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Zilurgisertib

September 30, 2026 2:34 am / Leave a comment

Zilurgisertib

CAS 2173389-57-4

MW 502.6 g/mol MFC₃₀H₃₈N₄O₃

Atebrioz, FDA 2026, APPROVALS 2026, L5Z9S25HO2, INCB 000928

2-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-5-[4-[(1R,5S)-3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]phenyl]pyridine-3-carboxamide

To reduce the volume of total new heterotopic ossification in adults and pediatric patients 12 years and older with fibrodysplasia ossificans progressiva

Zilurgisertib is an inhibitor of activin A receptor type 1 (activin receptor-like kinase 2; ALK2; ALK-2; ACVR1; ACTR-I), with potential anti-anemic and ossification suppressive activities. Upon administration, zilurgisertib targets, binds to and inhibits the activity of ALK-2. This prevents ALK2-mediated signaling and ALK2-mediated excessive bone morphogenetic protein (BMP) signaling. This may suppress heterotopic ossification (HO). As ALK-2 enhances the secretion of hepcidin, a peptide liver hormone and a key modulator of iron homeostasis, zilurgisertib is able to decrease hepcidin expression in the liver, thereby increasing and restoring plasma iron levels, enhancing erythropoiesis, and correcting anemia of chronic disease (ACD). ALK2, a serine/threonine receptor kinase and type I cell surface receptor for BMPs, is constitutively activated due to activating mutations in inflammatory conditions, various types of cancer, and in fibrodysplasia ossificans progressiva (FOP). Elevated serum hepcidin levels enhance storage of iron, reduce iron availability and causes iron deficiency anemia.

Zilurgisertib, sold under the brand name Atebrioz, is a medication used for the treatment of fibrodysplasia ossificans progressiva.^[1] It is an selective activin receptor-like kinase-2 (ALK2) inhibitor.^[1]^[2]

Zilurgisertib was approved for medical use in the United States in September of 2026.^[3]

Medical uses

Zilurgisertib is indicated to reduce the volume of total new heterotopic ossification (abrnomal bone formation) in people aged twelve years of age and older with fibrodysplasia ossificans progressiva.^[1]

Fibrodysplasia ossificans progressiva is a rare genetic disease caused certain mutations in the ACVR1/ALK2 gene which controls new bone growth.^[3] As a result, connective tissues such as muscle, tendons, and ligaments gradually turn into bone, causing limited movement, deformities, severe disability, and early death.^[3]

Adverse effects

Zilurgisertib can cause fetal harm based on data from animal studies.^[3]

The most common side effects include headache, joint pain, upper respiratory tract infection, nosebleeds, and nausea.^[3]

History

The effectiveness of zilurgisertib was evaluated in a randomized, double-blind, placebo‑controlled trial (NCT05090891) in which 63 participants with FOP were randomly assigned to receive zilurgisertib 100 mg or placebo once daily for 24 weeks followed by a 292-week, single-arm, open-label extension period during which participants received oral zilurgisertib 100 mg daily.^[3]

Society and culture

Legal status

Zilurgisertib was approved for medical use in the United States in September 2026.^[4] The US Food and Drug Administration granted the application for zilurgisertib fast track, priority review, and orphan drug designations for this indication.^[3]

Names

Zilurgisertib is the international nonproprietary name.^[5]

Zilurgisertib is sold under the brand name Atebrioz.^[3]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US242623881&_cid=P22-MUNHEN-48106-1

Example 34: 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (also named compound A herein)

To a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid TFA salt (Intermediate 14a, 4.10 g, 8.14 mmol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (2.17 g, 12.2 mmol) in anhydrous DMF (60 mL) was added N-methylmorpholine (2.24 mL, 20.4 mmol) and HATU (4.64 g, 12.2 mmol) under a nitrogen atmosphere at RT. The reaction mixture was stirred for 2 h and then diluted with a sat. aq. solution of NaHCO ₃ and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (Method 3b). Pure fractions were treated with a sat. aq. NaHCO ₃ solution and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄, filtered and concentrated under reduced pressure to give the title compound as an off-white solid. The absolute configuration as depicted was confirmed by X-ray crystallography of the title compound in a complex with the ALK-2 kinase domain. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.57 (d, 2H), 7.23 (d, 2H), 6.92 (s, 2H), 4.31 (s, 1H), 3.91-3.78 (m, 2H), 3.40 (bs, 1H), 3.33-3.24 (m, 2H), 3.11 (d, 1H), 2.57 (bs, 1H), 2.50-2.34 (m, 1H), 2.34 (bs, 1H), 2.12-1.94 (m, 6H), 1.90-1.72 (m, 3H), 1.71-1.51 (m, 6H), 1.51-1.34 (m, 2H), 1.31 (t, 1H), 0.82-0.68 (m, 1H). (UPLC-MS) t _R 0.54 min; ESI-MS 503 [M+H] ⁺. Chiral HPLC (ChiralPak Id, 5 μm, flow rate: 1 mL/min, detection wavelength: 270 nm, mobile phase: heptane:isopropanol 60:40 (+0.1% diethylamine)): t _R 18.7 min, 92.3% ee.

Alternative Example 34A: To a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid hydrochloride (1 kg, 1.683 mol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (343.9 g, 1.935 mol) in DMF (3500 mL) was added Et ₃N (681.2 g, 6.732 mol) and HATU (767.9 g, 2.019 mol) at RT. The reaction mixture was stirred at RT for 1 h. The mixture was heated to IT=45° C., 5% NH ₃.H ₂O solution (5200 g) was added. Stirred for about 30 min, another 5% NH ₃.H ₂O solution (1800 g) was added. The mixture was heated to IT=45° C. for 2 h. The mixture was cooled to IT=22° C. Filtered, the wet cake was washed with H ₂O (1500 mL×3). The wet cake was dried under vacuum at 45° C. for 24 h. The crude product was dissolved in acetone (3000 mL), then filtered to remove some undissolved solid. The filtrate was heated to IT=50° C. H ₂O (2000 mL) was added. The mixture was stirred at IT=50° C. for 30 min until a white precipitate formed. H ₂O (4000 mL) was added slowly. The mixture was stirred at IT=50° C. for 2 h. The mixture was cooled to IT=22° C. in 2 h, Filtered, the wet cake was washed with acetone:H ₂O=1:2 (v/v, 1000 mL×2). The wet cake was dried under vacuum at 45° C. for 24 h. total 760 g white solid was obtained (89% yield, 99.4% ee).

¹H NMR (DMSO-d6) δ: 8.32 (d, J=2.3 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.90 (s, 2H), 4.31 (s, 1H), 3.82 (m, 2H), 3.29 (m, 2H), 3.07 (d, J=8.5 Hz, 1H), 2.54 (d, J=8.3 Hz, 1H), 2.44 (dd, J=8.5, 3.5 Hz, 1H), 2.37 (m, 1H), 2.31 (td, J=10.2, 5.0 Hz, 1H), 2.04 (m, 6H), 1.80 (dt, J=7.9, 3.8 Hz, 1H), 1.71 (d, J=12.3 Hz, 1H), 1.65 (d, J=11.5 Hz, 1H), 1.62 (m, 6H), 1.38 (m, 1H), 1.34 (m, 1H), 1.29 (t, J=3.9 Hz, 1H), 0.73 (dd, J=7.9, 3.6 Hz, 1H).

¹³C NMR (DMSO-d6) δ: 167.80, 157.69, 148.28, 141.27, 134.91, 134.79, 126.40, 125.66, 123.53, 111.01, 66.22, 65.59, 59.10, 55.46, 52.04, 33.72, 31.92, 31.77, 30.59, 29.61, 24.14, 17.20.

MS(ESI-TOF): 503.3018 [M+H]+.

The starting material (hydrochloride salt) was obtained as follows:

Methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinate dihydrochloride (10 g, 19.5 mmol, 1.0 eq) was suspended in MeOH (31.7 g). A solution of NaOH (2.9 g, 72.2 mmol, 3.7 eq) in H ₂O (10 g) was then added. The reaction mixture was heated to 45±5° C. and stirred for more than 3 h, yielding a suspension.

To another flask containing acetone (200 g), 5˜6 N HCl in i-PrOH (14.8 g, 97.6 mmol, 5 eq) was added. The solution was heated to 47±3° C. Then the above MeOH suspension was added to the mixture dropwise and stirred at 47±3° C. for 3 h. The mixture was cooled down to 23±3° C. and stirred for 3 h. After filtration, the wet cake was washed with acetone (40 g). The wet cake was dried under vacuum at 55° C. for 8 h. 2-Amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid hydrochloride (12.3 g, 99.3% HPLC purity, 62.1% assay yield) was obtained as an off-white solid.

¹H NMR (DMSO-d6) δ: 11.53 (br s, 1H), 8.64 (br s, 1H), 8.54 (br s, 1H), 7.72-8.42 (m, 2H), 7.64 (br d, J=7.9 Hz, 2H), 7.38 (br d, J=7.8 Hz, 2H), 3.85-4.04 (m, 3H), 3.40-3.73 (m, 4H), 3.15-3.33 (m, 2H), 2.18 (br d, J=3.9 Hz, 1H), 1.95-2.12 (m, 4H), 1.88 (br d, J=10.0 Hz, 1H), 1.05 (br t, J=6.4 Hz, 1H).

¹³C NMR (DMSO-d6) δ: 167.2, 155.8, 144.3, 142.0, 139.6, 133.8, 127.7, 126.3, 124.1, 110.0, 65.8, 62.5, 55.7, 53.2, 29.9, 28.8, 28.7, 23.5, 16.6.

MS(ESI-TOF): 380.1974 [M+H] ⁺.

The starting material, 2-Amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinate dihydrochloride, was obtained as follows:

To a 500 mL round bottom flask were charged 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-3-ium chloride (20 g, 1 eq), EA (200 mL), and 25% K ₂CO ₃ (62 g). The mixture was stirred for 30 min until all solids were dissolved. After phase separation, the organic layer was concentrated. 2-Methyl-2-butanol (48 g, 60 mL) was added. The organic layer was concentrated. 2-Methyl-2-butanol (144 g, 180 mL) was added.

The mixture was transferred to a 500 mL Redlay. K ₂CO ₃ (18.8 g, 2.5 eq) and methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (16.8 g, 1.04 eq; see Intermediate 1e) were added. The mixture was degassed with N ₂ for three times. The mixture was heated to IT=50±5° C. within 1 h. Pd(dppf)Cl ₂ (1.2 g, 0.03 eq) was added. The mixture was heated to IT=70±3° C. and stirred for 2 h. After cooling to 22° C., H ₂O (120 g) and EA (180 g) were added and stirred for 30 min. MCC (6 g) was added and the mixture was filtered through MCC. The cake was washed with EA (54 g). After phase separation, the organic layer was washed with 5% NaCl (124 g). Quadrasil MP (Heavy metal scavenger from Johnson Matthey, 6 g) was then added to the organic layer. The mixture was heated to IT=55° C. for 8 h, filtered through MCC and washed with EA (54 g). Quadrasil MP (2 g) was added to the organic layer. The mixture was heated to IT=55° C. for 6 h, filtered through CMC and washed with EA (54 g). The organic layer was concentrated. Acetone (158 g, 200 mL) was added. After stirring at IT=22±3° C. for 30 min, the mixture was heated to IT=40±3° C. 15.5% HCl (38.4 g) was added dropwise with IT<50° C. The mixture was stirred at IT=45±3° C. for 1 h. The mixture was cooled to 22±3° C. The mixture was stirred at 22±3° C. for 1 h and filtered. The cake was washed with acetone (32 g×2). The wet cake was dried under vacuum at 50° C. for at least 8 h. The starting material was obtained, 22.5 g white solid (97.1% HPLC purity, 5.2% water content, 87% assay yield) was obtained.

¹H NMR (DMSO-d6) δ: 11.43 (br d, J=5.7 Hz, 1H), 8.62-8.80 (m, 2H), 7.85-8.58 (m, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.85-4.06 (m, 6H), 3.60-3.69 (m, 2H), 3.50-3.59 (m, 1H), 3.44 (brd, J=7.7 Hz, 1H), 3.14-3.31 (m, 2H), 2.21 (dt, J=8.4, 4.2 Hz, 1H), 1.94-2.12 (m, 4H), 1.76-1.93 (m, 1H), 1.07 (br t, J=7.1 Hz, 1H).

