Remibrutinib

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Remibrutinib

CAS 1787294-07-8

N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide

MW 507.5 g/mol, MF C27H27F2N5O3

APPROVALS 2025, FDA 2025, 9/30/2025, To treat chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment

Remibrutinib, sold under the brand name Rhapsido, is a medication used for the treatment of chronic spontaneous urticaria.[1] Remibrutinib is an oral, small molecule kinase inhibitor that inhibits Bruton’s tyrosine kinase (BTK).[1] It is taken by mouth.[1]

SYN

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01916

SYN

Example 6

N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide

(1) tert-Butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 8

To a solution of 4-amino-6-chloropyrimidin-5-ol (content 90%, 2.00 g, 12.37 mmol) in THF (120 mL) was added N-Boc-N-methyl-2-hydroxyethylamine (6.07 g, 34.64 mmol) followed by SMOPEX-301 (1 mmol/g, 30.90 g, 30.90 mmol). Then, a solution of DIAD (6.01 mL, 30.52 mmol) in THF (20 mL) was added slowly. The reaction mixture was stirred at 60 °C for 3 hr. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford an oil which was triturated with EtOAc and a white precipitate was formed. The solid was filtered off to afford INT 8. The mother liquor was concentrated and the residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0- 100%) to afford more INT 8 as a beige solid.

UPLC-MS: MS (ESI): [M+H]+ 303.1, rt = 0.86 min. 1H NMR (DMSO-d6): δ (ppm) 7.97 (s, 1H), 7.26 (s, br, 2H), 4.02-3.93 (m, 2H), 3.54 (t, 2H), 2.89 (s, br, 3H), 1.39 (s, 9H).

(2) tert-Butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2- methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 9

To a solution of INT 8 (447 mg, 1.48 mmol) in DME (7.0 mL) and water (1.0 mL) was added INT 5 (638 mg, 1.54 mmol) followed by aqueous sodium carbonate solution (1 M, 4.21 mL, 4.21 mmol). The mixture was degassed with argon for 10 min and bis(triphenylphosphine)palladium(II) dichloride (49.2 mg, 0.070 mmol) was added. The reaction mixture was stirred at 110 °C for 10 min in a microwave reactor. More INT 5 (232 mg, 0.56 mmol) was added and the reaction mixture was stirred at 110 °C for an additional 15 min in a microwave reactor. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0-100%) to afford INT 9 as an off-white solid.

UPLC-MS: MS (ESI): [M+H]+ 554.3, rt = 1.21 min. 1H NMR (DMSO-d6): δ (ppm) rotamers 9.76 (s, 1H), 8.19 (s, 1H), 7.74-7.53 (m, 2H) 7.20-6.85 (m, 5H), 3.57-3.48 (m, 2H), 3.29- 3.15 (m, 2H), 2.58 (s, 3H), 2.08-1.99 (overlapping s, 3H and m, 1H), 1.34 and 1.28 (s, 9H), 1.10-1.02 (m, 2H), 0.84-0.77 (m, 2H).

(3) N-(3-(6-Amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide, INT 10

To a solution of INT 9 (335 mg, 0.61 mmol) in DCM (5.0 mL) was added TFA (0.47 mL, 6.05 mmol). The reaction mixture was stirred at RT for 15 hr. The mixture was concentrated under reduced pressure. The residue was dried in vacuum to afford INT 10 as theTFA salt as a brown oil.

UPLC-MS: MS (ESI): [M+H]+ 454.3, rt = 0.73 min. 1H NMR (DMSO-d6): δ (ppm) 10.02 (s, 1H), 9.07-8.13 (s, v br, number of H cannot be assigned), 8.58 (s, 1H), 8.51 (s, br, 2H), 7.71-7.61 (m, 2H), 7.29-7.22 (m, 1H), 7.14-7.05 (m, 2H), 3.75-3.65 (m, 2H), 3.16-3.07 (m, 2H), 2.48 (s, 3H, overlapping with solvent peak), 2.12 (s, 3H), 2.10-1.99 (m, 1H), 1.11-1.03 (m, 2H), 0.83-0.76 (m, 2H).

(4) N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide

To a solution of acrylic acid (62 mg, 0.87 mmol) in DMF (4.0 mL) was added DIPEA (0.302 mL, 1.73 mmol) followed by T3P solution (50% in DMF) (0.438 mL, 0.750 mmol). The mixture was stirred at RT for 30 min. To a solution of INT 10 (containing 3.0 eq TFA, content 90%, 510 mg, 0.577 mmol) and DIPEA (0.302 mL, 1.731 mmol) in DMF (2.0 mL) at 0 °C was added dropwise the above solution. The reaction mixture was stirred at 0 °C for 30 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water (2x) and brine (2x), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica;

DCM/(MeOH with 2% aqueous ammonium hydroxide) gradient, 0-9%) to afford the title compound Example 6 as a white solid.

