE-83156-1
| Experimental Example 11 |
| (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diaza-spiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound I) |
| NMP (N-methylpyrrolidone, 102.6 g) was added to the reaction bottle (room temperature), and 20 g of compound (e) was added to the reaction bottle under stirring. 21.85 g of compound (f) was added to the reaction bottle, and 19.93 g (3 eq) of MeSO 3 H was added dropwise to the reaction flask (temperature was controlled at <40°C) 2 Bubble for 15-20 minutes. Heat the reaction to 85-90°C and react at 85-90°C for 12 hours before sampling and testing (HPLC). Sample testing (test method: dissolve 0.1 ml of the reaction solution in 2 ml of MeOH). Stop the reaction when compound (f) is <2.5%. Add NaOH solution (1M, 287 g) to the reaction solution to adjust the pH to 13. A large amount of solid precipitates and continue stirring for 2 hours. Filter the solid and wash the filter cake with water (40 g) until the filtrate is colorless. Collect the filter cake, filter and dry (55-60°C) to obtain an off-white crude product. Add methanol (268 g) to the reaction flask, then add the obtained solid, heat to 60°C to dissolve, add activated carbon (5.2 g) to the reaction flask, then stir at 60°C for 2.5 hours, cool to 30°C, filter, and concentrate the mother liquor under reduced pressure to obtain a gray-green solid. MeOH (155.5 g) was added to the reaction flask, followed by the solid obtained above. The mixture was heated under reflux until clear. Purified water (388 g) was added to the reaction flask and the temperature was naturally lowered to 15-20°C. A white solid precipitated. The solid was filtered and washed once with purified water (194 g). The filter cake was collected and dried to yield Compound I (32.5 g). 1 H NMR (400MHz, CD3OD): 8.36 (dd, J＝8.0, 4.4Hz, 1H), 8.03 (s, 1H), 7.69 (d, J＝8.8Hz, 1H), 7.65-7.55 (m, 1H), 7.51 (dd, J＝8.0 8.0Hz,1H),7.32-7.20(m,1H),6.66(d,J＝2.4Hz,1H),6.45(dd,J＝8.8,2.4Hz,1H),3.85(s,3H) ,3.18-3.06(m,4H),2.54-2.38(m,4H),2.30(s,3H),1.85(d,J＝13.6Hz,6H),1.74-1.54(m,8H). |
| Example 1: Preparation of Form A of Compound I: |
| 10 g of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diaza-spiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound I) was heated to reflux for complete dissolution with 45 ml of ethanol and 20 ml of purified water. The mixture was then cooled to 10-20° C., 50 ml of purified water was added, and the mixture was stirred at this temperature for 2-3 hours. The mixture was filtered and dried in vacuo at 50-60° C. to obtain 9.0 g of an off-white solid with a yield of 90%. X-ray powder diffraction analysis showed an XRPD pattern as shown in FIG1 . DSC-TGA analysis yielded pattern 2. |
Syn
https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182
Iruplinalkib. The final NSCLC treatment approved in 2023 was iruplinalkib (20), developed by Qilu Pharmaceutical Co., Ltd. and approved for use in China in June 2023.156,157 Iruplinalkib is a highly selective oral anaplastic kinase (ALK) and ROS1TKI,andis, therefore, an oral treatment for ALK-positive (ALK+) or ROS1-positive (ROS1+) NSCLC.156,157 This treatment is specifically meant for use by patients with locally advanced or metastatic ALK-positive NSCLC whose disease has progressed after crizotinib therapy, often due to the develop ment of crizotinib resistance. Although early syntheses were published 158 further optimized routes were disclosed by Qilu Pharmaceutical Co., Ltd.(Scheme 34 and Scheme 35).First, ethyl 2-cyanoacetate 20.1) and cyclic ketone20.2 were combined to generate spirocyclic imide 20.3 (Scheme 34). The cyano substituents were then removed by treating 20.3 with sulfuric acid followed
by sodiumhydroxide to form 20.5. Subsequent amide reduction via lithium aluminum hydride treatment revealed secondary amine 20.6, which underwent a substitution reaction with fluorophenyl 20.7 to produce intermediate 20.8. Next, addition of methyl iodide generated a quaternary amine (20.9). The
following hydrogenolysis step reduced the nitro group and removed the benzyl substituent using palladium on carbon to produce the final aniline fragment, 20.10. To generate the other fragment (20.16) to construct iruplinalkib, diethylphosphite (20.11) and methyl magnesium bromide were combinedtoproducedimethylphosphineoxide 20.12(Scheme35).Couplingthisproductwith2-iodoaniline
20.13andsubsequent selectiveSNArwithtrichloropyrimidine20.15 generated the resultingdichloropyrimidine20.16.Finally, a selective SNAr reaction yielded the desired product,
iruplinalkib(20).
(156) Yang, Y.; Zheng, Q.; Wang, X.; Zhao, S.; Huang, W.; Jia, L.; Ma,
C.; Liu, S.; Zhang, Y.; Xin, Q.; et al. Iruplinalkib (WX-0593), a novel
ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical
modelsfornon-smallcell lung cancer. Invest. New Drugs 2023, 41,254−
266.
(157) Keam, S. J. Iruplinalkib: first approval. Drugs 2023, 83, 1717−
1721.
