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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Dirozalkib

May 5, 2026 2:36 am / Leave a comment


Dirozalkib

CAS 1893419-37-8

MF C27H32ClN5O4S MW558.1 g/mol

 5-chloro-2-N-(6-methyl-5-piperidin-4-yl-2,3-dihydro-1,4-benzodioxin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine

2,4-Pyrimidinediamine, 5-chloro-2-[2,3-dihydro-7-methyl-8-(4-piperidinyl)-1,4-benzodioxin-5-yl]-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-

anaplastic lymphoma kinase (ALK) inhibitor, antineoplastic, XZP-3621, XZP 3621, Xuanzhu Biopharmaceutical, 2FH56C28YT

Dirozalkib (XZP-3621) is a novel, potent, and highly selective ALK/ROS1 tyrosine kinase inhibitor developed by Xuanzhu Biopharmaceutical to treat advanced ALK-positive non-small cell lung cancer (NSCLC). It demonstrated high efficacy (47.4% ORR, up to 89.3% in naive patients) in clinical trials and is designed to overcome resistance to earlier inhibitors.

Key Aspects of Dirozalkib

  • Indication: Treatment of adult patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).
  • Mechanism: Acts as a dual-target ALK/ROS1 tyrosine kinase inhibitor (TKI), effective against ALK fusion-positive cells and various resistance mutations.
  • Clinical Efficacy (Phase I/II): In studies, the drug showed significant antitumor activity with an Objective Response Rate (ORR) of 47.4% and an 89.3% ORR in ALK inhibitor-naive patients at 500 mg/day.
  • Safety Profile: No dose-limiting toxicities occurred; the maximum tolerated dose was 600 mg/day, with a recommended dose of 500 mg/day. Common adverse events included diarrhea.
  • Status: As of early 2026, the NDA (New Drug Application) for Dexitinib (Dirozalkib) was accepted by China’s NMPA, with potential for further market expansion.
  • OriginatorXuanzhu Biopharmaceutical
  • Class2 ring heterocyclic compounds; Amines; Aniline compounds; Antineoplastics; Chlorinated hydrocarbons; Piperidines; Pyrimidines; Small molecules; Sulfones
  • Mechanism of ActionAnaplastic lymphoma kinase inhibitors
  • RegisteredNon-small cell lung cancer
  • 26 Aug 2025Chemical structure information added.
  • 22 Aug 2025Registered for Non-small cell lung cancer (Late-stage disease) in China (PO) – First global approval
  • 22 Aug 2025Efficacy and adverse events data from a phase III trial in Non-small cell lung cancer released by Xuanzhu Biopharmaceutical
  • A Phase I Study of XZP-3621 in Chinese Patients With ALK or ROS1 Rearrangement Non-small Cell Lung CancerCTID: NCT05055232Phase: Phase 1Status: CompletedDate: 2025-07-24
  • Food Effect and Mass Balance Study of XZP-3621 TabletsCTID: NCT05034120Phase: Phase 1Status: CompletedDate: 2025-05-25
  • A Study of XZP-3621 in Chinese Patients With ALK Positive NSCLCCTID: NCT05482087Phase: Phase 2Status: Unknown statusDate: 2022-08-01
  • A Study to Evaluate and Compare the Efficacy and Safety of XZP-3621 Versus CrizotinibCTID: NCT05204628Phase: Phase 3Status: Unknown statusDate: 2022-01-24

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US412495595&_cid=P11-MOS0LI-66429-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016050171&_cid=P11-MOS088-57627-1

Example 3 Preparation of 2-((5-chloro-2-((7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide (compound 3)

(5) Preparation of 2-((5-chloro-2-((7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

75 mg (0.114 mmol) of tert-butyl 4-(8-((5-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid ester was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 12 hours. The starting material disappeared as detected by TLC. Water (20 mL) was added, and the mixture was separated. The aqueous phase was extracted twice with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:50) to obtain the final product (30 mg, yield 47.2%). 

[0415]Molecular formula: 

C26H31ClN6O4S Molecular weight: 559.08 LC-MS (m / z): 280.2 [ M /2+H ] +

[0416]

1H-NMR(400MHz,MeOD)δ:8.44(d,1H,J＝1.2),8.11(s,1H),7.86(d,1H,J＝1.2),7.56-7.60(m,1H),7.28-7.35(m,2H),4.26(s,4H),3.45-3.48(m,2H),3.06-3.15(m,3H),2.56-2.74(m,8H),2.17(s,3H),1.76-1.80(m,2H).

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References

/////////dirozalkib, anax labs, anaplastic lymphoma kinase (ALK) inhibitor, antineoplastic, XZP-3621, XZP 3621, Xuanzhu Biopharmaceutical, 2FH56C28YT

Darlifarnib

April 27, 2026 2:31 am / Leave a comment


Darlifarnib

CAS 2939824-30-1

MF C29H20N6O MW 468.51

14-amino-14-(3-methylimidazol-4-yl)-7-oxa-19-azapentacyclo[13.6.2.12,6.19,13.018,22]pentacosa-1(22),2(25),3,5,9,11,13(24),15(23),16,18,20-undecaene-10,20-dicarbonitrile


farnesyl transferase inhibitor, antineoplastic, KO-2806, KO 2806, T206317

Darlifarnib (KO-2806) is an investigational, orally active next-generation farnesyl transferase inhibitor (FTI) being developed by Kura Oncology to treat solid tumors, such as clear cell renal cell carcinoma (ccRCC). It inhibits the enzyme farnesyl transferase, blocking KRAS and mTORC1 signaling to induce tumor regression. It is often combined with other agents to overcome resistance. 