UPLC-MS: MS (ESI): [M+H]+ 508.3, rt = 0.95 min. 1H NMR (DMSO-d6): δ (ppm) rotamers 9.77 and 9.56 (s, total 1H), 8.25-8.14 (m, 1H), 7.79-7.50 (m, 2H), 7.17-6.93 (m, 5H), 6.70-6.55 (m, 1H), 6.06 (t, 1H), 5.59 (d, 1H), 3.63-3.40 (m, 4H), 2.80 and 2.49 (s, total 3H, peak at 2.49 overlapping with solvent peak), 2.09-1.93 (m, 4H), 1.11-1.00 (m, 2H), 0.85-0.76 (m, 2H).

PAT

SYN

Synthesis of Remibrutinib

DOI: 10.1055/s-0040-1707094

Publication Date: 2020

Publication Name: Synfacts

PAT

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Medical uses

Remibrutinib is indicated for the treatment of chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment[1]

Society and culture

Remibrutinib was approved for medical use in the United States in September 2025.[2]

Names

Remibrutinib is the international nonproprietary name.[3]

Remibrutinib is sold under the brand name Rhapsido.[2]

References

  1.  https://www.novartis.com/us-en/sites/novartis_us/files/rhapsido.pdf
  2.  “Novartis receives FDA approval for Rhapsido (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU)” (Press release). Novartis Pharmaceuticals. 30 September 2025. Retrieved 1 October 2025 – via PR Newswire.
  3.  World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 34 (1). hdl:10665/339768.

Further reading

  • Clinical trial number NCT05030311 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1 Antihistamines (REMIX-1)” at ClinicalTrials.gov
  • Clinical trial number NCT05032157 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1-antihistamines (REMIX-2)” at ClinicalTrials.gov
Clinical data
Trade namesRhapsido
License dataUS DailyMed: Remibrutinib
Routes of
administration		By mouth
ATC codeL04AA60 (WHO)
Legal status
Legal statusUS: ℞-only[1]
Identifiers
IUPAC name
CAS Number1787294-07-8
PubChem CID118107483
IUPHAR/BPS10457
DrugBankDB16852
ChemSpider78317000
UNIII7MVZ8HDNU
KEGGD12285
ChEMBLChEMBL4483575
PDB ligandN6Z (PDBe, RCSB PDB)
Chemical and physical data
FormulaC27H27F2N5O3
Molar mass507.542 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI
  1. Maurer M, Berger W, Gimenez-Arnau A, Hayama K, Jain V, Reich A, Haemmerle S, Lheritier K, Walsh P, Xia S, Storim J: Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. J Allergy Clin Immunol. 2022 Dec;150(6):1498-1506.e2. doi: 10.1016/j.jaci.2022.08.027. Epub 2022 Sep 9. [Article]
  2. Nuesslein-Hildesheim B, Ferrero E, Schmid C, Huck C, Smith P, Tisserand S, Rubert J, Bornancin F, Eichlisberger D, Cenni B: Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. J Neuroinflammation. 2023 Aug 26;20(1):194. doi: 10.1186/s12974-023-02877-9. [Article]
  3. Bozek A, Reich A: Evaluating remibrutinib in the treatment of chronic spontaneous urticaria. Immunotherapy. 2025 May;17(7):479-484. doi: 10.1080/1750743X.2025.2510892. Epub 2025 Jun 2. [Article]
  4. Kaul M, End P, Cabanski M, Schuhler C, Jakab A, Kistowska M, Kinhikar A, Maiolica A, Sinn A, Fuhr R, Cenni B: Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial. Clin Transl Sci. 2021 Sep;14(5):1756-1768. doi: 10.1111/cts.13005. Epub 2021 Apr 9. [Article]
  5. Gimeno R, Ribas-Llaurado C, Pesque D, Andrades E, Cenni B, Ambros B, Pujol R, Gimenez-Arnau AM: Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcepsilonR1 expression level and omalizumab clinical response. Clin Transl Allergy. 2023 Mar;13(3):e12227. doi: 10.1002/clt2.12227. [Article]
  6. Dorner T, Kaul M, Szanto A, Tseng JC, Papas AS, Pylvaenaeinen I, Hanser M, Abdallah N, Grioni A, Santos Da Costa A, Ferrero E, Gergely P, Hillenbrand R, Avrameas A, Cenni B, Siegel RM: Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjogren’s syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial. Ann Rheum Dis. 2024 Feb 15;83(3):360-371. doi: 10.1136/ard-2023-224691. [Article]
  7. FDA Approved Drug Products: RHAPSIDO (remibrutinib) tablets, for oral use [Link]
  8. Novartis: Novartis receives FDA approval for Rhapsido® (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU) [Link]

//////////Remibrutinib, APPROVALS 2025, FDA 2025, Rhapsido, LOU064, NVP-LOU064-NXA, LOU064-NXA, I7MVZ8HDNU, WHO 11062

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