Zemprocitinib

CAS 2417414-44-7

MF C16H19N5O2S MW 345.4 g/mol

N-[3-(3,5,8,10-tetrazatricyclo[7.3.0.0^2,6]dodeca-1,4,6,8,11-pentaen-3-yl)-1-bicyclo[1.1.1]pentanyl]propane-1-sulfonamide

N-[3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl]propane-1-sulfonamide
Janus kinase inhibitor, anti-inflammatory, LNK 01001, LG6MM3RP86

Zemprocitinib (also known as LNK01001) is a selective Janus kinase (JAK) 1 inhibitor, a type of small molecule drug being developed for inflammatory and autoimmune conditions like rheumatoid arthritis, atopic dermatitis, and ankylosing spondylitis. It works by blocking the JAK1 enzyme, reducing the inflammatory signals that cause these diseases, and has shown promising results in clinical trials, with development reaching Phase 3. 

Key Aspects:

• Drug Class: JAK1 Inhibitor.
• Mechanism: Blocks Janus Kinase 1, a key enzyme in inflammatory pathways.
• Developer: Initially Lynk Pharmaceuticals.
• Potential Uses: Rheumatoid Arthritis, Atopic Dermatitis, Ankylosing Spondylitis, Psoriasis, Alopecia Areata.
• Development Stage: Reached Phase 3 clinical trials for several indications.
• Chemical Info: CAS: 2417414-44-7; Formula: C16H19N5O2S. 

In Summary:

Zemprocitinib is an investigational drug targeting inflammation by inhibiting JAK1, with potential to treat various autoimmune disorders, showing strong efficacy in early clinical trials for conditions like rheumatoid arthritis. 

SYN

US20220009927

https://patentscope.wipo.int/search/en/detail.jsf?docId=US347660217&_cid=P21-MJDP3D-82397-1

Example 1

Step 1. 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1b)

Compound 1a (30 g, 0.2 mol) and TsCl (45 g, 0.24 mol) were dissolved in a mixture of acetone and water (600 mL, V:V=5:1) followed by the addition of NaOH (11.8 g, 0.29 mmol) at 0° C. After stirring at RT for 1 h, the mixture was concentrated to 100 mL of solvent and cooled with ice-water. The formed solid was filtered and dried to afford title product as a white solid (52 g, 86% yield). 1H NMR (400 MHz, CDCl 3) δ 8.30 (d, J=5.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.76 (d, J=4.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.18 (d, J=5.2 Hz, 1H), 6.69 (d, J=4.0 Hz, 1H), 2.37 (s, 3H).

Step 2. 4-Chloro-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1c)

To a mixture of compound 1b (5.0 g, 16.3 mmol) and 75 mL of DCM was added tetrabutylammonium nitrate (2.9 g, 21.3 mmol) portion-wise at 0° C. followed by trifluoroacetic anhydride (3.14 mL, 22.2 mmol) slowly. After stirring for 16 hrs at RT, another portion of tetrabutylammonium nitrate (0.58 g, 4.23 mmol) and trifluoroacetic anhydride (0.8 mL, 5.7 mmol) were added at 0° C. After warmed up to room temperature, the reaction mixture was stirred for 4 hrs at RT. The reaction mixture was diluted with DCM (150 mL), washed with water (30 mL×2) and then concentrated to dryness. The residue was triturated in MeOH to afford title product as a white solid (3.15 g, 55% yield). LC-MS (Method 2): t R=1.76 min, m/z (M+H) +=351.8.

Step 3. Tert-butyl 3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (Id)

Compound 1c (500 mg, 1.42 mmol), tert-butyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (313 mg, 1.71 mmol) and DIPEA (276 mg, 2.13 mmol) were dissolved in isopropanol (5 mL). The above solution was stirred at 120° C. for 2 hrs. After cooling, the formed solid was collected by filtering and dried to afford the title product as a brown solid (612 mg, 86% yield). 1H NMR (400 MHz, CDCl 3) δ 9.28 (s, 1H), 9.11 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.64 (d, J=5.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 6.96 (d, J=5.6 Hz, 1H), 2.48 (s, 6H), 2.40 (s, 3H), 1.47 (s, 9H).

Step 4. Tert-butyl 3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (le)

Compound 1d (600 mg, 1.22 mmol) was dissolved in MeOH (6 mL) followed by the addition of Pd/C (48 mg, 10% wt) in one portion. The mixture was hydrogenated (1 atm) at RT for 16 hrs. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep. TLC (PE:EtOAc=1:1) to afford the title product as a white solid (258 mg, 46% yield). LC-MS (Method 2): t R=1.64 min, m/z (M+H) +=469.0.

