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Balinatunfib

January 7, 2026 2:58 am / Leave a comment

Balinatunfib

CAS 2248726-53-4

MF C27H24F2N6O2, 502.5 g/mol

(1R,11R)-5-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^2,10.0^3,8.0^14,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

(7R,14R)-11-[2-(1-AMINOCYCLOBUTYL)-5-PYRIMIDINYL]-1-(DIFLUOROMETHOXY)-6,7-DIHYDRO-6-METHYL-7,14-METHANOBENZIMIDAZO[1,2-B][2,5]BENZODIAZOCIN-5(14H)-ONE

(7R,14R)-11-[2-(1-Aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

(7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methano[1,3]benzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one
tumor necrosis factor (TNF) signaling inhibitor, SAR441566, SAR 441566, PLY98MAN4C

OriginatorSanofi
ClassAmines; Anti-inflammatories; Antipsoriatics; Antirheumatics; Azabicyclo compounds; Benzimidazoles; Cyclobutanes; Fluorinated hydrocarbons; Heterocyclic compounds with 4 or more rings; Ketones; Phenyl ethers; Pyrimidines; Small molecules
Mechanism of ActionTumour necrosis factor alpha inhibitors
Phase IICrohn’s disease; Psoriasis; Rheumatoid arthritis; Ulcerative colitis
No development reportedInflammation
09 Dec 2025Sanofi plans a phase-I trial (In volunteers) in December 2025 (PO, Tablet), (NCT07272629)
29 Oct 2025Sanofi plans a phase II SPECIFI-IBD-LTS trial for Crohn’s Disease or Ulcerative Colitis ( Treatment-experienced) in unknown location (PO, Tablet) in December 2025 (NCT07222189)
16 Sep 2025Chemical structure information added.
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Balinatunfib (SAR441566) is an experimental drug which acts as a potent small molecule inhibitor of TNF. Rather than blocking TNF receptors, balinatunfib inactivates TNF directly by stabilising an inactive form of the TNF trimer which fails to bind to its target receptors. It is in early stage clinical trials for rheumatoid arthritis and other chronic autoimmune diseases.^[1][2]

SYN

https://www.chemical.ai/blog/humanai-synergy-in-retrosynthetic-analysis-and-route-optimization-of-balinatunfib

PAT

(WO 2016/050975,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016050975&_cid=P22-MK3F7M-67505-1

Intermediate 40

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

Intermediate 38 (5 g, 11.64 mmol) was suspended in toluene (22 mL) and cooled to 0°C before addition of diphenylphosphoryl azide (3.4 mL, 15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16 mmol). The mixture was allowed to warm up to r.t and stirred for 2 hours and subsequently at 45°C overnight. The reaction mixture was diluted with EtOAc (150 mL) and the organic phase washed with a saturated aqueous solution of ammonium chloride (50 mL) then a saturated solution of aqueous sodium bicarbonate (50 mL), and concentrated in vacuo. The crude residue thus obtained was solubilized in THF (100 mL) and water (10 mL), trimethylphosphine (17.46 mL, 17.46 mmol) was added and the reaction mixture stirred overnight. The mixture was concentrated in vacuo, partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was extracted with 0.2M HCl aq (3 x 200 mL). The combined acid layer was stirred in an ice bath, whilst 10% NaOH solution was added with stirring until pH increased to 10. The stirred was continued for further 15 minutes to complete precipitation. The precipitate was filtered, rinsed with water (20 mL), then dried under suction for 10 minutes before drying under high vacuum overnight to afford 3.92 g (78%) of the title compound as an off white solid. LCMS basic: RT 1.96 min. (ES+) 428/430 (M+H)⁺

EXAMPLE 11

(7R, 14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

Intermediate 40 (3.7 g, 8.6 mmol), activated molecular sieve 4A powder (1.2 g), potassium carbonate (1.5 equiv., 13 mmol) followed by dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.04 equiv., 0.35 mmol) were poured into the center of the 100 mL Glass Parr reaction vessel. 3 cycles of vacuum (~20 mmHg) followed by Argon were applied to the closed reactor.

Anhydrous dimethyl sulfoxide (35 mL) was added, followed by phenol 5M in DMSO (1.1 equiv., 9.5 mmol). The solution was degassed by 3 vacuum (~20 mmHg) / argon cycles followed by 3 cycles of vacuum / CO resulting in a final CO pressure of 1 bar.

The mixture was stirred and heated overnight at 100 °C under the CO atmosphere . The reaction was cooled to 30°C, the reactor vessel was opened and EtOAc (40 mL) was added. The resulting mixture was filtered on a pad of Celite, evaporated in vacuo to yield a green oil.

The residue thus obtained was taken up in EtOAc (100 mL) and the organic layer was washed with water, K₂CO₃ (saturated aqueous solution) and brine (saturated aqueous solution). The aqueous layer was then re-extracted with EtOAc (1 x 50 mL). The combined organic layers were dried over MgSO₄, filtered and evaporated to dryness. The obtained green solid (3.65 g), was taken up in EtOAc, the insoluble material was filtered and rinsed with Et₂O to afford 1.06 g (33.1%) of the title compound as a grey solid.

The filtrate can be purified by flash chromatography to provide additional product if required:

LCMS basic: MH+ m/z = 376, RT 1.90 minutes.

¹H NMR (300 MHz, DMSO) δ 9.12 (d, 1 H, J = 6.7 Hz), 8.23 (dd, 1 H, J = 7.0, 2.4 Hz), 7.60 (m, 5 H), 7.20 (dd, 1 H, J = 8.7, 2.1 Hz), 6.29 (d, 1 H, J = 7.1 Hz), 4.87 (dd, 1 H, J = 6.7 Hz, 6.7 Hz), 3.46 (m, 1 H), 2.72 (d, 1 H, J = 13.4 Hz).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US283322316&_cid=P22-MK3EWF-57090-1

Intermediate 3

(7R,14R)-11-Chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Example 11) (10 g, 26.6 mmol) in dry THF (135 mL), cooled to −78° C. under nitrogen, was added potassium bis(trimethylsilyl)amide (1M in THF, 30 mL, 30 mmol) dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 1 h prior to the addition of iodomethane (2.5 mL, 40 mmol) dropwise over 5 minutes. The reaction mixture was stirred at −78° C. for 1 h, then allowed to warm slowly to ambient temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride solution (600 mL) and extracted with EtOAc (2×800 mL). The organic extracts were dried (Na ₂SO ₄), filtered and concentrated in vacuo. Purification by flash chromatography on silica (elution with 5% MeOH/DCM) afforded the title compound (9.12 g, 88%) as a beige solid. δ _H(300 MHz, DMSO-d ₆) 8.33-8.21 (m, 1H), 7.87-7.33 (m, 5H), 7.22 (dd, J 8.7, 2.1 Hz, 1H), 6.23 (d, J 7.1 Hz, 1H), 5.22 (d, J 7.1 Hz, 1H), 3.55-3.41 (m, 1H), 3.33 (s, 3H), 2.81 (d, J 13.8 Hz, 1H). LCMS (ES+) [M+H] ⁺390.0, RT 1.10 minutes (Method 3).

Intermediate 17

tert-Butyl (1-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate

A flame-dried flask under nitrogen equipped with a reflux condenser was charged with Intermediate 3 (13.3 g, 34.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.61 g, 1.71 mmol), XPhos (1.63 g, 3.43 mmol), bis(pinacolato)diboron (9.85 g, 38.8 mmol) and potassium acetate (8.5 g, 87 mmol), then 1,4-dioxane (136 mL) was added. The resulting mixture was stirred at 100° C. for 22 h before Intermediate 16 (12.3 g, 37.4 mmol) and aqueous tribasic potassium phosphate solution (1.27 mol/L, 40 mL, 50.8 mmol) were added. The reaction mixture was heated under reflux for 3 h before being charged with additional tris(dibenzylideneacetone)dipalladium(0) (500 mg, 0.53 mmol), XPhos (510 mg, 1.07 mmol) and aqueous tribasic potassium phosphate solution (1.27 mol/L, 20 mL, 25.4 mmol). The mixture was stirred for 1 h, then cooled to room temperature, diluted with DCM (600 mL) and washed with brine (400 mL). The aqueous phase was extracted with DCM (500 mL), then the combined organic extracts were passed through a phase separator and concentrated in vacuo. Purification by flash chromatography on silica (elution with 0-5% MeOH/DCM) afforded the title compound (18.0 g, 88%) as an off-white solid. δ _H(400 MHz, CDCl ₃) 8.93 (s, 2H), 8.49 (dd, J8.2, 1.3 Hz, 1H), 7.84 (dd, J8.5, 0.7 Hz, 1H), 7.74-7.63 (m, 1H), 7.48-7.38 (m, 2H), 7.34-7.29 (m, 1H), 6.84 (t, J72.8 Hz, 1H), 6.31 (d, J7.2 Hz, 1H), 5.92 (s, 1H), 5.01 (d, J7.1 Hz, 1H), 3.53 (s, 3H), 3.51-3.43 (m, 1H), 2.90 (d, J 13.6 Hz, 1H), 2.84-2.57 (m, 3H), 2.22-2.07 (m, 3H), 1.43 (s, 9H). LCMS (ES+) [M+H] ⁺603.2, RT 1.25 minutes (Method 3).

