Ralometostat

 

Ralometostat

CAS 2760481-53-4

MF C21H23N5O2S MW409.51

(2R,5S)-N-(6-Amino-5-methyl-3-pyridinyl)-2-(5-benzothiazolyl)-5-methyl-α-oxo-1-piperidineacetamide

1-Piperidineacetamide, N-(6-amino-5-methyl-3-pyridinyl)-2-(5-benzothiazolyl)-5-methyl-α-oxo-, (2R,5S)-

N-(6-amino-5-methylpyridin-3-yl)-2-[(2R,5S)-2-(1,3-benzothiazol -5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide

N-(6-amino-5-methylpyridin-3-yl)-2-[(2R,5S)-2-(1,3-benzothiazol -5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide
antineoplastic, TNG908, TNG 908, X7CRL5YNN5

Ralometostat (also known as TNG908) is an experimental, orally active oncology drug designed to treat advanced or metastatic solid tumors. It is classified as a potent, brain-penetrant, and selective methylthioadenosine (MTA)-cooperative PRMT5 inhibitor.

Developed by Tango Therapeutics, the drug targets specific genetic deletions frequently found in various human cancers.

---

Mechanism of Action

Ralometostat relies on a concept called synthetic lethality.

• Target Deletion: It targets cancers that have a deletion of the methylthioadenosine phosphorylase (MTAP) gene. This deletion occurs in roughly 10% to 15% of all human cancers.
• The "Trap": When the MTAP gene is missing, a metabolite called MTA builds up heavily inside the tumor cells.
• Selective Killing: Ralometostat specifically binds to this PRMT5•MTA complex. This enables it to selectively kill MTAP-deleted cancer cells while sparing normal, healthy tissues.

This targeted approach bypasses the severe bone marrow toxicities caused by older, non-selective first-generation PRMT5 inhibitors.

Key Clinical Features

• Blood-Brain Barrier Penetration: The drug is chemically optimized to cross the blood-brain barrier. This makes it highly effective in evaluating tumors within the central nervous system (CNS).
• Therapeutic Targets: It is studied in clinical oncology settings for several tumor types, including:
  • Glioblastoma (GBM) and brain metastases.
  • Non-small cell lung cancer (NSCLC).
  • Malignant peripheral nerve sheath tumors (MPNST) and soft tissue sarcomas.
  • Urothelial carcinoma and cholangiocarcinoma.
  • Safety and Tolerability of TNG908 in Patients With MTAP-deleted Solid TumorsCTID:
  • NCT05275478
  • Phase:
  • Phase 1/Phase 2
  • Status:
  • Terminated
  • Date:
  • 2026-04-15

---

Chemical & Trial Profile

Development Phase: Evaluated in Phase I/II clinical trials (such as NCT05275478) as a standalone precision therapy and in combination with other targeted inhibitors

Ralometostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, ralometostat selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms and is essential for the viability of cancer and normal cells. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA binds to and partially inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors. This may spare normal, healthy cells that are without MTAP-deletions and lower systemic toxicity.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US358600101&_cid=P11-MSTR3S-83508-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US399951504&_cid=P11-MSTR3S-83508-1

Example 1. The synthesis of N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound (I)) and N-(6-amino-5-methylpyridin-3-yl)-2-((2S,5R)-2-(benzo [d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (Compound (Ia))

The enantiomers were separated by chiral HPLC (column: IC II, Hexane-IPA-MeOH, 50-25-25, 12 ml/min as mobile phase) to give the two individual enantiomers Compound (Ia)N-(6-amino-5-methylpyridin-3-yl)-2-((2 S, 5R)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (161 mg, 393.16 μmol, 97.28% yield) RetTime=32.4 min, [α]21D=−176.7°(c=0.1 g/100 mL, EtOH) and Compound (I)N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (160 mg, 390.72 μmol, 96.68% yield) RetTime=45.8 min, [α]21D=+191.5° (c=0.1 g/100 mL, EtOH).

