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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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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Recent Posts

Pilavapadin

November 18, 2025 10:11 am / Leave a comment


Pilavapadin

CAS1815613-42-3

MFC19H23F4N3O MW 385.4 g/mol

(2S)-1-{[2′,6-bis(difluoromethyl)[2,4′-bipyridin]-5-yl]oxy}-2,4-dimethylpentan-2-amine

(2S)-1-[[2-(difluoromethyl)-6-[2-(difluoromethyl)-4-pyridinyl]-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine
adaptor protein 2-associated kinase 1 (AAK1) inhibitor, LX9211, BMS-986176, LX 9211,  BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z

Pilavapadin (also known as LX9211 or BMS-986176) is an investigational, orally available small molecule developed by Lexicon Pharmaceuticals for the treatment of neuropathic pain, primarily diabetic peripheral neuropathic pain (DPNP). 

Key Information

  • Mechanism of Action: Pilavapadin is a selective inhibitor of AAK1 (AP2 associated kinase 1), a novel target identified through Lexicon’s gene science research. It is designed to inhibit the reuptake and recycling of neurotransmitters involved in pain signaling in the central nervous system without affecting opiate pathways.
  • Indication: It is being investigated for the management of chronic and debilitating conditions such as diabetic peripheral neuropathic pain (DPNP), chemotherapy-induced peripheral neuropathy (CIPN), and multiple sclerosis (MS) pain.
  • Development Stage: Pilavapadin has completed Phase 2 clinical trials for DPNP and is expected to advance to a Phase 3 trial.
  • Status/Designation: The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of pilavapadin in DPNP. 

Clinical Trial Results

Phase 2 studies (RELIEF-DPN-1 and PROGRESS) demonstrated that pilavapadin can provide meaningful pain reduction in adults with DPNP. 

  • In a post-hoc analysis of the PROGRESS study, the 10 mg dose was found to be effective, achieving a clinically meaningful, two-point reduction in average daily pain scores from baseline, with an acceptable safety and tolerability profile.
  • The data has been presented at several medical meetings, including the European Association for the Study of Diabetes (EASD). 
  • OriginatorBristol-Myers Squibb; Lexicon Pharmaceuticals
  • DeveloperLexicon Pharmaceuticals
  • ClassAnalgesics; Small molecules
  • Mechanism of ActionAdaptor-associated kinase 1 inhibitors
  • Phase IINeuropathic pain; Postherpetic neuralgia
  • 20 Jun 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain presented at 85th Annual Scientific Sessions of the American Diabetes Association (ADA-2025)
  • 13 May 2025Lexicon Pharmaceuticals plans an End of Phase 2 meeting with FDA for Pilavapadin
  • 13 May 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain released by Lexicon Pharmaceuticals
  • A Dose-ranging Study in Patients With Diabetic Peripheral Neuropathic Pain (DPNP)CTID: NCT06203002Phase: Phase 2Status: CompletedDate: 2025-08-29
  • Efficacy, Safety, and PK of LX9211 in Participants With Diabetic Peripheral Neuropathic PainCTID: NCT04455633Phase: Phase 2Status: CompletedDate: 2025-06-25
  • Efficacy and Safety of LX9211 in Participants With Postherpetic NeuralgiaCTID: NCT04662281Phase: Phase 2Status: CompletedDate: 2023-11-18

Molecular FormulaC19H23F4N3O.H3O4P

Molecular Weight483.4

CAS 2977251-24-2

SYN

US10155760,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US215884039&_cid=P11-MI4ESM-19570-1

Example 123

(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (2-(difluoromethyl)pyridin-4-yl)boronic acid

      To a 20 mL vial was added 4-chloro-2-(difluoromethyl)pyridine hydrochloride (180 mg, 0.900 mmol), hypodiboric acid (121 mg, 1.350 mmol), 2-(dicyclohexylphosphino))-2′,4′,6′-triisopropylbiphenyl (8.58 mg, 0.018 mmol), Xphos precatalyst (7.08 mg, 9.00 μmol) and potassium acetate (265 mg, 2.70 mmol) in ethanol (8.5 mL) to give a tan suspension (degassed before adding agents). The bottle was capped and heated at 80° C. for 1.5 h. LCMS showed the consumption of the starting material and formation of a new spot: (2-(difluoromethyl)pyridin-4-yl)boronic acid. The mixture was divided into parts and directly used in the next step of different reactions.

Part B: (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

      To a 5 mL vial was added (2-(difluoromethyl)pyridin-4-yl)boronic acid (25.9 mg, 0.15 mmol) was added potassium phosphate tribasic (1 mL, 0.500 mmol). After degassing for 5 min, Xphos precatalyst (4 mg, 5.08 μmol) and (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (26.5 mg, 0.079 mmol) and tetrahydrofuran (1 mL) were added. The vial was sealed and heated at 80° C. overnight for 18 h. Volatiles were blown off. The residue was partitioned between EtOAc and water. The organic layer was dried, filtered and concentrated. The residue was dissolved in MeOH and purified by prep-HPLC to afford (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (29.8 mg, 98%) as a colorless solid. 1H NMR (500 MHz, DMSO-d 6) δ 8.79 (d, J=5.2 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=5.1 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.31 (t, J=53.5 Hz, 1H), 7.04 (t, J=54.9 Hz, 1H), 3.96 (s, 2H), 3.46 (s, 2H), 1.80 (dp, J=12.5, 6.7, 6.3 Hz, 1H), 1.45 (qd, J=14.1, 5.6 Hz, 2H), 1.17 (s, 3H), 0.92 (dd, J=13.6, 6.6 Hz, 6H); 19F NMR (376 MHz, DMSO-d 6) δ −115.43 (d, J=55.2 Hz), −117.78-−119.55 (m); LCMS (ESI) m/e 386.0 [(M+H) +, calcd C 19H 24F 4N 3O, 386.2]; LC/MS retention time (method B): t R=1.85 min.

SYN

WO-2021216454-A1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021216441&_cid=P11-MI4EP8-16561-2

REF

PAT

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////////////Pilavapadin, LX9211, BMS-986176, LX 9211,  BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z

Paluratide

November 18, 2025 2:53 am / Leave a comment


Paluratide

CAS 2676177-63-0

MFC73H105F5N12O12 MW 1437.7 g/mol

1,11-anhydro[N-methyl-L-alanyl-(2S)-azetidine-2-carbonyl-N-ethyl-4-methyl-L-phenylalanyl-N-methylglycyl-3-{[3,5-difluoro-4-(trifluoromethyl)phenyl]methyl}-L-alanyl-L-prolyl-2-
aminocyclopentane-1-carbonyl-(2S)-N-methyl-3-cyclopentylglycyl-1-
(dimethylamino)-N-methyl-L-aspart-4-yl-N-methyl-L-leucyl-Lisoleucine]

(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-N,N,7,17,18,24,28,31-octamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,29,32,35-undecaoxospiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclopentane]-27-carboxamide
G-protein Ras (rat sarcoma virus) inhibitor, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X

Paluratide (development code LUNA18) was an investigational cyclic peptide KRAS inhibitor developed by Chugai Pharmaceutical, a member of the Roche Group, for the treatment of cancers with KRAS mutations.[1] The compound was notable as an orally bioavailable macrocyclic peptide that could target intracellular protein-protein interactions, a class of targets traditionally considered “undruggable.”[2]

Development was discontinued in July 2025 due to a narrow therapeutic window compared to competing KRAS inhibitors.[3]

Ras Inhibitor LUNA18 is an orally bioavailable cyclic peptide and Ras inhibitor, with potential antineoplastic activity. Upon oral administration, Ras inhibitor LUNA18 selectively targets, binds to and inhibits Ras, thereby inhibiting Ras-dependent signaling and inhibits proliferation of tumor cells in which Ras is overexpressed and/or mutated. Ras serves an important role in cell signaling, division and differentiation. Mutations of Ras may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

Paluratide (LUNA18 is synthesized using a novel liquid-phase peptide synthesis (LPPS) method, not traditional solid-phase methods, to overcome challenges with N-alkylated cyclic peptides. This process involves a convergent route of 24 telescoped chemical transformations, a final crystallization step, and a focus on specific strategies to manage side reactions like diketopiperazine formation and low reactivity of sterically hindered amino acids. 

Key aspects of the synthesis 

  • Liquid-phase synthesis: A novel, high-yielding LPPS process was developed to enable the large-scale production of paluratide. This is a departure from traditional solid-phase methods, which have limitations with solubility and waste.
  • Convergent synthetic route: The synthesis uses a convergent approach, meaning smaller fragments of the peptide are synthesized separately and then joined together. The overall process includes 24 telescoped chemical transformations followed by a final crystallization step.
  • Addressing synthesis challenges: Specific strategies were employed to overcome key difficulties:
    • Low reactivity: Amino acids with N-alkylation are sterically hindered, so more reactive and stable protecting groups were used to ensure efficient coupling.
    • Side reactions: The method was designed to prevent side reactions like diketopiperazine formation in intermediates and incomplete hydrolysis of active esters.
    • Instability: The peptide backbone is sensitive to acidic conditions, so a mildly acidic aqueous medium was chosen for workup and purification to maintain stability.
  • Protecting group selection: Cbz-protected amino acid active esters were preferred over Boc-protected ones because they are less prone to forming N-carboxyanhydrides (NCA) under activating conditions, which can reduce yield and purity.
  • Purification: A final crystallization step is used for purification. 

PAT

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.5c00260?ref=PDF

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US383248369&_cid=P20-MI3YXS-80609-1

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Mechanism of action

Paluratide functions as a pan-RAS inhibitor, targeting multiple RAS isoforms including KRAS, NRAS, and HRAS.[1] The compound binds with high affinity to KRASG12D, with a dissociation constant (Kd) of 0.043 nM, and blocks the interaction between KRASG12D and the guanine nucleotide exchange factor SOS1 with an IC50 of less than 2.2 nM.[4]

Unlike covalent KRAS inhibitors that target specific mutations (such as sotorasib for KRASG12C), paluratide was designed to inhibit RAS proteins through disruption of protein-protein interactions with guanine nucleotide exchange factors (GEFs).[1] This mechanism allows the drug to affect RAS signalling regardless of the specific mutation, theoretically providing broader applicability across different KRAS-mutant cancers. The compound also demonstrates activity against downstream signalling pathways, affecting ERK and AKT phosphorylation.[4]

Medical uses

Paluratide was being developed for the treatment of locally advanced or metastatic solid tumors harbouring RAS gene alterations.[5] The drug demonstrated significant cellular activity against multiple cancer types with KRAS mutations in preclinical studies, including colorectal cancer, gastric cancer, non-small cell lung cancer, and pancreatic cancer.[1]

Chemistry

Paluratide is an 11-member (11-mer) cyclic peptide with a molecular weight in the range of 1000–2000 g/mol, classified as a “middle-size” cyclic peptide.[1] The compound features extensive N-alkylation, a modification that reduces hydrogen bond donors and improves oral absorption while maintaining cellular permeability.[2] Its structure allows it to navigate the challenging boundary between small molecules and biologics, achieving properties of both classes. The compound demonstrated oral bioavailability ranging from 21% to 47% in preclinical animal studies without requiring special formulations.[1]

Discovery

Paluratide was discovered through Chugai Pharmaceutical’s cyclic peptide platform using an mRNA display library screening approach.[1] The initial hit compound, designated AP8747, was identified from the mRNA display library and subsequently underwent extensive chemical optimization without scaffold hopping (maintaining the basic cyclic peptide structure).[1] The optimization focused on increasing plasma stability, improving absorption, reducing clearance, and reducing hydrogen bond donors to achieve oral bioavailability.

The final clinical compound, LUNA18, emerged after modifications to four amino acid positions (positions 5, 7, 10, and 11) from an intermediate compound (compound 40). Key structure-activity relationship findings included: the side chain at position 5 preferring aromatic over aliphatic groups; physicochemical properties being adjustable at position 11; and biological activity enhancement through modifications at positions 7 and 10.[1]

Chugai also developed a novel synthetic methodology that enabled the broadly applicable synthesis of highly N-alkylated cyclic peptide-like drugs.[6] This method overcame three major technical challenges: formation of diketopiperazine, insufficient reactivity of amidation due to steric hindrance, and instability of cyclic peptides under acidic conditions. Using this approach, more than 4,000 cyclic peptides were synthesized with a process yield of 31% and final product purity of 97%.[6]

Clinical trials

A Phase 1 dose-escalation and cohort expansion study (NCT05012618) was initiated in August 2021 to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of paluratide administered as a single agent or in combination with other anti-cancer drugs.[5] The study, in the United States and Japan, was designed to enrol approximately 195 patients with locally advanced or metastatic solid tumors positive for documented RAS alterations.[5]

Paluratide was administered orally as capsules.[5] The study also evaluated combination therapy with cetuximab, an EGFR inhibitor.[5]

References

  1.  Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, et al. (August 2023). “Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor”. Journal of the American Chemical Society. 145 (30): 16610–16620. Bibcode:2023JAChS.14516610T. doi:10.1021/jacs.3c03886. PMID 37463267.
  2.  Ohta A, Tanada M, Shinohara S, Morita Y, Nakano K, Yamagishi Y, et al. (November 2023). “Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets”. Journal of the American Chemical Society. 145 (44): 24035–24051. Bibcode:2023JAChS.14524035O. doi:10.1021/jacs.3c07145. PMID 37874670.
  3.  Taylor NP (24 October 2025). “Roche axes 4 Chugai solid tumor assets in early-phase clear-out”. Fierce Biotech.
  4.  “LUNA18 (Paluratide) – KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor”. MedChemExpress.
  5.  “A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion)”. ClinicalTrials.gov. 29 July 2025. NCT05012618.
  6.  Nomura K, Hashimoto S, Takeyama R, Tamiya M, Kato T, Muraoka T, et al. (October 2022). “Broadly Applicable and Comprehensive Synthetic Method for N-Alkyl-Rich Drug-like Cyclic Peptides”. Journal of Medicinal Chemistry. 65 (19): 13401–13412. doi:10.1021/acs.jmedchem.2c01296. PMID 36109865.
  7.  “Chugai Announces 2025 2nd Quarter Results” (Press release). Chugai Pharmaceutical. 24 July 2025.
Clinical data
Other namesLUNA18
Routes of
administration		Oral administration
Legal status
Legal statusDevelopment discontinued
Identifiers
IUPAC name
CAS Number2676177-63-0
PubChem CID166509683
ChemSpider129321315
UNIIAW3YP3CD9X
Chemical and physical data
FormulaC73H105F5N12O12
Molar mass1437.707 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

//////Paluratide, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X

Padoprazan

November 16, 2025 2:45 am / Leave a comment


Padoprazan

CAS 2756367-23-2

MF C19H20FN3O4S MW 405.4 g/mol

1-[5-(2-fluorophenyl)-4-methoxy-1-(6-methoxypyridine-3-sulfonyl)-1Hpyrrol-3-yl]-N-methyl methanamine

1-[5-(2-fluorophenyl)-4-methoxy-1-[(6-methoxy-3-pyridinyl)sulfonyl]pyrrol-3-yl]-N-methylmethanamine

1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1    H -pyrrol-3-yl)- N -methylmethanamine    
proton pump inhibitor, 95BJ28E2RP, ID-120040002, ID 120040002

Padoprazan is a new-generation potassium-competitive acid blocker (P-CAB) used to treat acid-related disorders like gastroesophageal reflux, according to MedchemExpress.com and Patsnap Synapse. It works by inhibiting the proton pump in the stomach and is different from traditional proton pump inhibitors (PPIs) because it is not dependent on acid activation. Padoprazan is currently undergoing Phase 3 clinical trials in Korea, notes THE BIO (더바이오). 

Key facts about padoprazan

  • Drug class: Potassium-competitive acid blocker (P-CAB), a type of proton pump inhibitor, according to DrugBank and GlpBio.
  • Mechanism: It inhibits the proton pump in the stomach to reduce acid production and is not acid-activated like older PPIs, per DrugBank.
  • Indications: Used for acid-related conditions like gastroesophageal reflux, reports Patsnap Synapse.
  • Status: Currently undergoing Phase 3 clinical trials in Korea, says THE BIO (더바이오).
  • Development: It is a new-generation drug being developed by companies like Daewon Pharmaceutical. 


Padoprazan is a small molecule drug. The usage of the INN stem ‘-prazan’ in the name indicates that Padoprazan is a proton pump inhibitor, not dependent on acid activation. Padoprazan has a monoisotopic molecular weight of 405.12 Da.

PAT

SYN

WO-2021256861

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021256861&_cid=P22-MI13VU-05837-1

Synthesis Example 1. Synthesis of Example 1

[267]

 [Example 1] 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrol-3-yl)- N -methylmethanamine

[268]

 (1) Synthesis of step methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrole-3-carboxylate

[269]Methyl 5-(2-fluorophenyl)-4-methoxy-1  

H  -pyrrole-3-carboxylate (intermediate 1, 1.0 eq., 1.2 g, 4.8 mmol) was dissolved in THF (20.0 mL), and NaH (2.0 eq., 384.8 mg, 9.6 mmol) was added dropwise at 0 °C and stirred at room temperature for 10 min. 6-Methoxypyridine-3-sulfonyl chloride (1.5 eq., 1.6 g, 7.2 mmol) was added and stirred at room temperature for 1 h. Water was added to the reaction solution, and the mixture was extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carboxylate as a light brown solid. (1.85 g, 91.6%) 

[270]

 (2) Synthesis of step 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrol-3-yl)methanol

[271]Methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carboxylate (1.0 eq., 1.0 g, 2.38 mmol) was dissolved in THF (5.0 mL), and  1.0 M DIBAL in 

n  -hexane solution (5.0 eq., 11.9 mL, 11.9 mmol) was added dropwise at 0 °C, followed by stirring at room temperature for 1 h. The reaction solution was cooled to 0 °C, quenched with an aqueous Rochelle salt solution, and extracted with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrol-3-yl)methanol as a yellow oil. (654.8 mg, 70.2%) 

[272]

 (3) Synthesis of step 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrole-3-carbaldehyde

[273]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrol-3-yl)methanol (1.0 eq., 500.0 mg, 1.3 mmol) and Dess-Martin periodinane (1.0 eq., 540.4 mg, 1.3 mmol) were dissolved in DCM (10.0 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by column chromatography to give 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carbaldehyde as a pale brown solid. (388.2 mg, 78.1%) 

[274]

 (4) Step 1 Synthesis of (5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrol-3-yl)- N -methylmethanamine

[275]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carbaldehyde (1.0 eq., 385.0 mg, 0.99 mmol) was dissolved in THF (5.0 mL), and 2.0 M methylamine in THF (10 eq., 4.9 mL, 9.9 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was cooled to 0 °C, and NaBH 

4 (10 eq., 373.4 mg, 9.9 mmol) was added, followed by stirring at room temperature for 1 h. 6.0  

N  aqueous hydrogen chloride solution was slowly added dropwise to the reaction solution, and the resulting solid was filtered. The filtered solid was dissolved in water, 1  

N  aqueous sodium hydroxide solution was added, and extraction was performed with EA. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H  -pyrrol-3-yl)-  

N  -methylmethanamine as a white solid. (125.8 mg, 28.3%) [M+H] + : 405

SYN

WO-2023113474-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023113474&_cid=P22-MI1405-08231-1