EXAMPLE 6

(7R,14R)-11-[2-(1-Aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

To a solution of Intermediate 17 (18.0 g, 29.9 mmol) in 1,4-dioxane (25 mL) was added 4M hydrochloric acid in 1,4-dioxane (40 mL). The resulting mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was dissolved in water (500 mL) and washed with EtOAc (2×300 mL). The aqueous layer was basified to pH 9 with 2N aqueous sodium hydroxide solution, which resulted in precipitation of a solid. EtOAc (500 mL) was added and the mixture was stirred until all solids had dissolved. The residue was partitioned, then the aqueous layer was further extracted with EtOAc (500 mL). The combined organic layers were dried over Na ₂SO ₄and filtered, then concentrated in vacuo and dried overnight under high vacuum. The foamy residue was suspended in a mixture of diethyl ether and hexane (150 mL), then stirred and shaken vigorously, before being concentrated in vacuo, to afford the title compound (12.4 g, 83%) as a white amorphous solid. δ _H(400 MHz, DMSO-d ₆) 9.05 (s, 2H), 8.32-8.22 (m, 1H), 7.91-7.66 (m, 3H), 7.62 (dd, J8.5, 1.8 Hz, 1H), 7.53-7.46 (m, 2H), 6.31 (d, J7.1 Hz, 1H), 5.26 (d, J 7.2 Hz, 1H), 3.52 (dt, J 14.2, 7.3 Hz, 1H), 3.36 (s, 3H), 2.84 (d, J 13.8 Hz, 1H), 2.63 (dtd, J11.5, 5.6, 2.5 Hz, 2H), 2.38 (s, 2H), 2.16-2.05 (m, 2H), 2.04-1.91 (m, 1H), 1.87-1.73 (m, 1H). LCMS (ES+APCI) [M-NH ₂] ⁻486.0, RT 1.66 minutes (Method 2). LCMS (ES+) [M+H] ⁺503.0, RT 1.71 minutes (Method 1).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025008402&_cid=P22-MK3EWF-57090-1

(7R,14R)-1 l-[2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difhroromethoxy)-6-methyl-6,7-dihydro-7, 14-methanobenzimidazo[l,2-b][2,5]benzodiazocin-5(14H)-one.

PAT

Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2021252012-A1Priority Date: 2017-04-25
Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: KR-102565132-B1Priority Date: 2017-04-25Grant Date: 2023-08-08
Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2025127795-A1Priority Date: 2017-04-25
Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: CN-110582495-BPriority Date: 2017-04-25Grant Date: 2022-04-01
Fused Pentacyclic Imidazole DerivativesPublication Number: US-2017305932-A1Priority Date: 2014-10-03
Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: CN-110582495-APriority Date: 2017-04-25
Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2023250105-A1Priority Date: 2017-04-25
Fused pentacyclic imidazole derivatives as modulators of TNF activityPublication Number: US-10980814-B2Priority Date: 2017-04-25Grant Date: 2021-04-20
Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: EP-3939980-A1Priority Date: 2017-04-25
Process for preparing fused pentacyclic imidazole derivatives and uses thereof as modulators of tnf activityPublication Number: EP-3939980-B1Priority Date: 2017-04-25Grant Date: 2023-07-26
Preparation of bridged pentacyclic imidazole derivatives as modulators of tnf activity, intermeditates and their preparationPublication Number: WO-2025068505-A1Priority Date: 2023-09-29
DERIVATIVES OF COMBINED PENTACYCLIC IMIDAZOLES AS MODULATORS OF TNF ACTIVITYPublication Number: HR-P20211927-T1Priority Date: 2017-04-25
Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: CA-3058980-A1Priority Date: 2017-04-25
Fused pentacyclic imidazole derivatives as modulators of tnf activityPublication Number: EP-3615534-B1Priority Date: 2017-04-25Grant Date: 2021-09-15
Fused Pentacyclic Imidazole Derivatives as Modulators of TNF ActivityPublication Number: US-2020046723-A1Priority Date: 2017-04-25

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References

Vugler A, O’Connell J, Nguyen MA, Weitz D, Leeuw T, Hickford E, et al. (2022). “An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis”. Frontiers in Pharmacology. 13 1037983. doi:10.3389/fphar.2022.1037983. PMC 9709720. PMID 36467083.
Li Y, Ye R, Dai H, Lin J, Cheng Y, Zhou Y, et al. (January 2025). “Exploring TNFR1: from discovery to targeted therapy development”. Journal of Translational Medicine. 23 (1): 71. doi:10.1186/s12967-025-06122-0. PMC 11734553. PMID 39815286.

Identifiers

IUPAC name
CAS Number	2248726-53-4
PubChem CID	132042903
IUPHAR/BPS	13583
ChemSpider	129738176
Chemical and physical data
Formula	C₂₇H₂₄F₂N₆O₂
Molar mass	502.526 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////Balinatunfib, tumor necrosis factor (TNF) signaling inhibitor, SAR441566, SAR 441566, PLY98MAN4C

Atirmociclib

January 5, 2026 3:01 am / Leave a comment

Atirmociclib

CAS 2380321-51-5

MF C22H27ClFN5O3,
463.9 g/mol

(3S,4R)-4-[[5-chloro-4-[7-fluoro-2-(2-hydroxypropan-2-yl)-3-propan-2-ylbenzimidazol-5-yl]pyrimidin-2-yl]amino]oxan-3-ol

(3S,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan2-yl)-1H-1,3-benzimidazol-6-yl]pyrimidin-2-yl}amino)oxan-3-ol

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxpropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

D-threo-Pentitol, 1,5-anhydro-3-[[5-chloro-4-[4-fluoro-2-(1-hydroxy-1-methylethyl)-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinyl]amino]-2,3-dideoxy-
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6

Atirmociclib is an orally bioavailable inhibitor of cyclin-dependent kinase 4 (CDK4), with potential antineoplastic activity. Upon administration, atirmociclib selectively inhibits CDK4, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1-S-phase transition and leads to cell cycle arrest. This suppresses DNA replication and inhibits tumor cell proliferation. CDK4, a serine/threonine kinase, is upregulated in many tumor cell types and plays a key role in the regulation of both cell cycle progression from the G1-phase into the S-phase and tumor cell proliferation.

Atirmociclib (development code PF-07220060) is an investigational orally bioavailable and CDK4-specific inhibitor being developed by Pfizer for the treatment of various solid tumors, particularly hormone receptor-positive, HER2-negative breast cancer.^[1][2] The safety and efficacy of atirmociclib have not been established, as it remains in clinical development as of September 2025.^[3][4][5]

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02137

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0K3I-13424-1

Example A94 (Scheme A-15): Preparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)

A 2 L three-neck round bottom flask was charged with 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23) (112 g, 292 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (51.6 g, 336 mmol), and MeCN (1.1 L). DIPEA (132 g, 1.02 mol, 178 mL) was added at room temperature. The reaction mixture was heated to 80° C. (internal temperature) and stirred at the same temperature for 40 h to provide a brown solution. LCMS analysis showed remaining starting material. Additional 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (6.73 g, 43.8 mmol) was added at 80° C. (internal temperature) and the reaction was stirred at 80° C. (internal temperature) for an additional 10 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was taken up in 1:1 EtOAc/H ₂O (1.5 L). Some solids were precipitated. EtOH (100 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with H ₂O (2×300 mL), dried over Na ₂SO ₄, and filtered. To the filtrate was added sulfhydryl silica gel (Accela, 8 g, 0.7-1.4 mmol/g). The resulting mixture was stirred at room temperature for 1 h and then filtered through a pad of Celite. Treatment with sulfhydryl silica gel was repeated in identical fashion and the filtrate was concentrated to dryness. The crude residue was slurried in MeCN (500 mL) at room temperature for 16 h. The suspension was filtered and the filter cake was washed with MeCN (2×100 mL). The filter cake was slurried again with MeCN (300 mL) at room temperature for 6 h. The mixture was filtered and the filter cake was washed with MeCN (2×100 mL). The filter cake was collected and dried under vacuum and then dried in a drying oven (45° C. for 20 h, 50° C. for 64 h) to provide 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxpropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94) (90 g, 66% yield) as a white solid. ¹H NMR (400 MHz, 80° C., DMSO-d ₆) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.43 (d, J=11.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 5.80 (hept, J=7.0 Hz, 1H), 5.56 (s, 1H), 4.71 (d, J=5.3 Hz, 1H), 3.91-3.79 (m, 3H), 3.61-3.52 (m, 1H), 3.41-3.31 (m, 1H), 3.12-3.07 (m, 1H), 2.09-2.00 (m, 1H), 1.70 (s, 6H), 1.67-1.52 (m, 7H); ¹⁹F NMR (377 MHz, CDCl ₃) δ −127.2; m/z (ESI+) for (C ₂₂H ₂₇ClFN ₆O ₃), 464.2 (M+H) ⁺; [α] _D ²²=−12.6 (c=0.2, MeOH).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0KHW-23947-1

PAT

2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: KR-102661053-B1Priority Date: 2018-04-26Grant Date: 2024-04-26
2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: KR-20230152182-APriority Date: 2018-04-26
Cyclin dependent kinase inhibitorsPublication Number: US-11220494-B2Priority Date: 2018-04-26Grant Date: 2022-01-11
CYCLINE-DEPENDENT KINASE INHIBITORSPublication Number: PE-20201202-A1Priority Date: 2018-04-26
Cyclin dependent kinase inhibitorsPublication Number: US-2022089580-A1Priority Date: 2018-04-26
2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: HR-P20250254-T1Priority Date: 2018-04-26
Cyclin dependent kinase inhibitorsPublication Number: US-12378232-B2Priority Date: 2018-04-26Grant Date: 2025-08-05
2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitorsPublication Number: EP-3784664-B1Priority Date: 2018-04-26Grant Date: 2025-02-19
2-Amino-pyridine or 2-amino-pyrimidine derivatives as cyclin-dependent kinase inhibitorsPublication Number: CN-112313219-BPriority Date: 2018-04-26Grant Date: 2024-04-26

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Mechanism of action

Atirmociclib is designed as a CDK4-specific inhibitor, distinguishing it from dual CDK4/6 inhibitors currently approved for cancer treatment.^[6] The drug targets cyclin-dependent kinase 4, which plays a role in cell cycle regulation.^[1]^[7]^[8]

Atirmociclib functions as a selective inhibitor of the CDK4/cyclin D complex, which plays a crucial role in cell cycle regulation.^[4] The drug works by targeting the CDK4 kinase, rendering the retinoblastoma (Rb)/E2F transcription system inactive, which ultimately leads to cell cycle arrest in the G1 phase.^[4] This mechanism is particularly effective in tumors that have lost Rb cell cycle-suppressive function, a common feature in various solid tumors.^[5]

The selective nature of atirmociclib represents a significant advancement over existing dual CDK4/6 inhibitors.^[6] By specifically targeting CDK4 while limiting CDK6 inhibition, atirmociclib is designed to maintain antitumor efficacy while potentially reducing dose-limiting hematologic toxicities, particularly neutropenia, which is believed to be primarily driven by CDK6 inhibition.^[9]