(158) Liu, X.; Zhang, L.; Wan, H.; Zhu, Z.; Jin, J.; Qin, Y.; Mao, W.;
Yan, K.; Fang, D.; Jiang, W.; et al. Discovery and preclinical evaluations
of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant
mutations. Bioorg. Med. Chem. Lett. 2022, 66, No. 128730.
(159) Ding, Z.; Chen, S.; Liu, X.; Wan, H.; Zhang, L. Preparation,
intermediate and crystal form of spiroamine type arylphosphine oxide.
CN106928275, 2017.
(160) Ding, Z.; Zhang, M.; Chen, S.; Liu, X.; Zhu, Y.; Fan, C.;
Baoping, Z.; Chang, L.; Yang, Y.; Zheng, Q.; et al. Preparation,
intermediate and crystal form of spiroamine type arylphosphine oxide.
EP 3165530 A1, 2017.
(161) Lin, D.; Zhou, G.; Li, S.; Wang, X.; Zhang, Z.; Liu, Z.; Wang, X.
Polymorph of spirocycloaryl phosphorus oxide. CN 110407877, 2019.
(162) Gao, H.; Zhang, J.-Y.; Zhao, L.-J.; Guo, Y.-Y. Synthesis and
clinical application of small-molecule inhibitors and PROTACs of
anaplastic lymphoma kinase. Bioorg. Chem. 2023, 140, No. 106807.
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……
- [1]. Yang Y, et al. Iruplinalkib (WX 0593), a novel ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical models for non-small cell lung cancer. Invest New Drugs. 2023 Apr;41(2):254-266. [Content Brief][2]. Shi Y, et al. Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial. Signal Transduct Target Ther. 2022;7(1):25. [Content Brief]
/////////Iruplinalkib, china 2023, approvals 2023, Qilu Pharmaceutical, Z5F65W1YAZ, Qixinke, WX0593, WX 0593, FL006, FL 006, FL-006
Zongertinib
Zongertinib
CAS No. : 2728667-27-2,
BI-1810631, BI1810631
| Molecular Weight | 535.60 |
|---|---|
| Formula | C29H29N9O2 |
FDA 8/8/2025, Hernexeos, To treat adults with unresectable or metastatic non-squamous non-small cell lung cancer whose tumors have HER2 tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy
- N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide
- N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo(d)imidazol-5-yl)oxy)phenyl)amino)pyrimido(5,4-d)pyrimidin-2-yl)piperidin-4-yl)acrylamide
- 884-819-6
Zongertinib is an orally bioavailable inhibitor of the receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; ErbB2; HER-2), with potential antineoplastic activity. Upon oral administration, zongertinib covalently binds to and inhibits the activity of both wild-type and HER2 mutants, including HER2 mutants with exon 20 insertion (ex20ins) mutations. This prevents HER2-mediated signaling and may lead to cell death in HER2-expressing tumor cells. HER2, a receptor tyrosine kinase overexpressed on a variety of tumor cell types, plays an important role in tumor cell proliferation and tumor vascularization.
REF
Synthesis of zongertinib (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-
548 yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide)
Methods
Synthesis of Zongertinib (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide)
An overview of the synthetic routes to zongertinib and BI-3999 is shown in Supplementary Fig. S1, and graphical NMR spectra are shown in Supplementary Fig. S2.
3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (500 mg, 1.97 mmol) and 8-chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine hydrochloride (492 mg, 1.97 mmol) were suspended in isopropanol, and the resulting reaction mixture stirred at 50°C for 3 hours, at which time high-performance liquid chromatography–mass spectrometry (HPLC-MS) indicated full conversion. The reaction mixture was concentrated under reduced pressure, and the crude product was redissolved in dichloromethane and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated, and the resulting crude product was purified by column chromatography (SiO2, gradient of 0%–15% methanol in dichloromethane) to afford the product (840 mg).
N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidin-4-amine (860 mg, 90%, 1.80 mmol) was suspended in dichloromethane (30 mL), and the resulting mixture was cooled to 0°C to 5°C. mCPBA (3-chloroperbenzoic acid, 444 mg, 77%, 1.98 mmol) was added portionwise over 1 hour, and the resulting reaction mixture was stirred at room temperature overnight, at which time HPLC-MS indicated full conversion. The reaction mixture was diluted with dichloromethane and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated, and the resulting crude product which was used directly in the next step (767 mg, crude).
N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine (5.42 g, 80%, 9.73 mmol) was dissolved in N,N-dimethyl formamide (DMF, 50 mL) and diisopropylethylamine (2.8 mL, 16 mmol). 4-Boc-amino-1-piperidine (2.39 g, 11.9 mmol) was added, and the reaction was stirred at 60°C overnight. Then, the reaction mixture was concentrated, and the crude product was used directly in the next step (5.66 g, crude).
Tert-butyl (1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)carbamate (5.66 g, 9.73 mmol) was dissolved in dichloromethane (100 mL) and methanol (30 mL). Four mol/L HCl in dioxane (11 mL, 44 mmol) was added, and the resulting reaction mixture was heated to 45°C for 7 hours. HPLC-MS indicated some remaining starting material; therefore, the reaction mixture was stirred at room temperature overnight. Four mol/L HCl in dioxane (1 mL, 0.40 mmol) was added, and the reaction mixture was reheated to 45°C for 4 hours, at which time HPLC-MS indicated full conversion. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (SiO2, gradient of 0%–20% methanol in dichloromethane) to afford the product (4.5 g, 70% purity).