7) Preparation of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine free base[211]

 (1) Step: Synthesis of methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrole-3-carboxylate[212]Methyl 5-(2-fluorophenyl)-4-methoxy-1  

H  -pyrrole-3-carboxylate (intermediate 1, 1.0 eq., 920 g, 3.69 mol) was dissolved in DMF (9.2 L), and t-BuOK (2.0 eq., 828 g, 7.38 mmol) was added dropwise at 0 °C and stirred for 30 min. 6-Methoxypyridine-3-sulfonyl chloride (1.5 eq., 1.15 kg, 5.54 mol) was added and stirred at 0 °C for 1 h. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carboxylate as a white solid. (1.20 kg, 77.4%) [213]

 (2) Step: Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrol-3-yl)methanol[214]Methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carboxylate (1.0 eq., 1.1 kg, 2.62 mol) was dissolved in THF (11.0 L), and DIBAL 2.0 M in THF solution (3.0 eq., 3.93 L, 7.86 mol) was added dropwise at 0 °C, followed by stirring for 30 min. The reaction solution was quenched with 5% aqueous Rochelle’s salt solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrol-3-yl)methanol as a light yellow oil. (870 g, 84.8%) [215]

 (3) Step: Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrole-3-carbaldehyde[216]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrol-3-yl)methanol (1.0 eq., 830 g, 2.12 mol) and TEA (4.0 eq., 1.59 kg, 15.7 mol) were dissolved in DMSO (4.15 L), and SO 

3 -pyridine (4.0 eq., 1.35 kg, 8.48 mol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. Water was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carbaldehyde as a yellow solid. (722 g, 87.6%) [217]

 (4) Step: Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H -pyrrol-3-yl)- N -methylmethanamine[218]5-(2-Fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  

H  -pyrrole-3-carbaldehyde (1.0 eq., 715 g, 1.83 mol) was dissolved in methanol (7.2 L), and methylamine in methanol (5.0 eq., 916 g, 9.16 mol) was added. After stirring at room temperature for 1 h, the reaction mixture was concentrated, dissolved in ethanol (7.2 L), cooled to 0 °C, and NaBH 

4 (2.0 eq., 139 g, 3.66 mol) was added, and stirred at 0 °C for 1 h. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1  H  -pyrrol-3-yl)-  

N  -methylmethanamine as a brown oil. (347 g, 46.7%)

 <Example 1> Preparation of hydrochloric acid salt of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine About 500 mg of the free base of  1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine was weighed and placed in a glass vial, and then dissolved in 2 mL of ethanol while heating at 25°C. Then, 647.44 μL (2 M) hydrochloric acid was added to the vial. The sample was continuously stirred on a magnetic stirrer at room temperature for 24 hours, and after stirring for 24 hours, the solid precipitate was separated by centrifugation. Subsequently, the wet solid was dried at 40°C for 20 hours to obtain a grayish white dried powder.

SYN

WO-2023229322-A1

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/////////Padoprazan, proton pump inhibitor, 95BJ28E2RP, ID-120040002, ID 120040002

Ofirnoflast

November 15, 2025 3:13 am / Leave a comment


Ofirnoflast

CAS 2731294-23-6

MFC23H19F4N7O2 MW501.4 g/mol

N-[4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N’-{5-[1-
(trifluoromethyl)cyclopropyl]-1,2-oxazol-3-yl}urea
N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-3-ISOXAZOLYL)UREA
N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-1,2-OXAZOL-3-YL)UREA
OFIRNOLAST [USAN]
OFIRNOFLAST
UREA, N-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)-2-FLUOROPHENYL)-N’-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)-3-ISOXAZOLYL)-
OFIRNOFLAST [INN]
serine/ threonine-protein kinase Nek7 inhibitor, antiinflammatory, HT-6184, HT 6184, 54PY2PBN7S

Ofirnoflast is an investigational drug, a NEK7 inhibitor, that targets and disrupts the formation of the NLRP3 inflammasome, a key driver of chronic inflammation. Developed by Halia Therapeutics, it is being explored for conditions like myelodysplastic syndromes (MDS), obesity, and Alzheimer’s disease. The drug’s unique mechanism aims to address inflammation at a root cause level, potentially offering a new approach to treating these diseases. 

How it works

  • Ofirnoflast is a “first-in-class” molecule that selectively inhibits the NEK7 protein.
  • NEK7 is essential for the assembly of the NLRP3 inflammasome, a molecular complex that causes chronic inflammation.
  • By inhibiting NEK7, ofirnoflast prevents the inflammasome from forming and promotes its disassembly.
  • This approach aims to reduce inflammation without causing broad immunosuppression. 

Therapeutic applications

  • Myelodysplastic Syndromes (MDS): Ofirnoflast has completed a Phase 2 study for this condition and received Orphan Drug Designation from the FDA. It is being investigated for its potential to improve blood cell production by targeting the underlying inflammation.
  • Obesity: An ongoing Phase 2 study is exploring ofirnoflast in combination with semaglutide to target inflammation and metabolic issues.
  • Alzheimer’s Disease: Ofirnoflast is part of an early-stage program looking into its potential for this disease. 

Ofirnoflast is a first-in-class, orally bioavailable NEK7 inhibitor currently undergoing Phase 2 clinical evaluation. It disrupts NLRP3 inflammasome assembly by targeting NEK7’s scaffolding function—blocking complex formation independently of NLRP3 activation status, upstream of caspase activation, pyroptosis, and inflammatory cytokine release. This mechanism offers a novel therapeutic approach for chronic inflammation. Unlike NSAIDs, corticosteroids, cytokine-neutralising biologics, and NLRP3-directed small molecules—which are frequently limited by off-target effects, immunosuppression, or incomplete efficacy—ofirnoflast provides a targeted approach with fewer anticipated liabilities

  • A Ph2 Study to Evaluate the Safety, Efficacy and Tolerability of HT-6184 and Semaglutide in Obese Participants With T2DMCTID: NCT07172867Phase: Phase 2Status: Not yet recruitingDate: 2025-09-15
  • HT-6184 in Subjects With MDSCTID: NCT07052006Phase: Phase 2Status: Active, not recruitingDate: 2025-07-14
  • Evaluating Ability of HT-6184 to Reduce Inflammation and Pain After Third Molar ExtractionCTID: NCT06241742Phase: Phase 2Status: CompletedDate: 2025-03-30
  • Study to Evaluate HT-6184 in Healthy SubjectsCTID: NCT05447546Phase: Phase 1Status: CompletedDate: 2023-08-28

SYN

https://www.tandfonline.com/doi/full/10.1080/1061186X.2025.2542856

SYN

US11161852,

COMPD 10

SYN

WO2021242505

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021242505&_cid=P11-MHZPDU-32878-1

INTERMEDIATE D1

5-(4-AMINO-3-FLUOROPHENYL)-7-CYCLOPROPYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4- AMINE

A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h. Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 3% MeOH in DCM), affording

the title compound as a yellow solid (0.110 g, 73% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.13 (s, 1H), 7.05-7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS: 284.1 [M+H].

3-(1-(Trifluoromethyl)cyclopropyl)isoxazol-5-amine (precursor to E6) and 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (precursor to E7) were synthesized as reported in Synthesis 2013, 45, 171–173

EXAMPLE 5

1-(4-(4-AMINO-7-CYCLOPROPYL-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-2- FLUOROPHENYL)-3-(3-(1-(TRIFLUOROMETHYL)CYCLOPROPYL)ISOXAZOL-5-YL)UREA

The title compound was prepared following the general procedure for urea formation (Method A), starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.080 g, 0.282 mmol) and phenyl (3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)carbamate (E6, 0.088 g, 0.282 mmol), and was obtained as a white solid (0.031 g, 22% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.59 (bs, 1H), 8.84 (bs, 1H), 8.11-8.17 (m, 2H), 7.26-7.37 (m, 3H), 6.20 (s, 1H), 6.16 (bs, 2H), 3.55-3.61 (m, 1H), 1.45-1.49 (m, 2H), 1.38-1.43 (m, 2H), 1.03-1.08 (m, 4H). LCMS: 502.1 [M+H].

PAT

WO-2024249257

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024249257&_cid=P11-MHZP9H-30149-1

PAT

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Odentegravir

November 14, 2025 2:33 am / Leave a comment


Odentegravir

CAS 2495436-99-0

MF C20H18F3N3O4 MW421.4 g/mol

(7S)-12-hydroxy-1,11-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,4,5,6,7,11-hexahydro-3H-2,7-
methanopyrido [1,2-a][1,4]diazonine-10-carboxamide

(7S)-1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
(7S)-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-1,4,5,6,7,11-HEXAHYDRO-3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE
3H-2,7-METHANOPYRIDO(1,2-A)(1,4)DIAZONINE-10-CARBOXAMIDE, 1,4,5,6,7,11-HEXAHYDRO-12-HYDROXY-1,11-DIOXO-N-((2,4,6-TRIFLUOROPHENYL)METHYL)-, (7S)-

antiviral, H8B26JZ4A4, orb2664247

Odentegravir is a small molecule drug classified as a

HIV integrase inhibitor, indicated by the “-tegravir” stem in its name. It is a chemical compound with the molecular formula

has been used in research for its antiviral properties. 

  • Drug Class: HIV integrase inhibitor
  • Chemical Formula: C20H18F3N3O4cap C sub 20 cap H sub 18 cap F sub 3 cap N sub 3 cap O sub 4𝐶20𝐻18𝐹3𝑁3𝑂4
  • Molecular Weight: 421.12421.12421.12 Da (monoisotopic)
  • Classification: Small molecule drug 

SYN

WO-2020197991

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020197991&_cid=P12-MHY8KB-06018-1

Example 23: Preparation of racemic-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-

methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1) and (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2):

Synthesis of 12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26):

[0335] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) with (2,4,6-trifluorophenyl)methanamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added and the mixture was stirred at room

temperature. After overnight reaction, the reaction was concentrated to dryness, purified by silicon gel chromatography to obtain compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) MS (m/z) 512.06 [M+H]+.