¹³C NMR (DMSO-d6) δ: 165.0, 154.0, 143.5, 142.0, 140.1, 132.8, 127.7, 126.5, 124.2, 110.7, 65.8, 62.5, 55.6, 53.3, 53.3, 29.9, 28.9, 28.8, 23.6, 16.8.

MS(ESI-TOF): 394.2071 [M+H] ⁺.

The starting material, 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-3-ium chloride, was obtained as follows:

To a 1 L Redlay were charged (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexan-3-ium chloride (30 g, 1 eq), dihydro-2H-pyran-4(3H)-one (13.13 g, 1.2 eq) and THF (300 mL). The mixture was stirred at IT=22±5° C. for 1 h. NaBH(OAc) ₃ (30.1 g, 1.3 eq) was added portion wise while keeping IT<30° C. The mixture was stirred at IT=22±5° C. for 2 h. 6.2% HCl (93 g, 90 ml, 1.5 eq) was added while maintaining IT<30° C. and pH<2. The mixture was stirred for 10 min. 25% K ₂CO ₃ (259 g, 210 mL) was added to adjust pH=8-9. IPAc (300 mL) was added. The mixture was stirred for 10 min. After phase separation, H ₂O (150 g) was added to the organic layer. The mixture was stirred for 10 min. After phase separation, the organic layer was concentrated under vacuum (50-100 mbar, 50° C. water bath). IPA (120 g, 150 mL) was added. The organic layer was concentrated under vacuum (50-100 mbar, 50° C. water bath). IPA (144 g, 180 mL) was added. The mixture was filtered through CMC. The cake was washed with IPA (24 g×2). H ₂O (5 g) was added to the organic layer. 31% HCl (19.3 g) was added dropwise with IT<35° C. The mixture was stirred at IT=22±5° C. for 2 h and filtered. The cake was washed with IPA (48 g×2). The wet cake was dried under vacuum at 50° C. for at least 6 h. The desired product (31.4 g, 98% HPLC purity, 78% yield) was obtained as a white solid.

¹H NMR (DMSO-d6 and D ₂O) δ: 7.46 (br d, J=8.4 Hz, 2H), 7.15 (br d, J=8.4 Hz, 2H), 3.90 (br d, J=7.8 Hz, 3H), 3.62 (br s, 1H), 3.51 (br s, 2H), 3.16-3.38 (m, 3H), 2.05-2.21 (m, 1H), 1.93 (br s, 2H), 1.49-1.71 (m, 2H), 1.05-1.30 (m, 1H).

¹³C NMR (DMSO-d6) δ: 138.3, 131.9, 129.2, 120.4, 65.5, 62.3, 56.2, 53.9, 29.1, 28.9, 24.8, 23.0. MS(ESI-TOF): 322.0761 [M+H]+

The complete way of manufacture of Alternative Example 34 A is depicted in the following Reaction Scheme 34A:

The first compound in this scheme, A1, can be obtained as follows:

Step 1-2 Synthesis of 1c and 1d

PAT

Compound A [WO2021257532A1]

PAT

example 34 [US20210155606A1]

PAT

US10710980, Example 34

PAPERS

Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase-2 (ALK2) for the Treatment of Fibrodysplasia Ossificans ProgressivaPublication Name:ACS Medicinal Chemistry LettersPublication Date:2025-10-31PMCID:PMC12621050PMID:41256990DOI:10.1021/acsmedchemlett.5c00516
Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy AdultsPublication Name:European Journal of Drug Metabolism and PharmacokineticsPublication Date:2024-12-09PMCID:PMC11802711PMID:39652202DOI:10.1007/s13318-024-00926-z

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References

“Atebrioz FDA label” (PDF). files.mirumpharma.com.
Gangat N, Tefferi A (June 2025). “Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes”. American Journal of Hematology. 100 Suppl 4: 51–65. doi:10.1002/ajh.27659. PMID 40056069.
Center for Drug Evaluation and Research (25 September 2026). “FDA Approves Third Treatment for Fibrodysplasia Ossificans Progressiva”. U.S. Food and Drug Administration. U.S. Food and Drug Administration (FDA). Retrieved 27 September 2026. This article incorporates text from this source, which is in the public domain.
“Mirum Pharmaceuticals and Incyte Announce U.S. FDA Approval of Atebrioz (zilurgisertib) for Adult and Pediatric Patients with Fibrodysplasia Ossificans Progressiva” (Press release). Mirum Pharmaceuticals. 25 September 2026. Retrieved 27 September 2026 – via Business Wire.
World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

External links

“Zilurgisertib ( Code – C175551 )”. EVS Explore.
“Zilurgisertib Fumarate ( Code – C199021 )”. EVS Explore.
Clinical trial number NCT05090891 for “To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (Progress)” at ClinicalTrials.gov


Clinical data
Trade names	Atebrioz
Other names	INCB-000928, INCB000928
License data	US DailyMed: Zilurgisertib
Routes of administration	By mouth
Drug class	Kinase inhibitor (ALK2 selective)
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	2173389-57-4 2173390-29-7
PubChem CID	138628908 162623634
IUPHAR/BPS	11888
UNII	L5Z9S25HO2 1R349830SB
KEGG	D12547 D12548
ChEMBL	ChEMBL5314579
Chemical and physical data
Formula	C₃₀H₃₈N₄O₃
Molar mass	502.659 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////zilurgisertib, anax labs, Atebrioz, FDA 2026, APPROVALS 2026, L5Z9S25HO2, INCB 000928

#zilurgisertib, #anax labs, #Atebrioz, #FDA 2026, #APPROVALS 2026, #L5Z9S25HO2, #INCB 000928

Tavapadon

September 28, 2026 3:07 am / Leave a comment

Tavapadon

CAS No.:1643489-24-0
Formula:C₁₉H₁₆F₃N₃O₃
Molecular Weight:391.34

9/25/2026, Juvmo, FDA 2026, APPROVALS 2026, CEREVEL, CVL 751, PF 6649751, PF-06649751,

To treat Parkinson’s disease in adults

Tavapadon (PF-06649751) is an orally active and highly selective dopamine D1/D5 receptor partial agonist. Tavapadon is effective in enabling movement and reducing disability and has the potential for Parkinson’s disease.

Tavapadon (developmental code names CVL-751, PF-06649751) is a dopamine receptor agonist which is under development for the treatment of Parkinson’s disease.^[2]^[3]^[4] It is under development by Cerevel Therapeutics, which acquired tavapadon from Pfizer in 2018.^[2] It is taken by mouth.^[1]

Tavapadon acts as a highly selective partial agonist of the dopamine D₁ receptor (K_i = 9 nM; IATooltip Intrinsic activity = 65%) and the dopamine D₅ receptor (K_i = 13 nM; IA = 81%).^[3]^[4]^[1] It has no significant affinity or functional activity at the D₂-like receptors (D₂, D₃, D₄) (K_i ≥ 4,870 to 6,720 nM).^[1] Tavapadon also shows biased agonism for G_s-coupled signaling at the D₁-like receptors.^[1]^[3]

As of December 2024, tavapadon has completed phase 3 clinical trials for Parkinson’s disease.^[2]

OriginatorPfizer
DeveloperCerevel Therapeutics; Pfizer
ClassAntiparkinsonians; Small molecules
Mechanism of ActionDopamine D1 receptor agonists; Dopamine D5 receptor agonists
registrationParkinson’s disease
01 Dec 2025Cerevel Therapeutics completes a phase III TEMPO-4 trial in Parkinson Disease (In adults, In elderly in the US, Australia, Bulgaria, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Serbia, Spain, and Ukraine (PO) (NCT04760769)
28 Nov 2025No recent reports of development identified for phase-I development in Parkinson’s-disease(In volunteers) in USA (PO, Tablet)
26 Sep 2025Preregistration for Parkinson’s disease (Early-stage disease, In the elderly, In adults) in USA (PO)

The industrial synthesis of tavapadon typically proceeds via a convergent sequence:

Ether Formation: Coupling of a substituted phenol derivative (such as a 4-hydroxy-2-methylphenyl component) with a 2-halogenated-3-(trifluoromethyl)pyridine (e.g., 2-chloro-3-trifluoromethylpyridine) via nucleophilic aromatic substitution ($S_NAr$) or transition-metal-catalyzed cross-coupling to construct the biaryl ether framework.
Pyrimidine Ring Construction / Functionalization: Assembly or modification of the 1,5-dimethylpyrimidine-2,4-dione core onto the substituted aryl backbone, often utilizing base-catalyzed cyclizations (e.g., using methylating agents and urea/amide derivatives).
Chiral Resolution / Final Purification: Final isolation of the target enantiomer or specific crystalline form (as outlined in WO2023102087A1 and WO2023143321) to meet active pharmaceutical ingredient (API) regulatory grades.

PAT

W02014207601

Examples 7 and 8

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014207601&_cid=P12-MUKNR1-83868-1

Step 1. Synthesis of tert-butyl 4-bromo-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (C22).

Compound C2 (800 mg, 3.65 mmol), di-tert-butyl dicarbonate (99%, 966 mg, 4.38 mmol), triethylamine (0.62 mL, 4.4 mmol) and 4-(dimethylamino)pyridine (45 mg, 0.36 mmol) were combined in tetrahydrofuran (15 mL) and heated to 70 °C for 1 hour, then allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was purified via chromatography on silica gel (Gradient: 10% to 25% ethyl acetate in heptane) to provide the product as a white solid. Yield: 1.10 g, 3.45 mmol, 94%. ¹H NMR (400 MHz, CDCl₃) δ 3.64 (s, 3H), 2.12 (s, 3H), 1.61 (s, 9H).

Step 2. Synthesis of ten-butyl 4-[4-(benzyloxy)-2-methylphenyl]-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate ( C23).

A mixture of C22 (1.00 g, 3.13 mmol), [4-(benzyloxy)-2-methylphenyl]boronic acid (98%, 1.16 g, 4.68 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) – tert-butyl methyl ether adduct (S-Phos precatalyst) (119 mg, 0.156 mmol), and cesium carbonate (3.06 g, 9.39 mmol) in 2-methyltetrahydrofuran (10 mL) and water (3 mL) was heated at 50 °C for 66 hours. The reaction mixture was diluted with water and ethyl acetate, and then filtered to remove suspended solids. The filtrate was extracted several times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in a 1:3 mixture of ethyl acetate and heptane, stirred for several minutes, and filtered, providing the product as a white solid. Yield: 970 mg, 2.22 mmol, 71%. LCMS m/z 337.2 [(M-Boc)+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.48 (m, 5H), 6.91-7.01 (m, 3H), 5.10 (s, 2H), 3.01 (s, 3H), 2.16 (br s, 3H), 1.66 (s, 9H), 1.64 (s, 3H).

Step 3. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C24).

Racemate C25 (1.30 g, 3.32 mmol) was separated into its atropenantiomers via chiral chromatography (Column: Phenomenex Lux Cellulose-2; Gradient: heptane / ethanol). The first-eluting atropenantiomer, obtained as a tan solid that exhibited a negative (-) rotation, was designated as Example 7. Yield: 536 mg, 1.37 mmol, 41%. The second-eluting atropenantiomer, also obtained as a tan solid but with a positive (+) rotation, was designated as Example 8. Yield: 553 mg, 1.41 mmol, 42%. 7: LCMS m/z 392.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (ddq, J=4.9, 1.9, 0.6 Hz, 1H), 8.30 (br s, 1H), 8.05 (ddq, J=7.6, 1.9, 0.7 Hz, 1H), 7.13-7.21 (m, 4H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H). 8: LCMS m/z 392.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (br d, J=4.9 Hz, 1H), 8.30 (br s, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.13-7.22 (m, 4H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H).