Clinical development

Atirmociclib is currently being evaluated in clinical trials for the treatment of advanced solid tumors.^[1] Clinical studies are ongoing with estimated completion dates extending to 2027–2028, reflecting the early stage of development for this investigational compound.^[1]

Preclinical research published in Cancer Cell in March 2025 reported atirmociclib as a next-generation CDK4-selective inhibitor with enhanced anti-tumor activity and reduced predicted toxicity compared to FDA-approved dual CDK4/6 inhibitors, though these findings require validation in clinical studies.^[6]

Preclinical studies

Preclinical research has demonstrated that atirmociclib exhibits enhanced anti-tumor activity compared to FDA-approved dual CDK4/6 inhibitors while showing reduced predicted toxicity.^[6] Studies have shown that CDK4-selective inhibition can provide improved preclinical anti-tumor efficacy and safety profiles compared to dual CDK4/6 inhibition strategies.^[10]

The preclinical development program has explored combination approaches with various therapeutic modalities, including endocrine therapy, CDK2 inhibition, HER2 antibodies, and immune checkpoint inhibitors.^[6] These combination strategies are designed to counter resistance mechanisms to CDK4 inhibition and expand the potential therapeutic applications of cell cycle targeting therapy.^[6]

Clinical trials

Atirmociclib has entered clinical development as part of Pfizer’s extensive oncology pipeline.^[11] The clinical program is evaluating atirmociclib both as a single agent and in combination with other therapeutic approaches, particularly focusing on patients with hormone receptor-positive, HER2-negative breast cancer.^[9]^[12]^[13]^[14]^[15]^[16]^[17]

Early clinical studies have included heavily pretreated patient populations, including those who have previously received CDK4/6 inhibitor therapy.^[9] This approach allows for the evaluation of atirmociclib’s potential to overcome resistance to existing CDK4/6 inhibitors and provide therapeutic benefit in patients with limited treatment options.^[9]

Safety profile and toxicity

One of the key differentiating features of atirmociclib is its potential for improved safety profile compared to existing dual CDK4/6 inhibitors.^[6] The selective targeting of CDK4 while limiting CDK6 inhibition is specifically designed to reduce neutropenia, the most common dose-limiting toxicity associated with current CDK4/6 inhibitors.^[18]

The rationale for this approach is based on preclinical evidence suggesting that neutropenia is primarily driven by CDK6 inhibition rather than CDK4 inhibition.^[18] By selectively targeting CDK4, atirmociclib aims to maintain therapeutic efficacy while potentially allowing for higher or more sustained dosing without the dose-limiting hematologic toxicities that can compromise treatment outcomes with existing agents.^[18]

Regulatory status

As of September 2025, atirmociclib remains an investigational drug that has not received approval from the FDA or other regulatory agencies.^[5] The compound is part of Pfizer’s oncology development pipeline.^[5]

References

Pfizer (2 February 2025). A Phase 1/2A Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of Pf-07220060 as a Single Agent and as Part of Combination Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
Shapiro GI (March 2017). “The evolving role of cyclin-dependent kinase inhibitors in cancer management”. Clinical Advances in Hematology & Oncology. 15 (3): 174–177. PMID 28398270.
“CDK4 inhibitor PF-07220060”. http://www.cancer.gov. 2 February 2011. Retrieved 3 September 2025.
“Pfizer Pipeline”. Pfizer.
“Atirmociclib PF-07220060”. Pfizer Oncology Development. Retrieved 3 September 2025.
Chang J, Lu J, Liu Q, Xiang T, Zhang S, Yi Y, et al. (March 2025). “Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis”. Cancer Cell. 43 (3): 380–397.e7. doi:10.1016/j.ccell.2025.02.009. PMID 40068596.
Topacio BR, Zatulovskiy E, Cristea S, Xie S, Tambo CS, Rubin SM, et al. (May 2019). “Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein’s C-Terminal Helix”. Molecular Cell. 74 (4): 758–770.e4. doi:10.1016/j.molcel.2019.03.020. PMC 6800134. PMID 30982746.
Helsten T, Kato S, Schwaederle M, Tomson BN, Buys TP, Elkin SK, et al. (July 2016). “Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics”. Molecular Cancer Therapeutics. 15 (7): 1682–1690. doi:10.1158/1535-7163.MCT-16-0071. PMID 27196769.
“ESMO 2024 – combos could be the way forward for CDK2”. ApexOnco. 15 September 2024.
Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, et al. (March 2025). “CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety”. Cancer Cell. 43 (3): 464–481.e14. doi:10.1016/j.ccell.2025.02.006. PMID 40068598.
“Pfizer Highlights Diverse Oncology Portfolio and Combination Approaches at ESMO 2024”. Pfizer. 2024.
Pfizer (12 August 2025). A Phase 1/2a Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetic, Pharmacodynamic, and Anti-Tumor Activity of Pf-07248144 in Participants With Advanced or Metastatic Solid Tumors (Report). clinicaltrials.gov.
Pfizer (2 July 2025). An Interventional Safety and Efficacy Phase 1/2, Open-Label Study to Investigate Tolerability, Pk, and Antitumor Activity of Vepdegestrant (Arv-47/Pf-07850327), an Oral Proteolysis Targeting Chimera, in Combination With Pf-07220060 in Participants Aged 18 Years and Older With Er+/her2- Advanced or Metastatic Breast Cancer (Report). clinicaltrials.gov.
Pfizer (14 November 2024). A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PF-07220060 in Combination With Pf-07104091 Plus Endocrine Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
Pfizer (17 June 2025). (FOURLIGHT-3) (Report). clinicaltrials.gov.
Pfizer (13 March 2025). An Interventional, Open-Label, Randomized, Multicenter Phase 3 Study of PF-07220060 Plus Letrozole Compared to cdk4/6 Inhibitor Plus Letrozole in Participants Over 18 Years of Age With Hormone Receptor (Hr)-Positive, her2-Negative Advanced/Metastatic Breast Cancer Who Have Not Received Any Prior Systemic Anticancer Treatment for Advanced/Metastatic Disease (FOURLIGHT-1) (Report). clinicaltrials.gov.
Pfizer (15 November 2024). An Interventional, Open-Label, Randomized, Multicenter, Phase 2 Study of Pf-07220060 Plus Letrozole Compared to Letrozole Alone in Postmenopausal Women 18 Years or Older With Hormone Receptor-Positive, her2-Negative Breast Cancer in the Neoadjuvant Setting (Report). clinicaltrials.gov.
“Pfizer dials down its atirmociclib ambitions”. ApexOnco. 1 May 2025.

Identifiers

IUPAC name
CAS Number	2380321-51-5
PubChem CID	146219790
ChemSpider	115009592
UNII	S743GOJ5LJ
KEGG	D12834
ChEMBL	ChEMBL5187755
Chemical and physical data
Formula	C₂₂H₂₇ClFN₅O₃
Molar mass	463.94 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////Atirmociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6

Asaretoclax

January 4, 2026 2:34 am / Leave a comment

Asaretoclax

CAS 2363074-01-3

MF C47H57F2N7O7S, MW 902.1 g/mol

4-[4-[[2-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[(4-hydroxy-4-methylcyclohexyl)methylamino]-3-nitrophenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263

Asaretoclax is an orally bioavailable inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), with potential pro-apoptotic and antineoplastic activities. Upon oral administration, asaretoclax targets, binds to and inhibits the activity of Bcl-2. This restores apoptotic processes in tumor cells. Bcl-2 is overexpressed in many cancers and plays an important role in the negative regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival.

SYN

US11318134,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US309776623&_cid=P21-MJZ42N-73938-1

Example 34

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1l-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Intermediate 18

4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

Intermediate 18 was prepared following a procedure described in WO2014/165044A1. LC/MS (ESI) m/z 344.1 [M+H] ⁺.

Intermediate 30

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic Acid

Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 30-1) was prepared following the procedure described in Step 1, Route C for Intermediate 28 using Intermediate 24 in place of Intermediate 22. LCMS (ESI) m/z 591.2 [M+H] ⁺.

Step 2: Intermediate 30 was prepared following the procedure described in Step 5, Route B for Intermediate 26 using Intermediate 30-1 in place of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate. LCMS (ESI) m/z 577.5[M+H] ⁺.

Example 34 was prepared following General Procedure A using Intermediate 30 and Intermediate 18. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.70 (s, 1H), 11.40 (br s, 1H), 8.59-8.49 (m, 2H), 8.04 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.06 (d, J=9.2 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.99 (t, J=56.8 Hz, 1H), 4.25 (s, 1H), 3.33-3.25 (m, 2H), 3.18-3.05 (m, 4H), 2.97 (s, 2H), 2.40-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94 (s, 6H), 1.71-1.59 (m, 5H), 1.58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 1.27-1.20 (m, 2H), 1.18-1.09 (m, 2H), 1.10 (s, 3H), 0.83 (s, 6H); LC/MS (ESI) m/z 902.6 [M+H] ⁺.

SYN

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US384526484&_cid=P21-MJZ3XL-69589-1

PAT

Benzamide compounds

Publication Number: US-2021009543-A1

Priority Date: 2018-01-10

Benzamide compoundsPublication Number: CN-118084904-APriority Date: 2018-01-10
Benzamide compoundsPublication Number: EP-4556469-A1Priority Date: 2018-01-10
Benzamide compounds as bci inhibitors for the treatment of hivPublication Number: EP-3740487-B1Priority Date: 2018-01-10Grant Date: 2025-01-08
Benzamide compoundsPublication Number: US-11344546-B2Priority Date: 2018-01-10Grant Date: 2022-05-31
Benzamide compoundsPublication Number: US-11318134-B2Priority Date: 2018-01-10Grant Date: 2022-05-03

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/////////Asaretoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263

Doxecitine

January 3, 2026 2:34 am / Leave a comment

Doxecitine

CAS951-77-9

MF C9H13N3O4

11/3/2025, FDA 2025, To treat thymidine kinase 2 deficiency in patients who start to show symptoms when they are 12 years old or younger

CYTIDINE, 2′-DEOXY-
dCYD
DEOXYCYTIDINE

4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one

Doxecitine is a pyrimidine nucleoside used to treat thymidine kinase 2 deficiency.