Key Details About Darlifarnib

  • Mechanism of Action: As a FTI, darlifarnib binds to and inhibits farnesyl transferase, which prevents the activation of RAS oncogenes and inhibits downstream mTORC1 signaling, leading to tumor cell death.
  • Target Indications: Preclinical and early clinical data show potential in treating KRAS-mutant cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and clear cell renal cell carcinoma (ccRCC).
  • Combination Therapy: Data from the Phase 1 FIT-001 trial (presented in April 2026) showed that combining darlifarnib with the TKI cabozantinib demonstrated robust activity in patients with pretreated, advanced ccRCC.
  • Overcoming Resistance: Darlifarnib is designed to re-sensitize tumors that have become resistant to prior therapies, such as RAS inhibitors and tyrosine kinase inhibitors (TKIs).
  • Status: It is an investigational drug and not yet FDA-approved. 
  • OriginatorKura Oncology
  • ClassAntineoplastics; Small molecules
  • Mechanism of ActionFarnesyltranstransferase inhibitors
  • Phase IAdenocarcinoma; Colorectal cancer; Non-small cell lung cancer; Renal cell carcinoma; Solid tumours
  • 12 Jan 2026Kura Oncology plans the one or more expansion cohorts of KO 2806 and cabozantinib in patients with advanced renal cell carcinoma in the first half of 2026
  • 22 Oct 2025Pharmacodynamics data from a preclinical trial in Cancer presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2025 (AACR-NCI-EORTC-2025)
  • 18 Oct 2025Adverse events and efficacy data from a phase I trial in Non-small cell lung cancer, Renal cell carcinoma, Adenocarcinoma released by Kura Oncology

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=EB1BA4690FD8B3EC201C8F26854E2D57.wapp2nA?docId=US467104302&_cid=P20-MOGKLM-59141-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US437765371&_cid=P20-MOGKQ9-61489-1

Step A: Preparation of (058-1)

      Compound 054 (1.2 g, 2.61 mmol) was mixed with POCl3 (19.80 g, 129.13 mmol, 12.00 mL) at 25° C. The mixture was stirred at 100° C. for 1 h. The mixture was concentrated. To the residue was added NaOH (1 M in H 2O, 100 mL). The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was blended with another batch prepared from 0.5 g of 054. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 10%) to give 058-1 (1.3 g, 2.71 mmol, 73.35% yield) as a yellow solid. LCMS R t=1.79 min in 3.0 min chromatography, 10-80 CD, ESI calcd. for C 28H 20ClN 4O 2 [M+H] + 479.1, found 479.1.

Step B: Preparation of (058-2)

      To a solution of 058-1 (1.2 g, 2.51 mmol) in DMF (10 mL) was added Zn(CN)2 (2.69 g, 22.91 mmol, 1.45 mL) and Pd(PPh3)4 (579.07 mg, 501.12 μmol) in a three-neck bottom flask at 25° C. under N 2. The mixture was stirred at 100° C. for 2 h. The mixture was cooled to 25° C. and added into water (50 mL). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 3%) to give 058-2 (900 mg, 1.92 mmol, 76.51% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6) δ=8.33-8.22 (m, 2H), 8.10 (s, 1H), 7.94-7.76 (m, 2H), 7.69 (s, 1H), 7.52-7.39 (m, 2H), 7.28-7.02 (m, 5H), 6.36 (s, 1H), 5.54 (s, 2H), 3.56 (s, 3H).

Step C: Preparation of (rac)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (rac-058)

      To a solution of 058-2 (800 mg, 1.70 mmol) in DMI (8 mL) was added SOCl2 (1.01 g, 8.52 mmol, 618.05 μL). The mixture was stirred at 40° C. for 1 h. To NH 3 in MeOH (7 M, 100 mL) was added the above mixture at −10° C. The mixture was stirred at 25° C. for 30 min. The reaction mixture was poured into H 2O (100 mL). The aqueous layer was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 8%) to give rac-058 (550 mg, 1.17 mmol, 68.89% yield) as a yellow solid. LCMS R t=1.71 min in 3.0 min chromatography, 10-80CD, ESI calcd. for C 29H 21N 6O [M+H] + 469.2, found 469.2.

Step D: Preparation of (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile ((S)-058)

      rac-058 (500 mg, 1.07 mmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH 3H 2O EtOH]; B %: 45%-45%) to give (S)-058 (229.5 mg, 489.85 μmol, 45.90% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d 6) δ=8.37 (d, J=8.4 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.48-7.19 (m, 4H), 7.18-7.04 (m, 2H), 6.44 (s, 1H), 5.64-5.45 (m, 2H), 3.48 (s, 3H), 3.18 (s, 2H). LCMS R t=1.68 min in 3.0 min chromatography, 10-80CD, ESI calcd. for C 29H 21N 6O [M+H] + 469.2, found 469.2. HPLC R t=3.03 min in 8 min chromatography, 220 nm, purity 100%. Chiral HPLC (S)-058: R t=2.44 min in 4 min (ee 99.54%) (AD_ETOH_DEA_5_40_4ML_4MIN_5CM), ((R)-058: R t=1.93 min (ee 99.44%)).