PAT

WO2015162084 SIMILAR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015162084&_cid=P12-MUKNEL-70374-1

PAT

US9334247

PAT

WO2023102087A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023102087&_cid=P12-MUKNKO-77090-1

Tavapadon, 1 , 5-dimethy I -6-(2-methy 1 -4- { [3 -(tri fluoromethyl)pyri din-2-yl]oxy}phenyl)pyrimidine-2,4(lH,3H)-dione has the following chemical structure:

and is described in International Publication No. W02014/207601. As disclosed in International Publication No. W02014/207601, the class of compounds encompassing Tavapadon, may exist as conformational isomers due to hindered rotation about a single bond, i.e., atropisomerism. In the case of Tavapadon, the atropenantiomers or atropisomers may be designated as (-)-Tavapadon or (+)-Tavapadon, depending on the optical rotation, and can include any mixture thereof, including a racemic mixture, wherein the racemic mixture can be designated as (±)-Tavapadon. According to International Publication No.

W02014/207601, the compound Tavapadon may be obtained as a racemate (i.e., (±)-Tavapadon), which may be separated by chiral chromatography into two atropenantiomers. The atropisomer exhibiting an anticlockwise (negative) rotation on a polarimeter is denoted the (-)-atropenantiomer [i.e., (-)-Tavapadon], and the atropisomer exhibiting a clockwise (positive) rotation on a polarimeter is denoted the (+)-atropenantiomer [i.e., (+)-Tavapadon],

PAT

WO2023143321 (or corresponding US20250145588A1 / CN115974803A equivalents)

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References


Clinical data
Other names	CVL-751; PF-6649751; PF-06649751
Routes of administration	By mouth^[1]
Drug class	Dopamine receptor agonist
Identifiers
IUPAC name
CAS Number	1643489-24-0
PubChem CID	86764100
ChemSpider	48062699
UNII	PT4P8MJP8L
KEGG	D11431
ChEMBL	ChEMBL3697617
CompTox Dashboard (EPA)	DTXSID301337071
Chemical and physical data
Formula	C₁₉H₁₆F₃N₃O₃
Molar mass	391.350 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

Bezard E, Gray D, Kozak R, Leoni M, Combs C, Duvvuri S (2024). “Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson’s Disease”. CNS Neurol Disord Drug Targets. 23 (4): 476–487. doi:10.2174/1871527322666230331121028. PMC 10909821. PMID 36999711. Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors, [52] with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data). Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data). Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data). […] In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine’s intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).
“Tavapadon – Cerevel Therapeutics”. Adis Insight. Springer Nature Switzerland AG.
Cerri S, Blandini F (December 2020). “An update on the use of non-ergot dopamine agonists for the treatment of Parkinson’s disease”. Expert Opinion on Pharmacotherapy. 21 (18): 2279–2291. doi:10.1080/14656566.2020.1805432. PMID 32804544. S2CID 221163451.
Hall A, Provins L, Valade A (January 2019). “Novel Strategies To Activate the Dopamine D₁ Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation”. Journal of Medicinal Chemistry. 62 (1): 128–140. doi:10.1021/acs.jmedchem.8b01767. PMID 30525590. S2CID 54469910.

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Lirafugratinib

September 26, 2026 3:00 am / Leave a comment

Lirafugratinib

CAS No.:2549174-42-5
Formula:C₂₈H₂₄FN₇O₂
Molecular Weight:509.53

FDA 2026, APPROVALS 2026, Lyrfigtu, RLY-4008, RLY 4008, 23SEPT2026

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

To adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 gene fusion or other rearrangement

Lirafugratinib (RLY-4008) is an orally active, irreversible and highly selective FGFR2 inhibitor with an IC₅₀ of 3 nM. Lirafugratinib covalently binds to Cys491. Lirafugratinib targets FGFR2 primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs.

Lirafugratinib (Lyrfigtu) received FDA approval on September 23, 2026, for adults with previously treated, unresectable or metastatic cholangiocarcinoma involving FGFR2 gene fusions or rearrangements.

Overview & Mechanism

Drug Class: An oral, selective, and irreversible FGFR2 small-molecule inhibitor.
Developer/Marketed By: Developed by Relay Therapeutics and commercialized globally by Elevar Therapeutics.
How it Works: Covalently targets the FGFR2 kinase domain to inhibit tumor-driving signaling while sparing other FGFR proteins to limit off-target effects.

Efficacy

Clinical Trial: Assessed in the phase 1/2 REFOCUS trial (NCT04526106) involving 116 previously treated, FGFR-inhibitor-naive patients.
Key Metrics: Demonstrated an objective response rate of 46%, a median duration of response of 11.8 months, and a median progression-free survival of 11.3 months.

Dosing & Administration

Recommended Dose: 70 mg orally once daily on a continuous basis until disease progression or unacceptable toxicity.

Safety & Warnings

Common Adverse Events: Hand-foot syndrome, stomatitis, nail issues, and ocular/retinal toxicities.
Special Warnings: Includes precautions for ocular toxicity, hyperphosphatemia, soft tissue mineralization, and embryo-fetal risks

PAPER

https://pmc.ncbi.nlm.nih.gov/articles/PMC10861881

SEE https://pmc.ncbi.nlm.nih.gov/articles/instance/10861881/bin/pnas.2317756121.sapp.pdf

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g,
47.16 mmol), Cs2CO3 (22.99 g, 70.75 mmol), DMF (120 mL) and a stirbar. Iodomethane (8.03 g,
56.59 mmol) was added, and the solution was stirred for 1 h at room temperature. The reaction mixture was diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate
(300 mL) three times. The combined organic layers were washed with saturated brines, dried
over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was
purified by HPLC. Concentration in vacuo resulted in 5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (5 g, 47.1 % ) as an off-white solid.

5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (5 g, 22.12 mmol), DCM (50 mL) and TFA (2 mL) and a stirbar. 1-iodopyrrolidine-2,5-
dione (5.97 g, 26.54 mmol) was added, and the solution was stirred for 2 h at room temperature.
The reaction mixture was diluted with Na2SO3 solution (200 mL), and the aqueous phase was
extracted with DCM (200 mL) three times. The combined organic layers were washed with
saturated brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting
crude material was purified by HPLC. Concentration in vacuo resulted in 5-bromo-6-iodo-7-
methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4 g, 51.3 %) as a yellow solid.

tert-butyl (4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

A resealable reaction vial was charged with 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (4 g, 11.36 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)carbamate (4.35 g, 13.63 mmol), Pd(dppf)Cl2 (994.16 mg, 1.36 mmol), K3PO4 (7.22
g, 34.08 mmol), DMF (50 mL), H2O (6.25 mL) and a stir bar before being evacuated and purged
with nitrogen three times. The mixture was stirred for 2 h at 90 °C. The reaction mixture was
diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL)
three times. The combined organic layers were washed with brines, dried over sodium sulfate,
filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel
chromatography (eluting with MeOH/DCM = 1/40). Concentration in vacuo resulted in tert-butyl
(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 63.4%)
as a yellow solid.

6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with tert-butyl (4-(4-amino-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 7.19 mmol), DCM (50 mL) and TFA (12.5mL) and a stirbar. The solution was stirred for 1 h at room temperature. The reaction mixture
was diluted with H2O (100 mL), and the aqueous phase was extracted with DCM (50 mL) three
times. The pH of aqueous phase was adjusted to 7~8, then the aqueous phase was extracted with
DCM (100 mL) three times. The combined organic layers were washed with saturated brines,
dried over sodium sulfate, filtered, and concentrated in vacuo resulted in 6-(4-aminophenyl)-5-
bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 92.1%) as a yellow solid.

N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

A resealable reaction vial was charged with 6-(4-aminophenyl)-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 6.62 mmol), pyridine (785 mg, 9.93 mmol), DCM (100
mL) and a stir bar before being evacuated and purged with nitrogen three times. Methacryloyl
chloride (757.3 mg, 7.28 mmol) was added slowly at 0 oC. Then the mixture was stirred for 2 h
at room temperature. The reaction mixture was diluted with H2O (100 mL), and the aqueous
phase was extracted with DCM (100 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by silica gel chromatography (eluting with MeOH/DCM=1/40).
Concentration in vacuo resulted in N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (1.8 g, 70.5%) as an off-white solid.

2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine

A round bottomed flask was charged with 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol), 2-fluoro4-methylpyrimidine (704 mg, 6.28 mmol), Cs2CO3 (5.12 g, 15.7 mmol) and a stirbar. DMF (20
mL) was added, and the solution was stirred for 1 h at 100 oC. The reaction mixture was diluted
with H2O (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL) three
times. The combined organic layers were washed with saturated brines, dried over sodium
sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC.
Concentration in vacuo resulted in 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (1.48 g,
99.8 %) as an off-white amorphous solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A solution/mixture of 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (500.00 mg, 1.77
mmol), bis(pinacolato)diboron (672.75 mg, 2.65 mmol), KOAc (520 mg, 5.3 mmol) and
Pd(dppf)Cl2 (129.4 mg, 0.177 mmol) in DMF (10 mL) was stirred for 2 h at 80 oC under nitrogen
atmosphere. The resulting mixture was diluted with water and extracted with EA. The combined
organic layers were washed with brines, dried over anhydrous Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure. The residue was purified by HPLC.
Concentration in vacuo resulted in 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenoxy)-4-methylpyrimidine (430 mg, 73.7%) as a yellow solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A resealable reaction vial was charged with N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (100 mg, 0.259 mmol), 2-(2-fluoro-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (102.6 mg, 0.310 mmol),
Pd(DtBPF)Cl2 (16.9 mg, 0.026 mmol), CsF (118 mg, 0.776 mmol), DMF (2 mL), H2O (0.25
mL) and a stir bar before being evacuated and purged with nitrogen three times. The mixture was
stirred for 1 h at 90 °C. The reaction mixture was diluted with H2O (10 mL), and the aqueousphase was extracted with DCM (10 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by Pre-HPLC (Column: XBridge Prep C18 OBD Column, 19*150 mm,
5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25
mL/min; Gradient: 25% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min):
6.5). Concentration in vacuo resulted in N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-
yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide ( 27.2 mg,
20.6%) as an off-white solid. LC/MS(BAS1): [M+H]+= 510.20; tR =1.405 min. 1H NMR (400
MHz, DMSO-d6) δ 9.92 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.79 – 7.72 (m, 2H), 7.38
– 7.28 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (dd, J = 8.1, 2.1 Hz, 1H), 5.98 (s, 2H), 5.80 (s, 1H),
5.54 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 2.42 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H).

PAT

WIPO Patent Publication: WO2020231990A1 (and related family filings)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020231990&_cid=P20-MUHRQT-01820-1

PAT

United States Patents: US11780845

PAT

US20230192709

https://patentscope.wipo.int/search/en/detail.jsf?docId=US399951539&_cid=P20-MUHRKD-96615-1

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References

[1]. Vivek Subbiah, et al. RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations. Cancer Discov. 2023 Sep 6;13(9):2012-2031. [Content Brief]

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Floretyrosine F 18

September 16, 2026 2:44 am / Leave a comment

Floretyrosine F 18

CAS 178433-03-9

FormulaC₁₁H₁₄[¹⁸F]NO₃

Molecular Weight226.23 g/mol

FDA UNII1326R5J1IA

FDA 2026, APPROVALS 2026, Pixclara, TELIX PHARMACEUTICALS, GLIOMA, CANCER, TLX101-CDx, TLX101-Px, 1326R5J1IA, L-(18F)FET, O-(2-((18)F)fluoroethyl)-L-tyrosine

(2S)-2-amino-3-[4-(2-[¹⁸F]fluoroethoxy)phenyl]propanoic acid, (2S)-2-amino-3-[4-(2-(¹⁸F)fluoroethoxy)phenyl]propanoic acid

To use with positron emission tomography to differentiate recurrent or progressive glioma from treatment-related change in conjunction with other diagnostic evaluations

Floretyrosine F 18 (brand name Pixclara®, also known as 18F-FET) is a newly FDA-approved radiopharmaceutical imaging drug used in positron emission tomography (PET) scans for patients with glioma (brain cancer). Developed by Telix Pharmaceuticals, it received formal U.S. Food and Drug Administration (FDA) approval on September 14, 2026, making it the first and only approved FET-PET diagnostic tracer for brain tumors in the United States.

Primary Clinical Indication

Pixclara is indicated for use in both adult and pediatric patients (1 month of age and older).