Doxecitine is a synthetic form of the naturally occurring pyrimidine deoxyribonucleoside deoxycytidine. It is an essential component of the deoxyribonucleotide pool required for DNA synthesis and repair. Doxecitine is currently approved and marketed as a fixed-dose combination therapy with thymidine (KYGEVVI). This combination is the first and only approved treatment for Thymidine Kinase 2 deficiency.^5,6

Deoxycytidine is a deoxyribonucleoside, a component of deoxyribonucleic acid. It is similar to the ribonucleoside cytidine, but with one hydroxyl group removed from the C2′ position. Deoxycytidine can be phosphorylated at C5′ of the deoxyribose by deoxycytidine kinase, converting it to deoxycytidine monophosphate (dCMP), a DNA precursor.^[1] dCMP can be converted to dUMP and dTMP.

Doxecitine is the international nonproprietary name.^[2]

SYN

Graham A. Mock, Douglas H. Lovern, “N.sup.4 -substituted 2′-deoxycytidine compounds, oligonucleotides including N.sup.4 -labeled 2′-deoxycytidines, and a process for making oligonucleotides with N-modified 2′-deoxycytidines.” U.S. Patent US5633364, issued April, 1995.US5633364

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US37089691&_cid=P21-MJXONM-10154-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1982003079&_cid=P21-MJXONM-10154-1

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Chow E, Miller L, Clearman A, Arnold P, Koenig MK, Russo SN: Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency. Mol Genet Metab. 2025 Aug;145(4):109159. doi: 10.1016/j.ymgme.2025.109159. Epub 2025 Jun 3. [Article]
Mittur A, VanMeter SA, Orujov E, Glidden P: Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults. Clin Ther. 2024 Jul;46(7):576-587. doi: 10.1016/j.clinthera.2024.06.006. Epub 2024 Jul 18. [Article]
Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M: Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4. [Article]
FDA Approved Drug Products: KYGEVVI (doxecitine and doxribtimine) powder, for oral solution (November 2025) [Link]
UCB: New data on investigational therapy for thymidine kinase 2 deficiency presented at Muscular Dystrophy Association (MDA) 2025 Conference [Link]
PR Newswire: U.S. FDA approves KYGEVVI™ (doxecitine and doxribtimine), the first and only treatment for adults and children living with thymidine kinase 2 deficiency (TK2d) [Link]

Names


IUPAC name2′-deoxycytidine
Systematic IUPAC name4-Amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2(1H)-one
Other namesdoxecitine
Identifiers
CAS Number	951-77-9
3D model (JSmol)	Interactive image
ChEBI	CHEBI:15698
ChEMBL	ChEMBL66115
ChemSpider	13117
ECHA InfoCard	100.012.231
MeSH	Deoxycytidine
PubChem CID	13711
UNII	0W860991D6
CompTox Dashboard (EPA)	DTXSID70883620
InChI
SMILES
Properties
Chemical formula	C₉H₁₃N₃O₄
Molar mass	227.217
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references

References

Staub M, Eriksson S (2006). “The Role of Deoxycytidine Kinase in DNA Synthesis and Nucleoside Analog Activation”. In Peters GJ (ed.). Deoxynucleoside Analogs In Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. pp. 29–52. doi:10.1007/978-1-59745-148-2_2. ISBN 978-1-59745-148-2.
World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.
Kim KW, Roh JK, Wee HJ, Kim C (2016). “Molecular Targeted Anticancer Drugs”. In Kim KW, Roh JK, Wee HJ, Kim C (eds.). Cancer Drug Discovery: Science and History. Springer Netherlands. pp. 175–238. doi:10.1007/978-94-024-0844-7_9. ISBN 978-94-024-0844-7.
Guo M, Zhang L, Du Y, Du W, Liu D, Guo C, et al. (March 2018). “Enrichment and Quantitative Determination of 5-(Hydroxymethyl)-2′-deoxycytidine, 5-(Formyl)-2′-deoxycytidine, and 5-(Carboxyl)-2′-deoxycytidine in Human Urine of Breast Cancer Patients by Magnetic Hyper-Cross-Linked Microporous Polymers Based on Polyionic Liquid”. Analytical Chemistry. 90 (6): 3906–3913. doi:10.1021/acs.analchem.7b04755. PMID 29316399.
“FDA approves 1st drug for thymidine kinase 2 deficiency”. U.S. Food and Drug Administration. 3 November 2025. Retrieved 4 November 2025. This article incorporates text from this source, which is in the public domain.

External links

“Doxecitine ( Code – C420 )”. EVS Explore.
MeSH 68003841

/////////doxecitine, deoxycytidine, CYTIDINE, 2′-DEOXY-, dCYD, FDA 2025, APPROVALS 2025

Amogammadex

January 2, 2026 2:51 am / Leave a comment

Amogammadex

CAS 1309580-40-2

MF C88H136N8O56S8 MW2458.56

(2R)-2-acetamido-3-[[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)-10,15,20,25,30,35,40-heptakis[[(2R)-2-acetamido-2-carboxyethyl]sulfanylmethyl]-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.2^3,6.2^8,11.2^13,16.2^18,21.2^23,26.2^28,31.2^33,36]hexapentacontan-5-yl]methylsulfanyl]propanoic acid

L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-
AMOGAMMADEX [INN]
CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL)

cyclooctakis-(1→4)-{6-S-[(2R)-2-acetamido-2-carboxyethyl]-6-thio-α-Dglucopyranosyl}
rocuronium and vecuronium reversal agent, L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-
AMOGAMMADEX [INN]
CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL)

Pat

WO2012068981

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012068981&_cid=P21-MJW9RG-10499-1

CD-8

Weigh 23.7 g (0.088 mol) of N-acetylcysteine and measure 160 ml of dry DMF. Add both to a dry three-necked flask and stir until completely dissolved. Cool the reaction solution to approximately -10°C in a constant temperature bath. Slowly add 8.81 g of sodium hydride (60%) in portions under argon protection and mechanical stirring, maintaining the temperature below -5°C. After the addition is complete, continue stirring until no more bubbles emerge, then transfer the solution to approximately 5°C and react until no more bubbles emerge (approximately 2-3 hours).

With the temperature controlled at approximately 5°C in an ice bath, add 8.38 g (3.85 mmol) of DMF solution of 6-per-deoxy-6-per-iodo-γ-cyclodextrin to the reaction solution of the fully reacted N-acetylcysteine sodium salt. Under argon protection, mechanically stir to ensure homogeneity and continue stirring for 30 min. Gradually raise the temperature of the reaction solution to 70°C and react for 12 h. Then cool the reaction solution to room temperature, filter, wash the filter cake twice with DMF, and then wash with acetone until triphenylphosphine and triphenyloxyphosphine are removed. Dry under reduced pressure to obtain crude sodium salt. Dissolve the crude sodium salt in glacial acetic acid, and then pass dry hydrogen chloride gas into the solution under ice bath cooling. A white solid precipitates after 20 min. Filter after no more white solid precipitates (approximately 1 h). Dry acetone was gradually added to the filtrate, and a solid precipitated out. The mixture was filtered, and the filter cake was washed with acetone until there was no sour taste. The cake was dried under reduced pressure to obtain 6-per-deoxy-6-per-(N-acetylglycine methyl)thioether-γ-cyclodextrin (CD-8) with a yield of 48%.

Ή NMR spectra of CD-8 in heavy water (D2O ₎ : 52.02 (CH3,m,3H), 2.69,2.44 (CH2,m,2H), 3.02 (CH,m,H), 3.06,2.81 (CH2,m,2H), 3.73 (2CH,m,2H), 4.19 (CH,m,H), 4.74 (CH,m,H), 5.03 (CH,s,H) ppm.

PAT

CN102060941

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84636898&_cid=P21-MJW9XY-15988-1

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////////amogammadex

Alizulatide vixocianine

December 31, 2025 2:40 am / Leave a comment

Alizulatide vixocianine

CAS 2924859-51-6

MF C115H145N17O25S, 2,197.55

L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt

4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate

diagnostic imaging agent, 8M3Q8XZ6MJ

Alizulatide vixocianine is a polypeptide that can be discovered through polypeptide screening. Polypeptide screening is a research tool mainly based on immunoassay methods to identify active polypeptides. It can be applied to protein interaction, functional analysis, antigenic epitope screening, especially in the fields of active molecule research and development.

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/////////alizulatide vixocianine, diagnostic imaging agent, 8M3Q8XZ6MJ

Aleniglipron

December 30, 2025 2:42 am / Leave a comment

Aleniglipron

CAS 2685823-26-9

MF C49H55FN9O6P MW916.0 g/mol

3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX

Aleniglipron (development code GSBR-1290) is a small-molecule GLP-1 agonist developed by Structure Therapeutics.^[1] It is delivered orally and is in a Phase II trial as of 2023.^[2][3][4] In June 2024, Structure Therapeutics reported positive topline data from a Phase 2a obesity study in which GSBR-1290 demonstrated clinically meaningful and statistically significant placebo-adjusted mean weight loss and generally favorable safety and tolerability results.^[5]

Aleniglipron Phase 2 Body Composition StudyCTID: NCT07169942Phase: Phase 2Status: Active, not recruitingDate: 2025-10-31
A Dose-Range Study of Aleniglipron (GSBR-1290) in Participants Living With Obesity or Overweight With at Least One Weight-related ComorbidityCTID: NCT06703021Phase: Phase 2Status: Active, not recruitingDate: 2025-09-15
A Phase 2b, Dose-range Finding Study of the Efficacy and Safety of Multiple Doses of Aleniglipron (GSBR-1290) in Participants Living With Obesity or Overweight With at Least One Weight-related ComorbidityCTID: NCT06693843Phase: Phase 2Status: Active, not recruitingDate: 2025-08-26

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US367934715&_cid=P10-MJRZ0C-74156-1

Example 2: Synthesis of

3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 121a)

Step A: (4-bromo-2-fluorophenyl)diethylphosphine oxide

The mixture of 4-bromo-2-fluoro-1-iodobenzene (2.00 g, 6.60 mmol), diethylphosphine oxide (775 mg, 7.30 mmol), Pd ₂(dba) ₃(302 mg, 0.330 mmol) and XantPhos (382 mg, 0.660 mmol) in 40 mL of 1,4-dioxane was sparged with argon. Then triethylamine (1.30 g, 13.2 mmol) was added. The mixture was heated at 60° C. for 12 h under an atmosphere of argon. LCMS showed the reaction was completed. The mixture was concentrated, and the residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was dried and concentrated. The residue was purified with silica gel column chromatography (PE/EA/methanol=1:2:0.1) to provide (4-bromo-2-fluorophenyl)diethylphosphine oxide (1.50 g, 5.37 mmol, 80.6% yield) as a pale white solid.