[0336] Compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) (7 mg, 0.014 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stirred at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26). MS (m/z) 422.091 [M+H]+.1H NMR (400 MHz, DMSO-d6) d 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.24 – 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9 Hz, 1H), 4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 – 3.79 (m, 1H), 3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06 – 1.91 (m, 1H), 1.89 – 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J = 12.7 Hz, 1H).

Synthesis of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26-1):

[0337] Racemic 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) was separated by chiral HPLC separation (SFC chromatography on an IB 4.6X100mm 5mic column using MeOH(20) as co-solvent) to obtain compounds (7R)-12-(Benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) and (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2)

[0338] Compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-2) (20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-2). (MS (m/z) 422.123 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 10.59 (s, 1H), 10.39 (d, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 4.72 (s, 1H), 4.59 – 4.48 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.69 – 3.59 (m, 1H), 3.05 (ddd, J = 11.3, 6.7, 3.6 Hz, 1H), 1.97 (m, 1H), 1.87 – 1.71 (m, 3H), 1.67 – 1.55 (m, 1H), 1.10 (m, 1H).

[0339] Compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a-1) ((20 mg, 0.039 mmol) was dissloved in Tolune (1 mL), then followed by the addition of TFA (1 mL). The resulting mixture was stireed at rt for overnight. The solvent was removed under vacuo an the residue was purifed by HPLC to obtain the title compound (26-1). MS (m/z) 422.116 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 10.58 (s, 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H), 4.73 (s, 1H), 4.58 – 4.49 (m, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 – 3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d, J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 – 1.05 (m, 1H).

SYN

WO-2023196875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023196875&_cid=P12-MHY8FJ-02517-1

PAT

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//////Odentegravir, antiviral, H8B26JZ4A4, orb2664247

Nuvisertib

November 13, 2025 2:57 am / Leave a comment


Nuvisertib

CAS 1361951-15-6

MF C22H26ClF3N4O MW418.5 g/mol

2-[(1r,4r)-4-({3-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazin-6-yl}amino)cyclohexyl]propan-2-ol
serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4

The chemical structure for nuvisertib was obtained from proposed INN list 130 (Feb. 2024), in which the compound is described as a serine/ threonine kinase inhibitor with antineoplastic action. A structure match to clinical lead TP-3654 was made via PubChem. TP-3654 is declared as an orally available, second-generation pan-PIM kinase inhibitor [1-2].

References
1. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D et al.. (2014)
A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas.
Neoplasia, 16 (5): 403-12. [PMID:24953177]
2. Wu CP, Li YQ, Chi YC, Huang YH, Hung TH, Wu YS. (2021)
The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.
Int J Mol Sci, 22 (17). [PMID:34502348]

Nuvisertib is an orally available, second-generation and selective ATP-competitive inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) kinases, with potential antineoplastic activity. Upon oral administration, nuvisertib selectively binds to and prevents the activation of the PIM kinases. This prevents the activation of PIM-mediated signaling pathways and inhibits proliferation in cells that overexpress PIM. PIMs, constitutively active proto-oncogenic serine/threonine kinases, are upregulated in various types of cancers and play key roles in tumor cell proliferation and survival.

Nuvisertib, also known as TP-3654, is an oral, investigational, and highly selective PIM1 kinase inhibitor being studied in a Phase 1/2 clinical trial for intermediate- or high-risk myelofibrosis (MF). It is not currently an approved medication. 

Key Information

  • Mechanism of Action: Nuvisertib targets the PIM1 kinase pathway, which is often overactive in myelofibrosis and can promote cancer cell growth. By inhibiting this pathway, nuvisertib is being investigated for its potential to manage symptoms, reduce spleen size, improve blood counts, and slow the progression of bone marrow fibrosis.
  • Current Status: Nuvisertib is in ongoing Phase 1/2 clinical trials (NCT04176198) as a monotherapy and in combination with JAK inhibitors like ruxolitinib and momelotinib.
  • Designations: Nuvisertib has received Orphan Drug Designation for myelofibrosis

Study of TP-3654 in Patients With Advanced Solid Tumors

CTID: NCT03715504

Phase: Phase 1

Status: Completed

Date: 2023-11-14

SYN

WO2013013188

Example 31 

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US427659372&_cid=P10-MHWTVL-76212-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US130491286&_cid=P10-MHWU33-81462-1

31. 4-((3-(3-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)-trans-cyclohexyl)propan-2-ol (EX. 8-31)

      EX. 8-31 was prepared by similar procedures as in EX. 8-1 using 2-(trans-4-aminocyclohexyl)propan-2-ol.
1H-NMR (CD 3OD/400 MHz): δ 8.82 (s, 1H), 8.19 (m, 1H), 7.88 (s, 1H), 7.62 (m, 3H), 6.70 (d, J=9.6 Hz, 1H), 3.71 (m, 1H), 2.26 (m, 2H), 1.95 (m, 2H), 1.36 (m, 1H), 1.27 (m, 4H), 1.21 (s, 6H). MS (ES +, m/z): (M+H) +: 419.6.
      Alternatively, EX. 8-31 was prepared in 50 g scale employing the following procedures.
To a solution of trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (823 g, 3.38 mol) in EtOAc (4000 mL) was added EA/HCl (2500 mL). The mixture was stirred at 0° C. overnight. The reaction mixture was filtered and dried in vacuo to give a product of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid as white solid (604 g, 99.42% yield).
      A mixture of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid (720 g), BnBr (1700 g, 2.5 eq) and K 2CO 3 in DMF (8000 mL) was stirred at rt overnight. More BnBr (100 g) was added and the reaction mixture was heated to 50° C. and kept for 3 hrs. The reaction mixture was then poured into water and extracted with EtOAc and combined organic phase washed with brine and concentrated in vacuo to give crude trans-benzyl 4-(dibenzylamino)cyclohexanecarboxylate as white solid (1495 g, 93.9% yield).
      To a solution of trans-benzyl 4-(dibenzylamino)cyclohexanecarboxylate (290 g×5, 3.6 mol) in 2 L of THF under N 2 at 0° C., MeMgBr (800 mL) was added. The mixture was stirred at room temperature overnight and then quenched with 1.5 L of saturated NH 4Cl. The resulting mixture was extracted with EtOAc. The product was extracted with 1 M HCl to the aqueous phase, which was then wash with EtOAc. The aqueous phase was then neutralized with NaOH, extracted with EtOAc, washed with brine, dried with Na 2SO 4 and concentrated in vacuo to give the 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol as white solid (950 g, 78.3% yield).
      A mixture of 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol (120 g×8, 356 mmol) and Pd(OH) 2 (15 g×8) in methanol (1000 mL) and MeOH/NH 3 (100 mL) was stirred under H 2 (50 psi) at 50° C. for 72 hrs, then the catalyst was removed and the filtrate was concentrated in vacuo and The crude product was chromatographed on silica gel (DCM/MeOH 20:1-DCM/MeOH/NH 3 5:4:1) to give the 2-(trans-4-aminocyclohexyl)propan-2-ol as a pale yellow solid (210 g, 47.5% yield).
   6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine was prepared according to procedure in EX. 8-29.
      To a solution of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (100 g, 337 mmol) and 2-(trans-4-aminocyclohexyl)propan-2-ol (55 g, 350 mmol) in 400 mL of DMSO was added DIEA (90 g, 900 mmol) and CsF (45 g, 30 mmol). The mixture was stirred at 180° C. for 4 hour. The solid was removed and the filtrate was poured into a stirred solution of water (4 L) and EA (1 L), The solid formed was collected and recrystallized from EA to give EX. 8-31 (Free Base) as off white solid (70.58 g, 48.34%). From the mother liquid and the filtrate, a second batch of product was obtained after column chromatography (EA).
       1H NMR (MeOD/400 MHz): δ 8.80 (s, 1H), 8.17 (d, J=6.8 Hz, 1H), 7.85 (s, 1H), 7.62-7.58 (m, 3H), 6.68 (d, J=9.6 Hz, 1H), 3.72-3.65 (m, 1H), 2.30-2.24 (m, 2H), 1.95-1.90 (m, 2H), 1.37-1.22 (m, 5H), 1.16 (s, 6H). MS (ES +, m/z): (M+H) +: 419.3. Melting Point: 216.7° C.-219.3° C.
      To a production of EX. 8-31 (Free Base) (57 g, 136 mmol) in EA (10 L) was added HCl/EA until no further solid formed (about 100 mL of HCl/EA). The mixture was stirred at room temperature for half an hour and the solid was collected, washed with EA and dried under vacuo to give EX. 8-31 (HCl) (52.06 g, 91.33%) as off white solid.
       1H NMR (MeOD/400 MHz): δ 8.69 (s, 1H), 8.34 (s, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.75 (dd, J=7.6 Hz, 8.0 Hz, 1H), 7.23 (d, J=9.6 Hz, 1H), 3.73-3.66 (m, 1H), 2.24-2.20 (m, 2H), 1.97 (m, 2H), 1.37-1.25 (m, 5H), 1.16 (s, 6H). MS (ES +, m/z): (M+H) +: 419.2. Melting Point: 200.4° C.-201.6° C.