Its primary clinical purpose is to differentiate recurrent or progressive glioma from treatment-related changes (such as radiation necrosis or inflammation). Following chemotherapy or radiation, traditional MRI scans often show areas that “light up,” making it incredibly difficult for neuro-oncologists to tell whether a tumor is growing back or if the brain is simply healing from harsh treatments. Pixclara solves this diagnostic dilemma by providing metabolic clarity.

How It Works (Mechanism of Action)

Targeted Delivery: Floretyrosine F 18 is a synthetic amino acid analogue labeled with the radioactive isotope fluorine-18. [1, 2]
Cellular Uptake: Once injected intravenously, it specifically targets and binds to L-type amino acid transporters 1 and 2 (LAT1 and LAT2). These transporters are heavily overexpressed on the membranes of active glioma cells compared to healthy brain tissue.
PET Detection: The tumor cells rapidly absorb the tracer, and the energy emissions from the fluorine-18 isotope are captured by a PET scanner, creating a highly accurate metabolic map of the tumor.

Strategic & Future Impact

The approval aligns U.S. practice with international clinical guidelines—such as the National Comprehensive Cancer Network (NCCN) Guidelines®—which already recommend FET-PET imaging for brain tumor management. Furthermore, Telix Pharmaceuticals is currently conducting a Phase 3 registrational study to expand Pixclara’s indication to include the diagnosis and characterization of brain metastases (cancers that have spread to the brain from other parts of the body)

Fluoroethyl-l-tyrosine (¹⁸F), commonly known as [¹⁸F]FET, is a radiopharmaceutical tracer used in positron emission tomography (PET) imaging. This synthetic amino acid, labeled with the radioactive isotope fluorine-18, is a valuable radiopharmaceutical tracer for use in neuro-oncology for diagnosing, planning treatment, and following up on brain tumors such as gliomas. The tracer’s ability to provide detailed metabolic imaging of tumors makes it an essential tool in the clinical management of brain cancer patients. Continued advancements in PET imaging technology and the development of more efficient synthesis methods are expected to further enhance the clinical utility of [¹⁸F]FET.^[2]

Radiosynthesis

There are two common pathways for the radiosynthesis of [¹⁸F]FET. The first one utilizes a nucleophilic ¹⁸F-fluorination of ethyleneglycol-1,2-ditosylate with a subsequent ¹⁸F-fluoroethylation of a precursor di-sodium salt of L-tyrosine. This sequence requires two purification steps, two different precursors and a dual-reactor synthesis module which is not widely available in research or commercial centers.^[3]^[4]^[5] The schematic for this pathway is:^[6]

The second route of radiosynthesis is a direct nucleophilic ¹⁸F-fluorination a TET (O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine tert-butyl ester) protected precursor followed by acidic hydrolysis of protecting groups.^[3]^[4]^[7] The schematic for this pathway is:^[6]

REF

Fluorinated phenylalanines: synthesis and pharmaceutical applicationsPublication Name:Beilstein Journal of Organic ChemistryPublication Date:2020-05-15PMCID:PMC7237815PMID:32509033DOI:10.3762/bjoc.16.91
Solid-Phase Synthesis of O-(2-[18F]-Fluoro-ethyl)-l-tyrosinePublication Name:SynfactsPublication Date:2013-03-15DOI:10.1055/s-0032-1318420
Investigations into the synthesis, radiofluorination and conjugation of a new [18F]fluorocyclobutyl prosthetic group and its in vitro stability using a tyrosine model systemPublication Name:Bioorganic & Medicinal ChemistryPublication Date:2013-02-01PMID:23290251DOI:10.1016/j.bmc.2012.11.049
Microfluidic technology: An economical and versatile approach for the synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET)Publication Name:Bioorganic & Medicinal Chemistry LettersPublication Date:2012-03-15PMID:22342141DOI:10.1016/j.bmcl.2012.01.083
Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: Potential PET imaging agents for tumor detectionPublication Name:Bioorganic & Medicinal Chemistry LettersPublication Date:2011-08-15PMID:21752641DOI:10.1016/j.bmcl.2011.06.072
(18)F Labeled benzimidazole derivatives as potential radiotracer for positron emission tomography (PET) tumor imagingPublication Name:Bioorganic & Medicinal ChemistryPublication Date:2010-04-01PMID:20303769DOI:10.1016/j.bmc.2010.02.060
No carrier added synthesis of O-(2′-[18F]fluoroethyl)-l-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff basePublication Name:Bioorganic & Medicinal ChemistryPublication Date:2008-05-01PMID:18378460DOI:10.1016/j.bmc.2008.03.040
Solid-Phase Synthesis of O-(2-[18F]-Fluoro-ethyl)-l-tyrosine, DOI:10.1055/s-0032-1318420, Publication Date:2013, Publication Name:Synfacts

SYN

US20190223814/US249082034

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7C55DB9EE5B2E59D667F3571B796AE12.wapp1nB?docId=US249082034&_cid=P11-MU3HKD-32540-1

PAT

US20120189546

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73636763&_cid=P11-MU3HO5-37901-1

PAT

US20140235861

https://patentscope.wipo.int/search/en/detail.jsf?docId=US107206441&_cid=P11-MU3HO5-37901-1

Another example of an ¹⁸F-fluoroalkylation reaction to obtain a PET tracer is the reaction described by Wang et al (2006 J Radioanalyt Nuc Chem; 270(2): 439-43) used to obtain the ¹⁸F-labeled amino acid O-(2-[ ¹⁸F]fluoroethyl)-L-tyrosine ([ ¹⁸F]FET):

[ ¹⁸F]Fluoroethyl tosylate was prepared in step (i) by displacement of a tosyl group from 1,2-bistosyloxyethane by reaction with K ¹⁸F/Kryptofix 2.2.2 in acetonitrile at 90° C. for 10 minutes. The purified [ ¹⁸F]fluoroethyl tosylate was then reacted in step (ii) with a solution of L-tyrosine and 10% aqueous NaOH in DMSO (or di-Na-salt of L-tyrosine in DMSO) 20 minutes at 90° C. to obtain [ ¹⁸F]FET. In contrast to the method for preparation of ¹⁸F-labelled S-fluoroalkyl diarylguanidines as reported by Robins et al (supra), this method for preparation of [ ¹⁸F]FET uses a soluble base in the alkylation reaction. However, the reaction is still not ideal for carrying out on an automated synthesis device that uses a cassette due to the fact that and additional vial is required for the base used for the subsequent fluoroalkylation step.

PAT

Radiation radiation detector with position tracking system and its use in medical systems and proceduresPublication Number:

JP-2004512502-APriority Date:2000-08-21

Novel imaging agents and precursors and methods of preparation thereofPublication Number:CN-1234680-CPriority Date:2001-06-04Grant Date:2006-01-04
Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-2005055174-A1Priority Date:2000-08-21
Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-7826889-B2Priority Date:2000-08-21Grant Date:2010-11-02
Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-2004015075-A1Priority Date:2000-08-21
Radioactive emission detector equipped with a position tracking systemPublication Number:US-2014249402-A1Priority Date:2000-08-21
Tumor imaging compoundsPublication Number:CA-2479514-CPriority Date:2002-04-30Grant Date:2011-07-26
Protected tyrosine derivatives, method for the production thereof and use of the same for producing o-(2-[18f]-fluoroethyl)-l-tyrosinePublication Number:WO-02102765-A3Priority Date:2001-06-05
Protected tyrosine derivatives, method for the production thereof and use of the same for producing o-(2-[18f]-fluoroethyl)-l-tyrosinePublication Number:US-2004192954-A1Priority Date:2001-06-05
PROTECTED TYROSINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE PRODUCTION OF O-(2-?18 F)-FLUORETHYL)-L-TYROSINEPublication Number:AT-E289992-T1Priority Date:2001-06-05Grant Date:2005-03-15
Imaging agents, precursors thereof and methods of manufacturePublication Number:US-2003124059-A1Priority Date:2001-06-04
Radioactively labelled amino acid analogues, their preparation and usePublication Number:US-2006127306-A1Priority Date:2002-08-02
Radioactively labelled amino acid analogues, their preparation and usePublication Number:EP-1539250-A1Priority Date:2002-08-02
Tumor imaging compoundsPublication Number:US-7989649-B2Priority Date:2002-04-30Grant Date:2011-08-02
Tumor imaging compoundsPublication Number:US-2009240041-A1Priority Date:2002-04-30
Tumor imaging compoundsPublication Number:US-7544715-B2Priority Date:2002-04-30Grant Date:2009-06-09

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References

CID 54255856 from PubChem
Treglia G, Muoio B, Giovanella L (2020). “¹⁸F-FET”. In Calabria F, Schillaci O (eds.). Radiopharmaceuticals: A Guide to PET/CT and PET/MRI. Cham: Springer International Publishing. pp. 83–88. doi:10.1007/978-3-030-27779-6_4. ISBN 978-3-030-27778-9.
Bourdier T, Greguric I, Roselt P, Jackson T, Faragalla J, Katsifis A (July 2011). “Fully automated one-pot radiosynthesis of O-(2-[18F]fluoroethyl)-L-tyrosine on the TracerLab FX(FN) module”. Nuclear Medicine and Biology. 38 (5): 645–651. doi:10.1016/j.nucmedbio.2011.01.001. PMID 21718939.
Siddiq IS, Atwa ST, Shama SA, Eltaoudy MH, Omar WM (March 2018). “Radiosynthesis and modified quality control of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) for brain tumor imaging”. Applied Radiation and Isotopes. 133: 38–44. Bibcode:2018AppRI.133…38S. doi:10.1016/j.apradiso.2017.12.011. PMID 29275040.
Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al. (January 1999). “Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging”. Journal of Nuclear Medicine. 40 (1): 205–212. PMID 9935078.
Wang M, Glick-Wilson BE, Zheng QH (December 2019). “Facile fully automated radiosynthesis and quality control of O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) for human brain tumor imaging”. Applied Radiation and Isotopes. 154 108852. Bibcode:2019AppRI.15408852W. doi:10.1016/j.apradiso.2019.108852. PMID 31442794.
Mueller D, Klette I, Kalb F, Baum RP (July 2011). “Synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine based on a cartridge purification method”. Nuclear Medicine and Biology. 38 (5): 653–658. doi:10.1016/j.nucmedbio.2011.01.006. PMID 21718940.
Muoio B, Giovanella L, Treglia G (2018-09-04). “Recent Developments of 18F-FET PET in Neuro-oncology”. Current Medicinal Chemistry. 25 (26): 3061–3073. doi:10.2174/0929867325666171123202644. PMID 29173147.
Wang L, Lieberman BP, Ploessl K, Kung HF (January 2014). “Synthesis and evaluation of ¹⁸F labeled FET prodrugs for tumor imaging”. Nuclear Medicine and Biology. 41 (1): 58–67. doi:10.1016/j.nucmedbio.2013.09.011. PMC 3895945. PMID 24183614.
Lee TS, Ahn SH, Moon BS, Chun KS, Kang JH, Cheon GJ, et al. (August 2009). “Comparison of 18F-FDG, 18F-FET and 18F-FLT for differentiation between tumor and inflammation in rats”. Nuclear Medicine and Biology. 36 (6): 681–686. doi:10.1016/j.nucmedbio.2009.03.009. PMID 19647174.
Leung K (2004), “O-(2-[18F]Fluoroethyl)-L-tyrosine”, Molecular Imaging and Contrast Agent Database (MICAD), Bethesda (MD): National Center for Biotechnology Information (US), PMID 20641653, retrieved 2024-07-10
Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R (August 1999). “Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo”. Journal of Nuclear Medicine. 40 (8): 1367–1373. PMID 10450690.
Wang HE, Wu SY, Chang CW, Liu RS, Hwang LC, Lee TW, et al. (May 2005). “Evaluation of F-18-labeled amino acid derivatives and [18F]FDG as PET probes in a brain tumor-bearing animal model”. Nuclear Medicine and Biology. 32 (4): 367–375. doi:10.1016/j.nucmedbio.2005.01.005. PMID 15878506.
Rau FC, Weber WA, Wester HJ, Herz M, Becker I, Krüger A, et al. (August 2002). “O-(2-[(18)F]Fluoroethyl)- L-tyrosine (FET): a tracer for differentiation of tumour from inflammation in murine lymph nodes”. European Journal of Nuclear Medicine and Molecular Imaging. 29 (8): 1039–1046. doi:10.1007/s00259-002-0821-6. PMID 12173018.
Holzgreve A, Brendel M, Gu S, Carlsen J, Mille E, Böning G, et al. (2016-06-14). “Monitoring of Tumor Growth with [(18)F]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches”. Frontiers in Neuroscience. 10: 260. doi:10.3389/fnins.2016.00260. PMC 4906232. PMID 27378835.
“Product Characteristic of IASOglio©” (PDF). synektik.com.pl. 28 June 2024. Retrieved 28 June 2024.
Pauleit D, Floeth F, Herzog H, Hamacher K, Tellmann L, Müller HW, et al. (April 2003). “Whole-body distribution and dosimetry of O-(2-[18F]fluoroethyl)-L-tyrosine”. European Journal of Nuclear Medicine and Molecular Imaging. 30 (4): 519–524. doi:10.1007/s00259-003-1118-0. PMID 12589478.
Tang G, Tang X, Wang M, Luo L, Gan M (January 2004). “Radiation dosimetry of O-(3-[18F]fluoropropyl)-L-tyrosine as oncologic PET tracer based on the mice distribution data”. Applied Radiation and Isotopes. 60 (1): 27–32. doi:10.1016/j.apradiso.2003.10.005. PMID 14687633.
Mattsson S, Johansson L, Leide Svegborn S, Liniecki J, Noßke D, Riklund KÅ, et al. (July 2015). “Radiation Dose to Patients from Radiopharmaceuticals: a Compendium of Current Information Related to Frequently Used Substances” (PDF). Annals of the ICRP. 44 (2 Suppl): 7–321. doi:10.1177/0146645314558019. PMID 26069086.
“IASOglio”. Curium Pharma. Retrieved 2024-07-10.


Clinical data
Other names	¹⁸F-FET; O-(2-(¹⁸F)fluoroethyl)-l-tyrosine, O-(2-Fluorethyl)-l-thyrosine, l-(¹⁸F)FET^[1]
Routes of administration	Intravenous
ATC code	V09IX10 (WHO)
Identifiers
IUPAC name
CAS Number	178433-03-9
PubChem CID	9834479
ChemSpider	8010200
UNII	1326R5J1IA
CompTox Dashboard (EPA)	DTXSID601045942
Chemical and physical data
Formula	C₁₁H₁₄FNO₃
Molar mass	227.235 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////floretyrosine F 18, anax labs, FDA 2026, APPROVALS 2026, Pixclara, TELIX PHARMACEUTICALS, GLIOMA, CANCER, TLX101-CDx, TLX101-Px, 1326R5J1IA, L-(18F)FET, O-(2-((18)F)fluoroethyl)-L-tyrosine

#floretyrosine F 18, #anax labs, #FDA 2026, #APPROVALS 2026, #Pixclara, #TELIX PHARMACEUTICALS, #GLIOMA, #CANCER, #TLX101-CDx, #TLX101-Px, #1326R5J1IA, #L-(18F)FET, #O-(2-((18)F)fluoroethyl)-L-tyrosine

Rusfertide

August 30, 2026 2:34 am / Leave a comment

Rusfertide

MF
C₁₁₄H₁₈₁N₂₇O₂₈S₂ MW 2442.0 g/mol

isovaleryl-Asp-Thr-His-Phe-Pro-Cys(1)-Ile-Lys(2)-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys(1)-Lys-NH2.palmitoyl-Glu(2)-OH

(2S)-5-[4-[(3S,6S,9S,12S,15R,20R,26S,29S,32S,35S)-26-(4-aminobutyl)-6-benzyl-12-[(2S)-butan-2-yl]-32-(3-carbamimidamidopropyl)-3-(2-carboxyethyl)-15-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-3-carboxy-2-(3-methylbutanoylamino)propanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-20-[[(2S)-1,6-diamino-1-oxohexan-2-yl]carbamoyl]-29-(hydroxymethyl)-2,5,8,11,14,22,25,28,31,34-decaoxo-17,18-dithia-1,4,7,10,13,21,24,27,30,33-decazabicyclo[33.3.0]octatriacontan-9-yl]butylamino]-2-(hexadecanoylamino)-5-oxopentanoic acid

{Asp(N-(3-methyl-1-oxobutyl))}-Thr-His-Phe-Pro-Cys-Ile-{Lys(γGlu-C16 acid)}-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys-NH2 (disulfide bridge: Cys6-Cys16)

Mimrylo, APPROVALS 2026, FDA 2026, XM71MYX0IQ, PTG-300FB, PTG-300, TAK 121,

To treat erythrocytosis in adults with polycythemia vera

Rusfertide is a peptide mimetic of natural hepcidin, which targets and degrades ferroportin, reduces serum iron and transferrin-saturation, and thus regulates the production of red blood cells. Rusfertide ameliorates the polycythemia vera, β-thalassemia and hereditary hemochromatosis.

Rusfertide is an injectable peptide mimetic of hepcidin (hepcidin antimicrobial peptide; HAMP; putative liver tumor regressor; PLTR; liver-expressed antimicrobial peptide 1; LEAP-1) with potential use in the treatment of iron deficiency anemia and iron overload secondary to hematologic disorders. Upon administration, rusfertide mimics endogenous hepcidin, a protein primarily produced in hepatocytes, and increases hepcidin levels. As hepcidin plays a key role in the homeostasis of systemic iron, rusfertide may serve to normalize iron levels. Low levels of endogenous hepcidin are associated with iron overload secondary to excessive absorption of iron as seen in beta thalassemia and paradoxically with iron deficiency anemia.

Rusfertide, sold under the brand name Mimrylo, is a medication developed by Protagonist Therapeutics in partnership with Takeda for the treatment of polycythemia vera (PV).^[1][2][3]

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References


Clinical data
Trade names	Mimrylo
Other names	PTG-300; TAK-121
Identifiers
CAS Number	1628323-80-7
PubChem CID	155884410
DrugBank	DB17724
ChemSpider	129955617
UNII	XM71MYX0IQ
KEGG	D12064
ChEMBL	ChEMBL4650507
Chemical and physical data
Formula	C₁₁₄H₁₈₁N₂₇O₂₈S₂
Molar mass	2441.98 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

“Rusfertide – Protagonist Therapeutics”. AdisInsight. Springer Nature Switzerland AG.
Kremyanskaya M, Ginzburg YZ, Hoffman R (March 2026). “Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis”. Blood. 147 (12): 1278–1288. doi:10.1182/blood.2025028643. PMID 41100735.
“Protagonist and Takeda Announce ASCO Plenary Presentation Highlighting Full 32-Week Results from Phase 3 VERIFY Study of Rusfertide, Showing Reductions in Phlebotomy, Improved Hematocrit Control in Polycythemia Vera”. Takeda.

//////rusfertide, anax labs, Mimrylo, APPROVALS 2026, FDA 2026, XM71MYX0IQ, PTG-300FB, PTG 300, TAK 121,

#rusfertide, #anax labs, #Mimrylo, #APPROVALS 2026, #FDA 2026, #XM71MYX0IQ, #PTG-300FB, #PTG-300, #TAK 121,

Brepocitinib

August 28, 2026 2:41 am / Leave a comment

Brepocitinib

CAS 1883299-62-4

MF C₁₈H₂₁F₂N₇O MW389.4 g/mol

8/27/2026, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841

[(1S)-2,2-difluorocyclopropyl]-[(1R,5S)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone

To treat dermatomyositis in adults

Brepocitinib (brand name Lisraya) is an oral, once-daily dual TYK2/JAK1 inhibitor approved by the FDA for treating dermatomyositis in adults.

Developed by Roivant (via its subsidiary Priovant), it is the first oral targeted therapy indicated to manage this rare, debilitating autoimmune condition. Brepocitinib, sold under the brand name Lisraya, is a drug which acts as a dual inhibitor of JAK1 and TYK2, and was developed for the treatment of plaque psoriasis.^[1][2][3][4] It is used for the treatment of dermatomyositis.

Brepocitinib is an orally available, selective inhibitor of non-receptor tyrosine-protein kinase TYK2 (tyrosine kinase 2) and tyrosine-protein kinase JAK1 (Janus kinase 1; JAK1) with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, brepocitinib selectively binds to and inhibits the activation of TYK2 and JAK1, thereby disrupting TYK2 and JAK-1-dependent cytokine signaling. This may reduce inflammatory responses and prevent inflammation-induced damage caused by certain immunological diseases. TYK2 and JAK-1 are members of the Janus kinase family of non-receptor tyrosine kinases and are involved in signaling pathways affecting hematopoiesis, immunity and inflammation.

SYN

Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)

By: Fensome, Andrew ; et al

Journal of Medicinal Chemistry (2018), 61(19), 8597-8612

SYN

Preparation of aminopyrimidinyl derivatives as inhibitors of JAK kinases useful in therapy of diseases

Assignee: Pfizer Inc.

Inventors: Fensome, Andrew; et al

World Intellectual Property Organization

Patent#WO2016027195 A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016027195&_cid=P11-MTCC5U-40903-1

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0223523423008152

SYN

compound 23 [PMID: 30113844]

PAT

US9663526,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159751917&_cid=P11-MTCCDC-53135-1

Examples 7 and 8

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone and [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (Preparation 68, 318 mg, 2.61 mmol) in DCM (20 mL) was added 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Preparation 19, 700 mg, 2.17 mmol), HATU (1.02 g, 2.61 mmol and DIPEA (0.76 mL, 4.34 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with further ammonium chloride solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-12% MeOH and 1% NH ₄OH in DCM. The residue was dissolved in DCM and further washed with saturated aqueous ammonium chloride solution three times. The organic layer was collected, concentrated in vacuo and dried to afford the title compound (500 mg, 60%).

The title compound and its enantiomer may also be prepared according to the same method using racemic 2,2-difluorocyclopropane-1-carboxylic acid with additional chiral separation of the enantiomers after purification using the method below to afford:

Peak 1: Example 7

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

¹H NMR (400 MHz, DMSO-d ₆): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H), 3.80 (s, 3H), 4.14 (br s, 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1H), 7.44 (s, 1H), 7.74 (brs, 1H), 7.93 (d, 1H), 8.90 (brs, 1H). MS m/z 390 [M+H]; [α] _D ²⁰50.1 (c 1.27, EtOH)

PAT

New compounds for the inhibition of angiogenesis and use of thereofPublication Number:AU-2005223356-A1Priority Date:2004-03-24
Compositions and methods of use for modified release minoxidilPublication Number:US-2025325546-A1
Aminopyrimidinyl compoundsPublication Number:US-10980815-B2Priority Date:2014-08-21Grant Date:2021-04-20
Aminopyrimidinyl compounds as JAK inhibitorsPublication Number:MD-4800-C1Priority Date:2014-08-21
Aminopyrimidinyl compoundsPublication Number:US-2020330477-A1Priority Date:2014-08-21
Aminopyrimidinyl compoundsPublication Number:US-11197867-B2Priority Date:2014-08-21Grant Date:2021-12-14
Aminopyrimidinyl compoundsPublication Number:TW-201609706-APriority Date:2014-08-21

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References

Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, et al. (October 2018). “Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)”. Journal of Medicinal Chemistry. 61 (19): 8597–8612. doi:10.1021/acs.jmedchem.8b00917. PMID 30113844.
Forman SB, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, et al. (December 2020). “TYK2/JAK1 Inhibitor PF-06700841 in Patients with Plaque Psoriasis: Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial”. The Journal of Investigative Dermatology. 140 (12): 2359–2370.e5. doi:10.1016/j.jid.2020.03.962. PMID 32311398.
Martin G (February 2023). “Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors”. Dermatology and Therapy. 13 (2): 417–435. doi:10.1007/s13555-022-00878-9. PMC 9884727. PMID 36592300.
Caso F, Costa L, Triggianese P, Maione F, Bertolini N, Vastarella M, et al. (May 2023). “Recent developments for new investigational JAK inhibitors in psoriatic arthritis”. Expert Opinion on Investigational Drugs. 32 (5): 361–371. doi:10.1080/13543784.2023.2207737. PMID 37096862.


