Becondogrel

CAS 1416696-44-0

MF C16H16ClNO3S, MW 337.821

2-OXO-CLOPIDOGREL, (.ALPHA.S,7AS)-

(4S)-2-Oxoclopidogrel

THIENO(3,2-C)PYRIDINE-5(4H)-ACETIC ACID, .ALPHA.-(2-CHLOROPHENYL)-2,6,7,7A-TETRAHYDRO-2-OXO-, METHYL ESTER, (.ALPHA.S,7AS)-

Methyl (S)-(2-chlorophenyl)[(7aS)-2-oxo-2,6,7,7atetrahydrothieno[ 3,2-c]pyridin-5(4H)-yl]acetate

methyl (S)-(2-chlorophenyl)[(7aS)-2-oxo-2,6,7,7atetrahydrothieno[3,2-c]pyridin-5(4H)-yl]acetate
platelet aggregation inhibitor, D7X6820P1N, Copidogrel oxide, (4S)-2-Oxoclopidogrel

Becondogrel is an antiplatelet medication and an irreversible P2Y12 receptor antagonist. It is chemically known as 2-oxoclopidogrel, which is a direct metabolic intermediate of the widely used drug clopidogrel (Plavix). 

Key Characteristics

• Mechanism of Action: It prevents blood cells (platelets) from sticking together, which helps inhibit the formation of blood clots (thrombosis).
• Relationship to Clopidogrel: Standard clopidogrel is a prodrug that requires two metabolic steps in the liver to become active. Becondogrel is designed to bypass the first of these steps, potentially reducing the individual variability in effectiveness seen with clopidogrel due to genetic differences in liver enzymes (CYP450).
• Clinical Status: As of early 2025, becondogrel was included in the World Health Organization’s (WHO) proposed International Nonproprietary Name (INN) list, indicating its development for medical use

SYN

• [EP3290423B1]
• https://patentscope.wipo.int/search/en/detail.jsf?docId=EP213389219&_cid=P22-MNPFAY-18756-1

Example 3

(2S)-Methyl 2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(2-chlorophenyl)-acetate (IV-1)

[0042]  58.1 g (0.15 mol) of (R)-methyl 2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate (II-1), 32.3 g (0.17 mol) of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrochloride (III-1), and 37.8g (0.38 mol) of potassium bicarbonate were added to 500 ml of acetonitrile. The reaction was stirred under a nitrogen atmosphere at room temperature for 26 hrs. The reaction solution was allowed to stand and the insoluble material was filtered off, to obtain a dark red mother liquor. The solvent was evaporated under reduced pressure, and 35.4 g of an oil product was obtained after purification by flash column chromatography (petroleum ether:ethyl acetate = 4:1). Yield 70%. Recrystalization from ethanol afforded 18.1 g of a pure product (IV-1) as a white solid. mp: 146-148°C, ee = 97.5%, [α] _D ¹⁹ = +114.0° (c 0.5, MeOH); ¹H-NMR (300 MHz, CDCl ₃) δ 1.79-1.93 (m, 1 H), 2.30-2.40 (m, 1 H), 2.56-2.70 (m, 1 H), 3.00-3.27 (m, 2 H), 3.72 (s, 3 H), 3.79-3.93 (m, 1 H), 4.12-4.19 (m, 1 H), 4.89 (d, 1 H, J= 5.6 Hz), 6.00 (d, 1 H, J = 5.2 Hz), 7.26-7.50 (m, 4 H); ¹³C-NMR (75 MHz, CDCl ₃) δ 33.9, 34.0, 49.0, 49.7, 51.1, 51.6, 52.2, 52.4, 67.3, 76.6, 77.0, 77.4, 126.6, 126.8, 127.2, 129.8, 130.1, 132.7, 134.8, 167.2, 167.4, 170.8, 198.6; ESI-MS m/ z 338.1 [M+H] ⁺; HRMS Calcd for C ₁₆H ₁₇NO ₃SCl [M+H] ⁺ m/ z 338.0618, found 338.0626.

SYN

• [US2022028976]
• https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023204830&_cid=P22-MNPFG3-21704-1

PAT

WO2020233226 B CRYSTAL FORM OF TETRAHYDROTHIENOPYRIDINE COMPOUND, PREPARATION METHOD THEREFOR, COMPOSITION AND APPLICATION

. The chemical name of the compound with the Equation I structure is: (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothiophene[3,2-c]and pyridine-5(4H))yl)methyl acetate.

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development.Publication Name: The Journal of organic chemistryPublication Date: 2015-07-07PMID: 26151079DOI: 10.1021/acs.joc.5b00632
• Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl AlcoholPublication Name: The Journal of Pharmacology and Experimental TherapeuticsPublication Date: 2006-12PMID: 16943252DOI: 10.1124/jpet.106.110577
• Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel ResistancePublication Name: CirculationPublication Date: 2004-01-20PMID: 14707025DOI: 10.1161/01.cir.0000112378.09325.f9

PAT

• Solid preparation containing oxidized clopidogrel and preparation method thereforPublication Number: EP-4628079-A1Priority Date: 2022-12-02
• Method for treating blood plasma sample containing clopidogrel oxide, and measurement methodPublication Number: EP-4394372-A1Priority Date: 2021-08-23
• Crystalline form b of tetrahydrothienopyridine compound, preparation method, composition and application thereofPublication Number: US-2022289761-A1Priority Date: 2019-05-17
• B crystal form of tetrahydrothienopyridine compound, preparation method therefor, composition and applicationPublication Number: WO-2020233226-A1Priority Date: 2019-05-17
• B crystal form of tetrahydrothienopyridine compound, preparation method therefor, composition and applicationPublication Number: EP-3985009-A1Priority Date: 2019-05-17
• Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof
• Publication Number: EP-3290423-B1
• Priority Date: 2010-02-02
• Grant Date: 2021-07-21

//////////becondogrel, platelet aggregation inhibitor, D7X6820P1N, Copidogrel oxide, (4S)-2-Oxoclopidogrel

Balomenib

CAS 2939850-17-4

MF C33H34F3N7O2 MW617.7 g/mol

4-methyl-1-[[(2S)-5-oxomorpholin-2-yl]methyl]-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indole-2-carbonitrile

• 1H-Indole-2-carbonitrile, 4-methyl-1-[[(2S)-5-oxo-2-morpholinyl]methyl]-5-[[2-[6-(2,2,2-trifluoroethyl)-4-quinazolinyl]-2,7-diazaspiro[3.5]non-7-yl]methyl]-
• 4-methyl-1-[(2S)-5- oxomorpholin-2- yl]methyl]-5- [[2-[6-(2,2,2- trifluoroethyl) quinazolin-4-yl]-2,7- diazaspiro[3.5]nonan- 7-yl]methyl]indole-2- carbonitrile

4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-
yl}methyl)-1H-indole-2-carbonitrile
menin inhibitor, antineoplastic, ZE63-0302, 3BEG4BWN8E

Balomenib (also known as ZE63-0302) is an oral, small-molecule menin inhibitor currently in clinical development for metabolic and oncological conditions. It works by disrupting the protein-protein interaction between menin and KMT2A (formerly MLL), a mechanism that plays a critical role in both pancreatic beta-cell function and certain types of leukemia. 

Key Therapeutic Areas

• Type 2 Diabetes (T2D): Balomenib is being investigated as a potentially disease-modifying treatment to improve pancreatic beta-cell function and survival. As of late 2025, it has advanced into Phase 1b clinical trials specifically for adults with T2D to evaluate its effects on fasting glucose, insulin dynamics, and HbA1c.
• Oncology (AML): It is also a candidate for treating acute myeloid leukemia (AML) with KMT2A rearrangements or NPM1 mutations. Preclinical data suggests it may be more effective against resistance mutations than earlier menin inhibitors. 

Development and Safety

• Corporate Development: The drug was originally developed by Eilean Therapeutics. It is now the lead program for Clywedog Therapeutics, which is merging with Barinthus Biotherapeutics to focus on metabolic diseases.
• Safety Profile: Early trial results indicate a favorable safety profile. Notably, it was designed to minimize QTc prolongation (heart rhythm issues), a side effect common in other menin inhibitors.

• Сlinical Study Aiming to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of ZE63-0302 in Healthy VolunteersCTID: NCT06780124Phase: Phase 1Status: CompletedDate: 2026-01-22
• Study to Assess Safety, Tolerability, PK, and PD of Multiple Doses of ZE63-0302 Administrated Orally in T2DM Patients.CTID: NCT07234864Phase: Phase 1Status: RecruitingDate: 2026-01-22

SYN

US20250163061,

Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)

Compound was prepared using procedure described in the Example 45 and 5-formyl-4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P177 instead of 5-formyl-4-methyl-1-{[(2R)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P176. Compound 102 was obtained with yield 49%. ¹H NMR (400 MHz, DMSO-d ₆), δ: 8.46 (s, 1H), 7.99 (m, 2H), 7.73 (m, 2H), 7.52 (m, 1H), 7.46 (d, J=5.6 Hz, 1H), 7.31 (d, J=4.8 Hz, 1H), 4.54 (m, 1H), 4.20 (m, 2H), 4.05 (m, 1H), 3.90 (m, 4H), 3.52 (m, 2H), 3.35 (m, 1H), 3.17 (m, 1H), 2.39 (m, 2H), 1.79 (m, 4H). LCMS (ESI) [MH] ⁺: 618.