1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-amine (4.5 g, 70%, 6.9 mmol) was suspended in dichloromethane (150 mL) and triethyl amine (4 mL, 28 mmol), and dimethylaminopyridine (115 mg, 0.941 mmol) was added. Then, acroyloyl anhydride (1.36 g, 95%, 10.3 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour, at which time HPLC-MS indicated full conversion. The reaction mixture was diluted with dichloromethane (50 mL) and washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated, and the resulting crude product was purified by column chromatography (SiO2, gradient of 0%–20% methanol in dichloromethane) to afford the product (2.49 g).
1H NMR (DMSO-d6, 500 MHz) δ 9.58 (s, 1H), 9.08 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 8.10 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 2.2 Hz), 7.77 (dd, 1H, J = 8.8 Hz, J = 2.2 Hz), 7.57 (d, 1H, J = 8.8 Hz), 7.09 (d, 1H, J = 2.2 Hz), 7.00 (dd, 1H, J = 2.2, 8.5 Hz), 6.89 (d, 1H, J = 8.8 Hz), 6.20 (dd, 1H, J = 10.1, 17.0 Hz), 6.10 (dd, 1H, J = 2.2, 17.0 Hz), 5.6 (dd, 1H, J = 2.2, 9.8 Hz), 4.86 (m, 2H), 3.99 (m, 1H), 3.84 (s, 3H), 3.25 (m, 2H), 2.26 (s, 3H), 1.92 (m, 2H), and 1.43 (m, 2H).
Synthesis of BI-3999 (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acetamide)
6-(4-aminopiperidin-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine (100 mg, 208 mmol) and 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) were suspended in 5 mL dichloromethane. Acetic anhydride (25 μL, 0.23 mmol) was added, and the resulting reaction mixture was stirred at room temperature for one hour. Then, the reaction mixture was diluted with dichloromethane and washed with aqueous NaHCO3 and brine. Then, the layers were separated, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2, gradient of 0%–10% methanol in dichloromethane) to afford the product (75 mg).
1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 9.07 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.88 (d, 1H, J = 7.9 Hz), 7.84 (d, 1H, J = 2.5 Hz), 7.77 (dd, 1H, J = 2.7, 8.7 Hz), 7.57 (d, 1H, J = 8.9 Hz), 7.09 (d, 1H, J = 2.3 Hz), 7.00 (dd, 1H, J = 2.3, 8.6 Hz), 6.89 (d, 1H, J = 8.6 Hz), 4.85 (m, 2H), 3.90 (m, 1H), 3.84 (s, 3H), 3.23 (m, 2H), 2.26 (s, 3H), 1.88 (m, 2H), 1.82 (s, 3H), and 1.38 (m, 2H).
A) 1H NMR spectrum of zongertinib
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021213800&_cid=P10-ME52KD-62836-1
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- [1]. WHO Drug Informat ion – World Health Organization (WHO).[2]. Wilding Birgit, et al. Synthesis of diazino-pyrimidines as anticancer agents: World Intellectual Property Organization, WO2021213800. 2021-10-28.[3]. Li S, et al. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel). 2023 May 24;15(11):2899. [Content Brief]
////////////Zongertinib, Hernexeos, APPROVALS 2025, FDA 2025, lung cancer, BI-1810631, BI1810631, DRH7R67UVL
Aceclidine
Aceclidine
WeightAverage: 169.224
Monoisotopic: 169.110278727
Chemical FormulaC9H15NO2
CAS 827-61-2, 3-Acetoxyquinuclidine, 3-Quinuclidinol acetate (ester), Aceclidina, 0578K3ELIO
APROVAL 7/31/2025, Vizz. To treat presbyopia
1-azabicyclo[2.2.2]octan-3-yl acetate
Acetic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester(aceclidine)
MW: 169.22 MF: C9H15NO2
LD50: 78 mg/kg (M, i.p.); 36 mg/kg (M, i.v.); 165 mg/kg (M, p.o.); 102 mg/kg (M, s.c.);
45 mg/kg (R, i.v.); 225 mg/kg (R, s.c.)
CN: 1-azabicyclo[2.2.2]octan-3-ol acetate (ester)
WeightAverage: 205.68
Monoisotopic: 205.0869565
Chemical FormulaC9H16ClNO2
LD50: 27 mg/kg (M, i.v.); 165 mg/kg (M, p.o.);
45 mg/kg (R, i.v.)
Aceclidine (Glaucostat, Glaunorm, Glaudin, Vizz) is a parasympathomimetic miotic agent used in the treatment of narrow angle glaucoma.
Aceclidine was approved for medical use in the United States in July 2025.[2]
Medicinal properties
Aceclidine decreases intraocular pressure. It acts as a muscarinic acetylcholine receptor agonist.[3]
Chemistry
Aceclidine is an organic compound that is structurally related to quinuclidine. As such its alternative name is 3-acetoxyquinuclidine. Its protonated derivative has a pKa of 9.3.[4]
SYN
E. E. Mikhlina and M. V. Rubtsov, Zhur. Obschei
Khim, 30, 163 (1960). L. H. Sternbach and S. Kaiser, J. Am. Chem. Soc., 74, 2215 (1952). C. A. Grob, A. Kaiser and E. Renk, Helv. Chim.Acta, 40, 2170 (1957).