Compound (I): RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=47.098 min.

1H NMR (600 MHz, DMSO-d6) δ 0.98-1.06 (m, 3H), 1.30-1.42 (m, 1H), 1.66-1.75 (m, 1H), 1.82-1.91 (m, 1H), 1.95-2.04 (m, 3H), 2.06-2.23 (m, 1H), 2.26-2.35 (m, 1H), 2.76-3.27 (m, 1H), 3.38-4.06 (m, 1H), 5.26-5.60 (m, 1H), 5.60-5.76 (m, 2H), 7.39-7.46 (m, 1H), 7.50 (s, 1H), 7.92-8.01 (m, 1H), 8.01-8.06 (m, 1H), 8.13-8.20 (m, 1H), 9.37-9.43 (m, 1H), 10.50-10.70 (m, 1H).

LCMS(ESI): [M+H] + m/z: calcd 409.2; found 410.0; Rt=1.992 min.

Compound (Ia) RT (IC, Hexane-IPA-MeOH, 50-25-25, 0.6 ml/min)=35.176 min.

1H NMR (600 MHz, DMSO-d6) δ 1.00-1.05 (m, 3H), 1.27-1.40 (m, 1H), 1.64-1.75 (m, 1H), 1.82-1.93 (m, 1H), 1.95-2.04 (m, 3H), 2.07-2.25 (m, 1H), 2.27-2.35 (m, 1H), 2.75-3.27 (m, 1H), 3.42-4.11 (m, 1H), 5.28-5.59 (m, 1H), 5.60-5.74 (m, 2H), 7.40-7.45 (m, 1H), 7.49 (s, 1H), 7.94-8.01 (m, 1H), 8.01-8.06 (m, 1H), 8.13-8.19 (m, 1H), 9.36-9.42 (m, 1H), 10.52-10.58 (m, 1H).

LCMS(ESI): [M+H] + m/z: calcd 409.2; found 410.2; Rt=2.001 min.

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References

• Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted CancersPublication Name:Journal of Medicinal ChemistryPublication Date:2024-04-10PMCID:PMC11056935PMID:38595098DOI:10.1021/acs.jmedchem.4c00133
• [Intracellular protein breakdown. VI. Isolation, properties and biological significance of cathepsin D from rat liver]Publication Name:Acta biologica et medica GermanicaPublication Date:1976PMID:9765

PAT

Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful for the treatment of MTAP-deficient and/or MTA-accumulating cancersPublication Number:

KR-20230094196-APriority Date:

2020-07-31

• Compounds and methods of usePublication Number:US-2023113778-A1Priority Date:2020-07-31
• Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful in the treatment of MTAP deficiency and/or MTA accumulation cancersPublication Number:CN-116568677-APriority Date:2020-07-31
• Compounds and methods of usePublication Number:US-11999727-B2Priority Date:2020-07-31Grant Date:2024-06-04
• Compounds and methods of usePublication Number:US-2022127256-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-12264154-B2Priority Date:2020-07-31Grant Date:2025-04-01
• Crystalline form of n-(6-amino-5-methylpyridin-3-yl)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide, pharmaceutical compositions and methods of use thereofPublication Number:EP-4448517-A1Priority Date:2021-12-17
• Compounds and methods of usePublication Number:US-2024279219-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-2024228478-A1Priority Date:2020-07-31
• Compounds and methods of usePublication Number:US-11492350-B2Priority Date:2020-07-31Grant Date:2022-11-08
• Piperidin-1-yl-n-pyrydine-3-yl-2-oxoacetamide derivatives useful for the treatment of mtap-deficient and/or mta-accumulating cancersPublication Number:EP-4188920-A1Priority Date:2020-07-31
• Prmt5 inhibitors for use in methods of treating mta-accumulating cancerPublication Number:WO-2025217297-A1Priority Date:2024-04-09
• Prmt5 inhibitor for use in cancer therapyPublication Number:WO-2024170488-A1Priority Date:2023-02-13
• Methods of treatment of cancerPublication Number:TW-202423435-APriority Date:2022-08-15
• MTA synergizes with PRMT5 inhibitors for cancer treatmentPublication Number:CN-119730853-APriority Date:2022-08-15
• Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number:WO-2024038004-A1Priority Date:2022-08-15