PAT

Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Inhibitors of menin-mll interactionPublication Number: WO-2023107696-A2Priority Date: 2021-12-09
• Inhibitors of menin-mll interactionPublication Number: US-2025163061-A1Priority Date: 2021-12-09
• Inhibitors of menin-mll interactionPublication Number: EP-4444300-A2Priority Date: 2021-12-09

///////////balomenib, menin inhibitor, antineoplastic, ZE63-0302, 3BEG4BWN8E

Atebimetinib

CAS 2669009-92-9

MF C23H27FN4O6S MW506.5 g/mol

[4-[(dimethylamino)methyl]-3-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-2-oxochromen-7-yl] N,N-dimethylcarbamate

4-[(dimethylamino)methyl]-3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-2-oxo-2H-1-benzopyran-7-yl
dimethylcarbamate
MEK tyrosine kinase inhibitor, antineoplastic, IMM-104, IMM 104, Fast Track designation, TEL9243A3N

Atebimetinib (IMM-104) is an investigational oral, deep cyclic inhibitor (DCI) that targets the MAP kinase (MAPK) pathway in solid tumors, particularly RAS-mutant pancreatic cancer. Designed for rapid, pulsatile inhibition to minimize resistance and side effects, it is currently in Phase 2a trials, having shown promising, durable tumor shrinkage and high 1-year survival rates. 

Key Aspects of Atebimetinib:

• Mechanism of Action: As a DCI, it works differently from standard inhibitors by targeting MAPK with a short half-life, allowing for rapid “pulsing” that suppresses tumor growth while permitting healthy cells to recover, thus improving tolerability.
• Targeted Cancers: Primarily aimed at RAS-mutant advanced or metastatic solid tumors, including pancreatic ductal adenocarcinoma (PDAC).
• Clinical Trial Results: In a Phase 2a study (NCT05585320), the combination of atebimetinib with modified chemotherapy showed a 64% overall survival (OS) rate at 12 months for first-line pancreatic cancer patients.
• Fast Track Designation: In 2024, the FDA granted fast track designation for atebimetinib to treat patients with pancreatic adenocarcinoma who have progressed after one line of therapy.
• Advantage over Traditional Inhibitors: It is designed to avoid typical MAP kinase inhibitor adverse events like pyrexia (fever) while overcoming the rapid resistance often seen in other therapies. 

Atebimetinib is being developed by Immuneering Corporation.

Development Status

• FDA Designations: In 2024, the FDA granted atebimetinib Fast Track designation for patients with pancreatic adenocarcinoma (PDAC) who have progressed after one line of treatment.
• Future Plans: A global registrational Phase 3 trial, named MAPKeeper 301, is planned to begin dosing patients in mid-2026.

Clinical Trial Results (Phase 2a)

Recent data from the Phase 2a trial (as of early 2026) showed significant survival benefits when combined with modified chemotherapy (gemcitabine and nab-paclitaxel) for first-line pancreatic cancer: 

• Overall Survival (OS): Reported at 94% at 6 months, 86% at 9 months, and 64% at 12 months. This is roughly double the 1-year survival rate typically seen with standard chemotherapy alone (~35%).
• Progression-Free Survival (PFS): Median PFS reached 8.5 months.
• Disease Control Rate: Approximately 81% of patients achieved disease control.

SYN

WO2023076991 COMBINATION THERAPY FOR TREATING ABNORMAL CELL GROWTH

SYN

WO2025010293 MEK IMMUNE ONCOLOGY INHIBITOR PHARMACEUTICAL COMPOSITIONS

EXAMPLE 1A

Synthesis of Compound A

[0198] Compound A was prepared in 1 step:

[0199] 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) was suspended in methanol. Dimethylamine 2M was added and the formed reaction mixture was stirred until full conversion was observed. After full conversion the reaction was concentrated under reduced pressure. IM HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na CCE. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow amorphous solid.

[0200] Yield: Compound A was isolated as a light yellow solid (74% over 1 step). Analysis: LCMS (Method T): tR = 1.53 min; m/z calculated for [M+H]⁺ = 507.2, found = 507.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 – 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).

ADVT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Mek immune oncology inhibitor pharmaceutical compositionsPublication Number: WO-2025010293-A2Priority Date: 2023-07-03
• Inhibiting mitogen-activated protein (map)/erk kinase (mek)1 and mek2 and related methods of treatmentPublication Number: WO-2024220440-A1Priority Date: 2023-04-17
• Methods of treating cancer with a ras mutationPublication Number: WO-2024186693-A1Priority Date: 2023-03-03
• Combination therapy for treating abnormal cell growthPublication Number: WO-2023235356-A1Priority Date: 2022-06-03
• Combination therapy for treating abnormal cell growthPublication Number: WO-2023147297-A2Priority Date: 2022-01-25
• Methods of treating abnormal cell growthPublication Number: WO-2023081676-A1Priority Date: 2021-11-02
• Combination therapy for treating abnormal cell growthPublication Number: WO-2023076991-A1Priority Date: 2021-10-28
• Mek inhibitors and therapeutic uses thereofPublication Number: US-2023119327-A1Priority Date: 2020-01-10

//////atebimetinib, FLAX LAB, antineoplastic, IMM-104, IMM 104, Fast Track designation, TEL9243A3N

Anvumetostat

CAS 2790567-82-5

MF C22H19F3N4O3 MW444.4 g/mol

(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone

(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl){(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl}methanone
antineoplastic, AMG 193, QAT649EJ5E, PRMT5-IN-27,

Anvumetostat (also known as AMG 193) is an orally available, small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), primarily being developed for the treatment of advanced solid tumours with MTAP-null (methylthioadenosine phosphorylase-deficient) mutations. 

Mechanism of Action

• Targeting PRMT5: It is a potent and selective MTA-cooperative inhibitor of PRMT5.
• Synthetic Lethality: In cells where the MTAP gene is deleted (a common occurrence in various cancers), a metabolite called MTA (methylthioadenosine) accumulates. Anvumetostat selectively binds to the PRMT5-MTA complex, inhibiting its methyltransferase activity.
• Cellular Impact: By blocking PRMT5, the drug reduces the methylation of arginine residues in histones (H2A, H3, and H4), which can lead to decreased growth or death of cancer cells. 

Clinical Development

Anvumetostat was initially developed by Amgen, Inc. and is currently in clinical trials. Institute (.gov) +1

• Current Status: As of early 2026, it is in Phase 2 of global research and development.
• Study Focus: Trials are evaluating its efficacy both as a monotherapy and in combination with other treatments for adult patients with metastatic or locally advanced MTAP-null cancers. 

Key Identifiers

• Alternate Names: AMG 193, AMG-193.
• Chemical Class: Orally bioavailable small molecule.
• Genetic Biomarker: Specifically targets cancers with MTAP-null status

Anvumetostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, anvumetostat selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors.

SYN

[0163] Examples 481 and 482: (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone

[0164] Step 1: To a solution of 3-(4-(trifluoromethyl)phenyl)morpholine (0.100 g, 0.432 mmol, Enamine), 4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c][l,7]naphthyridine-8-carboxylic acid hydrochloride (138) (0.271 g, 0.649 mmol) and l,l’-dimethyltriethylamine (0.559 g, 0.755 mL, 4.32 mmol, Sigma- Aldrich Corporation) in DMF (4 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (0.202 g, 0.432 mmol, Sigma-Aldrich Corporation) and the resulting mixture was heated at 50 °C for 30 min. The reaction was brought to rt, diluted with water, sat.NaHCCh and extracted with EtOAc (3x). The combined organics were dried over Na₂SO4, filtered and concentrated. The residue was then chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-((2,4-dimethoxybenzyl)amino)- 1 ,3 -dihy drofuro [3 ,4-c] [ 1 ,7]naphthyridin-8-y 1) (3 – (4 -(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2% yield) as a light yellow solid, m/z (ESI): 595 (M+H)⁺.

[0165] To a solution of (4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c] [l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2 % yield) in DCM (2 mL) was added TFA (14.80 g, 10 mL, 130 mmol, Aldrich) and the resulting mixture was heated at 50 °C for 1 h. The reaction was concentrated, washed with 10% Na₂CO3 and extracted with DCM. The combined organics were concentrated and chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone as the TFA salt (0.078 g, 0.140 mmol, 32.3% yield) as an off-white solid, m/z (ESI): 445 (M+H)⁺.