PAT

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References

/////////////darlifarnib, ANAX LAB, farnesyl transferase inhibitor, antineoplastic, KO-2806, KO 2806, T206317

Daraxonrasib

April 25, 2026 2:29 am / Leave a comment


Daraxonrasib

CAS 2765081-21-6

MFC44H58N8O5S MW811.0 g/mol

trans-(1S,2S)-N-[(7S,13S)-21-ethyl-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5.19,13.022,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide

Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, RMC-6236, RMC 6236, B6T47Y2UAP, RAS-IN-2,

Daraxonrasib (formerly RMC-6236) is an investigational, orally administered “molecular glue” RAS inhibitor developed by Revolution Medicines for treating advanced solid tumors with RAS mutations, particularly metastatic pancreatic cancer. April 2026 Phase 3 trials showed it significantly improves survival, demonstrating high potential as a first-line treatment. 

Key Clinical Findings and Updates (as of April 2026):

  • Mechanism: It acts as a RAS(ON) inhibitor, targeting mutated and wild-type RAS proteins () to disrupt cancer signaling.
  • Breakthrough Results: Data from the RASolute 302 trial showed a substantial survival benefit in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).
  • High Response Rates: In trials, daraxonrasib combined with chemotherapy showed a 58% confirmed objective response rate (ORR) and 84% progression-free survival (PFS) at 6 months in untreated RAS-mutant metastatic pancreatic cancer.
  • Safety Profile: Generally well-tolerated, with side effects including rash, diarrhea, stomatitis, and nausea.
  • Recognition: Named the “2025 Molecule of the Year” by Drug Hunter for its, novel mechanism and clinical potential. 

Daraxonrasib is currently being studied in the Phase 3 RASolute 303 trial for first-line treatment of pancreatic cancer.

Daraxonrasib (RMC-6236) is a RAS inhibitor drug. It is undergoing testing by Revolution Medicines to treat advanced solid tumors with RAS mutations, especially metastatic pancreatic ductal adenocarcinoma (PDAC) containing KRAS G12X mutations.[1] It received a breakthrough therapy designation from the U.S. Food and Drug Administration.[2]

Daraxonrasib is orally active and multi-selective RAS inhibitor. It uses a tri-complex mechanism to target the active, GTP-bound form of RAS proteins, including mutant and wild-type forms. Unlike conventional RAS inhibitors, it first binds to the chaperone-like protein cyclophilin A to form a complex, which then attaches to active RAS. This interaction blocks downstream effector binding and inhibits oncogenic signaling.[3]

In 2026, Daraxonrasib clinical trial completed a phase 3 clinical trial (RASolute 302) to assess efficacy compared to standard-of-care chemotherapy.[4] The trial met all primary and key secondary endpoints, including progression-free survival (PFS). The company reported median survival of 13.2 months with daraxonrasib vs. 6.7 months with standard chemotherapy. The hazard ratio for death was 0.40 (a 60% reduction in risk of death; p < 0.0001). Daraxonrasib was generally well tolerated with a manageable safety profile and no new safety signals.[5]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024216048&_cid=P20-MODPOO-66335-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024216017&_cid=P20-MODPOO-66335-1

PATENT ATTORNEY DOCKET: 51432-038WO2 Part 4 – Purification of Compound A – (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1- methoxyethyl]-5-(4-

1.0equiv) at 25°C. The resulting suspension was stirred until solids were completely dissolved. The resulting methanol solution was filtered through microporous filter and transferred to another reactor. Then the reactor temperature was maintained at 25°C and slowly water (2.41kg, 1.0 V) water was added over a period of 30 minutes. The resulting cloudy solution was stirred for another 30 minutes at 25°C. Then a solution of methanol and water (3.42kg, 1:2, v/v) slowly over 1 hour. The resulting suspension was stirred for 2 hours at 25°C. Again, to the suspension additional water (2.48kg) slowly added over 1 hour. The final, suspension was stirred for additional 1 hour. Water (9.29kg, 3.75 V) was added to the suspension slowly over 2 hours and the mixture was stirred for at least for 16 hours at 25°C. The resulting suspension was filtered and washed with mixed solvent water: MeOH (3:2, v/v) twice (2x 2.2 kg), followed by water (4.91kg) washing. The wet cake was dried under reduced pressure and controlled humidity (temperature: 25 ± 5 ˚C, vacuum ≥ -0.085 MPa, humidity: 10%~20%) for 37 hours to afford Compound A as a white solid (2.68 kg, 99.4% a/a purity, 93.0% w/w assay, KF: 6.7%, 3.07 mol, 92% yield, Table 27).