//////////ralometostat, anax labs, antineoplastic, TNG908, TNG 908, X7CRL5YNN5

#ralometostat, #anax labs, #antineoplastic, #TNG908, #TNG 908, #X7CRL5YNN5

Ratutrelvir

 

Ratutrelvir

CAS 2929236-94-0

MF C27H32F3N5O4 MW547.6 g/mol

(1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxo-1,3-dihydroindol-3-yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

3-Azabicyclo[3.1.0]hexane-2-carboxamide, N-[(1S)-1-cyano-2-(2,3-dihydro-2-oxo-1H-indol-3-yl)ethyl]-3-[(2S)-3,3-dimethyl-1-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyl]-6,6-dimethyl-, (1R,2S,5S)-

(1R,2S,5S)-N-{(1S)-1-cyano-2-[(3RS)-2-oxo-2,3-dihydro-1H-indol-3-yl]ethyl}-3-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
protease inhibitor, antiviral, TRX01, 83-0060, TRX 01, VR2S5588W2,

Ratutrelvir is an investigational new drug that is being evaluated by Traws Pharma^[1] for the treatment of COVID-19 infections.^[2][3] It is a 3C-like protease inhibitor.^[3][4]

Clinical trials

Ratutrelvir is currently in a phase 2 clinical trial to test the effectiveness and safety of the drug in patients with COVID-19^[5] and a preliminary analysis of the results has been released.^[6]

Ratutrelvir (also known as TRX01 or 83-0060) is an investigational, oral antiviral medication being developed by Traws Pharma for the treatment of mild-to-moderate COVID-19.

Key Characteristics

• Mechanism: It functions as a covalent inhibitor of the SARS-CoV-2 main protease (\(M^{pro}\) / 3CL protease), preventing the virus from replicating.
• Ritonavir-Free: Unlike Paxlovid, ratutrelvir does not require a metabolic booster like ritonavir. This prevents severe drug-drug interactions and broadens its usability.
• Dosing: It is designed as a once-daily oral regimen taken over 10 days.

Clinical Development & Trial Results

According to Phase 2 data released by Traws Pharma in early 2026:

• Efficacy: Shows a comparable or faster time to sustained symptom resolution compared to Paxlovid.
• No Viral Rebound: Patients treated with ratutrelvir experienced no viral rebound events.
• Paxlovid-Ineligible Benefit: The drug successfully treated patients who could not take Paxlovid due to medical contraindications.
• Fewer Side Effects: It reported fewer treatment-related adverse events (10% vs 23.3% for Paxlovid) and avoids taste disturbances (dysgeusia).

PAT

[WO2023093834A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023093834&_cid=P11-MSWMDL-65476-1

Example 1: Preparation of (1R,2S,5S)-N-((2S)-1-amino-1-carbonyl-3-(2-carbonyldihydroindole-3-yl)propane-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 1) 

[0138]The synthesis route is as follows:

The structural characterization data of compound 1-P2 are as follows: 

[0153]m/z(ESI):548[M+H] 。 

[0154]

¹H NMR:(400MHz,DMSO-d6)δ10.58-10.41(m,1H),9.42-9.00(m,2H),7.39-7.26(m,1H),7.21-7.13(m,1H),7.03-6.78(m,2H),5.30-5.16(m,1H),4.44-4.30(m,1H),4.22(s,1H),4.00-3.86(m,1H),3.75-3.64(m,1H),3.58-3.47(m,1H),2.19-2.05(m,1H),1.63-1.54(m,1H),1.35(d,J＝7.7Hz,1H),1.04(s,3H),1.01-0.96(m,2H),0.94(s,2H),0.90-0.79(m,9H)。

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4879FE25FD0F775B266E953E785747E1.wapp1nB?docId=WO2026122604&_cid=P11-MSWM6K-58737-1

Synthesis of compound (I)

31.