PAT

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REF

https://news.us.sumitomo-pharma.com/2025-06-12-Sumitomo-Pharma-America-Announces-that-Nuvisertib-TP-3654-Has-Received-FDA-Fast-Track-Designation-for-the-Treatment-of-Myelofibrosis

– Nuvisertib (TP-3654), an investigational highly selective oral PIM1 kinase inhibitor, is being evaluated in patients with relapsed or refractory myelofibrosis (MF) –

– Nuvisertib demonstrated symptom and spleen responses correlating with cytokine modulation in the preliminary Phase 1/2 data recently presented at the European Hematology Association (EHA) 2025 Congress –

MARLBOROUGH, Mass., June 12, 2025 /PRNewswire/ — Sumitomo Pharma America, Inc. (SMPA) today announced that the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to nuvisertib (TP-3654) for the treatment of patients with intermediate or high-risk myelofibrosis (MF). The FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. Nuvisertib is an oral, investigational, highly selective inhibitor of PIM1 kinase, which demonstrated clinical activity including symptom and spleen responses correlating with cytokine modulation in the updated preliminary Phase 1/2 data presented at the European Hematology Association (EHA) 2025 Congress in Milan, Italy.

MF, a serious and rare type of blood cancer, is characterized by the buildup of fibrous tissues in the bone marrow which is caused by dysregulation in the Janus-associated kinase (JAK) signaling pathway. The clinical manifestations of MF include an enlarged spleen, debilitating symptoms and reduction in hemoglobin and/or platelets. MF affects 1 in 500,000 people worldwide.1

“This positive momentum for nuvisertib signals strong promise in our pipeline and reflects our dedication to addressing unmet medical needs on behalf of patients with myelofibrosis and their families,” said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. “Receiving FDA Fast Track Designation for nuvisertib in the treatment of myelofibrosis reinforces our confidence in its potential as a treatment option for patients facing a poor prognosis with limited treatment options. We are committed to working closely with the FDA to progress the clinical development of nuvisertib and bring an alternative treatment option to patients with myelofibrosis.”

Updated data from the ongoing Phase 1/2 study of nuvisertib in patients with relapsed/refractory MF were presented at the EHA Congress on June 12, 2025. Preliminary data showed that nuvisertib monotherapy appears to be well tolerated with no dose-limiting toxicities (DLTs). Evaluable patients showed clinical activity including a ≥25% spleen volume reduction (SVR25) in 22.2% of patients and a ≥50% reduction in total symptom score (TSS50) of 44.4% of patients, as well as improvement of bone marrow fibrosis (42.9% patients), hemoglobin (24% patients) and platelet count (26.7% patients). Data also showed that nuvisertib treatment led to significant cytokine modulation [reduction of pro-inflammatory cytokines (e.g. EN-RAGE, MIP-1β) and increase of anti-inflammatory cytokines (e.g. adiponectin)], which demonstrated significant (p<0.001) correlation with symptom and spleen responses. Preclinical2 and emerging clinical data support the development of nuvisertib in combination with JAK inhibitors for the treatment of patients with MF.

“The data observed to date demonstrate promising clinical activity for nuvisertib and the strong potential for selective PIM1 inhibition to slow the progression of myelofibrosis,” said Jatin Shah, MD, Chief Medical Officer, Oncology. “Patients with myelofibrosis are in need of new therapeutic approaches, including combination treatment options, that can provide increased and durable response rates with limited hematologic adverse events. The FDA Fast Track Designation reinforces the potential of nuvisertib to provide clinical benefits for patients with myelofibrosis, an unmet medical need.”

About Nuvisertib (TP-3654)
Nuvisertib (TP-3654) is an oral investigational selective inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.2,3 Nuvisertib was observed to inhibit proliferation and increase apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2 V617F mutation.3 Nuvisertib alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2 V617F and MPLW515L murine models of myelofibrosis.2 The safety and efficacy of nuvisertib is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to nuvisertib for the indication of myelofibrosis in May 2022. The Japan Ministry of Health, Labour and Welfare (MHLW) granted Orphan Drug Designation to nuvisertib for the treatment of myelofibrosis in November 2024.

About Sumitomo Pharma
Sumitomo Pharma Co., Ltd., is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.), and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women’s health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website https://www.us.sumitomo-pharma.com or follow us on LinkedIn.

The Sumitomo corporate symbol mark is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd.

©2025 Sumitomo Pharma America, Inc. All rights reserved.

References

  1. U.S. National Library of Medicine. (n.d.). Primary myelofibrosis: Medlineplus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/primary-myelofibrosis/
  2. Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2.
  3. Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412.

SOURCE Sumitomo Pharma America

///////Nuvisertib, serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4

Nurandociguat

November 12, 2025 8:49 am / Leave a comment


Nurandociguat

CAS 2781965-75-9

MF C30H36ClF2N5O2 MW 572.1 g/mol

1-[(3R)-1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl} piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid

1-[(3R)-1-[5-chloro-2-[4-[4-(2-methylpropyl)piperazin-1-yl]phenyl]phenyl]piperidin-3-yl]-5-(difluoromethyl)pyrazole-4-carboxylic acid
guanylate cyclase activator, BAY 3283142, LPU8429UK5

Nurandociguat is a small molecule drug candidate, previously known as BAY 3283142, that is a guanylate cyclase activator being developed by Bayer for cardiovascular conditions. The “ciguat” stem in its name indicates its function as a guanylate cyclase activator, a mechanism that is also being investigated for related drugs like runcaciguat. It is currently in clinical trials, including a Phase 2 program for chronic kidney disease (CKD). 

  • Drug class: Guanylate cyclase activator
  • Developer: Bayer
  • Previous name: BAY 3283142
  • Indication: Investigated for cardiovascular conditions
  • Current status: In clinical development, including a Phase 2 study for chronic kidney disease (CKD) 
  • OriginatorBayer
  • ClassAntihypertensives; Cardiovascular therapies; Hepatoprotectants; Urologics
  • Mechanism of ActionGuanylate cyclase stimulants
  • Phase IIRenal failure
  • Phase ICardiovascular disorders; Diabetic retinopathy; Hypertension; Liver disorders
  • 28 Sep 2025No recent reports of development identified for phase-I development in Renal-failure in Germany (PO, Immediate release)
  • 16 Sep 2025(CTIS2024-510856-11-00) (EudraCT2024-510856-11-00): Trial initiation and completion info added; updated DevT; Corrected intro to match DevT as most of the info about indication and countries missing
  • 28 May 2025No recent reports of development identified for phase-I development in Renal-failure(In volunteers, In adults) in Japan (PO, Immediate release)

Nurandociguat is a small molecule drug. The usage of the INN stem ‘-ciguat’ in the name indicates that Nurandociguat is a guanylate cyclase activator and stimulator. Nurandociguat has a monoisotopic molecular weight of 571.25 Da.

PAT

SYN

WO-2023237577

SYN

WO-2022122917

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022122917&_cid=P20-MHVQYD-96133-1

soluble guanylate cyclase (sGC) activators for use in the treatment and/or prophylaxis of ophthalmologic diseases, including non-proliferative diabetic retinopathy (NPDR), diabetic macular edema (DME), retinal ganglion cell/photoreceptor neurodegeneration and cataract, especially wherein the soluble guanylate cyclase (sGC) activators are compounds selected from the group consisting of

Example 1

1 – [ 1 – { 4-Chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5- (difluoromethyl)-lH-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 1)

Ethyl 1 – [ 1 – { 5-chloro-2- [(trifluoromethanesulfonyl)oxy]phenyl }piperidin-3-yl] -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylate (prepared in analogy to Example 11A, Enantiomer 1, 80.0 mg, 147 pmol) and l-(2-methylpropyl)-4- [4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18 A 62.8 mg, 97 % purity, 177 pmol) were placed under argon in toluene/ethanol (820/820 pl). 2 M sodium carbonate solution (220 pl, 2.0 M, 440 pmol) and tetrakis(triphenylphosphine)palladium(0) (8.52 mg, 7.37 pmol) were added and the mixture was stirred at 100°C. overnight. The reaction mixture was diluted with ethyl acetate and 1 M hydrochloric acid was added. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried with sodium sulfate, filtered off and evaporated. The crude mixture was dissolved with THF/ethanol (2.0/0.2 ml), 1 M lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred at room temperature overnight. A I M lithium hydroxide solution (740 pl, 740 pmol) was added again. After about 6 h the reaction mixture was evaporated at 50°C. The residue was dissolved in

SUBSTITUTE SHEET (RULE 26)

acetonitrile/water/0.25 ml trifluoroacetic acid and purified by preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% trifluoroacetic acid). The crude product was purified by means of thick layer chromatography (dichloromethane/methanol/formic acid: 10/1/0.1). The silica gel mixture was stirred with dichloromethane/1 M hydrochloric acid in dioxane (10/1) in ethanol, filtered off and carefully evaporated at 30°C and lyophilized. 34 mg of the target compound (36% of theory, purity 95%) were obtained.

LC-MS (Method 6): Rt = 1.23 min; MS (ESIpos): m/z = 572 [M-HC1+H]+

‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.004 (15.87), 1.015 (16.00), 1.500 (0.51), 1.521 (0.57), 1.728 (0.73), 1.750 (0.61), 1.897 (0.57), 1.917 (0.62), 1.975 (0.79), 2.122 (0.42), 2.133 (0.84), 2.144 (1.02), 2.156

(0.79), 2.571 (0.47), 2.587 (0.91), 2.610 (0.52), 3.004 (0.84), 3.022 (2.01), 3.026 (2.20), 3.038 (3.72), 3.048

(2.50), 3.065 (0.75), 3.154 (2.66), 3.161 (2.75), 3.169 (2.36), 3.177 (1.88), 3.224 (0.84), 3.237 (0.70), 3.589

(1.41), 3.602 (1.80), 3.825 (1.02), 3.841 (0.78), 3.866 (1.05), 3.882 (0.75), 4.223 (2.57), 4.445 (0.68), 4.463

(0.97), 4.481 (0.57), 7.045 (0.55), 7.055 (3.63), 7.070 (3.72), 7.084 (2.72), 7.087 (3.09), 7.110 (1.47), 7.113

(1.11), 7.123 (2.19), 7.127 (2.02), 7.163 (3.67), 7.177 (2.19), 7.215 (0.46), 7.428 (0.83), 7.495 (4.24), 7.510

(4.02), 7.515 (2.07), 7.602 (0.82), 7.959 (4.79), 9.484 (0.54).