PAT

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References

References

  1.  Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson AC, et al. (March 2025). “Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers”. Journal of Medicinal Chemistry. 68 (6): 6064–6083. doi:10.1021/acs.jmedchem.4c02314. PMID 40056080.
  2.  Sava J (July 1, 2025). “Daraxonrasib Earns FDA Breakthrough Status in Pancreatic Cancer”. Targeted Oncology. Retrieved October 12, 2025.
  3.  Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, et al. (June 2024). “Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers”. Cancer Discovery. 14 (6): 994–1017. doi:10.1158/2159-8290.CD-24-0027. PMC 11149917. PMID 38593348.
  4.  Clinical trial number NCT05379985 at ClinicalTrials.gov
  5.  Mast J (2026-04-13). “Revolution Medicines touts ‘unprecedented’ data for pancreatic cancer pill”. STAT. Retrieved 2026-04-13.
Clinical data
Other namesRMC-6236
Identifiers
IUPAC name
CAS Number2765081-21-6
PubChem CID164726578
IUPHAR/BPS13368
ChemSpider115275938
UNIIB6T47Y2UAP
KEGGD13265
ChEBICHEBI:746946
Chemical and physical data
FormulaC44H58N8O5S
Molar mass811.06 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

//////////daraxonrasib, anax labs, Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, RMC-6236, RMC 6236, B6T47Y2UAP, RAS-IN-2,

Dabogratinib

April 21, 2026 2:31 am / Leave a comment


Dabogratinib

CAS 2800223-30-5

MF C25H24Cl2N6O3S, 559.5 g/mol

5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridinyl]-1H-indazole

(R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole

[6-(5-{5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-1H-indazol-3-yl}pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl](methyl)-λ6sulfanedioneTYRA-300
fibroblast growth factor receptor inhibitor, antineoplastic, TYRA-300, TYRA 300, A1AV2, FH245S2JZJ

Dabogratinib (TYRA-300) is an orally active, highly selective inhibitor of fibroblast growth factor receptor 3 (FGFR3), designed to treat cancers with FGFR3 alterations and genetic diseases like achondroplasia. It shows potent tumor growth inhibition in preclinical studies and early phase I/II (SURF301) clinical activity against advanced bladder cancer and metastatic urothelial carcinoma. 

Key Aspects of Dabogratinib (TYRA-300)

  • Mechanism: It acts as a selective inhibitor of FGFR3 with a high selectivity over other isoforms (FGFR1/2/4), which helps minimize toxicity.
  • Target Indications: It is being developed for FGFR3-mutant cancers, including non-muscle invasive bladder cancer (NMIBC) and metastatic urothelial carcinoma, as well as pediatric achondroplasia.
  • Preclinical Performance: Studies showed that it reduces tumor growth and drives tumor regression, especially in xenograft models with FGFR3-activating mutations (e.g., S249C).
  • Clinical Trials:
    • SURF301 (Phase I/II): Ongoing study, Tyra Biosciences reported early efficacy in patients with advanced metastatic urothelial carcinoma (mUC) harboring FGFR3 mutations/fusions.
    • SURF302 (Phase II): Evaluating the drug in patients with FGFR3-altered, low-grade, intermediate-risk non–muscle invasive bladder cancer (NMIBC).
    • BEACH301 (Phase II): Studying the drug in children with achondroplasia, as it is designed to increase long-bone growth.
  • Properties: It is an orally bioavailable molecule with an IC50 of  for FGFR3. 

Dabogratinib is an orally bioavailable, selective inhibitor of human fibroblast growth factor receptor 3 (FGFR3), with potential antineoplastic activity. Upon oral administration, dabogratinib specifically targets and binds to certain FGFR3 activating gene alterations, and specifically the gatekeeper mutants V555L/M. This blocks FGFR3-mediated signaling and leads to an inhibition of tumor cell proliferation in FGFR3-overexpressing cells. FGFR3, a receptor tyrosine kinase, is involved in angiogenesis and in the proliferation, differentiation, and survival of tumor cells. FGFR3 expression is associated with poor prognosis. It is overexpressed by certain tumor cell types.

  • Efficacy and Safety of TYRA-300 in Participants With FGFR3 Altered Low Grade, Intermediate Risk Non-Muscle Invasive Bladder CancerCTID: NCT06995677Phase: Phase 2Status: RecruitingDate: 2026-04-09
  • A Study of TYRA-300 in Children With Achondroplasia: BEACH301CTID: NCT06842355Phase: Phase 2Status: RecruitingDate: 2026-03-06
  • Safety and Preliminary Anti-Tumor Activity of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors With FGFR3 Gene AlterationsCTID: NCT05544552Phase: Phase 1/Phase 2Status: Active, not recruitingDate: 2026-01-12

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US426725073&_cid=P21-MO801L-81314-1

Example 46. 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole

 (5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole. Triethylamine (20.5 uL, 0.148 mmol, 1.2 equiv) and methylsulfonyl chloride (9.5 uL, 0.123 mmol, 1.0 equiv) were sequentially added at room temperature to a solution of example 45 (59.0 mg, 0.123 mmol, 1 equiv) in anhydrous THE (3 mL). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure on to Celite (1 g). The product was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water. The fractions containing product were collected and lyophilized to give a white solid (45.0 mg, 65% yield). Analysis: LCMS: m/z=559.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.59 (s, 2H), 8.52 (dd, J=0.6, 2.2 Hz, 1H), 7.87 (dd, J=2.4, 8.6 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.09 (dd, J=2.3, 9.0 Hz, 1H), 6.54 (dd, J=0.4, 8.6 Hz, 1H), 6.10 (q, J=6.6 Hz, 1H), 4.17 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, J=6.6 Hz, 3H).