ASB

Synthesis of compound (I)

31.

ASB

PAT

• Compounds for treatment a coronavirus infectionPublication Number:WO-2023245162-A2Priority Date:2022-06-17
• Compounds for treatment a coronavirus infectionPublication Number:EP-4540227-A2Priority Date:2022-06-17
• Pyrrolidine antiviral compoundPublication Number:WO-2023093834-A1Priority Date:2021-11-26

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References

References

1.  WO 2023245162, Rogovoy B, Kysil V, Berishvili V, Pauza CD, Zapata JC, Moreno SM, Li H, Orry A, Lam PC, Abagyan R, Savchuk N, "Compounds for treatment a coronavirus infection", published 2023-12-21, assigned to Trawsfynydd Therapeutics Inc.
2.  "International Nonproprietary Names for Pharmaceutical Substances (INN) Recommended INN: List 94" (PDF). WHO Drug Information. 39 (3). World Health Organization: 809–1060 (976). 2025.
3.  "Travatrelvir - Traws Pharma". AdisInsight. Springer Nature Switzerland AG. Retrieved 5 July 2026.
4.  "Ratutrelvir | Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY.
5.  "Early-stage Trial to Determine a Safe and Effective Dose for Ratutrelvir in Patients With Mild to Moderate COVID-19". ClinicalTrials.gov. U.S. National Library of Medicine. 17 January 2026. Clinical trial record for NCT07157007. Retrieved 5 July 2026.
6.  Contagion Editorial Team (8 July 2026). "Traws Pharma Reports Differentiated COVID-19 and Influenza Antiviral Progress". Contagion Live.

Clinical data
Other names	83-0060, TRX01
Identifiers
IUPAC name
CAS Number	2929236-94-0
PubChem CID	169861725
IUPHAR/BPS	13737
UNII	VR2S5588W2
Chemical and physical data
Formula	C27H32F3N5O4
Molar mass	547.579 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

///////////ratutrelvir, anax labs, protease inhibitor, antiviral, TRX01, 83-0060, TRX 01, VR2S5588W2,

#ratutrelvir, #anax labs, #protease inhibitor, #antiviral, #TRX01, #83-0060, #TRX 01, #VR2S5588W2,

Iberdomide

 

Iberdomide

CAS 1323403-33-3

as HCl: 1560678-63-8

MW 449.5 g/mol, C₂₅H₂₇N₃O₅

(S)-3-(4-((4-(Morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

(3S)-3-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione

8/13/2026, APPROVAL 2026, FDA 2026, Zenbexus, cc-220, cc 220, 8V66F27X44, 79L3645KFI

To be used in combination with daratumumab and hyaluronidase-fihj and dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent

Iberdomide is a modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase), with immunomodulating and pro-apoptotic activities. Upon administration, iberdomide specifically binds to the cereblon (CRBN) part of the ligase complex, thereby affecting the ubiquitin E3 ligase activity, and targeting certain substrate proteins for ubiquitination. This induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3) which are transcriptional repressors in T-cells. This leads to a reduction of their protein levels, and the modulation of the immune system, including activation of T-lymphocytes. In addition, this leads to a downregulation of other proteins, including interferon regulatory factor 4 (IRF4), which plays a key role in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins.