[0166] Step 2: (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4- (trifluoromethy l)phenyl)morpholino)methanone and (R)-(4-amino- 1 ,3 -dihy drofuro [3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 2,2,2-trifluoroacetate were separated via preparative SFC using a Chiral Technologies AD column (150 x 21 mm, 5mm) with a mobile phase of 60% Liquid CO2 and 40% MeOH with 0.2% TEA using a flowrate of 80 mL/min to generate peak 1, (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of >99%, and peak 2, (R)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of 99.28%. Peak assignment determined by

SFC with AD column with 60% Liquid CO2 and 40% MeOH with 0.2% TEA and absolute

stereochemistry was arbitrarily assigned.

Peak 1: (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (481) as a white solid . m/z (ESI): 445 (M+H)⁺. NMR ¹H (400 MHz, DMSO-d₆) 5 ppm 8.67 – 9.03 (m, 1 H), 7.85 (s, 1 H), 7.77 (br s, 4 H), 7.07 (br s, 2 H), 5.75 (s, 1 H), 5.37 (br s, 2 H), 5.04 (br s, 2 H), 4.46 – 4.61 (m, 1 H), 3.89 (br dd, J=12.2, 3.3 Hz, 4 H), 3.58 (br d, ./=5,8 Hz, 1 H). ¹⁹F NMR (377 MHz, DMSO-d₆ ) 5 ppm -60.90 (br s, 3 F).

Peak 2: (R)-(4-amino- 1 ,3 -dihy drofuro [3 ,4-c] [ 1 ,7]naphthyridin-8-yl)(3 -(4-(trifluoromethyl)phenyl)morpholino)methanone (482) as a white solid, m/z (ESI): 445 (M+H)⁺. NMR ¹H (400 MHz, DMSO-d₆) 5 ppm 8.88 (br s, 1 H), 7.85 (s, 1 H), 7.77 (br d, J=1.7 Hz, 4 H), 7.07 (br s, 2 H),

5.69 – 5.78 (m, 1 H), 5.37 (br s, 2 H), 5.04 (br s, 2 H), 4.45 – 4.61 (m, 1 H), 3.89 (br dd, J=12.4, 3.3 Hz, 4 H), 3.51 – 3.64 (m, 1 H). ¹⁹F NMR (DMSO-d6, 377 MHz) 5 -60.90 (s, 3 F).

SYN

Example 4. Synthesis of Compound I – (4-amino-1 ,3-di hydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone

Reaction Scale 1

[0137] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (1.0 kg, 4.3 mol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (1.2 kg, 5.2 mmol, 1.2- equiv), and DMF, (6.6 kg, 7.0 V) were charged to a clean, dry reactor. To the mixture was added triethylamine (1.1 Kg, 13.8 mol, 2.6 equiv). The mixture was cooled to 10 ± 5 °C and O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) (1.67 kg, 5.2 mol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (0.94 Kg, 1 V) was added. The reaction mixture was warmed to 25 ± 5 °C and stirred over 18 hours. Water (1 .0 kg, 1 V) was charged followed by MeCN (1 .6 kg, 2 V) and the reaction mass was warmed to 45 °C. Next, water (7.0 Kg, 7 V) was added over 30 min. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (10 g, 22 mmol, 0.01 equiv), was charged and the mixture was stirred at 45 °C for over 2 hours before being cooled to 20 °C over 10 hours. Water (12.0 kg, 12 V) was added over 2 hours at 20 °C and further stirred for over 4 hours before being filtered. The reactor was rinsed with a mixture of 10% DMF in water (9.83 kg, 10 V) and the resulting rinse mixture was used to wash the cake. The reactor was rinsed with a mixture of water (10.0k kg, 10 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated once more with water (10.0k kg, 10V). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-

(trifluoromethyl)phenyl]morpholin-4-yl]methanone. LCMS: 445.20 ¹H NMR (400 MHz, DMS0-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, 0=8.7 Hz, 2H), 7.71 (d, 0=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, 0=3.5 Hz, 2H), 4.44 (br d, 0=12.3 Hz, 1 H), 4.08 (br d, 0=13.4 Hz, 1 H), 3.96 (dd, 0=12.3, 3.7 Hz, 1 H), 3.86 (br dd, 0=11 .4, 3.0 Hz, 1 H), 3.66 (td, 0=11 .4, 3.0 Hz, 1 H), 3.28 (m, 1 H).

Reaction Scale 2

[0138] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (85.0 g, 352.2 mmol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (99.6 g, 422.6 mmol, 1.2- equiv), and DMF, (674 mL, 8.7 mol, 7.9 V) were charged to a clean, dry 5 L reactor. To the mixture was added 1 -methylimidazole (75.2 g, 916.2 mmol, 2.6 equiv). The mixture was cooled to 0 °C and N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (118.6 g, 422.6 mmol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (170 mL, 2 V) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred overnight. Next, the reaction mass was warmed to 45 °C and 2-methyltetrahydrofuran, (169.2 mL, 2 V) was added followed by slow addition of water (850 mL, 10 V) over 30 min by addition funnel. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (1.6 g, 3.5 mmol, 0.1 equiv), was charged as a slurry in a 1 :1 v/v of DMF and water (31 .3 mL) and the mixture was stirred at 45 °C for approximately 12 hrs. Water (510 mL, 6 V) was added over 1 h 10 min by addition funnel and the mixture was further stirred at 45°C for 30 min before being filtered. The reactor was rinsed with water (340 mL, 4 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated twice more. The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. LCMS: 445.20 ¹H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, J=3.5 Hz, 2H), 4.44 (br d, J=12.3 Hz, 1 H), 4.08 (br d, J=13.4 Hz, 1 H), 3.96 (dd, J=12.3, 3.7 Hz, 1 H), 3.86 (br dd, J=11.4, 3.0 Hz, 1 H), 3.66 (td, J=11.4, 3.0 Hz, 1 H), 3.28 (m, 1 H).

Reaction Scale 3:

[0139] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (Compound A’) (20.0 g, 86.5 mmol, 1.0 equiv) was added to dimethylsulfoxide (400 mL) at 20 °C. To the mixture was added 1 ,T-carbonyldiimidazole (15.4 g, 95.2 mmol, 1.1 equiv) and the mixture was heated to 60 °C for 1 hour. A solution of (S)-3-(4-(trifluoromethyl)phenyl)morpholin-4-ium chloride (25.5 g, 95.2 mmol, 1.1 equiv) and dimethylsulfoxide (40 mL) was added, and the mixture was heated to 80 °C for 11 hours. The reaction mixture was cooled to 35 °C, then water (265 mL) was added, then the batch was cooled to 20 °C. The reaction was filtered, washed with 40% water:DMSO (80 mL), then washed with water (100 mL). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (Compound I). LCMS: 445.20 ¹H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, >3.5 Hz, 2H), 4.44 (br d, >12.3 Hz, 1H), 4.08 (br d, >13.4 Hz, 1 H), 3.96 (dd, >12.3, 3.7 Hz, 1 H), 3.86 (br dd, >11 .4, 3.0 Hz, 1 H), 3.66 (td, >11 .4, 3.0 Hz, 1 H), 3.28 (m, 1 H).

Recrystallization of Compound I

[0140] A clean, dry 5 L reactor was charged with (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (279.7 g, 0.6 mol, 1.0 equiv) followed by acetone (6.2 L,

22 V). The mixture was stirred at 40 °C for 15 minutes before cooling to 25 °C. The reactor was discharged into a flask and the reactor was rinsed with acetone and the process stream was polish-filtered back into the reactor.

The reactor jacket was set to 65 °C and the reaction volume was reduced to approximately 6 V by distillation at atmospheric pressure, crystallization was observed. The reaction temperature was set to cool to 20 °C over two hours. Heptane (2.8 L, 10 V) was added over two hours. The slurry was filtered and the cake was washed twice with a 4:1 Heptane/acetone mix (750 mL, 3 V each) and dried under vacuum with a nitrogen purge to afford (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methanone.

ADVT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Process for synthesizing naphthyridine derivatives and intermediates thereofPublication Number: EP-4396170-A1Priority Date: 2021-08-30
• PRMTS inhibitorsPublication Number: CN-116888120-APriority Date: 2020-12-16
• Prmts inhibitorsPublication Number: WO-2022132914-A1Priority Date: 2020-12-16
• Prmts inhibitorsPublication Number: EP-4263545-A1Priority Date: 2020-12-16
• Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number: EP-4572760-A1Priority Date: 2022-08-15
• Cancer treatments using mta-cooperative prmt5 inhibitorsPublication Number: WO-2023196545-A1Priority Date: 2022-04-08
• Process for the synthesis of naphthyridine derivatives and intermediates thereofPublication Number: CN-117897379-APriority Date: 2021-08-30
• Process for synthesizing naphthyridine derivatives and intermediates thereofPublication Number: WO-2023034786-A1Priority Date: 2021-08-30
• Process for Synthesizing Naphthyridine Derivatives and Intermediates ThereofPublication Number: US-2024360147-A1Priority Date: 2021-08-30
• Prmt5 inhibitor for use in cancer therapyPublication Number: WO-2024170488-A1Priority Date: 2023-02-13
• Cancer treatments using a prmt5 inhibitor and a mat2a inhibitorPublication Number: WO-2024118897-A1Priority Date: 2022-11-30
• Cancer treatments using a prmt5 inhibitor and a mat2a inhibitorPublication Number: EP-4626435-A1Priority Date: 2022-11-30
• MTA synergizes with PRMT5 inhibitors for cancer treatmentPublication Number: CN-119730853-APriority Date: 2022-08-15
• Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number: WO-2024038004-A1Priority Date: 2022-08-15

////////anvumetostat, ANAX LAB, antineoplastic, AMG 193, QAT649EJ5E, PRMT5-IN-27,

Andamertinib

CAS 2254145-43-0

MF C31H36N8O3 MW568.7 g/mol

N-[4-methoxy-2-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-5-[[6-(1-methylindazol-5-yl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide

N-(4-methoxy-2-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-5-{[6-(1-methyl-1H-indazol-5-yl)pyrimidin-4-yl]amino}phenyl)prop-2-enamide
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, PLB 1004, 5X3KAG7ZBW

Andamertinib (also known as PLB1004) is an investigational, orally bioavailable, and irreversible small-molecule inhibitor of the epidermal growth factor receptor (EGFR). It is primarily being developed to treat non-small cell lung cancer (NSCLC) with specific genetic mutations. 