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References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218585s000lbl.pdf
- “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 4 August 2025. Retrieved 5 August 2025.
- Shannon HE, Hart JC, Bymaster FP, Calligaro DO, DeLapp NW, Mitch CH, et al. (August 1999). “Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats”. The Journal of Pharmacology and Experimental Therapeutics. 290 (2): 901–907. doi:10.1016/S0022-3565(24)34979-1. PMID 10411607.
- Aggarwal VK, Emme I, Fulford SY (February 2003). “Correlation between pK(a) and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction: discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope”. The Journal of Organic Chemistry. 68 (3): 692–700. doi:10.1021/jo026671s. PMID 12558387.
External links
- Clinical trial number (NCT05656027 for “Phase 3 Evaluation of the Safety and Efficacy of LNZ101 for the Treatment of Presbyopia (CLARITY)” at ClinicalTrials.gov
- Clinical trial number (NCT05728944 for “Phase 3 Efficacy Study of LNZ101 for the Treatment of Presbyopia (CLARITY)” at ClinicalTrials.gov
- Clinical trial number (NCT05753189 for “Phase 3 Safety Study for the Treatment of Presbyopia Subjects” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Other names | LNZ101 |
| AHFS/Drugs.com | Vizz |
| License data | US DailyMed: Aceclidine |
| Routes of administration | Topical (ophthalmic solution) |
| ATC code | S01EB08 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1]In general: ℞ (Prescription only) |
| Identifiers | |
| IUPAC name | |
| CAS Number | 827-61-2 6109-70-2 |
| PubChem CID | 1979 |
| ChemSpider | 1902 |
| UNII | 0578K3ELIO |
| KEGG | D02750 |
| ChEMBL | ChEMBL20835 |
| CompTox Dashboard (EPA) | DTXSID2045658 |
| ECHA InfoCard | 100.011.431 |
| Chemical and physical data | |
| Formula | C9H15NO2 |
| Molar mass | 169.224 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
///////////Aceclidine, APPROVALS 2025, FDA 2025, Vizz. To treat presbyopia, 827-61-2, 3-Acetoxyquinuclidine, 3-Quinuclidinol acetate (ester), Aceclidina, 0578K3ELIO, Glaucostat
Ropotrectinib
Ropotrectinib
- CAS 1802220-02-5
- TPX-0005
- Augtyro
- 08O3FQ4UNP
WeightAverage: 355.373
Monoisotopic: 355.144453003
Chemical FormulaC18H18FN5O2
- repotrectinibum
- (3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one
- 1,15-Etheno-1H-pyrazolo(4,3-F)(1,4,8,10)benzoxatriazacyclotridecin-4(5H)-one, 11-fluoro-6,7,13,14-tetrahydro-7,13-dimethyl-, (7S,13R)-
- 1,15-Etheno-1H-pyrazolo(4,3-f)(1,4,8,10)benzoxatriazacyclotridecin-4(5H)-one, 11-fluoro-2,6,7,13-tetrahydro-7,13-dimethyl-, (14Z)-
- (1Z)-6-Fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo(13.5.2.04,9.018,22)docosa-1,4,6,8,15,19,21-heptaen-14-one
- (3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.0,.0,]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one
- (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14- tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- one
- (3R,6S,)-45-FLUORO-3,6-DIMETHYL-5-OXA-2,8-DIAZA-1(5,3)-PYRAZOLO(1,5-A)PYRIMIDINA-4(1,2)-BENZENANONAPHAN-9-ONE
- (7S,13R)-11-Fluoro-7,13-Dimethyl-6,7,13,14-Tetrahydro-1,15-Ethenopyrazolo[4,3-F][1,4,8,10]Benzoxatriazacyclotridecin-4(5H)-One
- 1,15-ETHENO-1H-PYRAZOLO(4,3-F)(1,4,8,10)BENZOXATRIAZACYCLOTRIDECIN-4(5H)-ONE, 11-FLUORO-6,7,13,14-TETRAHYDRO-7,13-DIMETHYL-, (7S,13R)-
Repotrectinib, sold under the brand name Augtyro, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[2][5] It is taken by mouth.[2] Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC.[2]
The most common adverse reactions include dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness.[5]
Repotrectinib was approved for medical use in the United States in November 2023,[5][6] and in the European Union in January 2025.[3][4] CHINA 2024
SYN
https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/slct.202405153
Synthesis of Repotrectinib
To a stirred solution of 5-{[(1R)-1-(2-{[(2S)-1-aminopropan-2-yl]oxy}-5-fluorophenyl)ethyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 15 (0.25 g, 0.000611 mol, 1.0 eq.) in DMF (4.0 mL, 16V) was slowly added to solution of DIPEA (0.6 mL, 0.00488 mol, 8.0 eq.) in DCM (1.8 mL, 7V) at 0-5 °C. Then FDPP (0.25 g, 0.000672 mol, 1.1 eq.) was added at 0-5 °C. The reaction mixture was allowed to stirr for 1-2h at 25-30 °C. The reaction was monitored by TLC for disappearance of starting material. Then the resulting reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine solution (20 mL). The separated organic layer was dried over sodium sulphate and concentrated under reduced pressure at 45 °C. The obtained crude product was purified by silica gel (60-120 mesh) column chromatography to get repotrectinib asawhite solid (0.18 g, 85%).
HRMS
SYN
https://pubs.acs.org/doi/10.1021/acs.oprd.3c00152
REF
https://pubs.acs.org/doi/10.1021/acs.oprd.4c00061
REF
US20180194777
https://patentscope.wipo.int/search/en/detail.jsf?docId=US222923082&_cid=P11-ME283N-03701-1
Example 1: Preparation of 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1)
Step 1: Preparation of ethyl 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (1-2)
Step 2: Preparation of 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1)
PATENT
https://patents.google.com/patent/US10246466B2/en
Step 1. To a solution of tert-butyl (R)-(2-hydroxypropyl)carbamate (1.00 g, 5.71 mmol) and tosyl chloride (1.14 g, 6.00 mmol) in DCM (29 mL) was added triethylamine (1.44 g, 14.28 mmol and the mixture was stirred at room temp for 48 hour. The reaction solution was concentrated under reduced pressure and the residue was purified with flash chromatography (ISCO system, silica (40 g), 0-20% ethyl acetate in hexane) to provide (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-methylbenzenesulfonate (1.12 g, 3.40 mmol, 59.54% yield).
Step 2. To a solution of A8 (100.00 mg, 0.290 mmol) and (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-methylbenzenesulfonate (143.50 mg, 0.436 mmol) in DMF (1.45 mL) was added K2CO3 (200.7 mg, 1.45 mmol) and heated at 80° C. with stirring for 16 hour. The reaction was cooled to ambient temperature and diluted with DCM (3 mL), filtered through a syringe filter, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-60% ethyl acetate in hexane) provided 93A (32.90 mg, 0.0656 mmol, 22.59% yield).
Step 3. To a solution of 93A (32.90 mg, 0.0656 mmol) in MeOH (3 mL) and THF (2 mL) was added LiOH aqueous solution (2M, 2 mL) at ambient temperature. The reaction solution was heated at 70° C. for 2 hours The reaction flask was cooled to ambient temperature, diluted with water and methanol, and then quenched with HCl aqueous solution (2 M, 2 mL) to pH<5. The mixture was extracted with DCM (3×5 mL), dried with Na2SO4, concentrated under reduced and dried on high vacuum overnight. To a solution of the acid product in DCM (4 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure and dried on high vacuum. To a solution of the de-Boc product and FDPP (27.62 mg, 0.0719 mmol) in DMF (1.6 mL) was added Hunig’s base (42.23 mg, 0.327 mmol) at room temperature. The mixture was stirred for 2.5 hours, and then quenched the reaction with 2 M Na2CO3 solution (2 mL). The mixture was stirred for 15 min then extracted with DCM (4×10 mL). The combined extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified with flash chromatography (ISCO system, silica (12 g), 0-10% methanol in dichloromethane) to provide 93 (10.1 mg, 0.0284 mmol, 43.49% yield for three steps).
PATENT
SYN
European Journal of Medicinal Chemistry 265 (2024) 116124
Repotrectinib (Augtyro) Repotrectinib, developed by Turning Point Therapeutics, Inc., was granted FDA approval on November 15, 2023. It is indicated to treat locally advanced or metastatic ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive non-small cell lung cancer (NSCLC). Repotrectinib is a highly effective inhibitor of ROS1 (ICtyrosine receptor kinase (TRK) (IC5050= 0.07 nM) and
=0.83/0.05/0.1 nM for TRKA/B/C) [87]. After undergoing currently approved targeted therapies, patients with tumors containing ROS1 and neurotrophic tyrosine kinase receptor (NTRK) gene fusions frequently acquire resistance mutations [88,89]. These mutations restrict the ability of drugs to bind to their
targets, ultimately resulting in the advancement of tumors. Repotrectinib, a novel tyrosine kinase inhibitor (TKI), is the pioneering drug developed to specifically target ROS1 or NTRK-positive metastatic
NSCLC and effectively combat the primary factors contributing to disease advancement [90].Preparation of Repotrectinib is described as Scheme 24 [91].Protecting the amino group of REPO-001 with Boc group in the presence of Kgave REPO-002, followed by intermolecular dehydration with
1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (REPO-003) to give the ester REPO-004. REPO-004 was reacted with chiral auxiliary REPO-005 to give REPO-006, which was reduced by NaBH4
to obtain REPO-007. Then REPO-008 was obtained by removing the chiral auxiliary under iodine conditions. Substitution of REPO-008 with REPO-009 gave REPO-010, which was further hydrolyzed under alkaline conditions to obtain REPO-011. Salt formation of REPO-011 with hydrochloric acid
yielded REPO-012, which underwent intramolecular condensation to obtain the product Repotrectinib.
[87] D. Zhai, W. Deng, Z. Huang, E. Rogers, J.J. Cui, The novel, rationally-designed,
ALK/SRC inhibitor TPX-0005 overcomes multiple acquired resistance
mechanisms to current ALK inhibitors, Cancer Res. 76 (2016) 2132.
[88] C. Keddy, P. Shinde, K. Jones, S. Kaech, R. Somwar, U. Shinde, M.A. Davare,
Resistance profile and structural modeling of next-generation ROS1 tyrosine
kinase inhibitors, Mol. Cancer Therapeut. 21 (2022) 336–346.
[89] E. Cocco, M. Scaltriti, A. Drilon, NTRK fusion-positive cancers and TRK inhibitor
therapy, Nat. Rev. Clin. Oncol. 15 (2018) 731–747.
[90] A. Drilon, S.I. Ou, B.C. Cho, D.W. Kim, J. Lee, J.J. Lin, V.W. Zhu, M.J. Ahn, D.
R. Camidge, J. Nguyen, D. Zhai, W. Deng, Z. Huang, E. Rogers, J. Liu, J. Whitten,
J.K. Lim, S. Stopatschinskaja, D.M. Hyman, R.C. Doebele, J.J. Cui, A.T. Shaw,
Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that
potently inhibits ROS1/TRK/ALK solvent-front mutations, Cancer Discov. 8
(2018) 1227–1236.
[91] J.J. Cui, E.W. Rogers, Gialir Macrocyclic Polymorph, 2018. US20180194777A1.
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Syn
European Journal of Medicinal Chemistry 291 (2025) 117643
Repotrectinib, developed by Bristol-Myers Squibb and marketed under the brand name Augtyro, is an oral tyrosine kinase inhibitor (TKI) targeting ROS1 and TRK oncogenic drivers. In 2024, NMPA condition
ally approved Repotrectinib for adult patients with ROS1-positive locally advanced or metastatic NSCLC [15]. Repotrectinib exerts its antitumor activity by inhibiting ROS1 and TRK kinases, thereby disrupting the downstream signaling pathways that facilitate tumor cell proliferation and survival [16]. This argeted mechanism is particularly effective against tumors that harbor ROS1 or NTRK gene fusions. The clinical efficacy of Repotrectinib has been through validated the Phase 1/2 TRIDENT-1 trial (NCT03093116) [17]. In the study cohort, treat ment-naïve patients harboring ROS1-positive NSCLC exhibited an overall response rate (ORR) of 79 %, characterized by a median duration of response (DOR) reaching 34.1 months. Conversely, among those who had previously received ROS1 TKI therapy, the ORR was documented at 38 %, accompanied by a median DOR of 14.8 months. With respect to safety profiles, the adverse event spectrum commonly encompassed dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea
[18,19]. These side effects are generally manageable, but patients should be monitored for potential severe adverse events.
The synthetic route of Repotrectinib, shown in Scheme 4, begins with condensation reaction between Repo-001 and Repo-002 to afford Repo-003, which is chlorinated to yield Repo-004 [20]. This intermediate undergoes nucleophilic substitution with Repo-005 to form Repo-006,
followed by second nucleophilic substitution with Repo-007 to produce Repo-008. Ester hydrolysis of Repo-008 affords Repo-009, which undergoes acid-mediated deprotection to generate Repo-010. Final
intramolecular amidation of Repo-010 delivers Repotrectinib. In parallel, Repo-011 and Repo-012 undergo condensation to form imine Repo-013, which undergoes Grignard addition to afford Repo-014.
Acidification of Repo-014 then yields Repo-005. Concurrently, Repo-015 undergoes nucleophilic substitution to generate Repo-007.
[15] S. Dhillon, Repotrectinib: first approval, Drugs 84 (2024) 239–246.
[16] T. Rais, A. Shakeel, L. Naseem, N. Nasser, M. Aamir, Repotrectinib: a promising
new therapy for advanced nonsmall cell lung cancer, Ann Med Surg (Lond) 86
(2024) 7265–7269.
[17] A. Drilon, S.I. Ou, B.C. Cho, D.W. Kim, J. Lee, J.J. Lin, V.W. Zhu, M.J. Ahn, D.
R. Camidge, J. Nguyen, D. Zhai, W. Deng, Z. Huang, E. Rogers, J. Liu, J. Whitten, J.
K. Lim, S. Stopatschinskaja, D.M. Hyman, R.C. Doebele, J.J. Cui, A.T. Shaw,
Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that
potently inhibits ROS1/TRK/ALK solvent-front mutations, Cancer Discov. 8 (2018)
1227–1236.
[18] Repotrectinib, Drugs and Lactation Database (Lactmed®), National Institute of
Child Health and Human Development, Bethesda (MD), 2006.
[19] H. Zhong, J. Lu, M. Wang, B. Han, Real-world studies of crizotinib in patients with
ROS1-positive non-small-cell lung cancer: experience from China, J Comp Eff Res
14 (2024) e240043.
[20] J.J. Cui, E.W. Rogers, Preparation of
Fluorodimethyltetrahydroethenopyrazolobenzoxatriazacyclotridecinone
Derivatives for Use as Antitumor Agents, 2017. US20180194777A1.
Repotrectinib is indicated for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer.[2][5]
In June 2024, the US Food and Drug Administration (FDA) expanded the indication to include the treatment of people twelve years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed following treatment or have no satisfactory alternative therapy.[7][8]
References
- “Register of Innovative Drugs”. Health Canada. 3 November 2006. Retrieved 23 May 2025.
- “Augtyro- repotrectinib capsule”. DailyMed. 15 November 2023. Archived from the original on 12 December 2023. Retrieved 12 December 2023.