Iberdomide, sold under the brand name Zenbexus, is an anti-cancer medication used for the treatment of multiple myeloma.^[1] It is a cereblon-modulating protein degrader^[1] and a thalidomide analog.^[2]. It is taken By mouth.^[1]

Iberdomide was approved for medical use in the United States in August 2026.^[3]

Medical uses

Iberdomide is indicated in combination with daratumumab, hyaluronidase, and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.^[3]

Society and culture

Legal status

Iberdomide was approved for medical use in the United States in August 2026.^[12] The U.S. Food and Drug Administration (FDA) granted the application for iberdomide priority review, breakthrough therapy, and orphan drug designations.^[3]

Names

Iberdomide is the international nonproprietary name.^[13]

Iberdomide is sold under the brand name Zenbexus.^[14]

SYN

compound 6 [PMID: 28425720]

SYN

https://pubs.acs.org/oprdfk/article-abstract/28/1/46/975719/Process-Development-and-Kilogram-Scale-Manufacture?redirectedFrom=fulltext

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011100380&_cid=P12-MSZHNS-67589-1

5.2 3-[4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO- 1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 3 : To the THF solution of methyl 5-amino-4-(4-(4- (morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (40 g, 83 mmol), was added potassium 2-methylpropan-2-olate (9.80 g, 87 mmol) portion wise at 0°C. The mixture was stirred at this temperature for 30 minutes. To the reaction mixture, was added 45 mL of 1N HCl solution, followed by 200 mL of saturated NaHCO₃ solution. The mixture was diluted with 500 mL of EtOAc at 0°C, stirred for 5 minutes and separated. The organic layer was washed with water (50 mL × 3) and brine (100 mL), and concentrated on rota-vap to give a white solid, which was stirred in diethyl ether (300 mL) to give a suspension. The suspension was filtered to give 3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione as white solid (28.5g, 72% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9 × 150 mm, 1 mL/min, 240 nm, gradient to 95/5 acetonitrile/0.1% H₃PO₄ in 5 min,: t_R = 4.78 min (98.5%); mp: 209-21 1 °C; ¹H NMR (DMSO-d₆) δ 1.86 - 2.09 (m, 1H, CHH), 2.29 - 2.38 (m, 4H, CH₂,CH₂), 2.44 (dd, J = 4.3, 13.0 Hz, 1H, CHH), 2.53 - 2.64 (m, 1H, CHH), 2.82 - 2.99 (m, 1H, CHH), 3.46 (s, 2H, CH₂), 3.52 - 3.61 (m, 4H, CH₂,CH₂), 4.18 - 4.51 (m, 2H, CH₂), 5.11 (dd, J = 5.0, 13.3 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.27 - 7.38 (m, 5H, Ar), 7.40 - 7.53 (m, 3H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 45.09, 51.58, 53.14, 62.10, 66.17, 69.41,

114.97, 115.23, 127.64, 128.99, 129.81, 129.95, 133.31, 135.29, 137.68, 153.50, 168.01,

170.98, 172.83; LCMS: 465; Anal Calcd for C₂₅H₂₇N₃O₅ + 0.86 H₂O: C, 64.63; H, 6.22; N,

9.04; Found: C, 64.39; H, 6.11; N, 8.89; H₂O, 3.24.

5.61 (S)-3-[4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3- DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

[386] Step 1 : Preparation of (S)-4-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid methyl ester

To a 2-L round bottom flask was charged methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (30 g, 103 mmol), 1,4-bis(bromomethyl)benzene (81 g, 308 mmol) and potassium carbonate (14.19 g, 103 mmol) and acetonitrile (1.2 L). The mixture was stirred at room temperature for 10 min and heated to 50°C for 12 hours. The reaction mixture was allowed to cool to room temperature. The mixture was filtered and the filtrate was concentrated on rota-vap. The resulted solid was dissolved in CH₂Cl₂ and loaded on 2 silica gel columns (330 g each) eluted using CH2Cl2/MeOH to give 4-[4-(4-bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid methyl ester as white solid (40g, 82%). ¹H NMR (DMSO-d₆) δ 1.98 - 2.13 (m, 1H, CHH), 2.14 - 2.23 (m, 1H, CHH), 2.23 - 2.32 (m, 2H, CHH, CHH), 3.50 (s, 3H, CH₃), 4.34 - 4.63 (m, 2H, CH₂), 4.67 - 4.80 (m, 3H, CH₂, NCH), 5.25 (s, 4H, CH₂), 7.19 (s, 1H, NHH), 7.24 - 7.34 (m, 2H, Ar), 7.41 - 7.54 (m, 5H, Ar), 7.58 (br. s., 1H, NHH)