PAT

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References

Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2024-09-11

PMID: 39258897

DOI: 10.1021/acs.jmedchem.4c01531

////////dabogratinib, anax lab, fibroblast growth factor receptor inhibitor, antineoplastic, TYRA-300, TYRA 300, A1AV2, FH245S2JZJ

Claturafenib

April 19, 2026 2:25 am / Leave a comment


Claturafenib

CAS 2754408-94-9

MF C18H15Cl2F2N5O3S MW490.3 g/mol

N-[2-chloro-3-[(5-chloro-3-methyl-4-oxoquinazolin-6-yl)amino]-4-fluorophenyl]-3-fluoroazetidine-1-sulfonamide

N-{2-chloro-3-[(5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-fluorophenyl}-3-fluoroazetidine-1-sulfonamide
B-Raf (BRAF) inhibitor, antineoplastic, PF-07799933, PF 07799933, ARRY440, ARRY 440, PC35M52J8T

Claturafenib (development code PF-07799933) is an investigational cancer drug currently being developed by Pfizer. It is a selective, orally active pan-mutant BRAF inhibitor designed to treat advanced solid tumours with specific genetic alterations

Mechanism of Action

Claturafenib belongs to a class of drugs that target the MAPK/ERK signaling pathway, which is often hijacked by cancer cells to promote uncontrolled growth. 

  • Pan-Mutant Inhibition: Unlike first-generation BRAF inhibitors, claturafenib inhibits multiple classes of BRAF mutations, including Class 1 (V600), Class 2, and Class 3 alterations.
  • Brain-Penetrant: It is designed to cross the blood-brain barrier, allowing it to potentially treat brain metastases or primary brain tumours.
  • Dimer Disruption: It works by disrupting the formation of BRAF-containing dimers, which are responsible for signaling in many resistant or non-V600 mutant cancers.
  • Selectivity: It is highly selective for mutant BRAF, significantly sparing normal (wild-type) cells to reduce off-target side effects. 

🏥 Clinical Status

As of April 2026, claturafenib is in Phase 1 clinical trials. 

  • Target Indications: Advanced solid malignancies, including melanoma, colorectal cancer (CRC), and non-small cell lung cancer (NSCLC).
  • Combination Therapy: It is being studied both as a single agent (monotherapy) and in combination with other drugs like binimetinib (a MEK inhibitor) or cetuximab (an EGFR inhibitor).
  • Ongoing Study: Clinical trial NCT05355701 is currently evaluating its safety, dosage, and efficacy in patients whose disease has progressed on other treatments. 
  • A Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors With BRAF Alterations.CTID: NCT05355701Phase: Phase 1Status: RecruitingDate: 2026-03-27
  • A Study to Learn About the Study Medicine Called PF-07799544 as Monotherapy or in Combination in People With Advanced Solid TumorsCTID: NCT05538130Phase: Phase 1Status: RecruitingDate: 2026-03-27

 Claturafenib is an orally bioavailable class 1 and 2 inhibitor of the serine/threonine-protein kinase B-raf (BRAF) protein, with potential antineoplastic activity. Upon oral administration, claturafenib selectively binds to and inhibits the activity of class 1 and 2 BRAF alterations. This inhibits the proliferation of tumor cells which express these BRAF alterations. BRAF, a member of the raf family of serine/threonine protein kinases, plays a role in the regulation of mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling pathways, which may be constitutively activated due to BRAF gene mutations. Mutated forms and fusions of BRAF are associated with a number of neoplastic diseases.

Property Value
Molecular Formula
Molecular Weight490.31 g/mol
CAS Number2754408-94-9
Other NamesARRY-440, PF07799933

📍 Note: Claturafenib is an investigational compound and has not yet been approved by the FDA or other regulatory agencies for general use

SYN

US12303509,

Example 126

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US374019464&_cid=P12-MO553W-18219-1

Example 126

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide

      A solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (90 mg, 0.42 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-fluoroazetidin-1-yl)sulfonyl)carbamate (218 mg, 0.429 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.042 mmol), Xantphos (62 mg, 0.10 mmol), and cesium carbonate (279 mg, 0.858 mmol) in toluene (2860 μL) was sparged with argon and heated to 110° C. overnight in a sealed vial. The solution was filtered through Celite®, concentrated, and the residue was stirred in 1 mL of DCM and 1 mL of TFA for 1 hour. The solution was concentrated and purified by reverse-phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product was partitioned between DCM and saturated NaHCO 3. The organic layer was washed with brine, dried over Na 2SO 4, filtered, and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide (78 mg, 37% yield). 1H NMR (400 MHz, CDCl 3) δ 7.94 (s, 1H), 7.56-7.52 (m, 1H), 7.51 (d, 1H), 7.19-7.14 (t, 1H), 6.99-6.95 (m, 1H), 6.72 (s, br, 1H), 6.47 (s, br, 1H), 5.35-5.15 (m, 1H), 4.25-4.10 (m, 4H), 3.57 (s, 3H); MS (apci, m/z)=490.1, 492.1 (M+H).

PAT

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References

////////claturafenib, ANAX, B-Raf (BRAF) inhibitor, antineoplastic, PF-07799933, PF 07799933, ARRY440, ARRY 440, PC35M52J8T

Cirtociclib

April 18, 2026 2:32 am / Leave a comment


Cirtociclib

CAS 2888704-84-3

MF C15H17F2N7O2 MW365.34 g/mol

N-[3-(difluoromethoxy)-1H-pyrazol-5-yl]-1-(oxan-4-ylmethyl)pyrazolo[3,4-b]pyrazin-6-amine

N-[5-(difluoromethoxy)-1H-pyrazol-3-yl]-1-[(oxan-4-yl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-amine
cyclin-dependent kinase inhibitor, antineoplastic, BLU-222, BLU 222, BLU 170298, U93X72ED47, CDK2 Inhibitor BLU-222

Cirtociclib (also known as BLU-222) is an investigational drug that acts as a highly selective inhibitor of cyclin-dependent kinase 2 (CDK2). It is being developed by Blueprint Therapeutics for the treatment of advanced solid tumours, particularly those with genetic drivers like CCNE1 amplification, which are common in certain ovarian and breast cancers

Certociclib is a small molecule drug. Certociclib is under investigation in clinical trial NCT05252416 ((VELA) Study of BLU-222 in Advanced Solid Tumors). Certociclib has a monoisotopic molecular weight of 365.14 Da.

Certociclib is an orally bioavailable inhibitor of cyclin-dependent kinase 2 (CDK2), with potential antineoplastic activity. Upon administration, certociclib selectively targets, binds to and inhibits the activity of CDK2. This may lead to cell cycle arrest, the induction of apoptosis, and the inhibition of tumor cell proliferation. CDK2, a serine/threonine kinase that plays an important role in the regulation of cell cycle progression and cellular proliferation, is overexpressed in certain tumor cells.

How It Works

  • Targeting CDK2: It binds to CDK2, a protein that regulates the cell cycle.
  • Cell Cycle Arrest: By inhibiting CDK2, the drug causes G1 arrest, preventing cancer cells from replicating.
  • Selectivity: It is designed to be “best-in-class” for its high selectivity for CDK2 over other kinases like CDK1, CDK4, or CDK6. 

Therapeutic Potential

  • Ovarian Cancer: Specifically targets high-grade serous ovarian cancer where CCNE1 is amplified.
  • Breast Cancer: Shows promise in treating hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer, especially when the cancer has become resistant to existing CDK4/6 inhibitors.
  • Combination Therapy: Researchers are testing it alongside other drugs, such as palbociclib, ribociclib, or chemotherapy agents like carboplatin, to enhance efficacy. 

Current Status

  • Clinical Trials: It is currently being evaluated in a Phase 1/2 clinical trial known as the VELA study (NCT05252416) for patients with advanced solid tumours.
  • Research Status: It is not yet approved for general medical use and is primarily available for research and clinical trial participants. 

(VELA) Study of BLU-222 in Advanced Solid Tumors

CTID: NCT05252416

Phase: Phase 1

Status: Terminated

Date: 2025-11-28

🌟 Key Point: Cirtociclib represents a new generation of precision medicine aimed at overcoming resistance to standard cancer therapies by specifically targeting the CDK2 pathway

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2026050766&_cid=P22-MO3PRU-93555-1

The structure of one CDK2 inhibitor, referred to herein as “a compound of formula (I)” or N-(5-(difluoromethoxy)-lH-pyrazol-3-yl)-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH-pyrazolo[3,4-b]pyrazin-6-amine is shown below:

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US398479580&_cid=P22-MO3PW2-97204-1

Example 2

N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

  A mixture of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 87, 780 mg, 3.09 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (554 mg, 3.72 mmol), tBuXphos Pd G3 (150 mg, 0.19 mmol) and KOAc (892 mg, 9.08 mmol) in dioxane (15 mL) was stirred at 90° C. for 6 h under N 2. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by prep-HPLC-4 to afford the title compound as a white solid (361.4 mg, 32%). LCMS m/z=366 [M+H] +; 1H NMR (400 MHz, DMSO-d 6) δ: 12.21 (s, 1H), 10.82 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.98 (d, 1H), 4.40 (d, 2H), 3.87-3.75 (m, 2H), 3.29-3.16 (m, 2H), 2.24-2.11 (m, 1H), 1.46-1.29 (m, 4H).

PAT

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References

/////////cirtociclib, cyclin-dependent kinase inhibitor, antineoplastic, BLU-222, BLU 222, BLU 170298, U93X72ED47, CDK2 Inhibitor BLU-222

Catadegbrutinib

April 15, 2026 2:36 am / Leave a comment


Catadegbrutinib

CAS 2736508-60-2

MF C47H54N12O4 MW851.0 g/mol

1,2,4-Oxadiazole-5-carboxamide, 3-(1,1-dimethylethyl)-N-[(1R)-1-[2-methyl-4-[6-[6-[4-[[1-[4-(tetrahydro-2,4-dioxo-1(2H)-pyrimidinyl)phenyl]-4-piperidinyl]methyl]-1-piperazinyl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]ethyl]-

3-tert-butyl-N-[(1R)-1-[4-[6-[6-[4-[[1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

3-tert-butyl-N-{(1R)-1-[13-methyl-82,84-dioxo-27H-2(4,6)-pyrrolo[2,3-d]pyrimidina-8(1)-[1,3]diazinana-4(1,4)-piperazina3(5,2)-pyridina-6(4,1)-piperidina-1(1),7(1,4)-dibenzenaoctaphan-14-yl]ethyl}-1,2,4-oxadiazole-5-carboxamide
Bruton tyrosine kinase degrader, antineoplastic, BGB-16673, BGB 16673, PF6GPZ4DYT, BTK-IN-29, Tacabrutideg

Catadegbrutinib (BGB-16673) is an orally active, potent Bruton’s tyrosine kinase (BTK) degrader, or chimeric degradation activator compound (CDAC). It works by targeting BTK for proteasomal degradation, showing high efficacy against wild-type and mutated forms (including C481S) in B-cell malignancies. It is under investigation for cancers such as CLL, SLL, and MCL. 

Key Details About Catadegbrutinib

  • Mechanism of Action: As a PROTAC-class molecule, it binds to BTK and recruits E3 ubiquitin ligase, causing polyubiquitination and degradation of the protein.
  • Target Potency: It shows strong degradation activity, with a  of  (concentration required for 50% degradation) and a  binding  of .
  • Clinical Potential: Developed for B-cell malignancies (chronic lymphocytic leukemia, mantle cell lymphoma) that have developed resistance to covalent and non-covalent BTK inhibitors.
  • Synonyms/Codes: BGB-16673, BGB-116673, BTK-IN-29, and recently listed in WHO proposed INN as tacabrutideg.
  • Status: Used primarily in research for treating B-cell malignancies, lymphomas, and potentially autoimmune diseases. 

Catadegbrutinib is designed to overcome resistance mechanism challenges seen with existing BTK inhibitors. 

SYN

[WO2021219070A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021219070&_cid=P22-MNZFN1-79965-1

Example 14: (R) -3- (tert-butyl) -N- (1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2-methylphenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide

[0357]

Step 1: tert-butyl 4- (5- (4-chloro-7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1- carboxylate

A mixture of 4-chloro-6-iodo-7H-pyrrolo [2, 3-d] pyrimidine (3 g, 10.73 mmol) , tert-butyl 4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (4.18 g, 10.73 mmol) , Na 2CO 3(1.25 g, 11.80 mmol) and Pd (dppf) Cl 2(0.39 g, 0.537 mmol) in dioxane (120 mL) and H 2O (20 mL) was stirred in a sealed tube at 85 ℃ overnight. After cooling, the reaction mixture was filtered and the solid was washed with 20 mL of MeOH and dried under vacuum to afford the product (4.05 g, 91%) . [M+H] += 415.0.

[0360]

Step 2: tert-butyl (R) -4- (5- (4- (4- (1- (3- (tert-butyl) -1, 2, 4-oxadiazole-5-carboxamido) ethyl) -3- methylphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate

A mixture of tert-butyl 4- (5- (4-chloro-7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate (0.9 g, 2.17 mmol) , (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide (0.94 g, 2.28 mmol) , Na 2CO 3(0.46 g, 4.34 mmol) and Pd (dppf) Cl 2(79.3 mg, 0.108mmol) in dioxane (60 mL) and H 2O (10 mL) was stirred in a sealed tube at 100 ℃ overnight. After cooling, the reaction mixture was filtered and the solid was washed with 5 mL of MeOH and dried under vacuum to afford the product (1.02 g, 70.6%) . [M+H] += 666.0.

[0363]

Step 3: (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (6- (6- (piperazin-1-yl) pyridin-3-yl) -7H- pyrrolo [2, 3-d] pyrimidin-4-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide, hydrogen chloride salt

To a solution of tert-butyl (R) -4- (5- (4- (4- (1- (3- (tert-butyl) -1, 2, 4-oxadiazole-5-carboxamido) ethyl) -3-methylphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate (1.02 g, 1.53 mmol) in DCM (50 mL) in a round bottom flask was added HCl in dioxane (4 N, 35 mL) at 0 ℃. The mixture was stirred for 2 h at 20 ℃. The precipitate was collected with filtration and dried in vacuum to afford the product (0.92 g, 100%) . 1H NMR (400 MHz, DMSO) δ H13.53 (s, 1H) , 10.06 (d, J = 7.5 Hz, 1H) , 9.33 (s, 2H) , 9.00 (s, 1H) , 8.93 (s, 1H) , 8.35 (d, J = 8.7 Hz, 1H) , 8.05 (d, J = 8.1 Hz, 1H) , 7.99 (s, 1H) , 7.75 (d, J = 8.0 Hz, 1H) , 7.55 (s, 1H) , 7.12 (d, J = 8.9 Hz, 1H) , 5.50-5.28 (m, 1H) , 3.89 (s, 4H) , 3.20 (s, 4H) , 2.57 (s, 3H) , 1.56 (d, J = 6.9 Hz, 3H) , 1.38 (s, 9H) . [M+H] += 566.3.