Key Clinical & Therapeutic Features

• Target Mutations: It specifically targets EGFR exon 20 insertion (ex20ins) mutations, which are often resistant to standard first- and second-generation EGFR inhibitors.
• Broad Selectivity: Beyond ex20ins, it also shows activity against classical mutations like Del19, L858R, and the resistance mutation T790M.
• Brain Penetration: Andamertinib is designed to cross the blood-brain barrier, making it potentially effective for patients with brain metastases.
• Clinical Performance: In phase 2 studies (e.g., the KANNON study), it demonstrated a confirmed objective response rate (ORR) of 42.7% and a median progression-free survival of 6.2 months in pretreated patients. 

Regulatory Status (as of Early 2026)

• China: A New Drug Application (NDA) was accepted by the National Medical Products Administration (NMPA) in May 2025 and granted priority review for treating NSCLC with EGFR ex20ins mutations.
• Global: It remains in various stages of clinical trials globally, including studies for first-line treatment and combination therapies with other agents like vebreltinib. 

Andamertinib is an orally bioavailable, mono-anilino-pyrimidine, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, andamertinib targets, binds to and irreversibly inhibits the activity of various EGFR mutations, including exon 20 insertion (Ex20ins) activating mutations, the gatekeeper mutation T790M, ExDel19, and L858R. This prevents EGFR-mediated signaling, induces cell death and inhibits tumor growth in tumor cells expressing these EGFR mutations. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.

SYN

[WO2018228446A1]

SYN

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: US-11352352-B2Priority Date: 2017-06-13Grant Date: 2022-06-07
• Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: EP-3640248-A1Priority Date: 2017-06-13
• Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: US-2020087296-A1Priority Date: 2017-06-13
• Aminopyrimidine derivatives, preparation method therefor and use thereofPublication Number: EP-3640248-B1Priority Date: 2017-06-13Grant Date: 2023-08-23

//////////andamertinib, FLAX LAB, antineoplastic, PLB 1004, 5X3KAG7ZBW

Amsulostat

CAS 2409963-83-1

MF C13H13FN2O2S MW280.32

2-Buten-1-amine, 3-fluoro-4-(8-quinolinylsulfonyl)-, (2Z)-

(2Z)-3-fluoro-4-(quinolin-8-ylsulfonyl)but-2-en-1-amine

(Z)-3-fluoro-4-quinolin-8-ylsulfonylbut-2-en-1-amine

(2Z)-3-fluoro-4-(quinolin-8-ylsulfonyl)but-2-en-1-amine
protein-lysine-oxidase (LOX) inhibitor, antifibrotic,  PXS 5505, LOX inhibitor PXS-5505, LOX-IN-3, pan-LOX inhibitor PXS-5505, DO94E28WYW, SNT 5505

Amsulostat is an orally available, small-molecule, irreversible inhibitor of all lysyl oxidases (LOX) family members, with potential antifibrotic activity. Upon oral administration, amsulostat targets, binds to and inhibits the activity of all enzymes in the LOX family. This prevents the post-translational oxidative deamination of lysine residues on target proteins, including collagen and elastin, and reduces the formation of deaminated lysine (allysine), the formation of inter- and intramolecular cross-linkages and may prevent remodeling of the extracellular matrix (ECM), thereby reducing fibrotic tissue formation in certain chronic fibrotic diseases. LOX is often upregulated in fibrotic tissue and plays a key role in fibrosis.

Amsulostat (formerly PXS-5505) is an orally available, investigational, pan-lysyl oxidase (pan-LOX) inhibitor designed by Syntara to treat fibrotic diseases and solid tumors. It works by preventing collagen cross-linking and remodeling of the extracellular matrix, effectively reducing fibrosis. The drug is currently in Phase 2 clinical trials for myelofibrosis, showing promise in reducing symptom burden and spleen volume, and is also being studied for myelodysplastic syndrome (MDS) and pancreatic cancer. 

Key Aspects of Amsulostat:

• Mechanism of Action: Irreversibly inhibits all LOX family members (LOX, LOXL1-4), reducing fibrotic tissue.
• Clinical Status (Myelofibrosis): Phase 2a data showed 73% of patients (who were suboptimal responders to ruxolitinib) achieved  reduction in total symptom score, with significant spleen volume reduction.
• Clinical Status (Other Cancers): Phase 2 trials (AZALOX) are evaluating its use in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). It is also being tested in combination with chemotherapy for pancreatic cancer to improve drug delivery to tumors.
• Regulatory Status: Has received Orphan Drug Designation for primary myelofibrosis from the FDA (USA) and EMA (Europe).
• Safety Profile: Clinical trials have reported it is well-tolerated with no treatment-related serious adverse events in early findings.

Amsulostat’s ability to target the stiff, fibrotic environment surrounding tumors makes it a promising “add-on” therapy to increase the effectiveness of existing cancer treatments, including chemotherapy and immunotherapy.

An orally available, small-molecule, irreversible inhibitor of all lysyl oxidases (LOX) family members, with potential antifibrotic activity. Upon oral administration, amsulostat targets, binds to and inhibits the activity of all enzymes in the LOX family. This prevents the post-translational oxidative deamination of lysine residues on target proteins, including collagen and elastin, and reduces the formation of deaminated lysine (allysine), the formation of inter- and intramolecular cross-linkages and may prevent remodeling of the extracellular matrix (ECM), thereby reducing fibrotic tissue formation in certain chronic fibrotic diseases. LOX is often upregulated in fibrotic tissue and plays a key role in fibrosis.

SYN

US12178791,

Compound 33

syn

(Z)-3-fluoro-4-(quinolin-8-ylsulfonyl)but-2-en-1-amine dihydrochloride (Compound 33)

[0282] White solid; m.p.150-153 °C; ¹H NMR (300 MHz, CD3OD) d ppm: 9.18 (d, J = 4.7 Hz, 1H), 8.70 (dd, J = 8.4, 2.6 Hz, 1H), 8.57 (d, J = 7.4 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.99– 7.68 (m, 2H), 5.22 (dt, J = 32.9, 7.4 Hz, 1H), 5.00 (d, J = 19.4 Hz, 2H), 3.60 (d, J = 7.7 Hz, 2H); LCMS: for C₁₃H₁₃FN₂O₂S calculated 280.1, found 281.1 [M+1]⁺.

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereofPublication Number: EP-3829520-B1Priority Date: 2018-08-03Grant Date: 2024-11-27
• Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereofPublication Number: US-2025082593-A1Priority Date: 2018-08-03
• Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereofPublication Number: US-2021353571-A1Priority Date: 2018-08-03
• Lox enzyme inhibiting methods and compositionsPublication Number: EP-4138824-A1Priority Date: 2020-04-21
• Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereofPublication Number: WO-2020024017-A1Priority Date: 2018-08-03
• Inhibitors of haloallylamine sulfone derivatives of lysyl oxidase and uses thereofPublication Number: KR-20210045984-APriority Date: 2018-08-03
• Halide allylamine derivate inhibitor for amine oxidase and its usePublication Number: TW-202019877-APriority Date: 2018-08-03
• Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereofPublication Number: US-12178791-B2Priority Date: 2018-08-03Grant Date: 2024-12-31
• Bithiazol deratives as inhibitors of lysyl oxidasesPublication Number: EP-4333843-A1Priority Date: 2021-05-13
• Inhibitors of lysyl oxidasesPublication Number: US-11712437-B2Priority Date: 2021-05-13Grant Date: 2023-08-01
• Method for selecting cancer patients for whom combination therapy of retinoid with cancer therapeutic agent is effective, and combination drug of retinoid with cancer therapeutic agentPublication Number: CN-115997122-APriority Date: 2020-06-26
• Method for selecting cancer patient for which combination therapy of retinoid and cancer treatment agent will be effective, and combined drug of retinoid and cancer treatment agentPublication Number: EP-4173639-A1Priority Date: 2020-06-26
• Method for selecting cancer patients for whom combination therapy with retinoid and cancer therapeutic agent is effective, and combination medicament with retinoid and cancer therapeutic agentPublication Number: US-2023301950-A1Priority Date: 2020-06-26