[387] Step 2: Preparation of (S)-4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester

To the CH₂Cl₂ solution of methyl 5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (36.5 g, 77 mmol) was added morpholine (14.72 ml, 169 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was added 200 mL of CH₂Cl₂, washed with water (100mL × 2) and brine (100 ml), dried in Na₂SO₄ and concentrated to give (S)-4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester as white foam (39 g, 100%). M.p. 66-68 °C; Waters Symmetry C-18, 3.9 X 150 mm, 5 micro, 1 mL/min, 240 nm, isocratic 15/85 CH₃CN/ 0.1% H₃PO₄ in H₂O: 7.92 min (99%). ¹H NMR (DMSO-d₆) δ 2.00 - 2.12 (m, 1HH CHH), 2.14 - 2.22 (m, 1H, CHH), 2.22 - 2.29 (m, 2H, CHH,CHH), 2.30 - 2.39 (m, 4H, CH₂,CH₂), 3.46 (s, 2H, CH₂), 3.50 (s, 3H, CH₃), 3.53 - 3.63 (m, 4H, CH₂,CH₂), 4.28 - 4.59 (m, 2H, CH₂), 4.73 (dd, J= 4.7, 10.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.14 - 7.23 (m, 1H, NHH), 7.26 - 7.39 (m, 4H, Ar), 7.41 - 7.51 (m, 3H, Ar), 7.58 (s, 1H, NHH). ¹³C NMR (DMSO-d₆) δ 24.82, 30.33, 44.78, 51.24, 53.12, 53.38, 62.09, 66.14, 69.35, 114.66, 115.12, 127.60, 129.00, 129.55, 130.18, 133.43, 135.31, 137.66, 153.42, 167.84, 171.73, 172.46; Anal Calcd for C₂₆H₃₁N₃O₆+ 0.3 H₂O: C% 64.13; H% 6.54; N% 8.63; Found: C% 63.89; H% 6.39; N% 8.56.

[388] Step 3: Preparation of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo- 1 , 3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To the THF solution of (S)-methyl 5-amino-4-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (45 g, 93 mmol) was added potassium 2-methylpropan-2-olate (10.49 g, 93 mmol) portion wise (2g X5) at -78 °C. The mixture was stirred at this temperature for 30 min then was added 250 mL of 1N HCl solution followed by 200 mL of saturated NaHCO₃ solution. The mixture was extracted with CH₂Cl₂ (150 mLx2). The organic layer was washed with water (50 mL × 3) and brine (100 mL), concentrated on rota-vap to give a white solid, which was then recrystallized from CH₃CN

(100 mL) to give (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione as white solid (32g, 76%). mp: 140-142 °C. LC-MS m/e= 450. HPLC: Waters Symmetry C₁₈, 5μm, 3.9 x 150 mm, 1 mL/min, 240 nm, isocratic

15/85 CH₃CN/0.1% H₃PO₄ in 5 min,: t_R = 5.61 min (99.5%); Chiral AGP C ₁₈ 4.0 × 150 mm, 5 μm 10/90 i-propanol/ 10 mM NH₄Ac in 20 min,: t_R = 10.07 min (99.5%); ¹H NMR