Example 2

1 – [ 1 – { 4-Chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid (Enantiomer 2)

Method A

A solution of ethyl l-[l-{4-chloro-4′-[4-(2-methylpropyl)piperazin-l-yl][l,T-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-lH-pyrazole-4-carboxylate (prepared in analogy to Example 17A, Enantiomer 2, 50.8 g, 84.6 mmol) in a THF/methanol mixture 9:1 (1.0 1) was treated with an aqueous solution of lithium hydroxide (850 ml, 1.0 M, 850 mmol) and stirred overnight at room temperature. The reaction mixture was

SUBSTITUTE SHEET (RULE 26)

concentrated, diluted with dichloromethane (1.5 1) and adjusted to pH = 2 with an aqueous solution of hydrogen chloride (2N). The resulting suspension was stirred 45 minutes at room temperature. The solid was filtered, washed with water and dried under vacuum affording 43 g (90 % yield) of the title compound.

LC-MS (Method 7): Rt = 1.27 min; MS (ESIpos): m/z = 572 [M+H]+

‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.002 (15.68), 1.013 (16.00), 1.080 (0.57), 1.092 (1.18), 1.103 (0.63), 1.498 (0.74), 1.519 (0.83), 1.719 (1.03), 1.741 (0.88), 1.902 (0.78), 1.908 (0.74), 1.922 (0.88), 1.928

(0.83), 1.943 (0.45), 1.978 (1.13), 1.994 (0.74), 2.102 (0.71), 2.112 (0.85), 2.123 (0.70), 2.571 (1.40), 2.591

(0.77), 2.882 (1.10), 3.018 (1.27), 3.035 (3.01), 3.053 (2.14), 3.239 (2.40), 3.254 (2.32), 3.368 (1.13), 3.379

(1.40), 3.391 (1.33), 3.403 (0.92), 3.493 (0.76), 4.463 (0.65), 4.482 (1.12), 4.500 (0.62), 7.033 (4.22), 7.048

(4.45), 7.074 (3.47), 7.077 (4.04), 7.100 (1.85), 7.103 (1.52), 7.113 (2.53), 7.117 (2.34), 7.162 (4.18), 7.175

(2.71), 7.439 (1.03), 7.481 (4.88), 7.495 (4.57), 7.526 (2.04), 7.613 (0.91), 7.952 (5.28).

Method B

1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylic acid hydrochloride (prepared in analogy to Example 3, Enantiomer 2, 31.2 mg, 51.3 pmol) were dissolved in 17 ml of dichloromethane and 1 ml of methanol. The solution was shaken once with 1.5 ml of saturated, aqueous sodium bicarbonate solution. The phases were separated. 5 ml of dichloromethane and 3 ml of methanol were added to the organic phase. The organic phase was then dried over sodium sulfate, filtered, evaporated and purified by preparative HPLC (RP18 column, acetonitrile/water gradient, neutral without acid addition). Product fractions were combined and lyophilized. 22 mg of the target compound (74% of theory) were obtained.

LC-MS (Method 3): Rt = 1.73 min; MS (ESIpos): m/z = 572 [M+H]+

‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 0.887 (15.60), 0.898 (16.00), 1.493 (0.64), 1.514 (0.70), 1.695 (0.89), 1.718 (0.74), 1.799 (0.48), 1.811 (0.88), 1.822 (1.12), 1.833 (0.92), 1.844 (0.48), 1.890 (0.68), 1.910

(0.74), 1.977 (0.93), 1.995 (0.62), 2.118 (3.91), 2.130 (3.66), 2.516 (5.14), 3.017 (1.09), 3.035 (2.76), 3.053

(1.94), 3.181 (5.03), 3.185 (5.02), 3.267 (1.53), 4.473 (0.55), 4.491 (0.96), 4.509 (0.54), 6.963 (3.96), 6.977

(4.06), 7.048 (3.13), 7.051 (3.31), 7.081 (1.60), 7.084 (1.26), 7.095 (2.21), 7.098 (1.89), 7.152 (3.52), 7.165

(2.42), 7.434 (4.45), 7.448 (4.50), 7.533 (1.51), 7.621 (0.67), 7.930 (4.14).

Example 3

1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 2)

SUBSTITUTE SHEET (RULE 26)

Method A

A suspension of 1 – [ 1 – { 4-chloro-4′- [4-(2-methylpropyl)piperazin- 1 -yl] [1,1 ’-biphenyl] -2-yl }piperidin-3-yl] -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid (prepared in analogy to Example 2, Enantiomer 2, 43.5 g, 76.0 mmol) in diethyl ether (870 ml) was treated with a solution of hydrogen chloride in diethyl ether (84 ml, 1.0 M, 84 mmol). The resulting mixture was stirred overnight at room temperature and evaporated affording 46.1 g (quant.) of the title compound.

LC-MS (Method 3): Rt = 1.72 min; MS (ESIpos): m/z = 572 [M+H]+

‘H-NMR (600 MHz, DMSO-d6) 5 [ppm]: 1.026 (15.64), 1.037 (16.00), 1.497 (0.56), 1.519 (0.61), 1.722 (0.78), 1.743 (0.65), 1.903 (0.59), 1.910 (0.53), 1.924 (0.66), 1.930 (0.61), 1.978 (0.82), 1.994 (0.50), 2.142

(0.45), 2.154 (0.91), 2.165 (1.11), 2.176 (0.89), 2.187 (0.45), 2.557 (0.64), 2.577 (1.02), 2.594 (0.55), 2.992

(1.81), 3.002 (2.77), 3.012 (1.87), 3.018 (1.15), 3.036 (2.40), 3.054 (1.60), 3.133 (1.12), 3.148 (1.19), 3.168

(0.53), 3.237 (0.88), 3.250 (0.76), 3.338 (0.81), 3.360 (1.42), 3.379 (0.88), 3.580 (1.61), 3.791 (0.89), 3.819

(1.25), 3.844 (0.81), 4.463 (0.89), 4.474 (0.97), 4.481 (1.26), 4.488 (0.99), 4.499 (0.88), 7.051 (3.56), 7.065

(3.77), 7.077 (2.72), 7.080 (3.14), 7.103 (1.42), 7.106 (1.13), 7.116 (2.00), 7.120 (1.84), 7.165 (3.40), 7.178

(2.22), 7.443 (0.84), 7.489 (4.04), 7.504 (3.79), 7.531 (1.66), 7.618 (0.72), 7.954 (4.33), 10.519 (0.49).

Method B

Ethyl 1 – [ 1 – { 5-chloro-2- [(trifluoromethanesulfonyl)oxy]phenyl }piperidin-3-yl] -5-(difluoromethyl)- 1 H-pyrazole-4-carboxylate (prepared in analogy to Example 14A, Enantiomer 2, 80.0 mg, 150 pmol) and l-(2-methylpropyl)-4- [4-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18 A 64.1 mg, 97 % purity, 180 pmol) were dissolved under argon in toluene/ethanol (0.83/0.83 ml). Tetrakis(triphenylphosphine)palladium(0) (8.69 mg, 7.52 pmol) and 2 M sodium carbonate solution (226 pl, 452 pmol) were added and the mixture was stirred at 100°C overnight. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was acidified with 1 M hydrochloric acid. The phases were

SUBSTITUTE SHEET (RULE 26)

separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The crude product was dissolved in THF/ethanol (3.9/0.39 ml), 1 M aqueous lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, the residue was dissolved in acetonitrile/TFA/water and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. The residue was mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30°C (twice) and then lyophilized. 53 mg of the target compound (55% of theory, purity 95%) were obtained.

LC-MS (Method 4): Rt = 0.91 min; MS (ESIpos): m/z = 572 [M-HC1+H]+

‘H-NMR (400 MHz, DMSO-d6) 5 [ppm]: 1.004 (15.46), 1.020 (16.00), 1.491 (0.44), 1.522 (0.50), 1.722 (0.68), 1.753 (0.55), 1.890 (0.47), 1.920 (0.55), 1.967 (0.84), 2.129 (0.76), 2.146 (0.96), 2.163 (0.76), 2.582

(0.91), 2.613 (0.48), 2.999 (0.86), 3.010 (1.71), 3.025 (3.88), 3.041 (2.30), 3.131 (0.88), 3.161 (1.25), 3.177

(2.08), 3.213 (1.75), 3.242 (1.16), 3.467 (1.06), 3.496 (0.84), 3.503 (0.60), 3.519 (0.54), 3.525 (0.50), 3.549

(0.75), 3.555 (0.84), 3.572 (1.57), 3.582 (1.48), 3.589 (1.38), 3.601 (2.78), 3.608 (1.89), 3.633 (0.44), 3.640

(0.41), 3.811 (0.94), 3.847 (1.32), 3.878 (0.71), 4.329 (0.49), 4.439 (0.46), 4.466 (0.73), 4.477 (0.52), 4.839

(0.49), 7.047 (3.30), 7.070 (3.64), 7.082 (2.61), 7.087 (3.29), 7.104 (1.46), 7.109 (0.86), 7.124 (2.34), 7.129

(2.03), 7.160 (3.99), 7.181 (1.96), 7.388 (0.88), 7.490 (4.02), 7.512 (3.81), 7.519 (2.20), 7.650 (0.72), 7.959

(3.78), 9.708 (0.41).