Clinical data
Trade names	Lisraya
Other names	PF-06700841
Identifiers
IUPAC name
CAS Number	1883299-62-4
PubChem CID	118878093
DrugBank	DB15003
ChemSpider	72380129
UNII	3X8387Q25N
ChEMBL	ChEMBL4297477
Chemical and physical data
Formula	C₁₈H₂₁F₂N₇O
Molar mass	389.411 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////brepocitinib, anax labs, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841, dermatomyositis

#brepocitinib, #anax labs, #APPROVALS 2026, #FDA 2026, #Lisraya, #PF 06700841, #3X8387Q25N, #PF-06700841, #dermatomyositis

Iberdomide

August 19, 2026 2:53 am / Leave a comment

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

ADVERISEMENT

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References

“U.S. Prescribing Information” (PDF). Packageinserts.bms.com. Retrieved 18 August 2026.
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.
“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.
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.
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.
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.
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.
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.
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.
Lonial, Sagar; Popat, Rakesh; Hulin, Cyrille; Jagannath, Sundar; Oriol, Albert; Richardson, Paul G; et al. (November 2022). “Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial”. The Lancet Haematology. 9 (11): e822–e832. doi:10.1016/S2352-3026(22)00290-3. PMID 36209764. S2CID 252779185.
Merrill, Joan T.; Werth, Victoria P.; Furie, Richard; van Vollenhoven, Ronald; Dörner, Thomas; Petronijevic, Milan; et al. (17 March 2022). “Phase 2 Trial of Iberdomide in Systemic Lupus Erythematosus”. New England Journal of Medicine. 386 (11): 1034–1045. doi:10.1056/NEJMoa2106535. PMID 35294813. S2CID 247499089.
Feuerstein, Adam (14 August 2026). “FDA clears Bristol multiple myeloma therapy, marking debut of new drug class”. STAT. Retrieved 14 August 2026.
World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.
“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

Zidesamtinib

July 24, 2026 2:44 am / Leave a comment

Zidesamtinib

CAS 2739829-00-4

MF C₂₂H₂₂FN₇O MW419.5 g/mol

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,9,10,11,23-hexazapentacyclo[19.3.1.0^2,6.0^8,12.0^13,18]pentacosa-1(25),2(6),4,8,11,13(18),14,16,21,23-decaen-22-amine

To treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer after receiving a ROS1 kinase inhibitor

FDA 2026, APPROVALS 2026, Jideytro, NVL-520, NUV-520, NU-520, NVL 520, NUV 520, NU 520, MX5KQV5XHC

Zidesamtinib (sold under the brand name Jideytro) is an oral, highly selective, next-generation kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) on July 22, 2026, to treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who have previously been treated with at least one ROS1 kinase inhibitor. Developed originally by Nuvalent and subsequently acquired by GSK, it represents a major milestone as GSK’s first approved therapeutic targeting lung cancer.

Mechanism of Action

Zidesamtinib functions by targeting and inhibiting the receptor tyrosine kinase c-ros oncogene 1 (ROS1). It is custom-engineered to solve the primary clinical challenges that limit previous therapies:

Overcoming Resistance Mutations: It binds tightly to wild-type ROS1 and remains robustly active against a broad array of treatment-emergent point mutants. This includes G2032R (the most common solvent-front resistance mutation), as well as S1986Y/F, L2026M, and D2033N mutations.
Blood-Brain Barrier Penetration: It features high central nervous system (CNS) penetrance to effectively treat and control brain metastases, which are frequent in aggressive ROS1-positive cancers.
TRK-Sparing Design: Unlike older dual-acting inhibitors, it deliberately avoids inhibiting the structurally similar tropomyosin receptor kinase (TRK) family. This minimizes off-target TRK-related neurological toxicities like severe dizziness and ataxia.

Clinical Trial Outcomes

The FDA approval was heavily supported by data from the ongoing global, single-arm, Phase 1/2 ARROS-1 clinical trial (N=117 heavily pretreated patients):

Overall Response: Delivered an Objective Response Rate (ORR) of 44% in patients who had exhausted alternative TKI options.
Subgroup Efficacy: Achieved a 51% ORR in patients who had received only one prior ROS1 inhibitor, a 54% ORR in those harboring the G2032R mutation, and an intracranial ORR of 48% for patients with active brain metastases.
Durability: Showed prolonged disease control, with a 12-month duration of response (DOR) rate standing at 69%.

Administration and Side Effects

Jideytro is formulated as an oral tablet taken once daily, with or without food. It demonstrates a highly tolerable safety profile, with only a 10% dose reduction rate and a 2% treatment discontinuation rate due to adverse events.

Common Adverse Reactions (≥ 15%): Edema (swelling), peripheral neuropathy, constipation, fatigue, and dyspnea (shortness of breath).
Warnings & Precautions: Includes risks of mild CNS reactions (dizziness, cognitive alterations), QTc interval prolongation, skeletal fractures, pancreatic toxicity, and interstitial lung disease (ILD)/pneumonitis.

Zidesamtinib, sold under the brand name Jideytro, is an anti-cancer medication used for the treatment of previously treated locally advanced or metastatic ROS1+ non-small cell lung cancer.^[1]^[2]^[3] It is taken by mouth once daily.^[1]^[2]^[3]

Medical uses

Indication

Zidesamtinib is a prescription medicine used to treat adults with non-small cell lung cancer that has spread within the chest or other parts of the body and is caused by an abnormal ROS1 gene, and who have received a ROS1 kinase inhibitor.^[1]^[2]^[3]

Mechanism of action

Zidesamtinib is a kinase inhibitor that works by blocking ROS1, an abnormal protein that drives some lung cancers to grow, including forms that have become resistant to earlier ROS1 treatments.^[4] Jideytro also works on the related proteins ALK and TRK. In laboratory and animal studies, Zidesamtinib stopped cancer cells with ROS1 changes from growing and slowed tumor growth, including tumors in the brain.^[2]

PAT

Example 5 [US383715659]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023056405&_cid=P10-MRYBTX-59205-1

Scheme 3. Synthesis of Compound 1.

[00548] Synthesis of Compound 5. To a reactor was charged THF (10 vol ), water (1 vol ), followed by Compound 6 (850.0 g, 2.68 mol, 1 equiv.) and Compound 7 (534.0 g, 3.22 mol, 1.2 equiv ) at 20~30°C. The solids were completely dissolved at 20~30°C while stirring for 15 min and K2CO3 (1.11 kg, 3 equiv.) was added in portions over 10-15 min at 20~30°C. The reaction mixture was fully refdled with nitrogen, and was added Pd(dppf)C12 (78.5 g, 0.04 equiv.) in one portion under nitrogen. The reaction mixture was fully refdled with nitrogen again, then heated to 60-65 °C and stirred at 60~65°C for 16 h under nitrogen. The reaction mixture was cooled to 20~30°C, fdtered through a 10 cm celite pad (2X, 2.4 kg celite). The combined fdtrates were washed with EtOAc (10 vol., 21 L) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The organic phase was stirred for 1 h at 40-45°C in 5 w% aqueous L-cysteine (2.0 eq., 1.61 kg in 30.6 kg water) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The resulting organic phase was concentrated at 45-50°C in vacuum to afford crude product as a light brown oil (2.28 kg). To the crude product was charged MTBE (228 mL, 0.1 vol. relative to crude product), heated to 50°C over 15 min, followed by isopropyl ether (2.28 L, 1 vol.) dropwise over 1 h at 45~50°C, then cooled to 10°C over 2 h. A large amount of solids came out and the resulting slurry was stirred for 2 h at 10-15°C. The solids were collected by fdtration, dried in oven at 45°C for 16 h to get crude Compound 5 as a pale-yellow solid (1.67 kg, 96.3% /220 nm, >99.9%/220 nm chiral purity). 1.67 kg of crude Compound 5 was purified by silica gel chromatography (EtOAc/ n-heptane=l: 1, 2.5X silica gel, 100-200 meshes) to get Compound 5 as an off-white solid (1.58 kg, 99.6%/220 nm, >99.9%/220 nm chiral purity, 97.9 w%, 72% yield). H NMR (400 MHz, DMSO) 5 7.44 (dd, J = 10.5, 2.5

Hz, 1H), 7.36 (s, 1H), 7.22 (dd, J = 8.3, 6.0 Hz, 1H), 7.16 – 7.08 (m, 2H), 5.25 (d, J = 4.2 Hz, 1H), 4.86 – 4.68 (m, 1H), 4.14 (s, 3H), 4.00 (q, J = 7.2 Hz, 2H), 3.72 (s, 2H), 1.27 (t, J = 7.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). MS (ESI, m/z): 330.20 (M + H)⁺.

[00549] In another example, a similar procedure was run in a 0.5:2 biphasic mixture of toluene and water (2.5 vol.) with a catalystic amount (e.g. 0.002 mol equiv.) Pd(Amphos)C12 (instead of 0.04 mol equiv. of PdidppfhCE) used as the catalyst. Potassium phosphate (K3PO4 3 H2O) substituted potassium carbonate (K2CO3) 3.0 mol equiv. as the base, and the amount of Compound 7 employed was 1.02 mol equiv. The improved process was conducted at 50 °C. At the end of the reaction, the organic layer was fdtered and treated with activated carbon and concentrated, and the final material was crystallized from toluene/heptane/water to give Compound 5 in 92% yield and 99.9% purity.

[00550] Synthesis of Compound 3. To a 50 L reactor was charged dichloromethane (11.25 L), Compound 5 (750 g, >99.9%/220 nm chiral purity) and triethylamine (920.0 g) at r t. (20~30°C). The resulting mixture was refilled with nitrogen and cooled to 0°C. To it was added a solution of MS2O (793.0 g) in dichloromethane (3.75 L) drop-wise over 45 min while keeping the temperature at 0~5°C. The reaction mixture was stirred at 0~5°C for 1 h under nitrogen. The reaction mixture was quenched with cooled water (7.5 L) at 5~15°C and separated. The organic phase was washed with cooled water (3.75 L) and separated. The organic phase was dried over anhydrous Na2SC>4, filtered and concentrated at 25~30°C in vacuum to around 2 vol., then switched to n-heptane (2.25 L) and concentrated at 25~30°C in vacuum to around 2 vol. of Compound 3 in n-heptane. n-heptane /EtOAc (3.0 L, lOv/lv) was added to the above mixture and the mixture was slurried for 1 h at 0~10°C under nitrogen and filtered. The filter cake was washed with n-heptane (1.5 L), dried in vacuum at 25~30°C for 5 h to afford Compound 3 as an off-white solid (845 g, 98.9 w%, 99.98%/220 nm chiral purity, 91% yield). H NMR (400 MHz, CDC13) 5 7.35 (dd, J = 9.6, 2.5 Hz, 1H), 7.24 – 7.18 (m, 2H), 7.12 (s, 1H), 7.08 (td, J = 8.3, 2.6 Hz, 1H), 5.78 (d, J = 6.4 Hz, 1H), 4.21 (s, 3H), 4.05 (q, J = 7.3 Hz, 2H), 3.90 – 3.76 (m, 2H), 2.78 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H), 1.40 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 408.20 (M + H)⁺.

[00551] In another example, triethylamine base (1.3 mol equiv.), MS2O (1.2 mol equiv.), and dichloromethane solvent (10 vol) were used. The reaction mixture was quenched with aqueous sodium bicarbonate to remove excess MS2O, and crystallization from dichloromenthane/hexane results in 98% yield with 100% purity of Compound 3.

[00552] Synthesis of Compound 2. A 20 L reactor was refilled with nitrogen, then charged with DMA (12.6 L) at r.t. (20~25°C) To the reactor was charged Compound 4 (390.0 g) and Compound 3 (840.0 g, 99.98%/220 nm chiral purity) in one portion at 20~25°C through a dry nitrogen flow. The reaction mixture was heated to 35°C over 15 min and stirred for 5-10 min at 35~40°C to get a clear solution. To the reaction mixture was charged powder K3PO4 (875.0 g) in one portion at 35~45°C. After complete addition, the resulting mixture was heated to 60°C over 20 min and stirred at 58~63°C for 1.5 h through a dry nitrogen flow. The reaction mixture was cooled to 25~30°C, filtered through a celite pad (5 cm, 1.5 kg) and rinsed the filter cake with EtOAc (2 L, 2-3 vol.). The filtrate was poured into water (16.8 L, 20 vol.) at 0-10°C, extracted with EtOAc (10 L, 12 vol.) and separated. The aqueous phase was extracted with EtOAc (5 L, 6 vol.). The combined organic phases were washed with water (5 L*3, 6 vol. *3), concentrated at 50°C in vacuum to afford crude product as a gray solid (956 g). The crude product was dissolved in EtOAc (950 mL, 1 vol. relative to crude product) at 35~40°C, then was added dropwise n-heptane (950 mL, 1 vol. relative to crude product) at 30~40°C over 20 min. The resulting mixture was cooled to 20~25°C over 30 min and stirred for 1 h at 30-40°C. Some solids came out slowly and n-heptane (1.9 L, 2 vol. relative to crude product) was added dropwise to the slurry mixture at 20~25°C over 30 min. The precipitates were stirred at 15~20°C for 3 h and filtered. The filter cake was washed with n-heptane (1.5 L) and dried in oven at 45-50°C for 16 h to afford Compound 2 as a pale-yellow solid (743 g, 98.6%/220 nm, 96.9 w%, 99.98%/220 nm chiral purity, 0.48%KF, 72% yield). H NMR (400 MHz, DMSO) 5 7.54 (dd, J = 10.2, 2.7 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.42 (s, 1H), 7.31 (dd, J = 8.5, 5.8 Hz, 1H), 7.22 (td, J = 8.4, 2.7 Hz, 1H), 7.17 (s, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.14 (s, 2H), 5.47 (q, J = 6.0 Hz, 1H), 4.22 (s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 3.78 (q, J = 16.1 Hz, 2H), 1.40 (d, J = 6.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 500.30 (M + H)⁺.

[00553] In another example, a process was developed where Compound 4 (1.1 mol equiv. to Compound 3) was used. Potassium phosphate base (K2PO4, 4. 1 mol equiv.) and DMA (16 vol.) were substituted with cesium carbonate (CS2CO3, 2.2 mol equiv.) and NMP (5.6 vol.). The reaction was carried out at 20~30°C. Following completion of the reaction, the crude product was precipitated with water. The material was then dissolved in ethyl acetate, washed with water, and treated with activated carbon. The product is subsequently crystallized from toluene/ethyl acetate/heptane to give Compound 2 in 80% yield and 99.9% purity.

[00554] Synthesis of Compound 1. To a reactor was charged t-AmOH (20 vol.), Compound 2 (700.0 g, 99.99% chiral purity) and potassium pivalate (588.0 g). The reaction mixture was fully refilled with nitrogen. To the reaction mixture was added cataCXium A (120.4 g) and Pd(OAc)2 (37.8 g) at r.t. under nitrogen. The resulting mixture was heated to 100°C and stirred for 18 h under nitrogen. The reaction mixture was cooled to 30°C , filtered through a celite pad and washed the filter cake with EtOAc (3 vol.). The filtrate was washed with water (5 vol. *2) and separated. The upper organic phase was concentrated in vacuum to afford a brown oil. The oil was dissolved in EtOAc (27 L) then added 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water), stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L) and separated. 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water) was charged to the above organic phase, stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L.) and separated. The organic phase was concentrated in vacuum at 45~50°C to afford a brown solid (1.12 kg). The crude solid (1.12 kg) was further purified by silica gel chromatography eluted with EtOAc/DCM (dry loading, 3X, 100-200 meshes, EtOAc:DCM=l : 1) to afford a pale-yellow solid ( 1.02 kg). The solid was dissolved in EtOAc (600 mL, 2 vol.) at 50~60°C, then was added n-heptane (1.8 L, 6 vol.) dropwise over 50 min at 50~60°C. A large of solids came out during addition. The resulting slurry was cooled to 15~20°C over 50 min and stirred for 30 min at 15~20°C. The slurry was concentrated in vacuum at 45~50°C to 2-3 vol. mixture, n-heptane (1.2 L, 4 vol.) was added to the

above mixture (2-3 vol.), concentrated in vacuum at 45~50°C to 2-3 vol. mixture. The mixture was cooled to 10~15°C over 2 h, stirred at 10~15°C for 1 h and filtered. The filtered cake was rinsed with n-heptane (600 mb) and dried in vacuum at 50°C for 20 h to afford Form 1 of Compound 1 as an off-white solid (280 g, 99.0%). H NMR (400 MHz, DMSO) 57.79 (dd, J = 10.3, 2.2 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.24 – 7.16 (m, 2H), 6.13 (s, 2H), 6.08 (d, J = 1.7 Hz, 1H), 5.31 – 5.23 (m, 1H), 4.16 (s, 3H), 4.05 – 3.94 (m, 2H), 3.78 (d, J = 15.6 Hz, 1H), 2.98 (d, J = 15.5 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). MS (ESI, m/z): 420.30 (M + H)⁺. XRPD (FIG. 1), TG/DTA (FIG. 2), DSC (FIG. 3), DVS (FIG. 4), and FT-IR (FIG. 5) results for a sample of Form 1 were obtained.

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References

“JIDEYTRO™ (zidesamtinib) for Patients”. Jideytro. 2026-02-05. Retrieved 2026-07-23.
“Jideytro: Uses, Dosage, Side Effects & Warnings”. Drugs.com. Retrieved 2026-07-23.
“Nuvalent Announces FDA Acceptance of New Drug Application for Zidesamtinib for the Treatment of TKI Pre-treated Patients with Advanced ROS1-positive NSCLC”. Nuvalent Investors. Retrieved 2026-07-23.
Wespiser M, Gille R, Pérol M (2026). “ROS1-positive non-small cell lung cancer: from genomics to treatment decisions”. Frontiers in Oncology. 16 1739598. doi:10.3389/fonc.2026.1739598. PMC 12907153. PMID 41704605.
“New FDA Drug Approvals for 2026”. Drugs.com. Retrieved 2026-07-23.
Center for Drug Evaluation and Research (2026-07-22). “Novel Drug Approvals for 2026”. FDA.

Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant MutationsPublication Name:Molecular Cancer TherapeuticsPublication Date:2025-05-09PMCID:PMC12214885PMID:40299789DOI:10.1158/1535-7163.mct-25-0025
Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design StrategiesPublication Name:Journal of Medicinal ChemistryPublication Date:2024-08-15PMID:39143914DOI:10.1021/acs.jmedchem.4c00361
NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance MutationsPublication Name:Cancer DiscoveryPublication Date:2022-12-13PMCID:PMC9975673PMID:36511802DOI:10.1158/2159-8290.cd-22-0968
Electron transport by C-type cytochromes. I. The reaction of horse heart cytochrome c with anionic reductantsPublication Name:Biophysics of structure and mechanismPublication Date:1975-02-19PMID:10021DOI:10.1007/bf00539772

PAT

Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number:WO-2023056405-A1Priority Date:2021-10-01
Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number:US-12043626-B2Priority Date:2021-10-01Grant Date:2024-07-23
Methods of treating solid tumor using heteroaromatic macrocyclic ether compoundsPublication Number:US-2024398768-A1Priority Date:2021-10-01
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-12054498-B2Priority Date:2020-05-05Grant Date:2024-08-06
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-2023107663-A1Priority Date:2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-11542278-B1Priority Date:2020-05-05Grant Date:2023-01-03
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:WO-2021226208-A2Priority Date:2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-2024352037-A1Priority Date:2020-05-05


Clinical data
Pronunciation	jih-DAY-troh^[1]^[2]
Trade names	Jideytro
Other names	NUV-520; NVL 520
AHFS/Drugs.com	jideytro
Routes of administration	By mouth
Drug class	Tyrosine kinase inhibitor
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name
CAS Number	2739829-00-4
PubChem CID	166560233
IUPHAR/BPS	12392
DrugBank	DB21623
ChemSpider	128922073
UNII	MX5KQV5XHC
KEGG	D12899
ChEBI	CHEBI:747901
ChEMBL	ChEMBL5314497
Chemical and physical data
Formula	C₂₂H₂₂FN₇O
Molar mass	419.464 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

////////zidesamtinib, anax labs, CANCER, FDA 2026, APPROVALS 2026, Jideytro, NVL-520, NUV-520, NU-520, NVL 520, NUV 520, NU 520, MX5KQV5XHC

#zidesamtinib, #anax labs, #CANCER, FDA 2026, #APPROVALS 2026, #Jideytro, #NVL-520, #NUV-520, #NU-520, #NVL 520, #NUV 520, #NU 520, #MX5KQV5XHC

Gedatolisib

July 22, 2026 2:43 am / Leave a comment

Gedatolisib

Approvals 3026, FDA 2026, 7/14/2026, Revtorpyk

PF-05212384; PF-5212384; PKI-587
CAS 1197160-78-3
Chemical Formula: C32H41N9O4
Molecular Weight: 615.72
1-(4-{[4-(Dimethylamino)-1-piperidinyl]carbonyl}phenyl)-3-{4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}urea
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
гедатолисиб [Russian] [INN]
غيداتوليسيب [Arabic] [INN]
吉达利塞 [Chinese] [INN]

1-(4-(4-(Dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

Urea, N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]-

96265TNH2R

In combination with fulvestran, to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting

Gedatolisib, sold under the brand name Revtorpyk, is an anti-cancer drug used for the treatment of breast cancer.^[1] It is under development by Celcuity, Inc. Gedatolisib is a kinase inhibitor.^[1] The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.^[2] Gedatolisib is administered by intravenous infusion.^[1]

Gedatolisib was approved for medical use in the United States in July 2026.^[1]^[3]

Medical uses

Gedatolisib is indicated in combination with fulvestrant, with or without palbociclib, for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting.^[1]

Synthesis of New Dialkyl 2,2′-[Carbonylbis(azanediyl)]dibenzoates via Curtius RearrangementDOI: 10.1055/s-0040-1706643Publication Date: 2021Publication Name: Synthesis
A New One-Pot Three-Component Synthesis of 4-Aryl-6-cycloamino-1,3,5-triazin-2-amines under Microwave IrradiationDOI: 10.1055/a-1401-2795Publication Date: 2021Publication Name: Synthesis

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US42900900&_cid=P22-MRVGV9-51327-1

Example 76

Preparation of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig’s base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010096619&_cid=P22-MRVGV9-51327-1

Scheme 1

Preparation of 1-(4-(4-(dimethylamino) piperidine-1-carbonyl)phenyl-3-(4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)

To a slurry of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)ureido)benzoic acid (7, 45.5 g, 0.09 mol) in dry THF (1.6 L) heated to 50 ⁰C was added N,N’-carbonyl diimidazole (28 g, 0.17 mol). The reaction mixture was heated for 2 hours and followed by dimethylaminopiperidine (8, 23.5 g, 0.18 mol) and stirred at 53 ⁰C for 16 hours. The reaction mixture was cooled to the room temperature and filtered. The cake was washed with 2-propanol and air-dried to give 97 % pure white powder in 88% yield (49.2 g, 0.08 mol). To the solids stirred in dimethyl acetamide (DMAC, 165 ml) at 70° C for 1 hour was added 2-propanol (640 ml) and the mixture was stirred at 65 ⁰C for additional 1 hour. The solids were filtered, washed with 2-propanol and dried in a vacuum oven at 70⁰C for 16 hour to give crystalline white powder (45 g) with >99% purity. The above-mentioned work up process and crystallization procedure gave a Pd residue of 20 ppm. Alternate procedures for the formation of 1-(4-(4-(dimethylamino) piperidine-1 – carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)

To the solution of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline (4, 18 g, 0.052 mol) in dichloromethane (300 ml) was added methyl 4-isocyanato benzoate (5, 10.5 g, 0.061 mol) and the reaction mixture was stirred for 5 hours. The separated solids were filtered, washed with ether and air dried to give beige solids (21 g, 0.04 mol). Yield 77%. 90 % pure by HPLC; Mass: 520.1 (M+H). Preparation of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7)

The mixture of methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)ureido)benzoate (6, 21 g, 0.04mol) and lithium hydroxide monohydrate (3.8 g, 0.09 mol) in THF (120 ml), MeOH (60 ml), and water (60 ml) was heated at 80 ⁰C for 3 hours. The dark brown solution was cooled to room temperature and made acidic with concentrated HCI. The solids were filtered, washed with water, washed with acetone , washed with ether, and dried in a vacuum oven at 60 ⁰C for 48 hours to give off white solids of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (19.2 g, 0.038 mol). Mass: 506.3 (M+H)⁺; Yield.94%. 1 -(4-(4-(dimethylamino) piperidine-1 -carbonyl)phenyl-3-(4-(4,6-dimorpholino- 1 ,3,5-triazine-2-yl)phenyl) urea (9)

The suspension of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7, 17 g, 33.66 mmol) and N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride (9.5 g, 49.5 mmol) in THF (200 ml) and acetonitrile (50 ml) was stirred for 10 min and followed by addition of 1-hydroxybenzotriazole hydrate (6.4 g, 47.88 mmol). The reaction mixture was stirred for 30 min and 4-dimethylaminopiperidine (8, 8.86 g, 69.2 mmol) was added by drops. After being stirred for additional 16 hours, the reaction mixture was concentrated to min. The solids were filtered and washed thoroughly with water (very fine suspension). The cake was slurred in hot ethanol, filtered and dried in a vacuum oven at 68 ⁰C for 16 hours to give off white solids (10.3 g, 16.77 mmol). M. p. 238-240 ⁰C. 99 % pure. Mass: 616.3 (M+H)⁺; Yield 50 %.