LCMS: m/z=279.0, 281.0 (M+H) ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.63-7.73 (m, 3H), 1.95-2.08 (m, 2H), 1.80-1.92 (m, 2H), 0.80-1.10 (m, 6H).

Step B: (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide

To a mixture of (4-bromo-2-fluorophenyl)diethylphosphine oxide (360 mg, 1.29 mmol) in 2 mL of methanol was added methylamine (9.8 M in methanol, 4 mL, 39.2 mmol). The mixture was heated at 80° C. for 3 h in a microwave reactor. LCMS showed most of the starting material was consumed. The mixture was concentrated, diluted with ethyl acetate (50 mL), and washed with water (30 mL). The organic layer was dried and concentrated. The resulting residue was purified with silica gel column chromatography (PE/EA/methanol=1:2:0.1) to provide (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (179 mg, 0.617 mmol, 47.9% yield) as a white solid.

LCMS: m/z=290.0, 292.0 (M+H) ⁺.

¹H NMR (600 MHz, DMSO-d ₆) δ 7.75-7.76 (m, 1H), 7.11 (dd, J=13.2, 8.4 Hz, 1H), 6.63-6.80 (m, 2H), 2.71 (d, J=5.4 Hz, 3H), 1.88-1.94 (m, 4H), 0.90-1.05 (m, 6H).

Step C: tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

The mixture of (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (310 mg, 1.07 mmol), tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (428 mg, 0.970 mmol), CuI (278 mg, 1.46 mmol), potassium carbonate (268 mg, 1.94 mmol), and (1S,2S)—N ¹,N ²-dimethylcyclohexane-1,2-diamine (208 mg, 1.46 mmol) in NMP (25 mL) was heated at 130° C. for 3 h under an atmosphere of argon. LCMS showed the reaction was completed. The mixture was added ethyl acetate (100 mL) and washed with water (50 mL*3). The organic layer was dried and concentrated. The residue was purified with silica gel column chromatography (PE/EA/methanol=1:4:0.3) to provide tert-butyl (5)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (530 mg, 0.810 mmol, 84.0% yield) as a pale yellow solid. LCMS: m/z=651.3 (M+H) ⁺.

¹H NMR (600 MHz, DMSO-d ₆) δ 7.73 (q, J=4.8 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 7.26 (dd, J=13.2, 8.4 Hz, 1H), 7.11 (d, J=6.6 Hz, 2H), 6.98 (s, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.86 (s, 1H), 5.12 (br. s, 1H), 4.13-4.34 (m, 1H), 3.02-3.19 (m, 1H), 2.69-2.74 (m, 4H), 2.61-2.69 (m, 1H), 2.19 (s, 6H), 1.89-1.95 (m, 4H), 1.43 (s, 9H), 1.17-1.18 (m, 3H), 0.95-1.05 (m, 6H).

Step D: (5)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

To a mixture of tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (520 mg, 0.800 mmol) in 1,4-dioxane (6 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 12 mL, 48.0 mmol).

The mixture was stirred at room temperature for 3 h. LCMS showed the reaction was completed. The mixture was concentrated, and the residue was dispersed in 40 mL of ethyl ether. The resulting solid was collected and dried in vacuo to provide (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (430 mg, 0.730 mmol, 91.7% yield) as a pale yellow solid.

LCMS: m/z=551.2 (M+H) ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.14 (s, 1H), 9.46-9.53 (m, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.27 (dd, J=12.8, 8.4 Hz, 1H), 7.13 (d, J=6.4 Hz, 2H), 6.93 (d, J=3.2 Hz, 1H), 6.90 (dt, J=8.4, 2.0 Hz, 1H), 6.86-6.87 (m, 1H), 4.55-4.59 (m, 2H), 3.58-3.62 (m, 1H), 3.28-3.33 (m, 1H), 3.03-3.10 (m, 1H), 2.90-3.05 (m, 1H), 2.73 (s, 3H), 2.20 (d, J=2.0 Hz, 6H), 1.88-1.97 (m, 4H), 1.36 (d, J=6.8 Hz, 3H), 0.90-1.05 (m, 6H).

Step E: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

To a mixture of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (272 mg, 0.710 mmol) and DMF (7 mL) in a 50 mL flask (flask A) were added HATU (810 mg, 2.13 mmol) and triethylamine (1.45 g, 14.3 mmol). The mixture was stirred at room temperature for 10 mins. In another 50 mL flask (flask B), (5)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (420 mg, 0.710 mmol) and triethylamine (2.90 g, 28.7 mmol) in 7 mL of DMF was stirred at room temperature for 10 mins. Then the mixture in flask B was added into flask A dropwise. The resulting mixture was stirred at room temperature for 12 h. LCMS showed most of the starting material was consumed. The mixture was diluted with DCM (100 mL) and washed with water (50 mL*3). The organic layer was dried and concentrated. The residue was purified with Prep-HPLC (0.01% hydrochloric acid in water and acetonitrile) to provide 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5 (4H)-one (290 mg) as a white solid.

LCMS: m/z=916.4 (M+H) ⁺.

¹H NMR (400 MHz, DMSO-d ₆, 80° C.) δ 11.58 (br. s, 1H), 7.66 (br. s, 1H), 7.52 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.05-7.30 (m, 5H), 6.70-6.95 (m, 4H), 5.56 (br. s, 1H), 4.45 (br. s, 1H), 3.95-3.99 (m, 2H), 3.40-3.70 (m, 3H), 2.83-2.90 (m, 3H), 2.60-2.80 (m, 3H), 2.22 (d, J=1.6 Hz, 6H), 1.88-1.96 (m, 4H), 1.58-1.80 (m, 7H), 1.43 (br. s, 3H), 1.17 (br. s, 3H), 0.95-1.10 (m, 6H).

PAT

Heterocyclic glp-1 agonistsPublication Number: EP-4097099-A1Priority Date: 2020-02-07
Heterocyclic GLP-1 agonistsPublication Number: CN-115698003-APriority Date: 2020-02-07
Heterocyclic glp-1 agonistsPublication Number: EP-4097099-B9Priority Date: 2020-02-07Grant Date: 2025-04-30
Heterocyclic glp-1 agonistsPublication Number: EP-4458834-A2Priority Date: 2020-02-07
Heterocyclic GLP-1 agonistsPublication Number: US-11926643-B2Priority Date: 2020-02-07Grant Date: 2024-03-12
Heterocyclic GLP-1 agonistsPublication Number: CN-119823184-APriority Date: 2020-02-07
Heterocyclic GLP-1 agonistsPublication Number: CN-119841865-APriority Date: 2020-02-07
Heterocyclic GLP-1 agonistsPublication Number: CN-119874775-APriority Date: 2020-02-07
Heterocyclic GLP-1 agonistsPublication Number: US-11492365-B2Priority Date: 2020-02-07Grant Date: 2022-11-08
Heterocyclic GLP-1 agonistsPublication Number: CN-115698003-BPriority Date: 2020-02-07Grant Date: 2024-10-11
Heterocyclic glp-1 agonistsPublication Number: US-2022213130-A1Priority Date: 2020-02-07
Heterocyclic glp-1 agonistsPublication Number: EP-4097099-B1Priority Date: 2020-02-07Grant Date: 2024-06-26
Heterocyclic glp-1 agonistsPublication Number: US-2023174565-A1Priority Date: 2020-02-07
Salts and solid forms of a compound having glp-1 agonist activityPublication Number: WO-2024125602-A1Priority Date: 2022-12-15
Salts and solid forms of a compound having glp-1 agonist activityPublication Number: EP-4634180-A1Priority Date: 2022-12-15
Heterocyclic glp-1 agonistsPublication Number: US-2024366639-A1Priority Date: 2021-08-12
Heterocyclic glp-1 agonistsPublication Number: WO-2023016546-A1Priority Date: 2021-08-12
Heterocyclic glp-1 agonistsPublication Number: WO-2021155841-A1Priority Date: 2020-02-07

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References

Mao, Ting; Meng, Qinghua; Zhang, Haizhen; Zhang, Jinqiang J.; Shi, Songting; Guan, Zhibo; Jiang, Xinglong; Zhang, Fang; Lei, Hui; Lin, Xichen (20 June 2023). “760-P: Discovery of GSBR-1290, a Highly Potent, Orally Available, Novel Small Molecule GLP-1 Receptor Agonist”. Diabetes. 72 (Supplement_1) 760-P. doi:10.2337/db23-760-P. S2CID 259430363.
“Structure Therapeutics Initiates Phase 2a Study of Oral GLP-1 agonist GSBR-1290 for the Treatment of Type 2 Diabetes and Obesity”. BioSpace. 25 May 2023. Retrieved 4 November 2023.
“Structure announces positive results from oral GLP-1 receptor agonist gsbr-1290”. Bariatric News. 2 October 2023. Retrieved 4 November 2023.
Satija, Bhanvi (29 September 2023). “Structure Therapeutics surges as early data from obesity pill tops expectations”. Reuters. Retrieved 4 November 2023.
“Structure Therapeutics Reports Positive Topline Data from its Phase 2a Obesity Study and Capsule to Tablet PK Study for its Oral Non-Peptide Small Molecule GLP-1 Receptor Agonist GSBR-1290”. BioSpace. 2024-06-03. Retrieved 2024-10-24.