[OC]D20 = -73.05°, c = 0.465g/100cm3, trichloromethane.

Enantiomer 2 has an absolute configuration of R as shown in example 3 A below.

1 – { 3(2?)- 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1H-pyrazole-4-carboxylic acid hydrochloride

Example 3A

1 – { 3(7?)- 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)- 1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate

SUBSTITUTE SHEET (RULE 26)

100 mg 1 – { 1 – [4-Chloro-4′-(4-isobutylpiperazin- 1 -yl) [biphenyl] -2-yl]piperidin-3-yl } -5-(difluoromethyl)-lH-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 2) (example 3) were solved at 60°C in 3,5 ml 2 -propanol, wherein the 2-propanol was dosed portion wise in lOOpl -portions at 60°C until a clear solution was obtained. Afterwards the vessel was closed with a septum and placed into a slowly cooling sand bath from 60°C to roomtemperature over the weekend -> small amounts of solids were detected. Thereafter the septum was provided with a canula, in order to slowly let the solvent evaporate. After 4 weeks crystals were collected and inspected under a microscope.

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/////////Nurandociguat, guanylate cyclase activator, BAY 3283142, LPU8429UK5

Nibrozetone

November 11, 2025 2:36 am / Leave a comment


Nibrozetone

CAS 925206-65-1

MF C5H6BrN3O5 MW268.02 g/mol

2-bromo-1-(3,3-dinitroazetidin-1-yl)ethan-1-one

2-Bromo-1-(3,3-dinitroazetidin-1-yl)ethanone

2-BROMO-1-(3,3-DINITROAZETIDIN-1-YL)ETHAN-1-ONE

anti-inflammatory, RRx-001, RRx 001, ABDNAZ

Nibrozetone is an investigational new drug that is being evaluated by EpicentRx for the treatment of oral mucositis in head and neck cancer patients. It is a small molecule that combines direct inhibition of the NLRP3 inflammasome, induction of NRF2, and release of nitric oxide under hypoxic conditions.[1][2] It has received Fast Track designation from the FDA for severe oral mucositis in head and neck cancer patients.[3]

Nibrozetone (RRx-001) is an investigational, multi-action small molecule drug that is being developed by EpicentRx for a range of conditions, including head and neck cancers, small cell lung cancer, and neurodegenerative diseases like Parkinson’s and ALS. Its mechanism involves inhibiting the NLRP3 inflammasome, activating the Nrf2 pathway, and releasing nitric oxide in hypoxic tumor environments, while also protecting healthy tissues. It is being evaluated for its potential to reduce the side effects of cancer treatments and as a disease-modifying therapy itself. 

How it works

  • Anti-inflammatory: Nibrozetone inhibits the NLRP3 inflammasome, which is a key driver of inflammation in several diseases.
  • Antioxidant: It activates the Nrf2 pathway, a cellular defense mechanism that protects against oxidative stress.
  • Tumor-specific delivery: It acts as a “hypoxia-activated” drug, releasing a nitric oxide-releasing radical only in the low-oxygen environment of tumors, which can be toxic to cancer cells.
  • Protective to normal tissue: The drug’s protective mechanisms are thought to keep it from causing harm to healthy tissues outside of the tumor environment. 

Current and potential uses

  • Oral mucositis: It is being studied to prevent and treat severe mouth sores that can be a side effect of head and neck cancer radiation therapy.
  • Small cell lung cancer (SCLC): It is being investigated in a Phase 3 trial for the treatment of SCLC.
  • Neurodegenerative diseases: Animal studies have shown promising neuroprotective effects in models of Parkinson’s and ALS.
  • Other potential applications: Research is ongoing for its use as a treatment for other conditions, including endometriosis, toxic exposures, and various types of cancers. 
  • RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)CTID: NCT02489903Phase: Phase 2Status: CompletedDate: 2025-03-17
  • RRx-001 for Reducing Oral Mucositis in Patients Receiving Chemotherapy and Radiation for Head and Neck CancerCTID: NCT05966194Phase: Phase 2Status: RecruitingDate: 2024-11-15
  • Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for the Treatment of Oral CancersCTID: NCT03515538Phase: Phase 2Status: CompletedDate: 2024-11-04
  • Safety and Pharmacokinetic Study of RRx-001 in Cancer SubjectsCTID: NCT01359982Phase: Phase 1Status: CompletedDate: 2024-11-01
  • RRx-001 Given With Irinotecan and Temozolomide for Pediatric Patients With Recurrent or Progressive Malignant Solid and Central Nervous System TumorsCTID: NCT04525014Phase: Phase 1Status: TerminatedDate: 2024-10-31

REF

PAT

SYN

WO-2011100090

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011100090&_cid=P11-MHTYGA-61308-1

Cyclic nitro compounds, such as ABDNAZ, are being investigated for their potential use in treating cancer. Methods of synthesizing ABDNAZ have been described, such as in United States Patent No. 7,507,842 to Bednarski et al.

(“Bednarski”). In Bednarski, ABDNAZ is synthesized by reacting

l-½rt-butyl-3,3-dinitroazetidine (DNAZ) with bromoacetyl bromide and boron trifluoride etherate. For every mole of ABDNAZ produced, a mole of a hydrogen bromide salt of DNAZ (DNAZ HBr) is also produced as a coproduct. The ABDNAZ is isolated from the DNAZ HBr by cooling the reaction mixture, adding

dichloromethane, and filtering the DNAZ HBr. Solid DNAZ HBr is sensitive to impact, friction, and other external stimuli and, therefore, must be handled carefully. The dichloromethane filtrate is washed with water, dried, and then the dichloromethane is evaporated, producing a crude ABDNAZ mixture. The product is washed sequentially with diethyl ether and dried under vacuum, yielding ABDNAZ that is approximately 98% pure and at a yield of approximately 75% (based on bromoacetyl bromide). The 2% of impurities remaining in the ABDNAZ are believed to include

bromoacetic acid, unreacted DNAZ, and DNAZ HBr. This method of producing ABDNAZ is referred to herein as the Bednarski process. While the Bednarski process provides ABDNAZ at a reasonable purity and yield, the purity is not sufficient for pharmaceutical uses. In addition, solid DNAZ HBr produced during the Bednarski process is an explosive compound, which adds to the complexity of producing

Example 2

Synthesis of ABDNAZ from DNAZ

A three neck round bottom flask (3 L) equipped with a magnetic stir bar and a water jacketed reflux condenser was charged with the dichloromethane solution of DNAZ (produced as described in Example 1). A nitrogen gas purge of the apparatus was initiated and, after ten minutes, boron trifluoride diethyletherate (6.37 mL, 52 mmol) was added, followed by bromoacetyl bromide (33.77 mL, 388 mmol). The flask was sealed, except for a small vent at the top of the condenser, and the solution was heated to a mild reflux. After six hours (± 0.5 hour), heating was stopped and dichloromethane (1000 mL) and distilled water (800 mL) were added, in that order, to the heterogeneous mixture. The two-phase system was stirred vigorously for sixteen hours, until all solids (DNAZ HBr) were dissolved. The two-phase system was then transferred to a separatory funnel. The aqueous phase was removed and the organic phase was washed with additional distilled water (4 x 500 mL). The organic phase was dried with sodium sulfate (100 g – 150 g) and then transferred to a single neck, round bottom flask. The solution was concentrated on a rotary evaporator to approximately half of its initial volume and then ethanol (250 mL) was added. The remaining dichloromethane was removed by a rotary evaporator, causing precipitation of clear, colorless crystals. The flask was chilled in an ice bath for thirty minutes. The precipitate was isolated by vacuum filtration, rinsed with additional cold ethanol (5 x 150 mL), and dried to afford pure ABDNAZ (56.04 g, 81% yield): Ή NMR

(d6-acetone) δ 4.02 (s, 2H, -CH2Br ), 4.96 (br s, 2H, ring -CH2), 5.36 (br s, 2H, ring -CH2); 13C NMR (d6-acetone) δ 25.58, 58.58, 60.53, 107.69, 167.48.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007022225&_cid=P11-MHTYDP-59218-1

Example 5: Synthesis of ABDNAZ
[00139] A 25 ml, three-neck, round bottom flask was charged with 7 ml of methylene chloride and 2.50 g (12.3 mmol) of t-BuDNAZ prepared as described in Archibald et at, Journal of Organic Chemistry, 1990, 2920. Under nitrogen, 0.16 ml (1.23 mmol) of boron trifluoride etherate was added. After stirring 5 min. at ambient temperature, 0.54 ml (6.15 mol) of bromoacetyl bromide was added. The solution was heated between 50-600C for 2 h. The darkened reaction mixture was cooled to ambient temperature, diluted with 50 ml methylene chloride, and filtered. The solid was identified as the HBr salt of t-BuDNAZ. The methylene chloride filtrate was washed with two 20 ml portions of water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The resultant solid was washed with three 20 ml portions of ethyl ether and dried under vacuum to yield 1.24 g (75.2% based on bromoacetyl bromide) of BrADNAZ as a white solid (mp = 124-1250C). 1H NMR (CDCl3): δ 3.76 (s, 2H), 4.88 (br s, 2H), 5.14 (br s, 2H); 13C NMR (CDCl3): δ 165.2, 105.0, 59.72, 57.79, 23.90. CaIc. for C5H6BrN3O5: %C 22.41, %H 2.26, %N 15.68; Found: %C 22.61, %H 2.36, %N 15.58.
HPLC/MS C-8 reverse phase column with acetonitrile/water mobile phase – m/e 266.95 (100%), 268.95 (98.3%). FT-IR 3014.24 (weak), 1677.66, 1586.30, 1567.65, 1445.55 (NO2), 1367.80, 1338.00, 1251.27 cm‘1.