(DMSO-d₆) δ 2.28 - 2.38 (m, 4H, CH₂,CH₂), 2.44 (dd, J= 4.2, 13.1 Hz, 1H, CHH), 2.53- 2.63 (m, 1H, CHH), 2.79 - 3 02 (m, 1H, CHH), 3.49 - 3.69 (m, 4H, CH₂,CH₂), 4.11 - 4.52

(m, 2H, CH₂), 5.11 (dd, J= 5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.33 (d, J= 7.7 Hz,

4H, Ar), 7.40 - 7.52 (m, 3H, Ar), 10.97 (s, ΙΗ, ΝΗ). ¹³C NMR (DMSO-d₆) δ 22.33, 31.18,

45.06, 51.55, 53.11, 62.07, 66.14, 69.38, 114.96, 115.20, 127.61, 128.97, 129.78, 129.93,

133.28, 135.27, 137.67, 153.48, 167.97, 170.95, 172.80. LC-MS: 465; Anal Calcd for

C₂₅H₂₇N₃O₅ C: 66.80%; H: 6.05%; N: 9.35%. Found: C:66.59%; H:5.79%; N:9.26%.

PAT

• PRMT5 inhibitors and uses thereofPublication Number:US-12448388-B2Grant Date:2025-10-21
• KRAS G12D modulating compoundsPublication Number:US-12448400-B2Grant Date:2025-10-21
• Arylmethoxy isoindoline derivatives and compositions comprising them and methods of use thereofPublication Number:ES-2956743-T3Priority Date:2010-02-11Grant Date:2023-12-27
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:AU-2013245487-A1Priority Date:2010-02-11
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:AU-2013245487-B2Priority Date:2010-02-11Grant Date:2016-03-10
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:EP-3599236-B1Priority Date:2010-02-11Grant Date:2023-08-23
• Treating cancerPublication Number:US-2025325586-A1
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:US-9822094-B2Priority Date:2010-02-11Grant Date:2017-11-21
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:EP-4289838-A2Priority Date:2010-02-11
• Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the samePublication Number:US-2018037567-A1Priority Date:2010-02-11
• Arylmethoxy isoindoline derivatives and compositions comprising them and methods of using themPublication Number:ES-2713482-T3Priority Date:2010-02-11Grant Date:2019-05-22
• Arylmethoxy Isoindoline Derivatives and Compositions Comprising and Methods of Using the SamePublication Number:US-2011196150-A1Priority Date:2010-02-11