[0366]

Step 4: (R) -3- (tert-butyl) -N- (1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) – yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2- methylphenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide

A mixture of (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (6- (6- (piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide, hydrogen chloride salt (0.06 g, 0.1 mmol) , 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (0.033 g, 0.11 mmol) and NaOAc (8.2 mg, 0.1 mmol) in DCM/EtOH (30 mL/10 mL) was stirred in a round bottom flask for 1 h at 20 ℃. Then NaBH 3CN (12.6 mg, 0.2 mmol) was added. The mixture was stirred overnight at 20 ℃. The mixture was concentrated to dryness and purified with silica gel column chromatography (MeOH in DCM from 0%to 12%gradient elution) to give the product (0.049 g, 57.8%) . 1H NMR (400 MHz, DMSO) δ H12.60 (s, 1H) , 10.27 (s, 1H) , 9.97 (d, J =6.1 Hz, 1H) , 8.79 (d, J = 18.7 Hz, 2H) , 8.18 (d, J = 7.8 Hz, 1H) , 8.09 (d, J = 7.0 Hz, 1H) , 8.04 (s, 1H) , 7.67 (d, J = 7.7 Hz, 1H) , 7.30 (s, 1H) , 7.13 (d, J = 6.9 Hz, 2H) , 6.97-6.92 (m, 3H) , 5.41-5.34 (m, 1H) , 3.71-3.68 (m, 4H) , 3.64-3.56 (m, 4H) , 2.70-2.64 (m, 4H) , 2.53 (s, 3H) , 2.47-2.43 (m, 4H) , 2.25-2.19 (m, 2H) , 1.84-1.81 (m, 2H) , 1.75-1.70 (m, 1H) , 1.56 (t, J = 9.1 Hz, 3H) , 1.37 (s, 9H) , 1.28-1.18 (m, 2H) .

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=EA391074258&_cid=P22-MNZFF3-74514-1

PAT

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References

/////////catadegbrutinib, Bruton tyrosine kinase degrader, antineoplastic, BGB-16673, BGB 16673, PF6GPZ4DYT, BTK-IN-29, Tacabrutideg

Birelentinib

April 12, 2026 2:34 am / Leave a comment


Birelentinib

CAS 2662512-15-2

MF C23H21F2N5O3 MW453.4 g/mol

[(2S,5S)-5-[4-amino-5-[4-(2,3-difluorophenoxy)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl]oxan-2-yl]methanol

[(2S,5S)-5-{4-amino-5-[4-(2,3-difluorophenoxy)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl}oxan-2-yl]methanol
tyrosine kinase inhibitor, antineoplastic, DZD8586, DZD 8586, Fast Track designation, BTK-IN-30, Z2F599L9GD

Birelentinib (also known as DZD8586) is a first-in-class, non-covalent dual inhibitor of LYN (lymphocyte-specific protein tyrosine kinase) and BTK (Bruton’s tyrosine kinase).

It is currently being developed by Dizal Pharmaceutical as an oral therapy for various B-cell malignancies. 

Clinical Status and FDA Designations

As of late 2025, birelentinib has received significant attention for its potential in treating resistant blood cancers: 

  • Fast Track Designation: In August 2025, the U.S. FDA granted Fast Track designation to birelentinib for adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
  • Target Population: It is specifically intended for those who have failed at least two prior therapies, including a covalent BTK inhibitor and a BCL-2 inhibitor.
  • Key Trials: It is being evaluated in multiple studies, including the Phase 3 Tai-Shan6 trial comparing it against standard treatments like bendamustine and rituximab. 

Unique Therapeutic Properties

Birelentinib is designed to overcome common drug resistance mechanisms found in existing treatments: 

  • Overcoming Resistance: It targets both BTK-dependent pathways (including the common C481X mutation) and BTK-independent B-cell receptor (BCR) signaling pathways.
  • Blood-Brain Barrier (BBB) Penetration: A notable feature is its ability to fully penetrate the blood-brain barrier, which may offer therapeutic benefits for patients with central nervous system (CNS) involvement.
  • Efficacy: Early Phase 1/2 data presented at the ASH Annual Meeting and EHA Congress in 2025 showed an Objective Response Rate (ORR) of 84.2% in heavily pretreated patients

Birelentinib is an orally bioavailable non-covalent dual inhibitor of tyrosine-protein kinases Lyn (LYN) and BTK (Bruton’s tyrosine kinase; Bruton agammaglobulinemia tyrosine kinase), with potential antineoplastic activity. Upon oral administration, birelentinib targets and inhibits both LYN and BTK, thereby blocking both BTK-dependent and BTK-independent B-cell antigen receptor (BCR) signaling pathways. This prevents the proliferation of malignant B-cells in which the BCR signaling pathway is overactivated. Birelentinib is able to cross the blood-brain barrier (BBB) and thus potentially useful in the treatment of central nervous system (CNS) metastases

SYN’

WO2021136219A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021136219&_cid=P11-MNV5BN-89185-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US395654826&_cid=P11-MNV57X-87450-1

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References

Btk inhibitors

Publication Number: WO-2021136219-A1

Priority Date: 2020-01-02

/////////birelentinib, tyrosine kinase inhibitor, antineoplastic, DZD8586, DZD 8586, Fast Track designation, BTK-IN-30, Z2F599L9GD

Balomenib

April 6, 2026 2:32 am / Leave a comment


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

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,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US456551731&_cid=P10-MNMKG0-25753-1

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

https://patentscope.wipo.int/search/en/detail.jsf?docId=US471589031&_cid=P10-MNMKG0-25753-1

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)

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References

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

Atebimetinib

April 5, 2026 2:28 am / Leave a comment


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

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References

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

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