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References

  1.  Oronsky B, Takahashi L, Gordon R, Cabrales P, Caroen S, Reid T (2023). “RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist”. Frontiers in Oncology. 13 1204143. doi:10.3389/fonc.2023.1204143. PMC 10258348. PMID 37313460.
  2.  Jayabalan N, Oronsky B, Cabrales P, Reid T, Caroen S, Johnson AM, et al. (April 2023). “A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation”. Drugs. 83 (5): 389–402. doi:10.1007/s40265-023-01838-z. PMC 10015535. PMID 36920652.
  3.  Ryan C (30 March 2023). “FDA Grants Fast Track Designation to RRx-001 for Severe Oral Mucositis in Head and Neck Cancer”. OncLive.
Clinical data
Other namesRrx-001
Identifiers
IUPAC name
CAS Number925206-65-1
PubChem CID15950826
DrugBankDB12060
ChemSpider13092644
UNII7RPW6SU9SC
KEGGD12720
ChEMBLChEMBL3526802
Chemical and physical data
FormulaC5H6BrN3O5
Molar mass268.023 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

/////////Nibrozetone, anti-inflammatory, RRx-001, RRx 001, ABDNAZ

Neladalkib

November 10, 2025 2:28 am / Leave a comment


Neladalkib

CAS 2739866-40-9

MF C23H22ClFN6O MW 452.9 g/mol

(19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentazapentacyclo[19.3.1.02,6.08,12.013,18]pentacosa-1(25),2(6),4,8,11,13(18),14,16,21,23-decaen-22-amine

anaplastic lymphoma kinase (ALK) inhibitor, antineoplastic, NVL-655, NVL 655, J32P26A6BC, ALK-IN-27


Neladalkib is a small molecule drug. The usage of the INN stem ‘-alkib’ in the name indicates that Neladalkib is a ALK (anaplastic lymphoma kinase) inhibitor. Neladalkib is under investigation in clinical trial NCT06765109 (Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC). Neladalkib has a monoisotopic molecular weight of 452.15 Da.

ALK Inhibitor NVL-655 is an orally bioavailable, brain-penetrant, selective small molecule inhibitor of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Upon oral administration, ALK inhibitor NVL-655 specifically targets, binds to and inhibits ALK fusion proteins and activating mutations, including the acquired resistance mutations solvent front mutation (SFM) G1202R and the compound mutations G1202R/L1196M and G1202R/G1269A. The inhibition of ALK leads to the disruption of ALK-mediated signaling and the inhibition of cell growth in ALK-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a variety of tumor cell types. NVL-655 is able to penetrate the blood-brain-barrier (BBB) and may therefore exert its activity against EGFR-driven central nervous system (CNS) primary tumors and CNS metastases.

  • Expanded Access Program of Neladalkib (NVL-655) for Patients With Advanced ALK+ NSCLC or Other ALK+ Solid TumorsCTID: NCT06834074Status: AvailableDate: 2025-09-22
  • Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLCCTID: NCT06765109Phase: Phase 3Status: RecruitingDate: 2025-08-29
  • A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)CTID: NCT05384626Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-07-24

SYN

WO2023196910

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023196910&_cid=P20-MHSIQF-58684-1

SYN

WO-2023196900

PAT

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Nefextinib

November 9, 2025 8:27 am / Leave a comment


Nefextinib

CAS 2070931-57-4

MF C22H23FN6OS MW 438.52

7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-[1-(piperidin4-yl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-2-amine

7-(4-FLUORO-2-METHOXYPHENYL)-6-METHYL-N-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL) THIENO (3,2-D)PYRIMIDIN-2-AMINE
tyrosine kinase inhibitor, antineoplastic, DL772G3NN7, MAX-40279, MAX 40279

Nefextinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) and FMS-like tyrosine kinase 3 (FLT3; CD135; STK1; FLK2), with potential antineoplastic activity. Upon oral administration, nefextinib binds to and inhibits both FGFR and FLT3, including FLT3 mutant forms, which results in the inhibition of FGFR/FLT3-mediated signal transduction pathways. This inhibits proliferation in FGFR/FLT3-overexpressing tumor cells. FGFR, a family of receptor tyrosine kinases, is upregulated in many tumor cell types. FLT3, a class III receptor tyrosine kinase (RTK), is overexpressed or mutated in most B-lineage neoplasms and in acute myeloid leukemias. They both play key roles in cellular proliferation and survival.

  • A Phase 2 Study to Evaluate the Safety and Efficacy of Max-40279-01 in Patients With Advanced Gastric Cancer or Gastroesophageal Junction CancerCTID: NCT05395780Phase: Phase 2Status: Unknown statusDate: 2022-06-02
  • MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)CTID: NCT03412292Phase: Phase 1Status: Unknown statusDate: 2022-01-19
  • MAX-40279-01 in Patients With Advanced Solid TumorsCTID: NCT04183764Phase: Phase 1Status: Unknown statusDate: 2022-01-19
  • Study of MAX-40279 in Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)CTID: NCT04187495Phase: Phase 1Status: Unknown statusDate: 2022-01-19
  • A Clincal Study of Max-40279-01 in Patients With Advanced Colorectal CancerCTID: NCT05130021Phase: Phase 2Status: Unknown statusDate: 2021-12-06

SYN

example 31 [CN106366093A]

SYN

WO-2017012559

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017012559&_cid=P22-MHRG1L-67142-1

Example 31 

[0488]N-[7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)-1H-pyrazol-4-amine (compound 31)

Synthesis of compound 31-e 

[0491]2,4-Dichloro-6-methylthiophene[3,2-d]pyrimidine (10 g, 45.6 mmol) was dissolved in tetrahydrofuran (100 mL) and ethanol (100 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (12.5 g, 198 mmol) was added in portions. The reaction mixture was brought to room temperature and stirred for 16 hours. It was then diluted with water (500 mL) and adjusted to pH 7 with 1 N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phase was washed successively with water (100 mL × 3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 31-e (7.5 g, yield: 88%). This product required no further purification. LC-MS (ESI): m/z = 187 [M+H] + . 

[0492]Synthesis of compound 31-d 

[0493]Compound 31-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0 °C, and activated manganese dioxide (35 g, 400 mmol) was added. The reaction mixture was brought to room temperature and stirred for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with chloroform (100 mL × 3). The combined filtrates were concentrated under reduced pressure to give a white solid 31-d (6.6 g, yield: 89%), which did not require further purification. LC-MS (ESI): m/z = 185 [M + H]+. 

[0494]Synthesis of compound 31-c 

[0495]Compound 31-d (3.1 g, 16.8 mmol) was dissolved in trifluoroacetic acid (30 mL) at 0 °C. N-iodosuccinimide (5.7 g, 25.3 mmol) was added in portions. The reaction mixture was brought to room temperature and stirred for 1 hour. The reaction was quenched with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phase was washed successively with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 31-c (4.9 g, yield: 94%). This product required no further purification. LC-MS (ESI): m/z = 311 [M + H] + . 

[0496]Synthesis of compound 31-b 

[0497]Compound 31-c (615 mg, 1.98 mmol), 2-methoxy-4-fluorophenylboronic acid (405 mg, 2.38 mmol), and sodium carbonate (630 mg, 5.94 mmol) were suspended in dioxane (5 mL) and water (5 mL). A [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (163 mg, 0.2 mmol) was added. The mixture was purged three times with nitrogen and heated to 80 °C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was separated into layers by dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to give a white solid 31-b (240 mg, yield: 39%). LC-MS (ESI): m/z = 309 [M+H] + . 

[0498]Synthesis of compound 31-a 

[0499]Compound 31-b (240 mg, 0.78 mmol) and compound 32-c (208 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (323 mg, 2.34 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (112 mg, 0.24 mmol), and tris(dibenzylacetone)palladium (134 mg, 0.24 mmol) were added. The reaction was carried out under nitrogen protection at 110 °C for 16 hours. After cooling to room temperature, the reaction mixture was separated into layers by dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow viscous oil 31-a (190 mg, yield: 45%). LC-MS(ESI): m/z = 539[M+H] + . 

[0500]Synthesis of Compound 31 

[0501]31-a (190 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated into layers by ethyl acetate (50 mL) and 1N hydrochloric acid aqueous solution (50 mL). The aqueous phase was adjusted to pH = 10 with saturated potassium carbonate aqueous solution, and a solid precipitated. The solid was filtered, and the filter cake was washed with water (20 mL × 3). The solid was dried under vacuum to give a light yellow solid 31 (22 mg, yield: 14%). LC-MS (ESI): m/z = 439 [M+H] + . 

[0502]

1H-NMR(400MHz,MeOD)δ:8.78(d,J＝5Hz,1H),7.87(s,1H),7.48(s,1H),7.35(m,1H),7.05(dd,J＝11Hz,J＝2Hz,1H),6.91(m,1H),4.10(m,1H),3.79(s,3H),3.22(m,2H),2.77(m,2H),2.47(s,3H),2.03(m,2H),1.73(m,2H)ppm

PAT

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//////////nefextinib, tyrosine kinase inhibitor, antineoplastic, DL772G3NN7, MAX-40279, MAX 40279

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DR ANTHONY MELVIN CRASTO

ANTHONY MELVIN CRASTO MY BLOGS......... ALL ABOUT DRUGS, WORLD DRUG TRACKER, MEDICINAL CHEM INTERNATIONAL, DRUG SYN INTERNATIONAL SCALEUP OF DRUGS,   MEDICINAL CHEM INTERNATIONAL, DRUG SYN INTERNATIONAL, SCALEUP OF DRUGS, EUREKAMOMENTS, and my new blog API SYNTHESIS INTERNATIONAL  
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I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP