Filgotinib

Filgotinib (GLPG0634) is a selective JAK1 inhibitor with IC50 of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2, respectively. Phase 2.

Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, and inflammatory disease that causes synovial joint symptoms and can limit range of motion in severe cases. The disease is associated with extra-articular manifestations, progressive disability, and comorbidities including cardiovascular disease and mental disorders. 50-70% of patients with RA are unable to achieve sustained clinical remission despite the availability of several treatments including disease-modifying anti-rheumatic drugs (DMARDS) like [methotrexate], interleukin-6 (IL-6) blockers, and tumor necrosis factor (TNF) inhibitors. New therapeutic developments target other inflammatory pathways implicated in RA including the Janus kinase (JAK) signaling pathway as seen with filgotinib. There are four JAK subtypes which include JAK1, JAK2, JAK3, and tyrosine kinase 2. Non-selective JAK inhibitors like [tofacitinib] target JAK1 and JAK3 subtypes with minimal activity at JAK2. In contrast, the newly approved filgotinib is a highly selective JAK1 inhibitor. JAK2 and JAK3 play important roles in both immune and hematologic functions; therefore, selectivity for JAK1 aims to improve the safety profile of filgotinib while maintaining clinical efficacy. Filgotinib is currently reserved for patients who cannot tolerate DMARDs, or who have been unable to achieve remission in response to one or more DMARDs.|Filgotinib is an orally bioavailable inhibitor of the tyrosine kinase Janus kinase 1 (JAK1), with potential anti-inflammatory and immunomodulating activities. Upon oral administration, filgotinib specifically targets, binds to, and inhibits the phosphorylation of JAK1, which interferes with JAK/STAT (signal transducer and activator of transcription)-dependent signaling. As JAK1 mediates signaling of many pro-inflammatory cytokines, JAK1 inhibition prevents cytokine signaling and activity in many inflammatory and immune-mediated processes and leads to a decrease in inflammation and activation of certain immune cells. JAK1 plays a key role in the signaling and activity of many cytokines and growth factors and is often dysregulated in a variety of autoimmune and inflammatory diseases, as well as some malignancies.

The intermediate (III) obtained in step E)With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1, 4-dioxane, The amidation reaction time was 4 h, The amidation reaction temperature was 50 ° C, The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1, 4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature, Adding methylene chloride and water, separating the organic phase with water, Then washed with brine, dried over magnesium sulfate, Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid, That is, Filgotinib, yield 91.2percentThe reaction of this step is the same as in Example 1.The starting material [5-(4-bromomethyl-phenyl)- l , 2, 4]triazolo[l , 5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N[5-(4-bromomethyl-phenyl)-l, 2, 4]triazolo[l, 5-a]pyridine-2-yl] amide (9 g; 24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23°C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23°C. The product was filtered dried under vacuum at 17 mbar and 50°C for 3 hours. Yield: 9.53 g (92percent of theory) purity (HPLC/UV, method A, 98.6percent t4-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1, 1-dioxo(Intermediate 1A) (20.18 g, 53 mmol), N-(5-Bromo-[1, 2, 4]triazolo[1, 5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7A) (16.45 g, 59 mmol), Pd(dppf)Cl2 (3.91 g, 5 mmol), 2CO3 (22.06 g, 160 mmol) was added in turn to a 250 mL three-vial flask.Then add 1, 4-dioxane (100 mL), Water (25mL), The temperature was raised to 90° C. under argon protection for 12 hours.After the reaction is over, Cool to room temperatureAdd 300 mL of dichloromethane to the reaction mixture.Then wash twice with water, 500mL each time, Drying the organic phase with anhydrous sodium sulfate, The organic phase is concentrated to dryness, The residue is subjected to column chromatography (eluent:Dichloromethane:methanol = 50:1) was purified to give the title product as a pale yellow solid, 11 g.

Molecular Weight:425.5
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:5
Exact Mass:425.15216079
Monoisotopic Mass:425.15216079
Topological Polar Surface Area:105
Heavy Atom Count:30
Complexity:715
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes