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Garsorasib
Garsorasib
Chemical Formula: C32H32F2N8O2
Exact Mass: 598.2616
Molecular Weight: 598.66
- CAS 2559761-14-5
- P491NE9G6Z
- D-1553
- 7-(2-amino-6-fluorophenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-4-[(2S,5R)-2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl]-6-fluoropyrido[2,3-d]pyrimidin-2-one
- 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoropyrido(2,3-d)pyrimidin-2(1H)-one
- Pyrido(2,3-d)pyrimidin-2(1H)-one, 7-(2-amino-6-fluorophenyl)-1-(4,6-dicyclopropyl-5-pyrimidinyl)-4-((2S,5R)-2,5-dimethyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl)-6-fluoro-
D 1553, Chia Tai Tianqing, CHINA 2024, APPROVALS 2024, Anfangning,
Garsorasib is an orally available inhibitor of the oncogenic KRAS substitution mutation, G12C, with potential antineoplastic activity. Upon oral administration, garsorasib selectively targets the KRAS G12C mutant and inhibits KRAS G12C mutant-dependent signaling. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021120045&_cid=P11-MEJTS8-41135-1
Example 5. Preparation and Solid state characterization of Compound 2
Step 1: To a mixture of 2, 6-dichloro-5-fluoronicotinic acid (23 g, 0.11 mol) in dichloromethane (300 mL) was added dimethylformamide (0.2 mL) . Oxalyl chloride (33 g, 0.26 mol) was then added slowly over 30 minutes at room temperature. The mixture was stirred at room temperature for an hour and then concentrated to give an oil which was dissolved in dioxane (50 mL) . The solution was added to ammonium hydroxide (150 mL) at 0℃ over 30 minutes. The resulting mixture was stirred at 0℃ for 30 minutes and then filtered. The filter cake was washed with cooled water (50 mL) and dried to afford 2-1.
[0183]
Step 2: A solution of 2-1 (11 g, 52.6 mmol) in 1, 2-dichloroethane (80 mL) was treated with oxalyl chloride (8.68 g, 68.4 mmol) . The mixture was stirred at 80℃ for 45 minutes and the reaction was concentrated. The residue was dissolved in acetonitrile (100 mL) , cooled to -10℃, and a solution of 1-1 (9.6 g, 55.2 mmol) in THF (30 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. The solution was diluted with a sat. aqueous NaHCO 3solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 4/1) to afford 2-2.
[0184]
Step 3: To a stirred solution of 2-2 (7.9 g, 19.3 mmol) in THF (100 mL) at -20℃ was added KHMDS (38.6 mL, 1 M in THF, 38.6 mmol) . The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with sat. aqueous NH 4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 2/1) to afford 2-3.
[0185]
Step 4: To a solution of 2-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol) in MeCN (20 mL) was added POCl 3(367 mg, 2.4 mmol) dropwise at room temperature. The resulting mixture was stirred at 80℃ for 45 minutes, followed by addition of DIEA (3.87 g, 30 mmol) and a solution of 1-5 (1.58 g, 4 mmol) in MeCN (10 mL) dropwise at -10℃. After stirring at room temperature for 1 hour, the reaction was quenched with ice-water and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane to dichloromethane/methanol = 10/1) to afford 2-4.
[0186]
Step 5: A mixture of 2-4 (8 mg, 0.15 mmol) , 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (42 mg, 0.18 mmol) , Pd (dppf) Cl 2(13 mg, 0.018 mmol) and KOAc (40 mg, 0.41 mmol) in dioxane (3 mL) /H 2O (1 drop) was stirred at 80℃ for 2 hours under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2SO 4and concentrated. The residue was purified by a Prep-HPLC (acetonitrile with 0.05%of TFA in water (30%to 65%) to afford 2. LCMS (ESI, m/z) : [M+H] += 599.1; HNMR (400 MHz, methanol-d 4, ppm) : δ 8.73 (s, 1H) , 8.26-8.22 (m, 1H) , 7.15-7.09 (m, 1H) , 6.84-6.74 (m, 1H) , 6.53 (d, J = 8.4 Hz, 1H) , 6.42-6.38 (m, 1H) , 6.30-6.24 (m, 1H) , 5.83-5.78 (m, 1H) , 5.01 (brs, 1H) , 4.91-4.83 (m, 1H) , 4.53-4.29 (m, 2H) , 3.96-3.89 (m, 1.5H) , 3.54-3.50 (m, 0.5H) , 1.82-1.75 (m, 1H) , 1.73-1.66 (m, 1H) , 1.47 (d, J = 6.8 Hz, 3H) , 1.37-1.27 (m, 3H) , 1.16-1.05 (m, 4H) , 1.03-0.97 (m, 2H) , 0.88-0.83 (m, 2H) . FNMR (376 MHz, methanol-d 4, ppm) : δ -114.9 (1F) , -125.6 (1F) .
[0187]
Compound 2 prepared via the above procedure was slurried in EtOAc, and filtered to provide Compound 2 in a crystalline form A. About 1.1%of residual EtOAc was detected by 1H-NMR, corresponding to weight loss at 120 –290 ℃ in TGA (FIG. 5B) . Two overlapped endothermic peaks were observed by DSC (FIG. 5B) . Compound 2 in Form A was heated to 250 ℃ and DSC profile of the residual solid was unchanged, suggesting the overlapped peak was due to melting with crystal form transformation. Thus, the starting material was an anhydrate.
[0188]
Form A was very soluble in DCM (> 92 mg/mL) and soluble (20 –33 mg/mL) in MeOH, butanone, THF, ACN and acetone. In other solvents, Form A was practically insoluble
SYN
CN112585129
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN321747237&_cid=P11-MEJTN6-36089-1
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Garsorasib (D-1553), marketed as Anfangning, is an orally bioavailable KRAS G12C inhibitor jointly developed by InventisBio and Chia Tai Tianqing Pharmaceutical Group [40]. This compound is specifically engineered to target the KRAS G12C mutation, a prevalent oncogenic driver in multiple cancers, including NSCLC. In 2024, the NMPA granted conditional approval for Garsorasib to treat adult patients with advanced NSCLC harboring the KRAS G12C mutation, who have undergone at least one prior systemic therapy regimen [41]. Garsorasib exerts its pharmacological effects through selective and irreversible binding to the KRAS G12C mutant protein, thereby immobilizing it in an inactive GDP-bound conformation. This binding event effectively disrupts the activation of downstream signaling path
ways, including mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K), resulting in diminished tumor cell proliferation and survival. The clinical efficacy of Garsorasib has been
confirmed in a Phase II clinical trial (NCT05383898) involving patients with advanced NSCLC harboring the KRAS G12C mutation. The trial reported an ORR of 52.0 % and a DCR of 88.6 %. Additionally, the
median PFS was observed to be 9.1 months, while the median overall survival (OS) reached 14.1 months, both indicative of significant antitumor activity within this patient cohort. In terms of safety, Garsorasib
exhibited a generally favorable tolerability profile [42]. The most common treatment-related adverse events included diarrhea, nausea, and elevated liver enzymes, which were predominantly of grade 1 or 2
severity.The synthesis of Garsorasib, depicted in Scheme 10, initiates with Suzuki-Miyaura coupling of Gars-001 and cyclopropylboronic acid, affording Gars-002 [43]. Gars-003 undergoes nucleophilic acylation with acryloyl chloride to yield Gars-004. TFA-mediated Boc deprotection of Gars-004 affords Gars-005. In parallel, Gars-006 is sequentially acylated with oxalyl chloride and aminated with ammonia to form Gars-007. DCE-mediated acylation of Gars-007, followed by concentration and coupling with Gars-002 in MeCN, produces Gars-008.KHMDS-catalyzed intramolecular cyclization of Gars-008 generates Gars-009. DIEA-catalyzed intermediate generation enables nucleophilic coupling with Gars-005 to assemble Gars-010. Final Suzuki-Miyaura coupling of Gars-010 with 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline delivers Garsorasib.
[40] W. Luo, J. Zhu, W. Zhang, A. Yu, W. Zhou, K. Xu, Efficacy and toxicity of drugs
targeting KRAS(G12C) mutation in non-small cell lung cancer: a meta-analysis,
Expert Rev. Anticancer Ther. 23 (2023) 1295–1303.
[41] Z. Li, X. Dang, D. Huang, S. Jin, W. Li, J. Shi, X. Wang, Y. Zhang, Z. Song, J. Zhang,
W. Zhuang, X. Liu, L. Jiang, X. Meng, M. Zhao, J. Zhou, L. Zhang, P. Wang, H. Luo,
J. Yang, S. Cang, X. Wang, L. Zhang, S. Lu, Garsorasib in patients with KRAS
(G12C)-mutated non-small-cell lung cancer in China: an open-label, multicentre,
single-arm, phase 2 trial, Lancet Respir. Med. 12 (2024) 589–598.
[42] Z. Li, Z. Song, Y. Zhao, P. Wang, L. Jiang, Y. Gong, J. Zhou, H. Jian, X. Dong,
W. Zhuang, S. Cang, N. Yang, J. Fang, J. Shi, J. Lu, R. Ma, P. Wu, Y. Zhang,
M. Song, C.W. Xu, Z. Shi, L. Zhang, Y. Wang, X. Wang, Y. Zhang, S. Lu, D-1553
(garsorasib), a potent and selective inhibitor of KRAS(G12C) in patients with
NSCLC: phase 1 study results, J. Thorac. Oncol. 18 (2023) 940–951.
[43] X. Dai, Y. Wang, Y. Jiang, Y. Liu, Z. Shi, Z. Wang, L. Tao, Z. Han, H. Niu, J. Weng,
Heterocyclic Compounds, Preparation Methods and Uses Thereof in the Treatment
of Cancers, 2020 CN112585129A.
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- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- D‐1553: A novel <scp>KRASG12C</scp> inhibitor with potent and selective cellular and in vivo antitumor activityPublication Name: Cancer SciencePublication Date: 2023-05-09PMCID: PMC10323112PMID: 37158138DOI: 10.1111/cas.15829
Methods of treating a ras protein-related disease or disorder
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- Heterocyclic compounds, preparation methods and uses thereofPublication Number: WO-2020233592-A1Priority Date: 2019-05-21
- Heterocyclic compounds, preparation and methods and uses thereofPublication Number: US-11091481-B2Priority Date: 2019-05-21Grant Date: 2021-08-17
- Heterocyclic compounds, preparation and methods and uses thereofPublication Number: US-2021198255-A1Priority Date: 2019-05-21
- Heterocyclic compounds, preparation methods and uses thereofPublication Number: US-2021355125-A1Priority Date: 2019-05-21
- Medicament for treatment and/or prevention of cancerPublication Number: WO-2023008462-A1Priority Date: 2021-07-27
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- Heterocyclic compounds, preparation methods and uses thereofPublication Number: US-11241437-B2Priority Date: 2019-12-18Grant Date: 2022-02-08
- Medicament for treatment and/or prevention of cancerPublication Number: AU-2022320304-A1Priority Date: 2021-07-27
- Medicament for treatment and/or prevention of cancerPublication Number: CA-3227706-A1Priority Date: 2021-07-27
- Medicines for the treatment and/or prevention of cancerPublication Number: CN-117677398-APriority Date: 2021-07-27
- Medicament for treatment and/or prevention of cancerPublication Number: EP-4378478-A1Priority Date: 2021-07-27
- Medicines for the treatment and/or prevention of cancerPublication Number: KR-20240041917-APriority Date: 2021-07-27
- Composition for preventing or treating c-myc-associated diseases through inhibition of expression of ubiquitin-specific protease 47 (usp47), and use thereofPublication Number: WO-2024085603-A1Priority Date: 2022-10-18
- Chimeric small molecules for labeling proteins with immunogenic moieties and methods of use thereofPublication Number: WO-2024081675-A2Priority Date: 2022-10-10
- Macrocyclic heterocycles and uses thereofPublication Number: US-11912708-B2Priority Date: 2022-04-20Grant Date: 2024-02-27
- Macrocyclic heterocycles and uses thereofPublication Number: US-2023339952-A1Priority Date: 2022-04-20
- Macrocyclic heterocycles and uses thereofPublication Number: WO-2023205701-A1Priority Date: 2022-04-20
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- Combination therapy and related methodsPublication Number: US-2024343813-A1Priority Date: 2023-02-06
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///////Garsorasib, D 1553, Chia Tai Tianqing, CHINA 2024, APPROVALS 2024, Anfangning, 2559761-14-5, P491NE9G6Z
Fulzerasib
Fulzerasib
GFH925
CAS No. : 2641747-54-6
| Molecular Weight | 617.07 |
|---|---|
| Formula | C32H30ClFN6O4 |
(7R)-16-chloro-15-(2-fluoro-6-hydroxyphenyl)-9-methyl-12-(4-methyl-2-propan-2-ylpyridin-3-yl)-5-prop-2-enoyl-2,5,9,12,14-pentazatetracyclo[8.8.0.02,7.013,18]octadeca-1(10),13,15,17-tetraene-8,11-dione
CHINA 2024, APPROVALS 2024, Innovent Biologics, DUPERT
Fulzerasib (Dupert®; Innovent Biologics/GenFleet Therapeutics) is an orally active small molecule inhibitor of the KRAS G12C mutant protein being developed for the treatment of solid tumors harboring the KRAS G12C oncogenic driver mutation, including non-small cell lung cancer (NSCLC) and colorectal cancer. Fulzerasib received its first approval on 21 August 2024 in China, for the treatment of adults with KRAS G12C-mutated advanced NSCLC who have received at least one line of systemic therapy. This conditional approval was based on the positive results of a single-arm, phase II study. This article summarizes the milestones in the development of fulzerasib leading to this first approval for KRAS G12C-mutated advanced NSCLC.
Fulzerasib (GFH925) is an irreversible KRAS G12C inhibitor, has a synergistic anti-cancer effect with cetuximab (HY-P9905)..
PAPER
https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03183
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021083167&_cid=P20-MEJIF1-91906-1
Step 1: Suspend 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) in a mixture of 1,4-dioxane (120 mL) and water (120 mL). Slowly add concentrated sulfuric acid (120 mL). Stir at 120°C for 36 hours. Pour the cooled reaction mixture into 200 mL of ice water, adjust the pH to 2-3 with sodium carbonate, and extract with ethyl acetate (1000 mL x 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and vacuum-dry the filtrate to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridine-2(1H)-one (24 g, Y: 85.7%) as a light brown solid. ES-API: [M+H]
[0537]Step 2: 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL). Sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added sequentially. The reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, Y: 92%) as a yellow solid. ES-API: [M+H]
[0538]Step 3: To a 100 mL three-necked round-bottom flask, add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakistriphenylphosphine palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane. Under nitrogen, stir at 100°C for 2-3 hours. After completion, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to afford 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude) as a pale yellow solid. ES-API: [M+H]
[0539]Step 4: 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL). Phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added sequentially. The reaction mixture was gradually heated to 80°C and stirred for 30 minutes. The reaction solution was concentrated, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined and washed once with 200 mL of saturated brine. The reaction mixture was dried over anhydrous sodium sulfate and filtered. The organic phase was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (EtOAc/PE: 0-50%) to afford 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.05 g, Y: 76%) as a yellow solid. ES-API: [M+H]
[0540]Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL). 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylate (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) were added sequentially. The reaction mixture was stirred at 120°C for 2 hours. 80 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated, and the crude product was purified on a flash silica gel column (EtOAc/PE: 0-80%) to afford 1-(tert-butyl)-3-methyl (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, Y: 77%) as a yellow solid. ES-API: [M+H]
[0541]Step 6: 1-(tert-Butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the reaction was stirred at 80 °C for 30 minutes. The reaction mixture was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. The mixture was dried and concentrated to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (2.70 g, crude) as a yellow solid. ES-API: [M+H]+ = 663.2.
[0542]Step 7: To a 150 mL sealed tube was added tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (2.7 g, 3.728 mmol), 30 mL of acetone, anhydrous potassium carbonate (2.2 g, 15.94 mmol), and iodomethane (5.4 g, 38.03 mmol). The tube was sealed and the reaction was stirred at 55°C for 18 hours. The reaction mixture was added with 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc/PE: 0-80%) to obtain (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (2.2 g, Y: 87%) as a yellow solid. ES-API: [M+H]
[0543]Step 8: Tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (517 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to afford (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (530 mg, crude), which was used directly in the next reaction. ES-API: [M+H]
[0544]Step 9: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (530 mg, 0.7549 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO₃
and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc/PE: 0-60%) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, Y: 59%) as a yellow solid. ES-API: [M+H]
[0545]Step 10: In an ice-water bath, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL), and then boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc/PE: 0-60%) to give (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z25, 233 mg, Y: 85%).
[0546]Step 11: Compound Z25 was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 25 ml/min, column temperature) to obtain: an atropisomer compound Z25-1 (76.8 mg, peak 1, retention time 2.531 min, Y: 34%).
1 H NMR (500 MHz, DMSO-d
6 )δ10.03(d,J＝18.4Hz,1H),8.52(d,J＝7.3Hz,1H),8.43(d,J＝4.7Hz,1H),7.23(d,J＝9.6Hz,2H),7.08(dd,J＝16 .6,10.5Hz,1H),6.74–6.62(m,2H),6.15(d,J＝16.8Hz,1H),5.75(d,J＝10.7Hz,1H),4.73(d,J＝14.2Hz,1H),4.4 6 (d, J = 12.9 Hz, 1H), 4.00 (s, 1H), 3.61 (d, J = 10.0 Hz, 1H), 3.51 (s, 1H), 3.34 (s, 3H), 3.22 (s, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.48–2.42 (m, 1H), 1.98 (d, J = 5.1 Hz, 3H), 1.03 (t, J = 6.9 Hz, 3H), 0.86 (t, J = 7.9 Hz, 3H). ES-API: [M+H]
+ = 617.2. And another atropisomer compound Z25-2 (70 mg, peak 2, retention time 3.683 min, Y: 31%).
1 H NMR (500MHz, CDCl
3 )δ8.64–8.59(m,1H),8.35(s,1H),8.07(s,1H),7.27–7.20(m,2H),7.14–7.02(m,1H),6.75–6.63(m,2H),6.39(dd,J＝17.0,2.0Hz,1H),5.88 –5.77(m,1H),4.91(d,J＝14.0Hz,1H),4.83(d,J＝13.0Hz,1H),3.72–3.58(m,2H),3.50(s,3H),3.43(d,J＝12.0Hz,1H),3.1 6(t,J＝13.0Hz,1H),2.91(t,J＝12.0Hz,1H),2.82-2.73(m,1H),1.93(s,3H),1.24(d,J＝7.0Hz,3H),1.12(d,J＝7.0Hz,3H). ES-API: [M+H]
+ =617.2. The isomers were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH=60:40, flow rate: 1 ml/min, column temperature=30°C).
Step 1: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (520 mg, crude), which was used directly in the next reaction. ES-API: [M+H]
[0550]Step 2: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (520 mg, 0.7549 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO₃
and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc/PE: 0-60%) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d₃)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (232 mg, Y: 48%) as a yellow solid. ES-API: [M+H]
[0551]Step 3: Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL), and boron tribromide (5.0 mL, 5.0 mmol) was added. The temperature was warmed to room temperature and the reaction was allowed to react overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc/PE: 0-60%) to give (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (Z26, 187 mg, Y: 79%). [M+H]
[0552]Step 4: Compound Z26 (187 mg, 0.302 mmol) was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 25 ml/min, column temperature) to obtain: an atropisomer compound, arbitrarily designated as Z26-1 (68.8 mg, peak 1, retention time 2.525 min, Y: 36.7%).
1 H NMR (500 MHz, DMSO-d
6 )δ10.03(d,J＝17.9Hz,1H),8.51(d,J＝7.4Hz,1H),8.43(d,J＝4.7Hz,1H),7.29–7.18(m,2H),7.08(dd,J ＝17.0,10.6Hz,1H),6.74–6.61(m,2H),6.15(d,J＝16.6Hz,1H),5.75(d,J＝11.5Hz,1H),4.73(d,J＝13.5 Hz, 1H), 4.46 (d, J = 12.3 Hz, 1H), 4.00 (s, 1H), 3.61 (d, J = 10.5 Hz, 1H), 3.50 (s, 1H), 3.22 (s, 1H), 2.65 (t, J = 12.5 Hz, 1H), 2.49–2.42 (m, 1H), 1.98 (d, J = 5.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.9 Hz, 3H). ES-API: [M+H]
+ = 620.3. Another atropisomer, arbitrarily designated Z26-2 (63.2 mg, peak 2, retention time 3.683 min, Y: 33.79%), was obtained.
1 H NMR (400 MHz, CDCl
3 )δ8.62(d,J＝4.8Hz,1H),8.35(s,1H),8.07(s,1H),7.24–7.20(m,2H),7.16–7.01(m,1H),6.74–6.6 3(m,2H),6.39(dd,J＝16.8,2.0Hz,1H),5.82(dd,J＝10.4,2.0Hz,1H),4.91(d,J＝13.6Hz,1H),4.83(d δ (d, J = 13.6 Hz, 1H), 3.71–3.57 (m, 2H), 3.42 (d, J = 12.0 Hz, 1H), 3.16 (t, J = 12.8 Hz, 1H), 2.91 (t, J = 12.0 Hz, 1H), 2.81–2.70 (m, 1H), 1.92 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H). ES-API: [M+H]
+ = 620.3. The isomeric compounds were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH = 60:40, flow rate: 1 ml/min, column temperature = 30°C).
PAT
- US12054497, Compound Z25-1
- US12054497, Compound Z25-2
- US12054497, Compound Z26-1
- US12054497, Compound Z26-2
PAT
CN112390818
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN319676055&_cid=P20-MEJIKL-96783-1
| Example 25 Preparation of Z25 |
| Step 1: To a 100 mL three-necked round-bottom flask was added (S)-2-chloro-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxo-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptyl[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester (1.4 g, 2.66 mmol), (2-amino-6-fluorophenyl)boronic acid (0.6 g, 3.87 mmol), Sphos-Pd-G2 (0.2 g, 0.21 mmol), Sphos (120 mg, 0.29 mmol), potassium phosphate (1.2 g, 5.66 mmol), 10 mL of dioxane, and 2 mL of water. The system was purged with nitrogen three times and then protected with nitrogen. The reaction was continued at 120°C for 2 h. 30 mL of ethyl acetate was added to the reaction solution, which was washed three times with 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column to give the target product, (S)-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester (845 mg, yield: 41%). ES-API: [M+H]+ = 602.2. |
| Step 2: Dissolve (S)-tert-butyl 2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene 7(5H)-carboxylate (800 mg, 1.33 mmol) in dichloromethane (8 mL), and add trifluoroacetic acid (2 mL). Stir at room temperature for 2 hours. The reaction mixture is concentrated to obtain the target intermediate, which is dissolved in dichloromethane (15 mL) and triethylamine (800 mg, 87.1 mmol) is added. Cool the reaction mixture to 0°C, and add acrylic anhydride (160 mg, 1.27 mmol) dropwise. Stir the reaction mixture at 0°C for 15 minutes. The reaction mixture was added with 40 mL of dichloromethane, washed with 50 mL of saturated aqueous NaHCO₃ and 40 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column to obtain the target product, Z25(S)-7-acryloyl-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11(12H)-one (250 mg, yield: 34%). ES-API: [M+H] ⁺ = 556.2. 1 H NMR (500MHz, DMSO) δ8.55 (d, J＝4.9Hz, 1H), 7.32 (d, J＝4.9Hz, 1H), 7.04 (dd, J＝ 14.8,8.0Hz,1H),6.95-6.80(m,1H),6.52(d,J＝8.3Hz,1H),6.36-6.13(m,4H) ,6.06-5.95(m,1H),5.78(d,J＝10.3Hz,1H),4.82-4.04(m,7H),3.56(s,1H),3 .25-3.18(m,1H),2.84-2.70(m,1H),1.98(d,J=5.2Hz,3H),1.15-0.95(m,6H). |
| Example 26 Preparation of Z26 |
| Step 1: To a solution of 7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (130 mg, 0.39 mmol) in acetonitrile (3 mL) were added phosphorus oxychloride (1 mL) and N,N-diisopropylethylamine (1 mL) sequentially. The mixture was stirred at 90°C for 2 h. The reaction mixture was concentrated to afford crude 4,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (130 mg). ES-API: [M+H] + = 349.3. |
| Step 2: To a solution of 4,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (130 mg, 0.37 mmol) in acetonitrile (3 mL) was added N,N-diisopropylethylamine (144 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (70 mg, 0.37 mmol) under ice-cooling. The mixture was stirred for 30 minutes. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The mixture was then purified on a flash silica gel column (0-100% ethyl acetate/petroleum ether) to obtain tert-butyl 4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (140 mg) as a white solid. ES-API: [M+H] + = 499.1. |
| Step 3: Under nitrogen protection, a mixture of tert-butyl 4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 0.28 mmol), 2-fluoro-6-hydroxyphenylboronic acid (44 mg, 0.42 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (13 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (10 mg, 0.02 mmol) and potassium phosphate (120 mg, 0.84 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was microwaved at 120 ° C for 1 h. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The filtrate was washed with saturated brine (50 mL x 3). The resulting organic phase was dried, concentrated, and purified on a flash silica gel column (0-100% ethyl acetate/petroleum ether) to afford tert-butyl 4-(7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridinyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, yield: 62%) as a white solid. ES-API: [M+H] + = 575.2. |
| Step 4: To a solution of tert-butyl 4-(7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridinyl[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.17 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) under ice-cooling. The mixture was stirred at room temperature for 2 h and concentrated to afford 7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(piperazin-1-yl)pyridin[4,3-d]pyrimidin-2(1H)-one (82 mg, theoretical) as a yellow oil. ES-API: [M+H] + = 475.2. |