////////////amsulostat, ANAX LAB, protein-lysine-oxidase (LOX) inhibitor, antifibrotic,  PXS 5505, LOX inhibitor PXS-5505, LOX-IN-3, pan-LOX inhibitor PXS-5505, DO94E28WYW, SNT 5505

Amezalpat

CAS 1616372-41-8

MF C34H41N3O4 MW555.7 g/mol

• [1,1′-Biphenyl]-3-acetic acid, 3′-[3-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-ethyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]propyl]-4-ethoxy-
• 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
• 3′-(3-(1-((4-(1,1-DIMETHYLETHYL)PHENYL)METHYL)-4-ETHYL-4,5-DIHYDRO-5-OXO-1H-1,2,4-TRIAZOL-3-YL)PROPYL)-4-ETHOXY(1,1′-BIPHENYL)-3-ACETIC ACID

2-[5-[3-[3-[1-[(4-tert-butylphenyl)methyl]-4-ethyl-5-oxo-1,2,4-triazol-3-yl]propyl]phenyl]-2-ethoxyphenyl]acetic acid

peroxisome proliferator-activated receptor alpha (PPARα) antagonist, antineoplastic, TPST 1120, FDA Fast Track,  Orphan Drug, 1EQ4LQN9N3

Amezalpat (formerly TPST-1120) is an investigational, oral, small-molecule inhibitor targeting peroxisome proliferator-activated receptor alpha (PPAR being developed by Tempest Therapeutics. It works by directly targeting tumor cells and reducing immune suppression in the tumor microenvironment. In combination with atezolizumab and bevacizumab, it has shown improved survival in hepatocellular carcinoma (HCC) patients, receiving FDA Fast Track and Orphan Drug designations. 

Key Details on Amezalpat

• Indication: Primarily being studied for unresectable or metastatic hepatocellular carcinoma (liver cancer).
• Mechanism: A selective, competitive antagonist of PPAR$$, which plays a role in fatty acid metabolism in cancer cells.
• Clinical Efficacy: A phase 1b/2 study indicated that adding amezalpat to standard-of-care (atezolizumab + bevacizumab) improved median overall survival to 21 months compared to 15 months for the control, according to Tempest Therapeutics.
• Trial Status: A pivotal Phase 3 study (NCT06680258) to evaluate this combination as a first-line treatment is planned for 2025.
• Other Potential Uses: Preclinical data suggests potential activity in other advanced solid tumors, including renal cell carcinoma. 

Disclaimer: Amezalpat is an investigational agent and is not yet approved by the FDA for widespread clinical use.

Amezalpat is an orally bioavailable, small molecule, selective and competitive antagonist of peroxisome proliferator activated receptor alpha (PPARa), with potential immunomodulating and antineoplastic activities. Upon oral administration, amezalpat targets, binds to and blocks the activity of PPARa, thereby blocking transcription of PPARa target genes leading to an intracellular metabolism shift from fatty acid oxidation (FAO) to glycolysis in FAO-dependent tumors and reducing the production of fatty acids in the tumor microenvironment (TME). As fatty acids are essential for tumor cell growth in FAO-dependent tumor cells and are needed for the metabolism of suppressive immune cells in the TME, including regulatory T-cells (Tregs), reducing the amount of fatty acids leads to a direct killing of FAO-dependent tumor cells. It also skews macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells, thereby stimulating an anti-tumor immune response and further killing tumor cells. Amezalpat also restores the natural inhibitor of angiogenesis thrombospondin-1 (TSP-1) and stimulator of interferon genes (STING) in the TME. PPARa, a ligand-activated nuclear transcription factor and metabolic checkpoint, regulates the expression of FAO genes and lipid metabolism. It plays a key role in immunosuppression in the TME. FAO is a metabolic pathway essential to tumor growth, survival and immunosuppression.

SYN

US20240041837,

Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid

SYN

US20240041837,

SYN

WO2014099503 TRIAZOLONE COMPOUNDS AND USES THEREOF

Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1, 1′-biphenyl]-3-yl)acetic acid

Pat

WO2025235527 CRYSTALLINE FORMS OF A PPAR ALPHA ANTAGONIST

2-(3′-(3-(l-(4-(tertbutyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,T-biphenyl]-3-yl)acetic acid, depicted below as Compound A

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Triazolone compounds and uses thereofPublication Number: US-2017239223-A1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: WO-2014099503-A1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: US-10568871-B2Priority Date: 2012-12-20Grant Date: 2020-02-25
• Triazolone compounds and uses thereofPublication Number: US-2024041837-A1Priority Date: 2012-12-20
• Compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and uses thereofPublication Number: BR-112015013350-B1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: US-2015344446-A1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: US-11666557-B2Priority Date: 2012-12-20Grant Date: 2023-06-06
• Triazolone compounds and uses thereofPublication Number: US-2020138790-A1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: US-9676754-B2Priority Date: 2012-12-20Grant Date: 2017-06-13
• Triazolone compounds and uses thereofPublication Number: CA-2894281-CPriority Date: 2012-12-20Grant Date: 2021-04-20
• Triazolone compounds and uses thereofPublication Number: WO-2024102620-A2Priority Date: 2022-11-09
• Triazolone compounds and uses thereofPublication Number: AU-2013363398-B2Priority Date: 2012-12-20Grant Date: 2017-06-01
• Triazolone compounds and uses thereofPublication Number: EP-2935228-B9Priority Date: 2012-12-20Grant Date: 2017-12-06
• Triazolone compounds and uses thereofPublication Number: CA-2894281-A1Priority Date: 2012-12-20
• Triazolone compounds and uses thereofPublication Number: EP-2935228-B1Priority Date: 2012-12-20Grant Date: 2017-08-02

/////////////amezalpat, ANAX LAB, antineoplastic, TPST 1120, FDA Fast Track,  Orphan Drug, 1EQ4LQN9N3

Alnodesertib

CAS 2267316-76-5

MF C18H24N6O2S MW388.49

4-[4-[(cyclopropyl-methyl-oxo-λ⁶-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine

4-[4-[(cyclopropyl-methyl-oxo-lambda6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine

(S)-({2-(2-aminopyridin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}imino)(cyclopropyl)(methyl)-λ6
-sulfanone
serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085

Alnodesertib (formerly known as ART0380) is an investigational, orally administered drug designed to treat various types of cancer. It is a selective inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein), a key kinase involved in DNA repair and cell cycle progression. 

Mechanism of Action

Alnodesertib works by disrupting the DNA Damage Response (DDR): 

• Targets ATR Kinase: It selectively inhibits ATR, which cancer cells rely on to fix DNA damage caused by rapid replication.
• Blocks Signaling: By blocking the phosphorylation of CHK1, it prevents the activation of DNA damage checkpoints.
• Induces Apoptosis: Inhibiting these repair pathways prevents cancer cells from surviving replication stress, ultimately leading to cell death (apoptosis). 

Clinical Status and Indications

As of early 2026, alnodesertib is undergoing several clinical trials: 

• Metastatic Colorectal Cancer (mCRC): The FDA granted Fast Track designation in September 2025 for alnodesertib in combination with irinotecan for adult patients with ATM-negative mCRC in the third-line setting.
• Ovarian Cancer: In March 2026, Artios Pharma reported that a Phase 2a study reached its primary endpoint, showing that adding a low dose of alnodesertib to gemcitabine improved progression-free survival in patients with platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
• Other Solid Tumours: It is being evaluated in the ongoing STELLA Phase 1/2a study for its potential across multiple solid tumour types characterized by high replication stress.

Key Facts

SYN

EXAMPLES 39a and 39b

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

and

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

[0648] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH(0.1% DEA) = 70:30; Flow rate: 80 g / min; 20 min; Column temperature: 35 °C; Back pressure: 100 bar; Column: Gilson-281, AY 20 x 250mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6mg, 25% yield, >99% ee) as a white solid and 39b (7.1mg, 27% yield, >99% ee) as a white solid.

[0649] 39a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or (S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD3OD) δ 8.03 – 7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J =5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J = 4.6 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.02 (dt, J = 11.3, 3.6 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.75 (dt, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.56 (m, 4H), 3.25 (tdJ, = 12.8, 3.8 Hz, 1H), 3.01 (td, J = 7.9, 4.0 Hz, 1H), 1.42 (dd, J = 10.2, 5.4 Hz, 1H), 1.31 (dt, J = 11.1, 6.2 Hz, 4H), 1.20 (dt,J = 11.3, 5.7 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388, found: 389 [M+H]⁺; R_t = 11.35 min.