Legal status

Legal status	Investigational
Identifiers
IUPAC name
CAS Number	2685823-26-9
PubChem CID	164809721
DrugBank	DB18551
UNII	Z6XCL6R9SX
Chemical and physical data
Formula	C₄₉H₅₅FN₉O₆P
Molar mass	916.008 g·mol⁻¹
InChI

//////////Aleniglipron, glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX

Limnetrelvir

December 29, 2025 2:44 am / Leave a comment

Limnetrelvir

CAS 2923500-04-1

MF C₂₇H₂₃F₄N₅O₄ MW 557.50

N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide

N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-
(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamide
antiviral, ABBV-903, ABBV 903, 4TPS988XGG

Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research.

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION

Example 1 – Synthesis of Compound (2) (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide

Compound 2F – Synthesis of 8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid

[00035] A suspension of 7-fluoroindoline-2,3-dione (55 g, 333 mmol), malonic acid (41.6 g, 400 mmol) and sodium acetate (68.3 g, 833 mmol) in acetic acid (500 mL) was heated at 112 °C overnight. The reaction mixture was cooled to room temperature and poured into cold 0.4 M aqueous HCl (2200 mL). The precipitate was collected by filtration and rinsed thoroughly with ice-cold water (~250 mL) followed by methyl tert-butyl ether (~100 mL) and then concentrated twice from acetonitrile with high vacuum. The materials were largely dissolved into 1 M aqueous NaOH (370 mL) and filtered through diatomaceous earth with a 0.1 M aqueous NaOH (50 mL) rinse. Then the filtrate was washed thrice with dichloromethane (3 x 200 mL) which removed the color. After this aqueous layer was filtered again through diatomaceous earth, it was acidified by the dropwise addition of concentrated aqueous HCl (33 mL, ~0.4 moles). The material was collected by filtration. After prolonged drying under heat and vacuum, the material was treated with water (1 L) and the mixture was made acidic by the addition of a small amount of 1 M aqueous HCl. The suspension was heated to 80 °C and then allowed to slowly cool to room temperature. The resulting material was collected by filtration, washed with 0.01 M aqueous HCl (150 mL) and dried under vacuum at 80 °C to provide the title compound (2F).¹H NMR (500 MHz, DMSO-d6) δ ppm 14.00 (bs, 1H), 12.07 (bs, 1H), 8.00 (dd, J = 8.2, 1.2 Hz, 1H), 7.49 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.23 (ddd, J = 8.2, 8.1, 5.2 Hz, 1H), 6.95 (s, 1H); ¹³C NMR (101 MHz, DMSO-d6, 90 °C) δ ppm 165.75 – 165.73 (m), 160.30, 148.75 (d, J = 246.0 Hz), 140.85 – 140.80 (m), 128.11 (d, J = 13.7 Hz), 123.85, 121.60 – 121.53 (m), 121.53 – 121.43 (m), 117.70 – 117.65 (m), 115.33 (d, J = 17.2 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆, 90 °C) δ ppm -130.47 (dd, J = 10.9, 5.3 Hz); MS (APCI, M+H⁺) m/z 208.

Compound 2G – Synthesis of (R)-N-(1-(4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (2)

00036] To a mixture of Compound 2F (29.84 g, 144 mmol) in anhydrous N,N-dimethylformamide (360 mL) was added DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-

methylmorpholinium chloride) (43.17 g, 156 mmol) over twelve minutes at room temperature. After the suspension had been stirred forty minutes, it was added over eight minutes to a suspension of Compound 2E (≤120 mmol) and N-methylmorpholine (16 mL, 146 mmol) in N,N-dimethylformamide (120 mL) with a N,N-dimethylformamide (20 mL) rinse. After forty minutes, the reaction mixture was added to rapidly stirred 0.1 M aqueous K2HPO4 (2.5 L) and extracted four times with 4:1 isopropyl acetate / heptanes then once with isopropyl acetate alone. The product, which had begun to precipitate out from the combined extracts, was separated by decantation and filtration, then washed with dichloromethane. The remaining aqueous phase was extracted twice more with isopropyl acetate and all the organic extracts were combined, then washed with additional 0.1 M aqueous K₂HPO₄ followed by water, dried (Na₂SO₄), and filtered. The filtrate was concentrated with the dichloromethane wash of the material collected above. The residue was concentrated, dissolved in acetonitrile / CH2Cl2, filtered, and purified by chromatography on silica (20 to 100% acetonitrile / CH2Cl2). The collected fractions were concentrated to a small volume, and stirred in ethyl acetate overnight.

[00037] The suspension was heated at 70 °C for twenty minutes, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether followed by methyl tert-butyl ether before being dried under vacuum with heat. The material obtained previously from the early extracts were also stirred in ethyl acetate, heated at 70 °C, then allowed to slowly cool to room temperature. Methyl tert-butyl ether was stirred in, the suspension was cooled to 0 °C, and the purified product was collected by filtration with rinses of 1:1 ethyl acetate / methyl tert-butyl ether rinse followed by methyl tert-butyl ether. The material was dried overnight under vacuum to provide the title compound (2).¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.96 (s, 1H), 9.03 – 8.84 (m, 1H), 8.21 – 8.18 (m, 1H), 7.98 – 7.93 (m, 1H), 7.56 – 7.50 (m, 1H), 7.49 – 7.43 (m, 1H), 7.21 – 7.15 (m, 1H), 6.66 – 6.59 (m, 1H), 4.51 – 4.40 (m, 1H), 3.73 – 3.55 (m, 6H), 3.54 – 3.22 (m, 6H), 2.29 – 2.18 (m, 1H), 2.07 – 1.95 (m, 1H); ¹H NMR (400 MHz, DMSO-d₆, 90 °C) δ ppm 11.47 (bs, 1H), 8.77 – 8.47 (m, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.1, 1.2 Hz, 1H), 7.39 (ddd, J = 11.0, 8.1, 1.2 Hz, 1H), 7.15 (ddd, J = 8.1, 8.1, 5.1 Hz, 1H), 6.60 (s, 1H), 4.54 – 4.43 (m, 1H), 3.74 – 3.20 (m, 12H), 2.31 – 2.21 (m, 1H), 2.06 – 1.96 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆, 90 °C) δ

ppm 166.61, 165.97, 161.31, 149.59 (d, J = 246.3 Hz), 148.95, 146.10 – 146.03 (m), 136.00, 135.65, 133.13 (q, J = 6.1 Hz), 128.84 – 128.63 (m), 123.76 (q, J = 273.7 Hz), 122.19, 122.16, 122.12, 121.60, 118.99 – 118.91 (m), 117.75, 116.17 (d, J = 17.3 Hz), 105.57, 66.04, 57.95, 51.06, 50.35, 47.74, 42.35, 31.54; ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -57.54 – -58.10 (m), -130.02 – -130.15 (m); ¹⁹F NMR (376 MHz, DMSO-d6, 90 °C) δ ppm -58.37 – -58.97 (m), -130.96 (dd, J = 11.0, 5.1 Hz). MS (APCI, M+H⁺) m/z 558.

PAT

Pyrrolidine Main Protease Inhibitors as Antiviral AgentsPublication Number: US-2024158368-A1Priority Date: 2022-10-14
Pyrrolidine main protease inhibitors as antiviral agentsPublication Number: WO-2024081351-A1Priority Date: 2022-10-14

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/////////limnetrelvir, antiviral, ABBV-903, ABBV 903, 4TPS988XGG

Aficamten

December 28, 2025 2:45 am / Leave a comment

Aficamten

C₁₈H₁₉N₅O₂, 337.4 g/mol

FDA 2025, APPROVALS 2025, Myqorzo, 12/19/2025, To treat symptomatic obstructive hypertrophic cardiomyopathy

CK-3773274, B1I77MH6K1, BAY-3723113; CK 3773274; CK 274; MYQORZO

N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1-methylpyrazole-4-carboxamide

OriginatorCytokinetics
DeveloperBayer; Cytokinetics; Sanofi
ClassAmides; Cardiovascular therapies; Heart failure therapies; Indenes; Oxadiazoles; Pyrazoles; Small molecules
Mechanism of ActionCardiac myosin inhibitors
Orphan Drug StatusYes – Hypertrophic cardiomyopathy
RegisteredHypertrophic cardiomyopathy
20 Dec 2025Cytokinetics plans to launch aficamten in the USA in second half of January 2026
19 Dec 2025Registered for Hypertrophic cardiomyopathy in USA (PO)
19 Dec 2025Aficamten carries a black box warning for the risk of heart failure

Aficamten, sold under the brand name Myqorzo, is a medication used for the treatment of symptomatic obstructive hypertrophic cardiomyopathy.^[1] It is a cardiac myosin inhibitor^[2] developed by Cytokinetics.^[3]^[4]

Aficamten binds directly to the motor domain of cardiac myosin and prevents it from entering the force-producing state.^[5] This lowers cardiac contractility, leading to reduced left ventricular outflow tract obstruction in people with hypertrophic cardiomyopathy.^[5]

Aficamten was approved for medical use in the United States in December 2025.^[6]

Medical uses

Aficamten is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms.^[1]^[6]

Symptomatic obstructive hypertrophic cardiomyopathy is an inherited condition where people have thickened heart muscle and reduced blood flow from the left side of the heart to the rest of the body, causing symptoms such as shortness of breath, fatigue, and potentially life-threatening cardiac events.^[6]

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019144041&_cid=P10-MJP428-30255-1

Example 15

Synthesis of Compound 184

1. Synthesis of Intermediate 15-2:

[0262] To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl] carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105 ^oC for 8 h, cooled to r.t., concentrated under reduced pressure, and purified by silica gel

chromatography (EA/PE, 1/9) to give 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid.

2. Synthesis of Intermediate 15-3:

[0263] To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (17.6 g, 53.4 mmol, 1.0 equiv) in DCM (120 mL) was added TFA (24 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL) and the pH was adjusted to 12 with sodium hydroxide solution (2 N). The mixture was then extracted with dichloromethane (200 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as a brown oil. 3. Synthesis of Compound 184:

[0264] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (6.1 g, 48.4 mmol, 1.0 equiv) in DMF (300 mL) were added DIEA (12.6 g, 97.5 mmol, 2.0 equiv), HOAt (19.8 g, 145.8 mmol, 3.0 equiv), and EDCI (28 g, 146.1 mmol, 3.0 equiv). The mixture was stirred for 15 min, and (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (11.2 g, 48.9 mmol, 1.0 equiv) was then added. The mixture was then stirred for 3 h, diluted with DCM, washed with NH₄Cl solution three times, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (EA/PE, 74/26) to give an intermediate product. The intermediate product was triturated with a mixture of EA and PE (1/10) to afford 14.5 g (88%) of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 184) as a white solid. LRMS (ES) m/z 338 (M+H). ¹H-NMR: (DMSO, 300MHz, ppm): į 8.41 (1H, d, J = 8.4 Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J = 7.9 Hz), 5.53 (1H, q, J = 8.3 Hz), 3.84 (3H, s), 3.13-2.81 (4H, m), 2.44 (1H, dd, J = 7.9, 4.7 Hz), 1.95 (1H, m), 1.33 (3H, t, J = 7.5 Hz).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021011807&_cid=P10-MJP428-30255-1

(R)-N-(5-(5-ethyl- 1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-l-yl)-1-methyl-1H-pyrazole-4-carboxamide,

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01290

PAT

Cardiac sarcomere inhibitorsPublication Number: US-10836755-B2Priority Date: 2018-01-19Grant Date: 2020-11-17
Cardiac sarcomere inhibitorsPublication Number: US-12065436-B2Priority Date: 2018-01-19Grant Date: 2024-08-20
Cardiac sarcomere inhibitorsPublication Number: US-2023119665-A1Priority Date: 2018-01-19
Cardiac sarcomere inhibitorsPublication Number: US-11472796-B2Priority Date: 2018-01-19Grant Date: 2022-10-18
Cardiac sarcomere inhibitorsPublication Number: US-2025059173-A1Priority Date: 2018-01-19
Dihydrobenzofuran and indene analogs as myocardial inhibitorsPublication Number: CN-117964573-APriority Date: 2018-01-19
Cardiac sarcomere inhibitorsPublication Number: TW-202436291-APriority Date: 2018-01-19
Dihydrobenzofurans and indene analogs as cardiomyome inhibitorsPublication Number: CN-111757875-BPriority Date: 2018-01-19Grant Date: 2024-01-09
Dihydrobenzofuran and indene analogs as myocardial inhibitorsPublication Number: CN-117924208-APriority Date: 2018-01-19
Dihydrobenzofuran and indene analogs as inotropic agentsPublication Number: CN-111757875-APriority Date: 2018-01-19
Cardiac sarcomere inhibitorsPublication Number: TW-I835770-BPriority Date: 2018-01-19Grant Date: 2024-03-21
Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitorsPublication Number: EP-3740481-A1Priority Date: 2018-01-19
Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitorsPublication Number: EP-3740481-B9Priority Date: 2018-01-19Grant Date: 2024-10-23
Cardiac sarcomere inhibitorsPublication Number: US-2021147399-A1Priority Date: 2018-01-19
Cardiac sarcomere inhibitorsPublication Number: EP-4491622-A2Priority Date: 2018-01-19

REF

Clinical Evaluation of the Effect of Aficamten on <scp>QT</scp>/<scp>QTc</scp> Interval in Healthy ParticipantsPublication Name: Clinical and Translational SciencePublication Date: 2025-04PMCID: PMC11979292PMID: 40200648DOI: 10.1111/cts.70218
Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of AficamtenPublication Name: Clinical PharmacokineticsPublication Date: 2025-02-05PMCID: PMC11954688PMID: 39907965DOI: 10.1007/s40262-025-01481-9
The clinical utility of cardiac myosin inhibitors for the management of hypertrophic cardiomyopathy: a scoping reviewPublication Name: Heart Failure ReviewsPublication Date: 2024-12-17PMCID: PMC11802616PMID: 39690360DOI: 10.1007/s10741-024-10476-w
Obstructive Hypertrophic Cardiomyopathy: A Review of New TherapiesPublication Name: Future CardiologyPublication Date: 2023-10PMID: 37933625DOI: 10.2217/fca-2023-0056
Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic CardiomyopathyPublication Name: American journal of cardiovascular drugs : drugs, devices, and other interventionsPublication Date: 2023-08-01PMID: 37526885DOI: 10.1007/s40256-023-00599-0
Synthesis of AficamtenPublication Name: SynfactsPublication Date: 2021-11-17DOI: 10.1055/s-0041-1737088
Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic CardiomyopathyPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-10-04PMID: 34606259DOI: 10.1021/acs.jmedchem.1c01290
Emerging Medical Treatment for Hypertrophic CardiomyopathyPublication Name: Journal of Clinical MedicinePublication Date: 2021-03-01PMCID: PMC7957690PMID: 33804412DOI: 10.3390/jcm10050951
Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle DiseasesPublication Name: International Journal of Molecular SciencesPublication Date: 2020-12-16PMCID: PMC7767104PMID: 33339418DOI: 10.3390/ijms21249599

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Contraindiations

Use with rifampin is contraindicated.^[1]

Adverse effects

The US prescription label for aficamten contains a boxed warning that it reduces left ventricular ejection fraction and can cause heart failure due to systolic dysfunction.^[1]

History

The effectiveness and safety of aficamten were studied in 282 adults with symptomatic obstructive hypertrophic cardiomyopathy randomly assigned to receive aficamten or placebo for 24 weeks.^[6] At the end of the study, participants receiving aficamten had an increase in exercise capacity measured by peak oxygen uptake compared to no change in exercise capacity among those receiving placebo.^[6] Also, 59 percent of participants receiving aficamten experienced an improvement in physical activity limitations (measured using the New York Heart Association Classification system) compared to 24 percent of individuals receiving placebo.^[6]

Society and culture

Legal status

Aficamten was approved for medical use in the United States in December 2025.^[6]^[7] The US Food and Drug Administration granted the application for aficamten orphan drug and breakthrough therapy designations.^[6]

In December 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Myqorzo, intended for the treatment of adults with obstructive hypertrophic cardiomyopathy.^[5] The applicant for this medicinal product is Cytokinetics (Ireland) Limited.^[5]

Names

Aficamten is the international nonproprietary name.^[8]

Aficamten is sold under the brand name Myqorzo.^[6]

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219083s000lbl.pdf ^{[bare URL PDF]}
Chuang, Chihyuan; Collibee, Scott; Ashcraft, Luke; Wang, Wenyue; Vander Wal, Mark; Wang, Xiaolin; et al. (October 2021). “Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy”. Journal of Medicinal Chemistry. 64 (19): 14142–14152. doi:10.1021/acs.jmedchem.1c01290. ISSN 0022-2623. PMID 34606259. S2CID 238355647.
Zhao, Xue; Liu, Hongzhong; Tian, Wei; Fang, Ligang; Yu, Mengyang; Wu, Xiaofei; et al. (2023). “Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study”. Frontiers in Pharmacology. 14 1227470. doi:10.3389/fphar.2023.1227470. PMC 10482267. PMID 37680714.
Sebastian, Sneha Annie; Padda, Inderbir; Lehr, Eric J.; Johal, Gurpreet (September 2023). “Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy”. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions. 23 (5): 519–532. doi:10.1007/s40256-023-00599-0. ISSN 1179-187X. PMID 37526885. S2CID 260348901.
“Myqorzo EPAR”. European Medicines Agency (EMA). 12 December 2025. Retrieved 22 December 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
“FDA approves drug to improve functional capacity and symptoms in adults with rare inherited heart condition”. U.S. Food and Drug Administration (FDA) (Press release). 22 December 2025. Retrieved 22 December 2025. This article incorporates text from this source, which is in the public domain.
“Cytokinetics Announces FDA Approval of Myqorzo (aficamten) for the Treatment of Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy to Improve Functional Capacity and Symptoms” (Press release). Cytokinetics. 19 December 2025. Retrieved 22 December 2025 – via GlobeNewswire News Room.
World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.

External links

Clinical trial number NCT05186818 for “Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (SEQUOIA-HCM) (SEQUOIA-HCM)” at ClinicalTrials.gov

Clinical data

Trade names	Myqorzo
Other names	CK-3773274
License data	US DailyMed: Aficamten
Routes of administration	By mouth
Drug class	Cardiac myosin inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	2364554-48-1
PubChem CID	139331495
DrugBank	DB18490
ChemSpider	114935503
UNII	B1I77MH6K1
KEGG	D12253
ChEMBL	ChEMBL4847050
PDB ligand	6I6 (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₈H₁₉N₅O₂
Molar mass	337.383 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////Aficamten, FDA 2025, APPROVALS 2025, Myqorzo, CK-3773274, CK 3773274, B1I77MH6K1, BAY 3723113; CK 3773274; CK 274, MYQORZO

Zoliflodacin

December 26, 2025 3:12 am / Leave a comment

Zoliflodacin

CAS 1620458-09-4
AZD-0914
AZD0914
FWL2263R77
ETX0914

MF C₂₂H₂₂FN₅O₇ MW 487.4 g/mol

FDA 2025, APPROVALS 2025, 12/12/2025, Nuzolvence

(4′R,6′S,7′S)-17′-fluoro-4′,6′-dimethyl-13′-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]spiro[1,3-diazinane-5,8′-5,15-dioxa-2,14-diazatetracyclo[8.7.0.0^2,7.0^12,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione

Spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione, 11-fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]-, (2R,4S,4aS)-

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione

To treat uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae

Zoliflodacin, sold under the brand name Nuzolvence, is an antibiotic used for the treatment of antibiotic-resistant Neisseria gonorrhoeae (gonorrhea).^[2] Zoliflodacin is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP).^[3] Zoliflodacin is taken by mouth.^[2]

The most common side effects include low white blood cell counts, headache, dizziness, nausea, and diarrhea.^[2]

Zoliflodacin was approved for medical use in the United States in December 2025.^[2]

SYN

Facile Synthesis of Spirocyclic Tetrahydroquinolines via C(sp3)–H Functionalization in a Cascade Redox ProcessDOI: 10.1055/s-0040-1720890Publication Date: 2022Publication Name: Synthesis
Synthesis of ZoliflodacinDOI: 10.1055/s-0040-1707088Publication Date: 2020Publication Name: Synfacts

SYN

SYN

US8889671, 5

SYN

WO-2022204231-A2

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US106042502&_cid=P11-MJMADN-82597-1

Example 5 was prepared from Intermediate 21. The title compound was isolated by reverse phase HPLC (10 mM ammonium acetate in water, CH ₃CN) as the first eluting of two components. ¹H NMR (400 MHz, DMSO-d ₆) δ: 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.5-3.6 (m, 2H), 3.8 (m, 1H), 3.9 (d, 1H), 4.0 (d, 1H), 4.2 (q, 1H), 4.6-4.7 (m, 2H), 7.6 (s, 1H), 11.5 (s, 1H), 11.8 (s, 1H). MS (ES) MH ⁺: 488.4 for C ₂₂H ₂₂FN ₅O ₇, [α] _D ²⁰=−92 (c=1; MeOH).

