Balinatunfib

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.
• You need to be a logged in or subscribed to view this c

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 ₄ and 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

1.  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.
2.  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