[0650] 39b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or (S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 7.97 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dt, J = 5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J = 12.7 Hz, 1H), 4.02 (dd, J = 11.4, 3.7 Hz, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.75 (dt, J = 11.4, 3.0 Hz, 1H), 3.66 – 3.55 (m, 4H), 3.25 (tdJ, = 12.9, 3.9 Hz, 1H), 3.05 – 2.97 (m, 1H), 1.41 (dt, J = 10.6, 5.2 Hz, 1H), 1.31 (dd, J = 11.8, 5.8 Hz, 4H), 1.20 (dt, J = 11.1, 5.6 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388, found: 389 [M+H]⁺; R_t = 15.22 min.

[0651] Alternatively, Example 39a can also be prepared from Int. CC, Isomer lb.

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• HETEROCYCLIC INHIBITORS OF KINASE ATRPublication Number: WO-2019014618-A1Priority Date: 2017-07-13
• Heterocyclic inhibitors of ATR kinasePublication Number: US-11434233-B2Priority Date: 2017-07-13Grant Date: 2022-09-06
• Heterocyclic inhibitors of ATR kinasePublication Number: US-10800769-B2Priority Date: 2017-07-13Grant Date: 2020-10-13
• Heterocyclic inhibitors of ATR kinasePublication Number: US-10392376-B2Priority Date: 2017-07-13Grant Date: 2019-08-27
• Heterocyclic inhibitors of atr kinasePublication Number: US-2019016713-A1Priority Date: 2017-07-13
• Heterocyclic inhibitors of atr kinasePublication Number: US-2020102296-A1Priority Date: 2017-07-13
• Heterocyclic inhibitors of atr kinasePublication Number: US-2021047311-A1Priority Date: 2017-07-13

///////alnodesertib, ANAX LAB, serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085

Alixorexton

CAS 2648347-56-0

MF C21H30N2O5S MW 422.5 g/mol

N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide

N-[(15S,16R)-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0^2,7.0^11,16]tricosa-2,4,6-trien-15-yl]methanesulfonamide

• Methanesulfonamide, N-[(4S,4aR,7alpha,10alpha)-1,2,3,4,4a,5,7,8,9,10,16,17-dodecahydro-17-oxo-7,10-ethanopyrido[1,2-d][1,7,4]benzodioxaazacyclotridecin-4-yl]-
• N-[(4S,4aR,7alpha,10alpha)-1,2,3,4,4a,5,7,8,9,10,16,17-Dodecahydro-17-oxo-7,10-ethanopyrido[1,2-d][1,7,4]benzodioxaazacyclotridecin-4-yl]methanesulfonamide
• N-[7,10-cis-(4S,4aR)-17-oxo-1,2,3,4,4a,5,7,8,9,10,16,17-dodecahydro-7,10-ethanopyrido[1,2-d][1,7,4]benzodioxaazacyclotridecin-4-yl]methanesulfonamide

N-[7,10-cis-(4S,4aR)-17-oxo-1,2,3,4,4a,5,7,8,9,10,16,17-dodecahydro-7,10-ethanopyrido[1,2-
d][1,7,4]benzodioxaazacyclotridecin-4-yl]methanesulfonamide
orexin-2 receptor agonist, ALKS 2680, Breakthrough Therapy designation, 3BRW4ARU66, TAK 994, firazorexton

Alixorexton (formerly ALKS 2680) is an investigational, once-daily, oral, selective orexin 2 receptor (OX2R) agonist being developed by Alkermes for treating narcolepsy and idiopathic hypersomnia. It has shown significant efficacy in Phase 2 trials (Vibrance-1, -2, -3) for improving wakefulness and received FDA Breakthrough Therapy designation in January 2026 for narcolepsy type 1.

• OriginatorAlkermes
• ClassSleep disorder therapies
• Mechanism of ActionOrexin receptor type 2 agonists
• Phase IIIdiopathic hypersomnia; Narcolepsy
• 09 Mar 2026Alkermes plans the phase III Brilliance NT1 trial for Narcolepsy in an undisclosed location (PO), in March 2026 (NCT07455383)
• 06 Jan 2026Alixorexton receives Breakthrough Therapy status for Narcolepsy in USA
• 12 Nov 2025Efficacy and adverse event data from the phase II VIBRANCE-2 trial in Narcolepsy released by Alkermes

Key Details About Alixorexton (ALKS 2680):

• Mechanism of Action: As an OX2R agonist, it targets the orexin system to treat the underlying cause of excessive daytime sleepiness by activating wake-promoting neurons.
• Target Indications: The drug is developed for Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2), and Idiopathic Hypersomnia (IH).
• Clinical Trial Results:
  • Vibrance-1 (NT1): Demonstrated significant improvements in wakefulness, reduced cataplexy rates, and improved alertness in phase 2 trials.
  • Vibrance-2 (NT2): Showed positive results, meeting primary endpoints in improving sleep latency and reducing daytime sleepiness.
  • Safety: Generally well-tolerated, with most adverse events reported as mild to moderate.
• Development Status: Following positive Phase 2 data, Alkermes is preparing for phase 3 development, with plans to advance the program in early 2026.

Alixorexton is distinct as a potential once-daily treatment in a novel, rapidly advancing therapeutic category for sleep disorders

Alixorexton (INNTooltip International Nonproprietary Name; developmental code name ALKS-2680) is an orexin receptor agonist which is under development for the treatment of sleep disorders, including narcolepsy and idiopathic hypersomnia.^[1][2][3] Alixorexton is being developed by Alkermes^[4] As of July 2025, it is in phase 2 clinical trials with planned advancement to a phase 3 study for the treatment of narcolepsy type 1.^[4]

Alixorexton, also known as TAK-994 or firazorexton, is a potent, orally bioavailable, brain-penetrant agonist that selectively targets the orexin 2 receptor (OX2R), with additional activity at the orexin 1 receptor (OX1R). Its mechanism of action involves mimicking the endogenous orexin neuropeptides, thereby promoting wakefulness. Preclinical studies have demonstrated that Alixorexton effectively suppresses fragmentation of wakefulness and reduces cataplexy-like episodes in mouse models of narcolepsy, indicating its potential as a therapeutic agent for sleep disorders.

• A Long-Term Study of ALKS 2680 in Subjects With Narcolepsy and Idiopathic HypersomniaCTID: NCT06767683Phase: Phase 2/Phase 3Status: RecruitingDate: 2026-03-04
• A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 2CTID: NCT06555783Phase: Phase 2Status: CompletedDate: 2026-02-27
• A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Idiopathic HypersomniaCTID: NCT06843590Phase: Phase 2Status: RecruitingDate: 2026-02-12
• A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 1 (ALKS 2680-201)CTID: NCT06358950Phase: Phase 2Status: CompletedDate: 2025-10-14

SYN

WO2021108628A1

To (2¹S,2⁴S,5²R, 5³5)-5³-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (900 mg, 2.613 mmol, 1 equiv.) and DIPEA (1.69 g, 13.064 mmol, 5 equiv.) in DCM (148 mL) was added MsCl (900 mg, 7.858 mmol, 3 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3 x 200 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford racemic crude product (800 mg, 72.46%) as a solid. The crude product was purified by prep-SFC to afford N-((2¹S,2⁴S,5²R,5³S)-6-oxo-3,8-dioxa-5(2, 1)-piperidina-1(1, 2)-benzena-2(1, 4)-cyclohexanacyclooctaphane-5³-yl)methanesulfonamide (270.6 mg, 27.1%) as a solid and its enantiomer, N-((2¹R,2⁴R,5²,5³R)-6-oxo-3,8-dioxa-5(2, 1)-piperidina-1(1, 2)-benzena-2(1, 4)-cyclohexanacyclooctaphane-5³-yl)methanesulfonamide (361.4mg, 36.1%) as a solid. LCMS (ESI): m/z calculated for C₂₁H₃₀N₂O₅S [M+H]⁺ = 423.19, found [M+H]⁺ = 423.15; ¹H NMR (400 MHz, CDCl₃): δ 7.19 (td, J = 7.7, 1.8 Hz,

1H), 7.11 (dd, J = 7.5, 1.7 Hz, 1H), 6.96 – 6.86 (m, 1H), 6.77 (dd, J = 8.0, 1.1 Hz, 1H), 5.24 (dd, J = 9.8, 4.9 Hz, 1H), 5.14 (d, J = 10.5 Hz, 1H), 4.34 (dd, J = 14.1, 9.4 Hz, 2H), 3.84 (t, J = 9.2 Hz, 1H), 3.73 (d, J = 14.9 Hz, 3H), 3.60 – 3.46 (m, 2H), 3.09 (s, 3H), 2.77 – 2.49 (m, 2H), 2.33 – 2.16 (m, 1H), 2.06 (d, J = 12.8 Hz, 2H), 2.00 – 1.82 (m, 2H), 1.68 (d, J = 11.5 Hz, 2H), 1.10 – 1.45 (m, 4H).

SYN

CREDIT MEDKOO

Synthetic Reference

Preparation of substituted macrocyclic derivatives for use in the treatment of narcolepsy or cataplexy

Assignee: Alkermes, Inc.