- “Augtyro EPAR”. European Medicines Agency (EMA). 14 November 2024. Retrieved 16 November 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “Augtyro PI”. Union Register of medicinal products. 14 January 2025. Retrieved 16 January 2025.
- “FDA approves repotrectinib for ROS1-positive non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 15 November 2023. Archived from the original on 16 November 2023. Retrieved 17 November 2023. This article incorporates text from this source, which is in the public domain.
- “U.S. Food and Drug Administration Approves Augtyro (repotrectinib), a Next-Generation Tyrosine Kinase Inhibitor (TKI), for the Treatment of Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)” (Press release). Bristol Myers Squibb. 16 November 2023. Archived from the original on 16 November 2023. Retrieved 17 November 2023 – via Business Wire.
- “FDA grants accelerated approval to repotrectinib for adult and pediatric participants with neurotrophic tyrosine receptor kinase gene fusion-positive solid tumors”. U.S. Food and Drug Administration. 13 June 2024. Archived from the original on 13 June 2024. Retrieved 13 June 2024. This article incorporates text from this source, which is in the public domain.
- “Cancer Accelerated Approvals”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 6 December 2024.
- Turning Point Therapeutics, Inc. (5 February 2024). A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1) (Report). clinicaltrials.gov. Archived from the original on 18 June 2024. Retrieved 18 June 2024.
- “Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024”. European Medicines Agency (EMA). 15 November 2024. Retrieved 16 November 2024.
Further reading
- Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, et al. (October 2018). “Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations”. Cancer Discovery. 8 (10): 1227–1236. doi:10.1158/2159-8290.CD-18-0484. PMID 30093503.
External links
- “Repotrectinib (Code C133821)”. NCI Thesaurus. 25 September 2023. Retrieved 17 November 2023.
| Clinical data | |
|---|---|
| Trade names | Augtyro |
| Other names | TPX-0005 |
| AHFS/Drugs.com | Augtyro |
| License data | US DailyMed: Repotrectinib |
| Routes of administration | By mouth |
| Drug class | Tyrosine kinase inhibitor |
| ATC code | L01EX28 (WHO) |
| Legal status | |
| Legal status | CA: ℞-only[1]US: ℞-only[2]EU: Rx-only[3][4] |
| Identifiers | |
| CAS Number | 1802220-02-5 |
| PubChem CID | 135565923 |
| DrugBank | DB16826 |
| ChemSpider | 64853849 |
| UNII | 08O3FQ4UNP |
| KEGG | D11454 |
| ChEBI | CHEBI:229220 |
| ChEMBL | ChEMBL4298138 |
| PDB ligand | 7GI (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C18H18FN5O2 |
| Molar mass | 355.373 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
- (3R,6S,)-45-FLUORO-3,6-DIMETHYL-5-OXA-2,8-DIAZA-1(5,3)-PYRAZOLO(1,5-A)PYRIMIDINA-4(1,2)-BENZENANONAPHAN-9-ONE
- (7S,13R)-11-Fluoro-7,13-Dimethyl-6,7,13,14-Tetrahydro-1,15-Ethenopyrazolo[4,3-F][1,4,8,10]Benzoxatriazacyclotridecin-4(5H)-One
- 1,15-ETHENO-1H-PYRAZOLO(4,3-F)(1,4,8,10)BENZOXATRIAZACYCLOTRIDECIN-4(5H)-ONE, 11-FLUORO-6,7,13,14-TETRAHYDRO-7,13-DIMETHYL-, (7S,13R)-
////////Ropotrectinib, FDA 2023, APPROVALS 2023, Turning Point , EU 2025, APPROVALS 2025, EMA 2025, Augtyro, TPX 0005, CHINA 2024, APPROVALS 2024
Donafenib
Donafenib
CAS 1130115-44-4, CM-4307, Zepsun, 41XGO0VS1U
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-(trideuteriomethyl)pyridine-2-carboxamide
- 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)phenoxy)-N-(2H3)methylpyridine-2-carboxamide
- Sorafenib-d3
- Sorafenib D3
- Donafenib (Sorafenib D3)
- Sorafenib-methyl-d3
- d3-sorafenib
CM-4307 is under investigation in clinical trial NCT03602495 (Donafenib in 131I-Refractory Differentiated Thyroid Cancer).
Donafenib, sold under the brand name Zepsun, is a pharmaceutical drug for the treatment of cancer.
In China, donafenib is approved for the treatment of unresectable hepatocellular carcinoma in patients who have not previously received systemic treatment.[1][2]
Donafenib is a kinase inhibitor that targets Raf kinase and various receptor tyrosine kinases.[3] It is a deuterated derivative of sorafenib with improved pharmacokinetic properties.[4][5]
Donafenib is an orally available multikinase inhibitor that targets Raf kinase and various receptor tyrosine kinases (RTKs), with potential antineoplastic activity. Upon oral administration, donafenib binds to and blocks the activity of Raf kinase, and inhibits Raf-mediated signal transduction pathways. This inhibits cell proliferation in Raf-expressing tumor cells. In addition, this agent may inhibit unidentified RTKs, and thus may further block tumor cell proliferation in susceptible tumor cells. Raf, a serine/threonine protein kinase, plays a key role in the Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. Deregulation of this pathway often results in tumor cell proliferation and survival.
SYN
ACS Omega 2021, 6, 5532−5547.
https://pubs.acs.org/doi/10.1021/acsomega.0c05908
Syn
Donafenib (Zepsun). Donafenib (31), developed by Suzhou Zelgen Biopharmaceuticals, is a deuterated derivative of sorafenib, a multikinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). 222 HCC is the most common type of primary liver cancer in adults and the third leading cause of cancer-related deaths worldwide.223,224 Donafenib inhibits Raf kinase and VEGFR tyrosine kinases,
thereby preventing the proliferation of tumor cells. 225 The presence of the deuterated methyl group in donafenib improves metabolic stability with prolonged half-life, lower systemic clearance, and higher systemic exposure.226 Donafenib has been shown to significantly improve the overall survival
of patients with HCC when compared against sorafenib, with favorable safety and tolerability.227 228
In June 2021, donafenib was first approved in China for treating unresectable HCC in patients who have not previously received systemic treatment.
A gram-scale synthesis of donafenib was recently disclosed by Luo and co-workers (Scheme 55).229
The synthetic sequence commenced with amidation of methyl ester 31.2 using methan-d3-amine hydrochloride (31.1) as the deuterium source, affording CD 3-amide 31.3 in high yield (98%). SNAr
displacement with aminophenol 31.4 in DMSO provided diaryl ether 31.5. Finally, reaction of the aniline moiety with isocyanate 31.6 delivered donafenib (31) in 79% yield from 31.3
(222) Mousa, A. B. Sorafenib in the treatment of advanced
hepatocellular carcinoma. Saudi J. Gastroenterol 2008, 14, 40−42.
(223) Forner, A.; Llovet, J. M.; Bruix, J. Hepatocellular carcinoma.
Lancet 2012, 379, 1245−1255.
(224) Vogel, A.; Meyer, T.; Sapisochin, G.; Salem, R.; Saborowski,
A. Hepatocellular carcinoma. Lancet 2022, 400, 1345−1362.
(225) Gong, X.; Qin, S. Study progression of anti-angiogenetic
therapy and its combination with other agents for the treatment of
advanced hepatocellular carcinoma. Hepatobiliary Surg. Nutr. 2018, 7,
466−474.
(226) Zhong, L.; Hou, C.; Zhang, L.; Zhao, J.; Li, F.; Li, W.
Synthesis of deuterium-enriched sorafenib derivatives and evaluation
of their biological activities. Mol. Divers. 2019, 23, 341−350.
(227) Qin, S.; Bi, F.; Gu, S.; Bai, Y.; Chen, Z.; Wang, Z.; Ying, J.; Lu,
Y.; Meng, Z.; Pan, H.; et al. Donafenib versus sorafenib in first-line
treatment of unresectable or metastatic hepatocellular carcinoma: A
randomized, open-label, parallel-controlled phase II-III trial. J. Clin.
Oncol. 2021, 39, 3002−3011.
(228) Keam, S. J.; Duggan, S. Donafenib: First approval. Drugs 2021,
81, 1915−1920.
(229) Li, C.; Zhong, J.; Liu, B.; Yang, T.; Lv, B.; Luo, Y. Study on
typical diarylurea drugs or derivatives in cocrystallizing with strong H
bond acceptor DMSO. ACS Omega 2021, 6, 5532−5547.
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References
- Keam SJ, Duggan S (November 2021). “Donafenib: First Approval”. Drugs. 81 (16): 1915–1920. doi:10.1007/s40265-021-01603-0. PMID 34591285.
- Chen R, Ielasi L, di Carlo A, Tovoli F (February 2023). “Donafenib in hepatocellular carcinoma”. Drugs of Today. 59 (2): 83–90. doi:10.1358/dot.2023.59.2.3507751. hdl:11585/955557. PMID 36811408.
- “Donafenib”. NCI Cancer Dictionary. National Cancer Institute, National Institutes of Health.
- Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, et al. (September 2021). “Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial”. Journal of Clinical Oncology. 39 (27): 3002–3011. doi:10.1200/JCO.21.00163. PMC 8445562. PMID 34185551.
- Qin S, Bi F, Xu J, Du C, Fan Q, Zhang L, et al. (2020). “P-86 Comparison of the pharmacokinetics of donafenib and sorafenib in patients with advanced hepatocellular carcinoma: An open-label, randomized, parallel-controlled, multicentre phase II/III trial”. Annals of Oncology. 31: S117 – S118. doi:10.1016/j.annonc.2020.04.168.
| Clinical data | |
|---|---|
| Trade names | Zepsun |
| Other names | CM-4307 |
| Legal status | |
| Legal status | Rx in China |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1130115-44-4 |
| PubChem CID | 25191001 |
| DrugBank | DB15414 |
| ChemSpider | 23937167 |
| UNII | 41XGO0VS1U |
| ChEMBL | ChEMBL4297490 |
| CompTox Dashboard (EPA) | DTXSID90648995 |
| Chemical and physical data | |
| Formula | C21H16ClD3F3N4O3 |
| Molar mass | 470.87 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////Donafenib, ZEPSUN, CHINA 2021, APPROVALS 2021, Suzhou Zelgen, 1130115-44-4, CM 4307, 41XGO0VS1U, Sorafenib D3
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