| Step 5: Under ice bath, add N,N-diisopropylethylamine (110 mg, 0.85 mmol) to a solution of 7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(piperazin-1-yl)pyridin[4,3-d]pyrimidin-2(1H)-one (82 mg, 0.17 mmol) in dichloromethane (3 mL). After the reaction solution becomes clear, add acrylic anhydride (21 mg, 0.17 mmol) dropwise and stir for 5 minutes. The reaction solution is washed with saturated sodium bicarbonate solution (5 mL). The organic phase is dried, concentrated, and purified by preparative HPLC (ammonium bicarbonate system) to obtain a light yellow solid Z26 (12.44 mg, purity: 100%, yield: 14% ) . NMR (500MHz, DMSO) δ12.86(s,1H),9.26(s,1H),8.59(d,J＝4.9Hz,1H),7.35(d,J＝4.9Hz,1H),7.29(d d,J＝15.0,8.2Hz,1H),6.86(dd,J＝16.7,10.4Hz,1H),6.77(d,J＝8.3Hz,1H),6.73-6.66(m,2H),6.21( dd,J＝16.6,2.3Hz,1H),5.77(dd,J＝10.4,2.3Hz,1H),4.07(d,J＝5.0Hz,4H),3.88(d,J＝36.8Hz,4H),2 .76(dt,J＝13.6,6.8Hz,1H),1.96(s,3H),1.10(d,J＝6.7Hz,3H),1.04(d,J＝6.7Hz,3H).ES-API:[M+H] + =529.2. |
SYN
Fulzerasib is an orally active KRAS G12C inhibitor developed by Innovent Biologics. It selectively targets the KRAS G12C mutation in NSCLC [36,37]. In 2024, the NMPA approved Fulzerasib (brand name: Dupert) for treating adult patients with advanced NSCLC harboring the KRAS G12C mutation who have progressed after prior systemic therapy. Fulzerasib irreversibly binds to the KRAS G12C mutant protein, locking it in an inactive GDP-bound state, thereby inhibiting downstream signaling pathways such as MAPK and PI3K. This action effectively suppresses cancer cell proliferation and survival. The clinical efficacy of Fulzerasib was demonstrated in a Phase II trial (NCT05009303) involving patients with advanced NSCLC and KRAS G12C mutations [38]. In the clinical trial, Fulzerasib demonstrated an ORR of 49.1 % and a disease control rate (DCR) of 90.5 %, with a median PFS of 9.7 months, reflecting robust antitumor efficacy. The agent exhibited favorable tolerability, characterized by manageable toxicity. Treatment-related adverse events were predominantly mild to moderate in severity, with the most frequently reported being diarrhea, nausea, and elevated liver enzymes [38]. The safety profile was consistent with other KRAS G12Cinhibitors, making it a viable therapeutic option.
The synthetic route of Fulzerasib, shown in Scheme 9, initiates with H2SO4-mediated decyanation of Fulz-001, affording Fulz-002 [39]. Nitrosation of Fulz-002 with NaNO2 yields Fulz-003, which undergoes
Suzuki-Miyaura coupling with (2-fluoro-6-methoxyphenyl)boronic acid to construct Fulz-004. Phosphochlorination with POCl3 under DIPEA catalysis converts Fulz-004 to Fulz-005. Nucleophilic displacement with methyl (R)-1-N-Boc-piperazine-3-carboxylate assembles Fulz-006. Fe-mediated tandem Mannich cyclization/nitro reduction transforms Fulz-006 into bicyclic amine Fulz-007. Methylation with MeI generates Fulz-008, followed by TFA-mediated Boc cleavage to afford Fulz-009.
Acrylation with acryloyl chloride produces Fulz-010. Selective O-demethylation followed by chiral HPLC resolution delivers Fulzerasib
[36] Y.N. Lamb, Correction: fulzerasib: first approval, Drugs 85 (2025) 281.
[37] Y.N. Lamb, Fulzerasib: first approval, Drugs 84 (2024) 1665–1671.
[38] Q. Zhou, X. Meng, L. Sun, D. Huang, N. Yang, Y. Yu, M. Zhao, W. Zhuang, R. Guo,
Y. Hu, Y. Pan, J. Shan, M. Sun, Y. Yuan, Y. Fan, J. Huang, L. Liu, Q. Chu, X. Wang,
C. Xu, J. Lin, J. Huang, M. Huang, J. Sun, S. Zhang, H. Zhou, Y.L. Wu, Efficacy and
safety of KRASG12C inhibitor IBI351 monotherapy in patients with advanced
NSCLC: results from a phase 2 pivotal study, J. Thorac. Oncol. 19 (2024)
1630–1639.
[39] F. Zhou, T. Jiang, W. He, L. Cai, H. Yang, Z. Liu, J. Lan, Preparation of
Heteroaromatic Ring Dihydropyrimidinone Derivatives as KRAS Gene Mutation
Inhibitors Useful in the Treatment of Cancer, 2021. CN112390818A.
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- [1]. Rafael Rosell, et al. KRAS G12C-mutant driven non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol. 2024 Mar:195:104228. [Content Brief][2]. Vanesa Gregorc, et al. KROCUS: A phase II study investigating the efficacy and safety of fulzerasib. Free access.June 05, 2024
- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- Fulzerasib: First ApprovalPublication Name: DrugsPublication Date: 2024-11-26PMID: 39587006DOI: 10.1007/s40265-024-02120-6
- Substituted heterocyclic compounds, their preparation methods and medicinal usesPublication Number: CN-117645614-APriority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: EP-4328229-A2Priority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: US-12054497-B2Priority Date: 2019-10-30Grant Date: 2024-08-06
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: US-2024158417-A1Priority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: EP-4053118-B1Priority Date: 2019-10-30Grant Date: 2024-10-09
- Substituted heterocyclic and cyclic compounds, their preparation and medical usePublication Number: CN-113853373-BPriority Date: 2019-10-30Grant Date: 2022-08-05
- Substituted heterocyclic ring compound, preparation method and medical application thereofPublication Number: CN-115057872-APriority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: EP-4053118-A1Priority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, method for preparing same, and pharmaceutical use thereofPublication Number: KR-20220106765-APriority Date: 2019-10-30
- Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereofPublication Number: US-2023084095-A1Priority Date: 2019-10-30
- Polymorph of kras inhibitor, preparation method therefor, and use thereofPublication Number: WO-2023116895-A1Priority Date: 2021-12-24
- Polymorph of kras inhibitor, preparation method therefor, and use thereofPublication Number: EP-4455147-A1Priority Date: 2021-12-24
- Polymorph of kras inhibitor, preparation method therefor, and use thereofPublication Number: US-2025051333-A1Priority Date: 2021-12-24
- Key intermediate of kras inhibitor and preparation method thereforPublication Number: WO-2022198904-A1Priority Date: 2021-03-26
- A key intermediate of a KRAS inhibitor and its preparation methodPublication Number: CN-116848111-APriority Date: 2021-03-26
- Pharmaceutical composition, and preparation method therefor and use thereofPublication Number: WO-2024061267-A1Priority Date: 2022-09-21
- Pharmaceutical composition, use thereof, and method for treating cancerPublication Number: WO-2023186075-A1Priority Date: 2022-04-01
- Pharmaceutical composition, use thereof, and method for treating cancerPublication Number: EP-4506004-A1Priority Date: 2022-04-01
- Polymorphs of KRAS inhibitors, methods of making and uses thereofPublication Number: CN-118451081-APriority Date: 2021-12-24
- Polymorph of kras inhibitor and preparation method for polymorph and use thereofPublication Number: TW-202327593-APriority Date: 2021-12-24
////////Fulzerasib, CHINA 2024, APPROVALS 2024, Innovent Biologics, DUPERT, GFH925, GFH 925, IBI351, IBI 351
Golidocitinib
Golidocitinib
CAS 2091134-68-6
- AZD-4205
- AZD4205
- UNII-3BY9Z3M34G
- 3BY9Z3M34G
WeightAverage: 489.584
Monoisotopic: 489.260071274
Chemical FormulaC25H31N9O2
(2R)-N-[3-[2-[(3-methoxy-1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide
- (2R)-N-(3-(2-((3-methoxy-1-methylpyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide
- (ALPHAR)-N-(3-(2-((3-METHOXY-1-METHYL-1H-PYRAZOL-4-YL)AMINO)-4-PYRIMIDINYL)-1H-INDOL-7-YL)-ALPHA,4-DIMETHYL-1-PIPERAZINEACETAMIDE
- (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide
- (R)-N-(3-(2-(3-Methoxy-1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide
Approvals 2024, china 2024, DZD 4205, DIZAL, Gao Ruizhe,
Golidocitinib is a pharmaceutical drug for the treatment of cancer. In June 2024, it was given conditional approval in China for the treatment of relapsed or refractory peripheral T-cell lymphoma.[1]
Golidocitinib is classified as a Janus kinase inhibitor.[2][3]
Golidocitinib is an orally available inhibitor of Janus-associated kinase 1 (JAK1), with potential antineoplastic activity. Upon oral administration, golidocitinib inhibits JAK-dependent signaling and may lead to an inhibition of cellular proliferation in JAK1-overexpressing tumor cells. The JAK-STAT (signal transducer and activator of transcription) signaling pathway is a major mediator of cytokine activity and is often dysregulated in a variety of tumor cell types. Additionally, JAK1 may be a primary driver of STAT3 phosphorylation and signaling, which plays a role in neoplastic transformation, resistance to apoptosis, tumor angiogenesis, metastasis, immune evasion, and treatment resistance.
GOLIDOCITINIB is a small molecule drug with a maximum clinical trial phase of II (across all indications) and has 4 investigational indications.
PAT
US9714236, https://patentscope.wipo.int/search/en/detail.jsf?docId=US193702885&_cid=P11-MEHX78-54823-1
Example 32: (2R)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide
| The procedure described above for Example 32 was repeated using the indicated Intermediates to give Examples 33-42 described in Table 12: |
[TABLE-US-00012]
| TABLE 12 Starting m/z ExampleIntermediatesNMR δ (400 MHz)[M + H]+Yield % 3325 and 38DMSO-d6 with D2O 1.28 (3H, d), 2.2750413 (3H, s), 2.73 (3H, s), 2.85-3.34 (8H, m), 3.44 (1H, q), 3.63 (3H, s), 374 (3H, s), 7.04 (1H, t), 7.19 (1H, d), 7.55 (1H, s), 7.91 (1H, s), 8.08 (2H, s), 8.26 (1H, s) -two exchangeable protons not observed3425 and 37DMSO-d6 1.26 (3H, d), 2.16 (3H, s),50472 2.33 (3H, s), 2.38 (4H, s), 2.57-2.62 (4H, m), 3.33 (1H, q), 3.67 (3H, s), 3.79 (3H, s), 7.00 (1H, t), 7.41 (1H, d), 7.66 (1H, s), 7.96 (2H, t), 8.14 (1H, s), 8.22 (1H, s), 9.65 (1H, s), 11.28 (1H, s)3530 and 37Methanol-d4 1.34 (3H, t), 1.40 (3H, d),51816 2.32 (3H, s), 2.37 (3H, s), 2.50-2.80 (8H, m), 3.38 (1H, q), 3.69 (3H, s), 4.34 (2H, q), 7.05-7.20 (2H, m), 7.69 (1H, s), 7.85 (1H, s), 8.23 (1H, s), 8.17 (1H, d)-three exchangeable protons not observed3626 and 37DMSO-d6 1.26 (3H, d), 2.27 (3H, s),52448 2.24-2.52 (4H, m), 2.53-2.70 (4H, m), 3.30-3.36 (1H, m), 3.69 (3H, s), 3.78 (3H, s), 7.02 (1H, s), 7.40 (1H, d), 7.65 (1H, s), 8.32 (1H, s), 8.48 (1H, s), 9.69 (1H, s), 11.42 (1H, s)3727 and 37DMSO-d6 1.26 (3H, d), 2.17 (3H, s),56849 2.23-2.45 (4H, m), 2.46-2.71 (4H, m), 3.30-3.32 (1H, m), 3.68 (3H, s), 3.78 (3H, s), 7.01 (1H, s), 7.37 (1H, d), 7.64 (1H, s), 8.42 (1H, s), 8.45-8.56 (2H, m), 9.70 (1H, s), 11.36 (1H, s)3825 and 39Chloroform-d 1.19 (3H, d), 1.35 (3H, d),51819 2.10 (1H, m), 2.26 (1H, m), 2.38 (6H, m), 2.69 (2H, t), 2.89 (3H, m), 3.72 (3H, s), 3.91 (1H, q), 4.00 (3H, s), 6.57 (1H, s), 6.80 (1H, d), 7.15 (1H, t), 7.68 (1H, d), 7.84 (1H, s), 8.06-8.36 (2H, m), 9.88 (1H, s), 11.15 (1H, s)3929 and 37Methanol-d4 1.34 (3H, t), 1.43 (3H, d),52225 2.35 (3H, s), 2.50-2.85 (8H, m), 3.41 (1H, q), 3.79 (3H, s), 4.24 (2H, q), 7.10- 7.22 (2H, m), 7.68 (1H, s), 8.13 (1H, d), 8.16 (1H, d), 8.43 (1H, s)-three exchangeable protons not observed4031 and 37Methanol-d4 1.33 (3H, t), 1.42 (3H, d),53822 2.35 (3H, s), 2.63-2.71 (4H, m), 2.77- 2.81 (4H, m), 3.42 (1H, q), 3.76 (3H, s), 4.26 (2H, q), 7.10-7.20 (2H, m), 7.70 (1H, s), 8.28 (2H, m), 8.48 (1H, m)-three exchangeable protons not observed4128 and 37Chloroform-d 1.41 (3H, d), 2.29 (3H, s),48836 2.36 (3H, s), 2.42 (3H, s), 2.67-2.80 (8H, m), 3.38 (1H, q), 3.80 (3H, s), 6.42 (1H, s), 6.82 (1H, d), 7.12 (1H, t), 7.69 (1H, d), 7.88 (1H, s), 8.21 (2H, m), 9.74 (1H, s), 11.18 (1H, s)4228 and 38DMSO-d6 1.27 (3H, d), 2.12 (3H, s),4884 2.17 (3H, s), 2.35 (3H, s), 2.40 (4H, s), 2.57-2.63 (4H, m), 3.72 (3H, s), 7.03 (1H, t), 7.43 (1H, d), 7.81 (1H, s), 7.97 (1H, d), 8.19 (2H, m), 8.37 (1H, s), 9.68 (1H, s), 11.33 (1H, s) |
SYN
CN108368091
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN225024309&_cid=P11-MEHXD5-59000-1
| Example 32: (2R)-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide |
| |
| 3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-amine (180 mg, 0.54 mmol, Intermediate 23), (R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride (158 mg, 0.64 mmol, Intermediate 37) and HATU (408 mg, 1.1 mmol) were stirred together in THF (5 mL) to give an orange solution. Diisopropylethylamine (0.38 mL, 2.2 mmol) was added at 25°C. The resulting suspension was stirred at 25°C for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaCl. 2 CO 3 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 10 minutes.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 10 minutes.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 4 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 4 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 4 hours.Then the mixture was stirred for 3 hours . δ (DMSO, 400 MHz) 1.26 (3H, d), 2.16 (3H, s), 2.25-2.45 (4H, m), 2.51-2.70 (4H, m), 3.71 (3H, s), 3.80 (3H, s), 7.05 (1H, t), 7.13 (1H, d), 7.38 (1H, d), 7.70 (1H, s), 8.16-8.31 (4H, m), 9.62 (1H, s), 11.35 (1H, s) – the α-proton of the amide is obscured by the residual water peak; m/z (ES+), [M+H]+＝490. |
| The above procedure for Example 32 was repeated using the indicated intermediates to obtain Examples 33-42 described in Table 12: |
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Golidocitinib, also known as DZD4205, is an oral, selective Janus kinase 1 (JAK1) inhibitor developed by Dizal Pharmaceutical. It is designed to target aberrant JAK/STAT signaling pathways implicated in
various malignancies, particularly peripheral T-cell lymphoma (PTCL) [31]. In 2024, Golidocitinib was granted conditional approval by the NMPA under the brand name Gao Ruizhe, for the treatment of adult patients with relapsed or refractory PTCL who have received at least one line of systemic therapy. This agent exerts its therapeutic effects through selective inhibition of JAK1, thereby disrupting the JAK/STAT signaling pathway [32]. This inhibition leads to reduced proliferation and increased apoptosis of malignant T-cells in PTCL [33]. The clinical efficacy of Golidocitinib was demonstrated in the Phase II JACKPOT8 Part B study (NCT04105010), a multinational, single-arm trial evaluating its use in patients with r/r PTCL [34]. The investigation demonstrated an ORR of 44.3 % in patients with PTCL, with sustained efficacy noted across diverse PTCL subtypes. In terms of safety profile, Golidocitinib exhibited favorable tolerability. Hematologic adverse events such as anemia, neutropenia, and thrombocytopenia were the predominant treatment-related toxicities, yet they were effectively controlled through dose modifications and supportive interventions.
The synthetic route of Golidocitinib, shown in Scheme 8, initiates with amino protection of Goli-001 to afford Goli-002 [35]. Bromination of Goli-002 with Br2 yields Goli-003, which undergoes Miyaura bor
ylation with Goli-004 to form Goli-005. Suzuki-Miyaura coupling of Goli-005 with Goli-006 generates Goli-007. Deprotection of Goli-007 produces Goli-008, which undergoes p-TsOH-mediated nucleophilic
substitution with Goli-009 to yield Goli-010. Reduction of Goli-010 affords Goli-011, followed by amidation with Goli-012 to deliver Golidocitinib. Concurrently, Goli-012 is prepared via Tf2 0- Mediated
nucleophilic substitution between Goli-013 and Goli-014.
[31] S.J. Keam, Golidocitinib: first approval, Drugs 84 (2024) 1319–1324.
[32] K. Chen, X. Guan, Z. Yang, Y. Zhou, Z. Liu, X. Deng, D. Liu, P. Hu, R. Chen,
Pharmacokinetic characteristics of golidocitinib, a highly selective JAK1 inhibitor,
in healthy adult participants, Front. Immunol. 14 (2023) 1127935.
[33] M.B. Nierengarten, Golidocitinib favorable for relapsed/refractory T-cell
lymphoma, Cancer 130 (2024) 1191–1192.
[34] Y. Song, L. Malpica, Q. Cai, W. Zhao, K. Zhou, J. Wu, H. Zhang, N. Mehta-Shah,
K. Ding, Y. Liu, Z. Li, L. Zhang, M. Zheng, J. Jin, H. Yang, Y. Shuang, D.H. Yoon,
S. Gao, W. Li, Z. Zhai, L. Zou, Y. Xi, Y. Koh, F. Li, M. Prince, H. Zhou, L. Lin, H. Liu,
P. Allen, F. Roncolato, Z. Yang, W.S. Kim, J. Zhu, Golidocitinib, a selective JAK1
tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell
lymphoma (JACKPOT8 part B): a single-arm, multinational, phase 2 study, Lancet
Oncol. 25 (2024) 117–125.
[35] A.B.M. Aastrand, N.P. Grimster, S. Kawatkar, J.G. Kettle, M.K. Nilsson, L.L. Ruston,
Q. Su, M.M. Vasbinder, J.J. Winter-Holt, D. Wu, W. Yang, T. Grecu, J. McCabe, R.
D. Woessner, C.E. Chuaqui, Preparation of Substituted 2-(piperazin-1-yl)-N-[3-[2-
[(1H-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl] Propanamide as Selective
JAK1 Inhibitors for Treating Cancers and Immune Disorders, 2017
CN108368091A.
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References
- Keam SJ (October 2024). “Golidocitinib: First Approval”. Drugs. 84 (10): 1319–1324. doi:10.1007/s40265-024-02089-2. PMID 39298087.
- Song Y, Malpica L, Cai Q, Zhao W, Zhou K, Wu J, et al. (January 2024). “Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study”. The Lancet. Oncology. 25 (1): 117–125. doi:10.1016/S1470-2045(23)00589-2. PMID 38092009.
- Jin J, Zhang L, Zou L, Li Z, Wu H, Zhou K, et al. (2024). “Maintenance Therapy of Golidocitinib, a JAK1 Selective Inhibitor, in Patients with Peripheral T Cell Lymphomas after First-Line Systemic Therapy: Updates of the Phase 2 Study (JACKPOT26)”. Blood. 144: 6368. doi:10.1182/blood-2024-211891.
| Clinical data | |
|---|---|
| Trade names | 高瑞哲 (Gao Ruizhe) |
| Other names | AZD-4205, AZD4205, JAK1-IN-3 |
| Legal status | |
| Legal status | Rx in China |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2091134-68-6 |
| PubChem CID | 126715380 |
| DrugBank | DB18057 |
| ChemSpider | 71117616 |
| UNII | 3BY9Z3M34G |
| KEGG | D12502 |
| ChEMBL | ChEMBL4577523 |
| Chemical and physical data | |
| Formula | C25H31N9O2 |
| Molar mass | 489.584 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- Golidocitinib: First ApprovalPublication Name: DrugsPublication Date: 2024-09-19PMID: 39298087DOI: 10.1007/s40265-024-02089-2
- Recent Developments in the Use of Kinase Inhibitors for Management of Viral InfectionsPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-02-04PMID: 33539089DOI: 10.1021/acs.jmedchem.0c01467
- Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 InhibitorPublication Name: Journal of Medicinal ChemistryPublication Date: 2020-04-16PMID: 32297743DOI: 10.1021/acs.jmedchem.9b01392
- Sexuality in a healthcare settingPublication Name: Modern healthcare. [Short-term care ed.]Publication Date: 1976-05PMID: 5656
//////////Golidocitinib, approvals 2024, china 2024, DZD 4205, DIZAL, Gao Ruizhe, AZD-4205, AZD4205, UNII-3BY9Z3M34G, 3BY9Z3M34G
Oritinib
Oritinib
- CAS 2035089-28-0
- MESYLATE CAS 2180164-79-6
- SH-1028
- SK593H37SC
- N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
- 539.7 g/mol, C31H37N7O2
- rilertinib
CHINA 2024, Nanjing Sanhome Pharmaceutical.
N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
Oritinib is an investigational new drug currently under investigation for its potential use in cancer treatment.[1][2] As a epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, oritinib targets specific enzymes involved in the signaling pathways that regulate cell division and survival, which are often dysregulated in cancer cells.[1]
Oritinib (SH-1028), an irreversible third-generation EGFR TKI, overcomes T790M-mediated resistance in non-small cell lung cancer. Oritinib (SH-1028), a mutant-selective inhibitor of EGFR kinase activity, inhibits EGFRWT, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750 and EGFRd746-750/T790M kinases, with IC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively.
PAT
https://patents.google.com/patent/CN115974845B/en
Reaction condition optimization experiment:
The experimental group numbered 1 referred to in table 1 below is the preparation of 1-methyl-3- (2-chloro-4-pyrimidinyl) indole, which was prepared as follows:
To a 10mL reaction tube, 2, 4-dichloropyrimidine (74.5 mg,0.05 mol), zinc triflate (67.3 mg,0.37 equiv), scandium triflate (7.4 mg,0.03 equiv) and 1-methylindole (78.6 mg,1.2 equiv) were added under inert gas atmosphere, and acetonitrile (2.5 mL) were heated to 80℃to react for 24 hours. The reaction was quenched with 30ml of ethyl acetate, the above mixture was added to a separating funnel, 50ml of saturated aqueous sodium carbonate and 50ml of saturated aqueous ammonium chloride were added thereto, and the mixture was shaken for 2 minutes, and the organic phase was taken after the liquid in the separating funnel had settled and separated. The aqueous phase was rinsed with 30ml of ethyl acetate under shaking for 2 times, the whole organic phase was collected, silica gel powder and anhydrous sodium sulfate were added thereto, and the mixture was dried under reduced pressure and packed into a silica gel column. Sequential gradient elution was performed using 250ml (PE: EA: triethylamine 16:4:1), 250ml (PE: EA: triethylamine 15:5:1), 250ml (PE: EA: triethylamine 40:20:3) as developing reagent. The eluent is collected and dried under reduced pressure to obtain pale yellow solid with the yield of 90 percent.
The nuclear magnetic resonance spectrum of 1-methyl-3- (2-chloro-4-pyrimidinyl) indole is as follows:
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝5.9Hz,2H),8.40(dd,1H),7.82(d,J＝5.4Hz,1H),7.56(dd,1H),7.28(pd,J＝7.1,1.4Hz,2H),3.88(s,3H).
13C NMR(101MHz,DMSO)δ164.55,160.32,158.75,137.84,134.83,125.30,122.81,121.74,121.64,114.43,110.90,110.76,33.31.