Inventors: Pennington, Lewis D.; et al

United States

Patent#US20210155636 A1

Example 1.1

 Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[2-(benzyloxy)phenyl]cyclohexan-1-one (210 g, 749 mmol, 1.00 equiv.) in tetrahydrofuran (2.1 L). This was followed by the addition of L-selectride (1 mol/L in THF) (1123 mL, 5257 mmol, 1.50 equiv.) dropwise with stirring at 0 degrees C. The resulting solution was stirred for 4 hr at room temperature. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate, and the organic phase was washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) to give 137 g (64%) of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol as a solid. ¹H NMR (400 MHz, CDCl ₃): δ 7.45-7.26 (6H, m), 7.16 (1H, dd), 6.98-6.90 (2H, m), 5.09 (2H, s), 4.13 (1H, s), 3.12-3.02 (1H, m), 1.93-1.82 (4H, m), 1.73-1.41 (4H, m).

 Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed NaH (60% wt, 26.9 g, 2.00 equiv.) in tetrahydrofuran (200 mL). This was followed by the addition of a solution of (1s, 4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol (95 g, 336 mmol, 1.00 equiv.) in THF (200 mL) dropwise with stirring at 50-55 degrees C. After stirring for 2 hr, to this was added a solution of 3-bromo-2-(bromomethyl)pyridine (143.5 g, 571 mmol, 1.70 equiv.) in THF (550 mL) dropwise with stirring at 50-55 degrees C. The resulting solution was stirred for 14 hr at 50-55 degrees C. The reaction mixture was cooled. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:2) to give 94 g (62%) of 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy) phenyl]cyclohexyl]oxy]methyl)pyridine as a solid. ¹H NMR (400 MHz, CDCl ₃): δ 8.57 (1H, d), 7.90 (1H, dd), 7.48-7.26 (6H, m), 7.18-7.14 (2H, m), 6.98-6.91 (2H, m), 5.12 (2H, s), 4.77 (2H, s), 3.86 (1H, s), 3.17-3.10 (1H, m), 2.20-2.15 (2H, m), 1.98-1.88 (2H, m), 1.69-1.57 (4H, m).

  Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Xantphos (10.7 g, 18 mmol, 0.10 equiv.), Cs ₂CO ₃ (84 g, 258 mmol, 1.39 equiv.), 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy) phenyl]cyclohexyl]oxy]methyl)pyridine (84 g, 185 mmol, 1.00 equiv.), Pd ₂(dba) ₃ (8.5 g, 9 mmol, 0.05 equiv.) and tert-butyl carbamate (26 g, 222 mmol, 1.20 equiv.) in dioxane (840 mL). The resulting solution was stirred for 5 hr at 100 degrees C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:4) to provide 74 g (82%) of tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid.

    Into a 2-L 3-necked round-bottom flask, was placed tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (74 g, 151 mmol, 1.00 equiv.) and Pd/C (7.4 g, 10% wt) in ethyl alcohol (740 mL), then, hydrogen gas was through in. The resulting solution was stirred for 14 hr at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:2) to provide 51.36 g (85%) of tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid. LCMS (ESI): m/z [M+H] ⁺=399.1; ¹H NMR (300 MHz, CDCl ₃): δ 8.65 (1H, s), 8.47 (1H, d), 8.19 (1H, q), 7.26-7.21 (1H, m), 7.09-7.03 (1H, m), 6.92-6.86 (1H, m), 6.75 (1H, q), 5.77 (1H, s), 4.84 (1H, s), 3.80 (1H, s), 2.94-2.93 (1H, m), 2.15-2.06 (2H, m), 1.88-1.47 (7H, m), 1.45 (9H, s), 1.26 (1H, d).

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (8 g, 20.075 mmol, 1 equiv.), K ₂CO ₃ (13.97 g, 100.35 mmol, 5 equiv.), acetone (120 mL) and ethyl bromoacetate (5.03 g, 30.119 mmol, 1.5 equiv.). The resulting solution was stirred for 24 hr at 50 degrees C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) to provide ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (8.7 g, 89.43%) as a yellow oil. LCMS (ESI): m/z [M+H] ⁺=485.

To a stirred mixture of ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (7.89 g, 16.268 mmol, 1 equiv.) in MeOH (142 mL) and AcOH (15.8 mL) were added PtO ₂ (1.85 g, 8.142 mmol, 0.50 equiv.) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 hr at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was concentrated under reduced pressure. The reaction was quenched with sat. NaHCO ₃ (aq.) at 0 degrees C. The resulting mixture was extracted with CH ₂Cl ₂ (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure to afford diastereomeric cis and trans mixture (7 g, 88.7%) as a solid. The crude product was purified by Prep-TLC (DCM/MeOH=20:1) to afford cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g) and trans-racemic mixture (1.7 g). LCMS (ESI): m/z [M+H] ⁺=491.

Into a 500 mL round-bottom flask purged and maintained with an atmosphere of nitrogen, was placed cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g, 8.356 mmol, 1 equiv.), MeOH (30 mL), THF (60 mL), H ₂O (30 mL) and lithium hydroxide (83 mg, 3.465 mmol, 5 equiv.). The reaction was stirred for 2 hr at room temperature. The reaction was concentrated and the residue was purified by reverse phase flash with the following conditions, then freezing-drying to afford 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (2.35 g, 60.8%) as a solid. LCMS (ESI): m/z [M+H] ⁺=463

  Into a 2000-mL round-bottom flask was added 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (100 mg, 0.216 mmol, 1 equiv.), MeCN (36 mL), DMF (9 mL), HATU (124 mg, 0.326 mmol, 1.51 equiv.) and DIPEA (56 mg, 0.436 mmol, 2.02 equiv.) under nitrogen atmosphere. The resulting solution was stirred for 3 hr at room temperature. LCMS showed full conversation. The resulting mixture was concentrated. The crude product tert-butyl ((2 ¹S,2 ⁴S,5 ²R,5 ³S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 ³-yl)carbamate was used directly for the next step without purification. LCMS (ESI): m/z [M+H] ⁺=445.

 Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed crude mixture tert-butyl ((2 ¹S,2 ⁴S,5 ²R,5 ³S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 ³-yl)carbamate (2 g, 4.499 mmol, 1 equiv.), DCM (120 mL), TFA (40 mL). The resulting solution was stirred for 1 hr at 25 degrees C. LCMS showed full conversation. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford (2 ¹,S,2 ⁴S,5 ²R,5 ³S)-5 ³-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (800 mg, 51.6%) as a solid. LCMS (ESI): m/z [M+H] ⁺=345.

To (2 ¹S,2 ⁴S,5 ²R,5 ³S)-5 ³-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (900 mg, 2.613 mmol, 1 equiv.) and DIPEA (1.69 g, 13.064 mmol, 5 equiv.) in DCM (148 mL) was added MSCl (900 mg, 7.858 mmol, 3 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×200 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford racemic crude product (800 mg, 72.46%) as a solid. The crude product was purified by prep-SFC to afford N-((2 ¹S,2 ⁴S,5 ²R,5 ³S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 ³-yl)methanesulfonamide (270.6 mg, 27.1%) as a solid and its enantiomer, N-((2 ¹R,2 ⁴R,5 ²S,5 ³R)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 ³-yl)methanesulfonamide (361.4 mg, 36.1%) as a solid. LCMS (ESI): m/z calculated for C ₂₁H ₃₀N ₂O ₅S [M+H] ⁺=423.19, found [M+H] ⁺=423.15; ¹H NMR (400 MHz, CDCl ₃): δ 7.19 (td, J=7.7, 1.8 Hz, 1H), 7.11 (dd, J=7.5, 1.7 Hz, 1H), 6.96-6.86 (m, 1H), 6.77 (dd, J=8.0, 1.1 Hz, 1H), 5.24 (dd, J=9.8, 4.9 Hz, 1H), 5.14 (d, J=10.5 Hz, 1H), 4.34 (dd, J=14.1, 9.4 Hz, 2H), 3.84 (t, J=9.2 Hz, 1H), 3.73 (d, J=14.9 Hz, 3H), 3.60-3.46 (m, 2H), 3.09 (s, 3H), 2.77-2.49 (m, 2H), 2.33-2.16 (m, 1H), 2.06 (d, J=12.8 Hz, 2H), 2.00-1.82 (m, 2H), 1.68 (d, J=11.5 Hz, 2H), 1.10-1.45 (m, 4H).

REF

CHEMICAL.AI

https://www.chemical.ai/blog/chemairs-in-action-accelerating-the-discovery-and-optimization-of-synthetic-routes-for-alks-2680-a-selective-orexin-2-receptor-agonist-developed-by-alkermesep21

Published Synthetic Route to ALKS 2680 (Alkermes)

The total synthesis of ALKS 2680 was originally reported in US2021/0155636 A1, beginning with a stereoselective reduction of ketone 4a to afford alcohol 5a (Scheme 1). The patented route employed L-selectride for facial selectivity.

To optimize this step, ChemAIRS proposed an alternative asymmetric hydrogenation utilizing an Ir/f-AmphBINOL catalyst system. This enantioselective methodology has demonstrated excellent control over both enantio- and diastereoselectivity, delivering chiral alcohols in up to 99% ee and a cis/trans ratio of 99:1. [DOI: 10.1021/acs.orglett.3c03550]

Another key transformation in the Alkermes route is the macrocyclization of intermediate 11a using HATU/DIPEA in a mixed MeCN/DMF solvent system to deliver macrocycle 12a.