Step 5. Tert-butyl 3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentane-1-carboxylate (1f)

Compound 1e (258 mg, 0.55 mmol), triethyl orthoformate (204 mg, 1.37 mmol) and p-toluenesulfonic acid (10 mg, 0.05 mmol) were dissolved in toluene (6 mL). The mixture was stirred for 16 hrs at 120° C. After cooling, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (elute: PE:EtOAc=1:1) to afford the title product as a brown solid (191 mg, 73% yield). 1H NMR (400 MHz, CDCl 3) δ 8.91 (s, 1H), 8.10 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.27-7.25 (m, 2H), 6.83 (d, J=4.4 Hz, 1H), 2.71 (s, 6H), 2.35 (s, 3H), 1.51 (s, 9H).

Step 6. 3-(6-Tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6LF)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (1g)

To a solution of compound 1f (191 mg, 0.40 mmol) in DCM (2 mL) was added TFA (1 mL). After stirring for 16 hrs at RT, the mixture was concentrated to dryness to afford crude title product as a brown solid (170 mg, 100% yield). LC-MS (Method 2): t R=1.47 min, m/z (M+H) +=423.0

Step 7. Tert-butyl (3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6LF)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1h)

To a mixture of compound 1g (153 mg, 0.36 mmol) in tert-butanol (7.2 mL) was added DPPA (130 mg, 0.47 mmol) and TEA (73 mg, 0.72 mmol) under N 2. The mixture was stirred at RT for 30 minutes and then raised to 90° C. and stirred for another 16 hrs. After cooling, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (elute: DCM:MeOH=50:1) to afford the title product as a brown solid (160 mg, 89% yield). LC-MS (Method 2): t R=1.71 min, m/z (M+H) +=494.0.

Step 8. Tert-butyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1i)

To a solution of compound 1h (160 mg, 0.32 mmol) in MeOH (3 mL) and water (3 mL) was added NaOH (300 mg, 7.5 mmol). After stirring for 4 hrs at RT, the mixture was concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were concentrated to dryness and the residue was purified by chromatography on silica gel (elute: DCM:MeOH=20:1) to afford the title product as a white solid (60 mg, 55% yield). 1H NMR (400 MHz, CDCl 3) δ 9.99 (s, 1H), 9.81 (s, 1H), 7.80 (s, 1H), 7.39 (d, J=4.4 Hz, 1H), 6.36 (d, J=4.4 Hz, 1H), 5.30 (br s, 1H), 2.80 (s, 6H), 1.50 (s, 9H).

Step 9. 3-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetate (1j)

To a solution of compound 1i (60 mg, 0.18 mmol) in DCM (2 mL) was added TFA (0.5 mL). After stirring for 1 hour at RT, the mixture was concentrated to dryness to afford crude title product as a brown solid (100 mg, 100% yield). LC-MS (Method 2): t R=0.309 min, m/z (M+H) +=240.0

Step 10. N-(3-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (1)

To a solution of compound 1j (40 mg, 0.16 mmol) and TEA (51 mg, 50 mmol) in DMF (1 mL) was added propane-1-sulfonyl chloride (28 mg, 0.5 mmol) at 0° C. After stirring for 3 hrs at RT, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were concentrated to dryness. The residue was purified prep. HPLC (Method A) to afford the title product as a white solid (10 mg, 18% yield). LC-MS (Method 1): t R=2.71 min, m/z (M+H) +=346.0. 1H NMR (400 MHz, DMSO-d 6) δ 11.94 (s, 1H), 8.59 (d, J=1.6 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 6.70 (d, J=1.6 Hz, 1H), 3.08 (d, J=8.8 Hz, 2H), 2.70 (s, 6H), 1.74-1.72 (m, 2H), 1.73 (d, J=6.0 Hz, 3H).

PAT

• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: ES-2993867-T3Priority Date: 2018-11-01Grant Date: 2025-01-10
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: JP-2024147699-APriority Date: 2018-11-01
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: EP-3856742-B1Priority Date: 2018-11-01Grant Date: 2024-10-02
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2022009927-A1Priority Date: 2018-11-01
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2023357247-A1Priority Date: 2018-11-01
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2023339950-A1Priority Date: 2018-11-01
• Tricyclic Janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: AU-2019372677-B2Priority Date: 2018-11-01Grant Date: 2024-05-30
• Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: TW-202432555-APriority Date: 2018-11-01

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///////////Zemprocitinib, Janus kinase inhibitor, anti-inflammatory, LNK 01001, LG6MM3RP86