PATENT

WO 2009143317

WO 2010096619

WO 2012148540

WO 2014151147

PATENT

US 20170119778

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2636-2645

http://pubs.acs.org/doi/abs/10.1021/jm901830p

J. Med. Chem., 2010, 53 (6), pp 2636–2645

DOI: 10.1021/jm901830p

Abstract

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)

MS (ESI) m/z = 616.7. HRMS: calcd for C₃₂H₄₁N₉O₄ + H⁺, 616.335 43; found (ESI-FTMS, [M + H]⁺), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) ¹H NMR (DMSO-d₆) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C₃₂H₄₁N₉O₄: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2011), 21(16), 4773-4778.

http://www.sciencedirect.com/science/article/pii/S0960894X11008468

PAPER

New and Practical Synthesis of Gedatolisib

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00298

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00298

Abstract

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; t_R = 2.598 min, purity: 99.34%

Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. Med. Chem. Res. 2014, 23, 5188– 5196 DOI: 10.1007/s00044-014-1084-z
Khafizova, G.; Potoski, J. R. PCT Int. Appl. WO 2010096619, 2010.
Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos Santos, E. G.; Zask, A.; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.; Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M. PCT Int. Appl. WO 2009143317, 2009.

REFERENCES

1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.

2: Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res. 2012 Aug;176(2):542-8. doi: 10.1016/j.jss.2011.10.045. Epub 2011 Nov 21. PubMed PMID: 22261591.

3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.

4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.

5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.

6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.

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References

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
TRIAZINE COMPOUNDS AS P13 KINASE AND MTOR INHIBITORSPublication Number: PT-2294072-TPriority Date: 2008-05-23
TRIASINE UNITS AS P13 KINASE INHIBITORS AND MOTORPublication Number: ME-01111-BPriority Date: 2008-05-23
HER2 mutation inhibitorsPublication Number: US-12447153-B2Grant Date: 2025-10-21
Anti-hiv compoundsPublication Number: US-2025326779-A1
Aryl aminopyrimidines as dual MerTK and TYRO3 inhibitors and methods thereofPublication Number: US-12448365-B2Grant Date: 2025-10-21

References

https://celcuity.com/revtorpyk/REVTORPYK_PI_2026.pdf
Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, et al. (August 2011). “Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors”. Bioorganic & Medicinal Chemistry Letters. 21 (16): 4773–8. doi:10.1016/j.bmcl.2011.06.063. PMID 21763134.
“FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer”. U.S. Food and Drug Administration (FDA). 14 July 2026. Retrieved 20 July 2026. This article incorporates text from this source, which is in the public domain.
Sabatini DM (November 2017). “Twenty-five years of mTOR: Uncovering the link from nutrients to growth”. Proceedings of the National Academy of Sciences of the United States of America. 114 (45): 11818–11825. Bibcode:2017PNAS..11411818S. doi:10.1073/pnas.1716173114. PMC 5692607. PMID 29078414.
Tian T, Li X, Zhang J (February 2019). “mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy”. International Journal of Molecular Sciences. 20 (3): 755. doi:10.3390/ijms20030755. PMC 6387042. PMID 30754640.
Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y (July 2019). “Targeting mTOR for cancer therapy”. Journal of Hematology & Oncology. 12 (1) 71. doi:10.1186/s13045-019-0754-1. PMC 6612215. PMID 31277692.
Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K (October 2021). “PI3K inhibitors are finally coming of age”. Nature Reviews. Drug Discovery. 20 (10): 741–769. doi:10.1038/s41573-021-00209-1. PMC 9297732. PMID 34127844. S2CID 235437841.
Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R (December 2016). “Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors”. JAMA Oncology. 2 (12): 1565–1573. doi:10.1001/jamaoncol.2016.0891. PMID 27388585.
Anderson EJ, Mollon LE, Dean JL, Warholak TL, Aizer A, Platt EA, et al. (2020). “A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer”. International Journal of Breast Cancer. 2020 3759179. doi:10.1155/2020/3759179. PMC 7322582. PMID 32637176.
Clinical trial number NCT01420081 for “A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer” at ClinicalTrials.gov
Clinical trial number NCT01925274 for “A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer” at ClinicalTrials.gov
Clinical trial number NCT02438761 for “PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)” at ClinicalTrials.gov
Clinical trial number NCT03698383 for “Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer” at ClinicalTrials.gov
Clinical trial number NCT03911973 for “Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers” at ClinicalTrials.gov
Clinical trial number NCT03065062 for “Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors” at ClinicalTrials.gov
Clinical trial number NCT02626507 for “Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer” at ClinicalTrials.gov
“Celcuity Announces FDA Approval of Revtorpyk (gedatolisib) for the Treatment of HR+/HER2-, PIK3CA Wild-Type Locally Advanced or Metastatic Breast Cancer” (Press release). Celcuity. 14 July 2026. Retrieved 20 July 2026 – via GlobeNewswire.
World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 73”. WHO Drug Information. 29 (1). hdl:10665/331088.

External links

Clinical trial number NCT05501886 for “Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (VIKTORIA-1)” at ClinicalTrials.gov


Clinical data
Trade names	Revtorpyk
Other names	PF-05212384; PKI-587
AHFS/Drugs.com	revtorpyk
License data	US DailyMed: Gedatolisib
Routes of administration	Intravenous infusion
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	1197160-78-3
PubChem CID	44516953
IUPHAR/BPS	7940
DrugBank	DB11896
ChemSpider	24644946
UNII	96265TNH2R
KEGG	D10635
ChEMBL	ChEMBL592445
CompTox Dashboard (EPA)	DTXSID40152557
Chemical and physical data
Formula	C₃₂H₄₁N₉O₄
Molar mass	615.739 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES

/////////Gedatolisib, anax labs, approvals 3026, FDA 2026, PF 05212384, PF 5212384, PKI-587, PF-05212384, PF-5212384, PKI 587, gedatolisib, antitumor agent, PHASE 3, PFIZER, гедатолисиб , غيداتوليسيب , 吉达利塞 , 96265TNH2R

O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

Journal of Medicinal Chemistry (2017), 60(17), 7524-7538 PQR 309

#Gedatolisib, #anax labs, #approvals 3026, #FDA 2026, #PF 05212384, #PF 5212384, #PKI-587, #PF-052123842, #PF-5212384; #PKI 587, #gedatolisib, #antitumor agent, #PHASE 3, #PFIZER, #гедатолисиб , #غيداتوليسيب , #吉达利塞 , #96265TNH2R

Gadoquatrane

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

Gadoquatrane

CAS2048221-65-2MW2579.0 g/mol

FDA 2026, APPROVALS 2026, Ambelvist, OZG7J613HK, BAY-1747846, BAY 1747846

2-[4,10-bis(carboxylatomethyl)-7-[1-oxo-1-[[2-oxo-2-[[3-[[2-[2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]propanoylamino]acetyl]amino]-2,2-bis[[[2-[2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]propanoylamino]acetyl]amino]methyl]propyl]amino]ethyl]amino]propan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;tetrakis(gadolinium(3+))

TETRAGADOLINIUM (4,10-BIS(CARBOXYLATOMETHYL)-7-(3,6,12,15-TETRAOXO-16-(4,7,10-TRIS-(CARBOXYLATOMETHYL)-1,4,7,10-TETRAAZACYCLODODECAN-1-YL)-9,9-BIS(((((2-(4,7,10-TRIS-(CARBOXYLATOMETHYL)-1,4,7,10-TETRAAZACYCLODODECAN-1-YL)PROPANOYL)AMINO)ACETYL)-AMINO)METHYL)-4,7,11,14-TETRAAZAHEPTADECAN-2-YL)-1,4,7,10-TETRAAZACYCLODODECAN-1-YL)ACETATE

To detect and visualize lesions with abnormal vascularity, in conjunction with MRI

Gadoquatrane (marketed as AMBELVIST®) is a low-dose, macrocyclic gadolinium-based contrast agent (GBCA) developed by Bayer for use in magnetic resonance imaging (MRI). It is designed to enhance the visualization of lesions in the central nervous system (CNS) and other body regions in adult and pediatric patients.

Core Highlights:

Lower Gadolinium Exposure: It requires a dose of 0.04 mmol/kg, which results in 60% less gadolinium exposure compared to standard macrocyclic GBCAs.
Regulatory Approval: The FDA approved it in June 2026 for use in adults and pediatric patients, including term neonates. It was also approved in Japan in March 2026.
Efficacy & Safety: Phase III clinical trials (the QUANTI studies) showed it effectively detects lesions with abnormal vascularity while maintaining an efficacy and safety profile comparable to other standard macrocyclic agents.
Structure: Gadoquatrane features a tetrameric, macrocyclic structure that gives it high relaxivity and stability in the body

SYN

https://patents.google.com/patent/US20250114485A1

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PAT

Gadolinium chelate compounds for use in magnetic resonance imagingPublication Number: US-11491245-B2Priority Date: 2015-06-04Grant Date: 2022-11-08
Gadolinium chelate compounds for use in magnetic resonance imagingPublication Number: US-2025114485-A1Priority Date: 2015-06-04
Formulation of contrast media and process of preparation thereofPublication Number: US-2024252690-A1Priority Date: 2018-11-23
Formulation of contrast media and process of preparation thereofPublication Number: US-12303573-B2Priority Date: 2018-11-23Grant Date: 2025-05-20
New gadolinium chelate compounds for use in magnetic resonance imagingPublication Number: EP-3611169-A1Priority Date: 2015-06-04
New gadolinium chelate compounds for use in magnetic resonance imagingPublication Number: US-2023113481-A1Priority Date: 2015-06-04
New gadolinium chelate compounds for use in magnetic resonance imagingPublication Number: EP-3303307-B1Priority Date: 2015-06-04Grant Date: 2019-09-04
Generation of artificial contrast-enhanced computed tomography imagesPublication Number: US-2024346718-A1Priority Date: 2023-04-13
Generation of artificial contrast-enhanced radiological imagesPublication Number: WO-2024100233-A1Priority Date: 2022-11-12
Generation of artificial contrast-enhanced radiological imagesPublication Number: EP-4616420-A1Priority Date: 2022-11-12
Automated analysis of radiological imagesPublication Number: WO-2024083466-A1Priority Date: 2022-10-17
Formulation of contrast media and process of preparation thereofPublication Number: US-11944690-B2Priority Date: 2018-11-23Grant Date: 2024-04-02

/////////gadoquatrane, anax labs, FDA 2026, APPROVALS 2026, Ambelvist, OZG7J613HK, BAY-1747846, BAY 1747846

#gadoquatrane, # labs, FDA 2026, #APPROVALS 2026, #Ambelvist, #OZG7J613HK, #BAY-1747846, #BAY 1747846

	Bosmolisib – N… on Bosmolisib
	Cenacitinib –… on Cenacitinib
	Emestedastat –… on Emestedastat
	Enrupatinib –… on Enrupatinib
	Evetifator – N… on Evetifator

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Radiosynthesis

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Examples 7 and 8

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone and [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

Peak 1: Example 7

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

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Example 76

Preparation of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

Abstract

Abstract

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