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References

References

1.  "U.S. Prescribing Information" (PDF). Packageinserts.bms.com. Retrieved 18 August 2026.
2.  Gao, Shaobing; Wang, Shichao; Song, Yongping (December 2020). "Novel immunomodulatory drugs and neo-substrates". Biomarker Research. 8 (1): 2. doi:10.1186/s40364-020-0182-y. PMC 6953231. PMID 31938543.
3.  "FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma". U.S. Food and Drug Administration (FDA). 13 August 2026. Retrieved 16 August 2026.  This article incorporates text from this source, which is in the public domain.
4.  Ye, Ying; Gaudy, Allison; Schafer, Peter; Thomas, Michael; Weiss, Daniel; Chen, Nianhang; et al. (May 2021). "First-in-Human, Single- and Multiple-Ascending-Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator". Clinical Pharmacology in Drug Development. 10 (5): 471–485. doi:10.1002/cpdd.869. PMC 8246954. PMID 32969202.
5.  Bjorklund, Chad C.; Kang, Jian; Amatangelo, Michael; Polonskaia, Ann; Katz, Mark; Chiu, Hsiling; et al. (April 2020). "Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN". Leukemia. 34 (4): 1197–1201. doi:10.1038/s41375-019-0620-8. ISSN 1476-5551. PMC 7214241. PMID 31719682.
6.  van de Donk, Niels W.C.J.; Popat, Rakesh; Larsen, Jeremy; Minnema, Monique C.; Jagannath, Sundar; Oriol, Albert; et al. (5 November 2020). "First Results of Iberdomide (IBER; CC-220) in Combination with Dexamethasone (DEX) and Daratumumab (DARA) or Bortezomib (BORT) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)". Blood. 136 (Supplement 1): 16–17. doi:10.1182/blood-2020-137743. S2CID 228828103.
7.  Thieblemont, Catherine; Munoz, Javier; Tucci, Alessandra; Visco, Carlo; Cartron, Guillaume; Corradini, Paolo; et al. (15 November 2022). "Iberdomide (CC-220) Monotherapy or in Combination with an Anti-CD20 Monoclonal Antibody As Effective Therapy in Patients with Relapsed/Refractory Lymphoma: Early Results from a Phase 1/2 Study". Blood. 140 (Supplement 1): 569–572. doi:10.1182/blood-2022-162559. S2CID 256795199.
8.  Lonial, Sagar; Amatangelo, Michael; Popat, Rakesh; Minnema, Monique C.; Zonder, Jeffrey A.; Larsen, Jeremy; et al. (13 November 2019). "Translational and Clinical Evidence of a Differentiated Profile for the Novel CELMoD, Iberdomide (CC-220)". Blood. 134 (Supplement_1): 3119. doi:10.1182/blood-2019-124298. S2CID 209233746.
9.  Amatangelo, Michael; Bjorklund, Chad C.; Kang, Jian; Polonskaia, Ann; Viswanatha, Sridevi; Thakurta, Anjan (29 November 2018). "Iberdomide (CC-220) Has Synergistic Anti-Tumor and Immunostimulatory Activity Against Multiple Myeloma in Combination with Both Bortezomib and Dexamethasone, or in Combination with Daratumumab in Vitro". Blood. 132 (Supplement 1): 1935. doi:10.1182/blood-2018-99-113383. S2CID 91382999.
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14.  "U.S. FDA Grants Accelerated Approval to Bristol Myers Squibb's First CELMoD Therapy Zenbexus, in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone (ZDd) for Patients with Multiple Myeloma, as Early as First Relapse". Bristol Myers Squibb (Press release). 13 August 2026. Retrieved 16 August 2026.

External links

• "Iberdomide ( Code - C129048 )". EVS Explore.
• "Iberdomide Hydrochloride ( Code - C141516 )". EVS Explore.
• Clinical trial number NCT04975997 for "Open-label Study Comparing Iberdomide, Daratumumab and Dexamethasone (IberDd) Versus Daratumumab, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (EXCALIBER-RRMM)" at ClinicalTrials.gov

Clinical data
Trade names	Zenbexus
Other names	CC-220
AHFS/Drugs.com	zenbexus
License data	US DailyMed: Iberdomide
Routes of administration	By mouth
Drug class	Cereblon-modulating protein degrader
ATC code	None
Legal status
Legal status	US: ℞-only[1]
Identifiers
IUPAC name
CAS Number	1323403-33-3as HCl: 1560678-63-8
PubChem CID	67335295as HCl: 72793904
IUPHAR/BPS	9618
DrugBank	DB12101
ChemSpider	52085251
UNII	8V66F27X44as HCl: 79L3645KFI
KEGG	D11134as HCl: D11135
ChEMBL	ChEMBL3989927
Chemical and physical data
Formula	C25H27N3O5
Molar mass	449.507 g·mol−1
3D model (JSmol)	Interactive imageas HCl: Interactive image
SMILES
InChI

////////iberdomide, ANAX LABS, APPROVAL 2026, FDA 2026, Zenbexus, APPROVAL 2026, FDA 2026, Zenbexus, cc-220, cc 220, 8V66F27X44, 79L3645KFI

#iberdomide, #ANAX LABS, #APPROVAL 2026, #FDA 2026, #Zenbexus, #APPROVAL 2026, #FDA 2026, #Zenbexus, #cc-220, #cc 220, #8V66F27X44, #79L3645KFI