PAT
CN109705118
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN242181067&_cid=P20-MEGI3F-20821-1
| Step 1: Synthesis of 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole |
| |
| In a 100L vertical jacketed glass reactor, add ethylene glycol dimethyl ether (39.15kg) and 2,4-dichloropyrimidine (3.915kg). Cool the solid-liquid mixture to below 10°C, then add anhydrous aluminum chloride (3.855kg) in batches, controlling the addition rate to keep the temperature below 30°C. After the addition is complete, stir at 25±5°C for 30 minutes, then add 6,7,8,9-tetrahydropyrido[1,2-a]indole (4.500kg). Raise the temperature to 60±5°C and react for 3 hours. Monitor by HPLC until the 6,7,8,9-tetrahydropyrido[1,2-a]indole content does not exceed 1.0%, confirming the reaction is complete. The reaction solution was cooled to below 25° C., purified water (90.0 kg) was added, stirred, and filtered. The filter cake was added to acetonitrile (17.8 kg), slurried, filtered, and dried to obtain a yellow powdery solid, a total of 6.652 kg, with a yield of 89.2%. |
| Step 2: Synthesis of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-amine |
| |
| To a 500L glass-lined reactor, sec-butyl alcohol (80.82kg), 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (6.652kg), 4-fluoro-2-methoxy-5-nitroaniline (4.363kg), and p-toluenesulfonic acid monohydrate (4.816kg) were added to obtain a solid-liquid mixture. The reaction mixture was heated to reflux, and the solid gradually dissolved. As the reaction proceeded, a yellow solid precipitated. After reflux for 7.5 hours, the reaction was monitored by HPLC to confirm completion. Heating was stopped, the reaction mixture was cooled to below 15°C, stirred for 1 hour, and the solid was centrifuged and filtered. Acetonitrile (31.5kg) was added to the filter cake, and the mixture was slurried at 25±5°C for 1.5 hours. The mixture was centrifuged and dried to obtain the title compound, a total of 9.548kg, with a yield of 94.0%. |
| Step 3: Synthesis of N 1 -(2-dimethylaminoethyl)-5-methoxy-N 1 -methyl-2-nitro-N 4 -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)phenyl-1,4-diamine |
| |
| To a 100 L vertical jacketed glass reactor, add N,N-dimethylacetamide (44.7 kg), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-amine (9.548 kg), N,N,N’-trimethylethylenediamine (3.380 kg), and N,N-diisopropylethylamine (4.841 kg). Under nitrogen, the reaction mixture was reacted at 85±5°C for 2 hours and monitored by HPLC until the reaction was complete. The reaction solution was cooled to below 70°C, purified water (95.5 kg) was added, filtered, and dried to obtain the title compound, a total of 8.206 kg, with a yield of 72.2%. |
| Step 4: Synthesis of N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-N 4 -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)benzene-1,2,4-triamine |
| |
| A 100 L vertical jacketed reactor was charged with anhydrous ethanol (32.39 kg), purified water (14.32 kg), N 1 -(2-dimethylaminoethyl)-5-methoxy-N 1 -methyl-2-nitro-N 4 -(4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)phenyl-1,4-diamine (4.103 kg), reduced iron powder (2.224 kg), and ammonium chloride (2.129 kg). The reaction mixture was refluxed for 1.5 hours and monitored by HPLC until the reaction was complete. The reaction mixture was cooled to below 50°C and filtered through diatomaceous earth to remove the solid. The filtrate was concentrated, and tetrahydrofuran (3.45 kg) and purified water (34.71 kg) were added to the residue. The mixture was slurried, filtered, and dried to obtain 3.244 kg of the title compound in an 84.0% yield. |
| Step 5: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide |
| |
| Add N,N-dimethylacetamide (48.6 kg) to a 100 L vertical jacketed glass reactor. Raise the temperature to 40°C, then add N₁- ( 2-(dimethylamino)ethyl)-5-methoxy- N₁ -methyl- N₄- (4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (6.487 kg). Then, begin the dropwise addition of 3-chloropropionyl chloride (1.777 kg). Control the addition rate to no more than 60°C. After the addition is complete, cool the reaction mixture and stir at 40±5°C for 1 hour. Sample the mixture and monitor the reaction by HPLC until complete. Add purified water (0.253 kg) and stir for 30 minutes. |
| The reaction mixture was heated at 80±5°C, triethylamine (13.52 kg) was added, and the temperature was raised to 95±5°C. After reacting for 2 hours, the reaction was complete as determined by HPLC. The temperature was then lowered, and methanol (83.0 kg) was added. The mixture was then cooled and crystallized, filtered, and dried to obtain 4.953 kg of the title compound, with a yield of 68.6% and a purity of 97.37%. |
| Step 6: Purification of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide |
| Anhydrous ethanol (31.25 kg) was added to a 100 L reactor and heated to above 70°C. The crude N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide prepared in step 5 was added. The reaction mixture was heated and stirred under nitrogen until dissolved. The reaction mixture was cooled to below 10°C, the precipitated solid was centrifuged and dried under vacuum at 60±5°C for more than 12 hours to obtain 4.559 kg of the title compound with a yield of 92.1% and a purity of 98.73%. 1 H NMR (300 MHz, DMSO-d 6 )δ10.20(s,1H),8.65(s,1H),8.34(d,1H),8.11(s,1H),8.06(d,1H),7.43(d, 1H),7.19-7.03(m,3H),6.98(s,1H),6.57-6.41(m,1H),6.28-6.15(m,1H),5.8 2-5.71(m,1H),4.09(t,2H),3.84(s,3H),3.18(t,2H),3.06-2.92(m,2H),2.66 (s,3H),2.47-2.40(m,2H),2.27(s,6H),2.08-1.96(m,2H),1.87-1.74(m,2H). ESI-Ms m/z: 540.3 [M+H] + . |
| Example 2: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide |
| |
| The preparation method is the same as that in step 5 of Example 1, except that N,N-dimethylacetamide is replaced by N,N-dimethylformamide. The purity of the obtained title compound is 69%. |
| The N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide of the present invention prepared according to the above method has a high yield and purity, mild reaction conditions, easy purification, stable process, easy operation, environmental friendliness, and can meet the requirements of industrial-scale production and application. |
Syn
European Journal of Medicinal Chemistry 291 (2025) 117643
Oritinib represents a third-generation EGFR TKI engineered by Nanjing Sanhome Pharmaceutical. This agent specifically targets both EGFR-sensitizing mutations and the T790 M resistance mutation,
thereby addressing resistance mechanisms linked to prior-generation EGFR-TKIs. In 2024, the NMPA granted approval for Oritinib to treat adult patients with locally advanced or metastatic NSCLC who have experienced disease progression during or following EGFR-TKI therapy and possess confirmed EGFR T790 M mutation-positive status. The mechanism of action of Oritinib involves irreversible binding to mutant EGFR, including the T790 M variant, which in turn suppresses down stream signaling pathways responsible for tumor cell proliferation and survival [28]. The mechanism of Oritinib effectively inhibits tumor growth in patients harboring T790M-mediated resistance to first- and second-generation EGFR-TKIs. Clinical efficacy was established in a Phase II trial (NCT03823807) enrolling patients with EGFR T790 Mmutation-positive NSCLC who had experienced disease progression following prior EGFR-TKI therapy. This study documented an ORR of 60.5 % and a median PFS of 9.6 months, highlighting substantial anti
tumor efficacy in this specific patient cohort. In terms of safety, Oritinib exhibited favorable tolerability. The predominant treatment-related adverse events were rash, diarrhea, and elevated liver enzymes, pri
marily of mild (Grade 1) or moderate (Grade 2) severity. No dose-limiting toxicities were encountered, and the overall safety profile aligned with those observed for other third-generation EGFR-TKIs [29].
The synthetic route of Oritinib Mesylate, shown in Scheme 7, begins with nucleophilic substitution reaction between Orit-001 and Orit-002 to yield Orit-003, which further reacts with Orit-004 via nucleophilic substitution to produce Orit-005 [30]. Orit-005 subsequently undergoes another nucleophilic substitution with Orit-006 to generate Orit-007. Following this, Orit-007 is reduced to form Orit-008. Finally, an amidation reaction between Orit-008 and Orit-009 affords Oritinib.
[28] C. Zhou, A. Xiong, L. Miao, J. Chen, K. Li, H. Liu, Z. Ma, H. Wang, Z. Lu, J. Shen,
P51.03 oritinib (SH-1028), a third-generation EGFR-TKI in advanced NSCLC
patients with positive EGFR T790M: results of a single-arm phase Ib trial,
J. Thorac. Oncol. 16 (2021) S1119–S1120.
[29] C. Zhou, A. Xiong, J. Zhao, W. Li, M. Bi, J. Chen, K. Li, L. Miao, Y. Mao, D. Wang,
7MO oritinib (SH-1028) a third-generation EGFR tyrosine kinase inhibitor in
locally advanced or metastatic NSCLC patients with positive EGFR T790M: results
of a single-arm phase II trial, Ann. Oncol. 33 (2022) S31.
[30] L. Zhao, W. Fu, W. Wu, J. Liu, J. Jin, Method for Preparing Tricyclic Compound as
EGFR Kinase Inhibitor, 2019. CN109705118A.
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References
- Xiong A, Ren S, Liu H, Miao L, Wang L, Chen J, et al. (October 2022). “Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial”. Journal of Thoracic Oncology. 17 (10): 1216–1226. doi:10.1016/j.jtho.2022.06.013. PMID 35798241.
- “Rilertinib – Nanjing Sanhome Pharmaceutical”. AdisInsight. Springer Nature Switzerland AG.
| Clinical data | |
|---|---|
| Other names | SH-1028 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2035089-28-0 |
| PubChem CID | 122666966 |
| ChemSpider | 115007246 |
| UNII | SK593H37SC |
| Chemical and physical data | |
| Formula | C31H37N7O2 |
| Molar mass | 539.684 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- Safety, efficacy, and pharmacokinetics of SH‐1028 in EGFR T790M‐positive advanced non–small cell lung cancer patients: A dose‐escalation phase 1 studyPublication Name: CancerPublication Date: 2023-02-22PMID: 36813747DOI: 10.1002/cncr.34697
- SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung CancerPublication Name: Frontiers in PharmacologyPublication Date: 2021-04-27PMCID: PMC8111447PMID: 33986687DOI: 10.3389/fphar.2021.665253
- [1]. Luwei Han, et al. SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer. Front Pharmacol. 2021 Apr 27;12:665253. [Content Brief]
/////////Oritinib, CHINA 2024, APPROVALS 2024, 2035089-28-0, SH 1028, SK593H37SC, rilertinib, Oritinib mesylate, Nanjing Sanhome Pharmaceutical,
Envonalkib
Envonalkib
- CAS 1621519-26-3
- QB7KTQ7VW9
- 5-((1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((2S)-2-methyl-1-piperazinyl)(3,3′-bipyridin)-6-amine
- 506.4 g/mol, C24H26Cl2FN5O2
TQ-B3139, Chia Tai Tianqing, Anluoqing, cancer
ENVONALKIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
SYN
https://patentscope.wipo.int/search/en/WO2014117718
Example 27: 5-[(2,6-dichloro-3-fluorophenyl)ethoxy-4′-methoxy-6′ …
Step 1: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperazin-1-yl)-3,3′-bipyridin-6-amine
To dioxane (10 mL) and water (1.5 mL) were added tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperidin-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-aminopyridine (140 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol) and cesium carbonate (179 mg, 0.55 mmol), the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C. overnight. After cooling, the mixture was separated by silica gel column chromatography to give 5-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6-(5-(2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine) (70 mg) in a yield of 42%. MS m/z [ESI]: 606.2 [M+1].
Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-3,3′-bipyridin-6-amine
To a stirred dichloromethane solution (10 mL) of 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine (67 mg, 0.11 mmol) was added trifluoroacetic acid (1 mL) and stirred for 1 hour. The pH was adjusted to greater than 13 with sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by column chromatography (with dichloromethane:methanol = 8:1 as eluent) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperidin-1-yl)-3,3′-bipyridin-6-amine (30 mg). Yield: 55%, MS m/z [ESI]: 506.1[M+1]. 1H-NM (400 MHz, CDC1 3 ):5= 7.94(1H, s), 7.71(1H, s), 7.28-7.32(lH, m), 7.07(1H, t, J=8.4Hz), 6.97(1H, s), 6.04-6.13(2H, m), 4.86 (2H : s), 4.57-4.59(lH, m), 4.03 (1H, d, J=14Hz), 3.76(3H, s), 3.07-3.33(4H, m), 2.88-3.00(lH, m), 1.84(3H, d, J=6.8Hz), 1.34 (3H, d, J=6.8Hz).
SYN
CN107949560
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US154015806&_cid=P11-MEF9W1-27198-1
Example 27: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine
General Synthetic Methods:
Step 1: (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate
Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Envonalkib, also known as TQ-B3139, is a novel small-molecule TKI, developed by Chia Tai Tianqing Pharmaceutical Group. It targets ALK, ROS1, and c-Met kinases, exhibiting potent antitumor activity against cancers harboring these genetic alterations. In 2024, the NMPA approved Envonalkib under the brand name Anluoqing for the treatment of adult patients with ALK-positive locally advanced or metastatic NSCLC who have not received prior ALK inhibitor therapy [24]. Envonalkib exerts its therapeutic effects through selective inhibition of the kinase activities of ALK, ROS1, and c-Met, thereby interrupting the downstream signaling pathways that are crucial for tumor cell proliferation and survival [25]. The inhibition of these targets results in cell cycle arrest and apoptosis in cancer cells。The clinical efficacy of Envonalkib was evidenced in a Phase III randomized, open-label, multicenter clinical trial (NCT04009317), which compared Envonalkib with crizotinib in treatment-naïve patients with ALK-positive advanced NSCLC [25,26]. In the reported study, Envonalkib demonstrated a me dian PFS of 24.87 months, which was markedly superior to the 11.60 months achieved with crizotinib (hazard ratio [HR] = 0.47, p < 0.0001). Notably, in patients harboring brain metastases, Envonalkib exhibited a
central nervous system objective response rate (CNS-ORR) of 78.95 %, a substantial improvement over the 23.81 % observed with crizotinib. In terms of safety profile, Envonalkib was generally well-tolerated. Treat ment-related adverse events (TRAEs) of Grade ≥3 were noted in 55.73 % of patients receiving Envonalkib, contrasting with the 42.86 % incidence in the crizotinib cohort. The predominant TRAEs encompassed elevated liver enzymes, neutropenia, and gastrointestinal symptoms, all of which
were amenable to effective management through appropriate support ive care measures. The regulatory approval of Envonalkib thus in troduces a novel therapeutic modality for patients with ALK-positive NSCLC, effectively addressing a significant unmet medical need within this patient population [25].
The synthesis of Envonalkib, illustrated in Scheme 6, initiates with Mitsunobu coupling of Envo-001 and Envo-002, affording Envo-003 [27]. Sequential reduction and NBS-bromination converts Envo-003 to
Envo-005 via Envo-004. Miyaura borylation of Envo-005 constructs Envo-006, which undergoes Suzuki-Miyaura cross-coupling with Envo-007 followed by deprotection to deliver Envonalkib. In parallel,
Envo-009 reacts with Envo-010 through Buchwald-Hartwig cross coupling to form Envo-011. This intermediate is brominated to produce Envo-007, which is used in the Suzuki-Miyaura coupling with Envo-006
[24] X. Li, Y. Xia, C. Wang, S. Huang, Q. Chu, Efficacy of ALK inhibitors in Asian
patients with ALK inhibitor-naïve advanced ALK-Positive non-small cell lung
cancer: a systematic review and network meta-analysis, Transl. Lung Cancer Res.
13 (2024) 2015–2022.
[25] Y. Yang, J. Min, N. Yang, Q. Yu, Y. Cheng, Y. Zhao, M. Li, H. Chen, S. Ren, J. Zhou,
W. Zhuang, X. Qin, L. Cao, Y. Yu, J. Zhang, J. He, J. Feng, H. Yu, L. Zhang, W. Fang,
Envonalkib versus crizotinib for treatment-naive ALK-Positive non-small cell lung
cancer: a randomized, multicenter, open-label, phase III trial, Signal Transduct
Target Ther 8 (2023) 301.
[26] R. Garcia-Carbonero, A. Carnero, L. Paz-Ares, Inhibition of HSP90 molecular
chaperones: moving into the clinic, Lancet Oncol. 14 (2013) e358–e369.
[27] F. Gong, X. Li, R. Zhao, X. Zhang, X. Xu, X. Liu, D. Xiao, Y. Han, Process for
Preparation of Pyridine Substituted 2-aminopyridine Protein Kinase Inhibitor
Crystal, 2017. CN107949560B.
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- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- Efficacy of ALK inhibitors in Asian patients with ALK inhibitor-naïve advanced ALK-positive non-small cell lung cancer: a systematic review and network meta-analysisPublication Name: Translational Lung Cancer ResearchPublication Date: 2024-08-31PMCID: PMC11384493PMID: 39263024DOI: 10.21037/tlcr-24-604
- Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trialPublication Name: Signal Transduction and Targeted TherapyPublication Date: 2023-08-14PMCID: PMC10423717PMID: 37574511DOI: 10.1038/s41392-023-01538-w
- Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine in Wistar ratsPublication Name: British Journal of PharmacologyPublication Date: 2021-10-31PMID: 34519023DOI: 10.1111/bph.15680
//////////Envonalkib, china 2024, approvals 2024, TQ-B3139, TQ B3139, Chia Tai Tianqing, Anluoqing, cancer, QB7KTQ7VW9
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.
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
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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.
[1] Y. Liu, Y. Cheng, G. Huang, X. Xia, X. Wang, H. Tian, Preclinical characterization of
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.
[4] Q. Zhao, T. Wang, H. Wang, C. Cui, W. Zhong, D. Fu, W. Xi, L. Si, J. Guo, Y. Cheng,
H. Tian, P. Hu, Phase I pharmacokinetic study of an oral, small-molecule MEK
inhibitor tunlametinib in patients with advanced NRAS mutant melanoma, Front.
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.
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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]
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New Drug Approvals 