The conversion of (pyridin-3-yl)methanesulfonamide 7a to (piperidin-3-yl)methanesulfonamide 8a was facilitated by Rh/C-catalyzed hydrogenation in EtOH/AcOH, followed by kinetic resolution using (+)-mandelic acid for stereochemical enrichment (WO2017/135306).

The macrocycle was constructed via intramolecular reductive etherification using Et₃SiH/TMSOTf in DCM (doi.org/10.1002/ejoc.201300135), providing the final scaffold in a late-stage cyclization strategy conducive to structural diversification.

PAT

• Substituted macrocyclic compounds and related methods of treatmentPublication Number: US-11542276-B2Priority Date: 2019-11-25Grant Date: 2023-01-03
• Substituted Macrocyclic Compounds and Related Methods of TreatmentPublication Number: US-2021155636-A1Priority Date: 2019-11-25
• Substituted macrocyclic compounds and related methods of treatmentPublication Number: US-2023339969-A1Priority Date: 2019-11-25

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

References

1.  “Alixorexton – Alkermes”. AdisInsight. Springer Nature Switzerland AG. Retrieved 2025-07-30.
2.  Morse AM (May 2025). “Enhancing the Management of Hypersomnia: Examining the Role of the Orexin System”. Seminars in Neurology. 45 (3): 410–419. doi:10.1055/a-2589-3825. PMID 40239951.
3.  Prakash BA, Shah I, Ni G, Vasudevan S, Jagannath A, Foster RG (May 2025). “Dreaming of Better Treatments: Advances in Drug Development for Sleep Medicine and Chronotherapy”. Journal of Sleep Research. 34 (5) e70087. doi:10.1111/jsr.70087. PMID 40346938.
4.  Chen E (2025-07-21). “Alkermes drug helped narcolepsy patients stay awake in Phase 2 trial”. STAT. Retrieved 2025-07-30.

/////////alixorexton, anax lab, orexin-2 receptor agonist, ALKS 2680, Breakthrough Therapy designation, 3BRW4ARU66, TAK 994, firazorexton, CHEMICAL AI

Zeprumetostat

CAS 2098545-98-1

MF C32H44N4O4 MW 548.7 g/mol

CHINA 2025, APPROVALS 2025

N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-(piperidin-1-ylmethyl)-1-benzofuran-4-carboxamide

• 4-Benzofurancarboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-
• N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-4-benzofurancarboxamide

N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-[(piperidin-1-yl)methyl]-1-benzofuran-4-carboxamide
enhancer of zeste homolog 2 (EZH2) inhibitor, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554

The chemical structure for zeprumetostat was obtained from WHO proposed INN list 131 (August 2024). The INN record describes the compound as an enhancer of zeste homolog 2 (EZH2) inhibitor and antineoplastic. The chemical structure is claimed in patent WO2017084494A1 [3]. Based on Hengrui’s declared development pipeline, we predicted at that time that zeprumetostat was likely the INN for their EZH2 inhibitor clinical lead SHR2554.

Zeprumetostat is an orally available selective inhibitor of the histone lysine methyltransferase (HMT) enhancer of zeste homolog 2 (EZH2), with potential antineoplastic activity. Upon oral administration, zeprumetostat selectively targets, binds to and inhibits the activity of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 on lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased proliferation of EZH2-expressing cancer cells. EZH2, an HMT class enzyme and the catalytic subunit of the polycomb repressive complex 2 (PRC2), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation; its expression is correlated with tumor initiation, progression, stem cell self-renewal, migration and angiogenesis.

Zeprumetostat is a small molecule drug. The usage of the INN stem ‘-metostat’ in the name indicates that Zeprumetostat is a histone N-methyltransferase inhibitor. Zeprumetostat has a monoisotopic molecular weight of 548.34 Da.

• Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCLCTID: NCT07372352Phase: Phase 2Status: RecruitingDate: 2026-01-28
• EZH2 Inhibitor Zeprumetostat in Combination Therapy for Patients With Relapsed or Refractory Mature T-cell and NK-cell LymphomasCTID: NCT07339527Phase: Phase 1/Phase 2Status: Not yet recruitingDate: 2026-01-14

PAT

WO2017084494

xample 2 

[0234]N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide

5-Ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid 1n (1.0 g, 2.4 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (696 mg, 3.6 mmol), 1-hydroxybenzotriazole (490 mg, 3.6 mmol), and N,N-diisopropylethylamine (1.56 g, 12.1 mmol) were added. The mixture was stirred for 1 hour, and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride 2a (593 mg, 3.0 mmol, prepared by the method disclosed in patent application “WO2014097041”) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, excess water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V = 8:1). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide 2 (750 mg, white solid), yield: 57%. 

[0237]MS m/z(ESI):549.7[M+1] 

[0238]

¹H NMR(400MHz,DMSO-d ₆):δ11.48(s,1H),8.15(t,1H),7.39(s,1H),6.46(s,1H),5.86(s,1H),4.32(d,2H),3.83(d,2H),3.54(s,2H),3.21(t,2H),3.01-3.07(m,2H),2.92-2.97(m,1H),2.77-2.82(m,2H),2.39(brs,4H),2.23(s,3H),2.11(s,3H),1.64-1.67(brd,2H),1.47-1.55(m,6H),1.36-1.37(brd,2H),1.02(t,3H),0.82(t,3H).

PAT

WO2019091450]

The method for preparing compounds from Formula IIa to Formula Ia provided by this invention can be specifically referred to in the methods for preparing amides disclosed in PCT applications WO2017084494A, WO2012142513, WO2013039988, WO2015-141616, and WO2011140325.

In a 25 mL three-necked flask, starter IIa (50 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (34.5 mg, 0.18 mmol), 1-hydroxybenzotriazole (23.67 mg, 0.18 mmol), and N,N-diisopropylethylamine (77.89 mg, 0.6 mmol) were mixed and dissolved in 3 mL of N,N-dimethylformamide and stirred until homogeneous. Then, starter 3-(aminomethyl)-4,6-dimethylpyridine-2(1H)-one hydrochloride (24.9 mg, 0.13 mmol) was added and the mixture was stirred at room temperature until the thin-layer chromatography showed that starter IIa had disappeared. The reaction was then terminated. Excess water was added to the reaction solution, and the mixture was extracted with a mixed solvent of dichloromethane and methanol. The organic phases were combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a dichloromethane-methanol eluent system to give 30.1 mg of white solid, yield 47.0%. [0151]m/z[M+H] 

⁺＝549.6 [0152]

^1H NMR(400MHz,DMSO-d6)ppm 11.51(s,1H)8.17(t,1H)7.39(s,1H)6.47(s,1H)5.86(s,1H)4.32(d,2H)3.83(d,2H)3.53(s,2H)3.21(t,2H)3.04(d,2H)2.94(br.s .,1H)2.79(d,2H)2.38(br.s.,4H)2.23(s,3H)2.08-2.14(m,3H)1.65(d,2H)1.44-1.56(m,6H)1.36(d,2H)1.02(t,3H)0.81(t,3H).

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-11059811-B2Priority Date: 2015-11-19Grant Date: 2021-07-13
• Derived from benzofuran, method of preparing it and using it in medicinePublication Number: ES-2760510-T3Priority Date: 2015-11-19Grant Date: 2020-05-14
• Benzofuran derivative, a method for production thereof and use thereof in medicinePublication Number: RU-2727198-C2Priority Date: 2015-11-19Grant Date: 2020-07-21
• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2020354349-A1Priority Date: 2015-11-19
• BENZOFURAN DERIVATIVE, ITS USES AND ITS PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITIONPublication Number: BR-112018007876-B1Priority Date: 2015-11-19
• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2018327394-A1Priority Date: 2015-11-19
• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-B1Priority Date: 2015-11-19Grant Date: 2019-10-30
• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-10759787-B2Priority Date: 2015-11-19Grant Date: 2020-09-01
• Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-A1Priority Date: 2015-11-19
• Crystal of benzofuran derivative free base and preparation methodPublication Number: US-11155537-B2Priority Date: 2017-05-18Grant Date: 2021-10-26
• Use of ezh2 inhibitor combined with btk inhibitor in preparing drug for treating tumorPublication Number: US-2021030736-A1Priority Date: 2017-05-18
• Use of EZH2 inhibitor combined with BTK inhibitor in preparing drug for treating tumorPublication Number: US-11065239-B2Priority Date: 2017-05-18Grant Date: 2021-07-20
• Crystal of benzofuran derivative free base and preparation methodPublication Number: US-2021130333-A1Priority Date: 2017-05-18
• Determination and preparation method of benzofuran derivative free basePublication Number: KR-102612379-B1Priority Date: 2017-05-18Grant Date: 2023-12-12

//////////zeprumetostat, ANAX LAB, CHINA 2025, APPROVALS 2025, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554