Also isolated from the synthesis of Example 5 as the second eluting component from HPLC purification was (2S,4R,4aR)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione

¹H NMR (400 MHz, DMSO-d ₆) δ: 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.6-3.7 (m, 2H), 3.8-4.0 (m, 1H), 3.9 (d, 1H), 4.1 (d, 1H), 4.2 (q, 1H), 4.6-4.7 (m, 2H), 7.6 (s, 1H), 11.5 (s, 1H), 11.8 (s, 1H). MS (ES) MH ⁺: 488.4 for C ₂₂H ₂₂FN ₅O ₇, [α] _D ²⁰=+224 (c=1; MeOH).

Alternative Synthesis of Example 5

A solution of Intermediate 22 (1.14 g, 2.71 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (0.346 g, 2.71 mmol) in acetic acid (8 mL) and of water (2 mL) was heated at 110° C. for 2 hours. The solvent was removed and the reaction mixture was purified using Super Critical Fluid Chromatography (Chiralpak IC column with 30% methanol and 70% CO ₂mobile phase). The first eluting compound was further purified by dissolving in acetonitrile (30 mL) and diluting with water (60 mL) to give the title compound as a solid. (0.910 g, 69.0% yield). ¹H NMR (300 MHz, DMSO-d ₆) δ: δ 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.6-3.7 (m, 2H), 3.8 (m, 1H), 3.9 (d, 1H), 4.1 (d, 1H), 4.2 (q, 1H), 4.6-4.75 (m, 2H), 7.6 (s, 1H), 11.4 (s, 1H), 11.8 (s, 1H). MS (ES) MH ⁺: 488 for C ₂₂H ₂₂FN ₆O ₇.

Also isolated from the synthesis of Alternative Synthesis of Example 5 as the second component eluting from the HPLC purification was (2R,4R,4aR)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione:

¹H NMR (300 MHz, DMSO-d ₆) δ: 1.0 (d, 3H), 1.3 (d, 3H), 1.4 (d, 3H), 3.1 (d, 1H), 3.5-4.3 (m, 7H), 4.5-4.8 (m, 2H), 7.6 (s, 1H), 11.5 (br. s., 1H), 11.7 (br. s., 1H). MS (ES) MH ⁺: 488 for C ₂₂H ₂₂FN ₅O ₇.

SYN

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/mic90

2.3.2 Chemical synthesis

The synthesis of zoliflodacin described below was reported in 2015 [47]. The first step, starting from 2,3,4-trifluorobenzaldehyde, consists of the protection of the aldehyde function to an acetal group. After deprotonation using n-BuLi, formylation is performed with DMF to introduce an aldehyde group, which is then converted to oxime using hydroxylamine. Chlorination with N-chlorosuccinimide (NCS), followed by reaction with L-alaninol and intramolecular S_NAr allows the formation of the benzisoxazole ring. The oxazolidinone moiety is obtained using 1,1′-carbonyldiimidazole (CDI). The deprotection of the aldehyde is then performed in acidic conditions followed by another S_NAr at the ortho position of the aldehyde using (2R,6S)-2,6-dimethylmorpholine. Finally, a Knoevenagel condensation between the aldehyde and hexahydropyrimidine-2,4,6-trione is performed, followed by an intramolecular rearrangement consisting in an [1-5] hydride shift and then intramolecular cyclization leading to zoliflodacin (Fig. 5).

PAT

High throughput screening assay to identify DNA topoisomerase inhibitorsPublication Number: US-12234504-B1Priority Date: 2023-10-16Grant Date: 2025-02-25
Treatment of pathogenic neisseria sp. infection with triazole antifungal agentsPublication Number: US-2025281464-A1Priority Date: 2022-04-29
Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: WO-2022204231-A2Priority Date: 2021-03-26
Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: EP-4313040-A2Priority Date: 2021-03-26
Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: EP-4313040-A2Priority Date: 2021-03-26

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Medical uses

Zoliflodacin is indicated for the treatment of uncomplicated urogenital gonorrhea in people who weigh at least 77 pounds (35 kg).^[2]

Susceptible bacteria

Zoliflodacin has shown in vitro activity against the following species of bacteria:^[4] Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Chlamydia trachomatis

Adverse effects

Animal studies showed that zoliflodacin might cause birth defects, pregnancy loss, or male fertility problems.^[2]

Mechanism of action

It has a mechanism of action which involves inhibition of bacterial type II topoisomerases.^[4]^[5]^[6]

History

Compound PNU-286607, discovered in a high-throughput screen for compounds with antibiotic activity.

A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed at Pharmacia & Upjohn identified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity.^[7]

Subsequent research at AstraZeneca led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused benzisoxazole ring,^[8] which allowed for an exploration of different groups at the 3-position of the heterocycle. This work was continued at Entasis Pharmaceuticals where extensive optimization resulted in the discovery of ETX0914.^[4]

Researchers tested zoliflodacin in a study with 930 participants who had uncomplicated urogenital gonorrhea.^[2] Two-thirds of participants received a single 3-gram dose of zoliflodacin dissolved in water.^[2] The other third received the standard treatment of ceftriaxone shot plus azithromycin pill.^[2] The study measured how well the medicines cleared the bacteria 4 to 8 days after treatment.^[2] The study showed 91% of participants who took zoliflodacin were cured and 96% of participants who received the standard treatment were cured.^[2]

Society and culture

Legal status

Zoliflodacin was approved for medical use in the United States in December 2025.^[3]

The US Food and Drug Administration (FDA) granted the application for zoliflodacin fast track, qualified infectious disease product, and priority review designations for the uncomplicated urogenital gonorrhea indication.^[2] The FDA approval for zoliflodacin was granted to Entasis Therapeutics.^[2]

Names

Zoliflodacin is the international nonproprietary name.^[9]

Zoliflodacin is sold under the brand name Nuzolvence.^[3]

References

https://innovivaspecialtytherapeutics.com/wp-content/uploads/2025/12/NUZOLVENCE-zoliflodacin-Full-Prescribing-Information-December-2025.pdf ^{[bare URL PDF]}
“FDA Approves Two Oral Therapies to Treat Gonorrhea”. U.S. Food and Drug Administration (FDA) (Press release). 12 December 2025. Retrieved 13 December 2025. This article incorporates text from this source, which is in the public domain.
Pierre G (12 December 2025). “Nuzolvence (Zoliflodacin) Receives U.S. FDA Approval”. Global Antibiotic Research & Development Partnership (GARDP). Retrieved 13 December 2025.
Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, et al. (July 2015). “Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases”. Scientific Reports. 5 (1) 11827. Bibcode:2015NatSR…511827B. doi:10.1038/srep11827. PMC 4501059. PMID 26168713.
Bradford PA, Miller AA, O’Donnell J, Mueller JP (June 2020). “Zoliflodacin: An Oral Spiropyrimidinetrione Antibiotic for the Treatment of Neisseria gonorrheae, Including Multi-Drug-Resistant Isolates”. ACS Infectious Diseases. 6 (6): 1332–1345. doi:10.1021/acsinfecdis.0c00021. PMID 32329999.
Pisano L, Giovannuzzi S, Supuran CT (June 2024). “Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing”. Expert Opinion on Therapeutic Patents. 34 (6): 511–524. doi:10.1080/13543776.2024.2367005. PMID 38856987.
Miller AA, Bundy GL, Mott JE, Skepner JE, Boyle TP, Harris DW, et al. (August 2008). “Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors”. Antimicrobial Agents and Chemotherapy. 52 (8): 2806–2812. doi:10.1128/AAC.00247-08. PMC 2493097. PMID 18519725.
Basarab GS, Brassil P, Doig P, Galullo V, Haimes HB, Kern G, et al. (November 2014). “Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization”. Journal of Medicinal Chemistry. 57 (21): 9078–9095. doi:10.1021/jm501174m. PMID 25286019.
World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 76”. WHO Drug Information. 30 (3). hdl:10665/331020.

External links

Clinical trial number NCT03959527 for “Zoliflodacin in Uncomplicated Gonorrhoea” at ClinicalTrials.gov

Clinical data

Trade names	Nuzolvence
Other names	AZD0914; ETX0914
AHFS/Drugs.com	Nuzolvence
License data	US DailyMed: Zoliflodacin
Routes of administration	By mouth
Drug class	Antibacterial
ATC code	None
Legal status
Legal status	US: ℞-only^[1]^[2]
Pharmacokinetic data
Bioavailability	97.8%
Metabolism	Liver
Onset of action	Fasted: 1.5–2.3 hFed: 4 h
Elimination half-life	5.3–6.3 h
Excretion	Feces (79.6%)Urine (18.2%)
Identifiers
IUPAC name
PubChem CID	76685216
DrugBank	12817
UNII	FWL2263R77
KEGG	D11726
Chemical and physical data
Formula	C₂₂H₂₂FN₅O₇
Molar mass	487.444 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

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Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

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(7R,14R)-11-Chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

tert-Butyl (1-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate

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Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)

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Example 34

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1l-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Intermediate 18

4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

Intermediate 30

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic Acid

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Example 2: Synthesis of

Step A: (4-bromo-2-fluorophenyl)diethylphosphine oxide

Step B: (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide

Step C: tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Step D: (5)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

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Medical uses

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