Brepocitinib

CAS 1883299-62-4

MF C₁₈H₂₁F₂N₇O MW389.4 g/mol

8/27/2026, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841

[(1S)-2,2-difluorocyclopropyl]-[(1R,5S)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone

• [(1S)-2,2-difluorocyclopropyl]-[(1S,5R)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone
• Methanone, ((1S)-2,2-difluorocyclopropyl)(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-4-pyrimidinyl)-3,8-diazabicyclo(3.2.1)oct-8-yl)-
• ((1S)-2,2-difluorocyclopropyl)-((1S,5R)-3-(2-((1-methylpyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo(3.2.1)octan-8-yl)methanone

To treat dermatomyositis in adults

Brepocitinib (brand name Lisraya) is an oral, once-daily dual TYK2/JAK1 inhibitor approved by the FDA for treating dermatomyositis in adults.

Developed by Roivant (via its subsidiary Priovant), it is the first oral targeted therapy indicated to manage this rare, debilitating autoimmune condition. Brepocitinib, sold under the brand name Lisraya, is a drug which acts as a dual inhibitor of JAK1 and TYK2, and was developed for the treatment of plaque psoriasis.^[1][2][3][4] It is used for the treatment of dermatomyositis.

Brepocitinib is an orally available, selective inhibitor of non-receptor tyrosine-protein kinase TYK2 (tyrosine kinase 2) and tyrosine-protein kinase JAK1 (Janus kinase 1; JAK1) with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, brepocitinib selectively binds to and inhibits the activation of TYK2 and JAK1, thereby disrupting TYK2 and JAK-1-dependent cytokine signaling. This may reduce inflammatory responses and prevent inflammation-induced damage caused by certain immunological diseases. TYK2 and JAK-1 are members of the Janus kinase family of non-receptor tyrosine kinases and are involved in signaling pathways affecting hematopoiesis, immunity and inflammation.

SYN

Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)

By: Fensome, Andrew ; et al

Journal of Medicinal Chemistry (2018), 61(19), 8597-8612

SYN

Preparation of aminopyrimidinyl derivatives as inhibitors of JAK kinases useful in therapy of diseases

Assignee: Pfizer Inc.

Inventors: Fensome, Andrew; et al

World Intellectual Property Organization

Patent#WO2016027195 A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016027195&_cid=P11-MTCC5U-40903-1

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0223523423008152

SYN

compound 23 [PMID: 30113844]

PAT

US9663526,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159751917&_cid=P11-MTCCDC-53135-1

Examples 7 and 8

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone and [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (Preparation 68, 318 mg, 2.61 mmol) in DCM (20 mL) was added 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Preparation 19, 700 mg, 2.17 mmol), HATU (1.02 g, 2.61 mmol and DIPEA (0.76 mL, 4.34 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with further ammonium chloride solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-12% MeOH and 1% NH 4OH in DCM. The residue was dissolved in DCM and further washed with saturated aqueous ammonium chloride solution three times. The organic layer was collected, concentrated in vacuo and dried to afford the title compound (500 mg, 60%).

The title compound and its enantiomer may also be prepared according to the same method using racemic 2,2-difluorocyclopropane-1-carboxylic acid with additional chiral separation of the enantiomers after purification using the method below to afford:

Peak 1: Example 7

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

1H NMR (400 MHz, DMSO-d 6): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H), 3.80 (s, 3H), 4.14 (br s, 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1H), 7.44 (s, 1H), 7.74 (brs, 1H), 7.93 (d, 1H), 8.90 (brs, 1H). MS m/z 390 [M+H]; [α] D 2050.1 (c 1.27, EtOH)

PAT

• New compounds for the inhibition of angiogenesis and use of thereofPublication Number:AU-2005223356-A1Priority Date:2004-03-24
• Compositions and methods of use for modified release minoxidilPublication Number:US-2025325546-A1
• Aminopyrimidinyl compoundsPublication Number:US-10980815-B2Priority Date:2014-08-21Grant Date:2021-04-20
• Aminopyrimidinyl compounds as JAK inhibitorsPublication Number:MD-4800-C1Priority Date:2014-08-21
• Aminopyrimidinyl compoundsPublication Number:US-2020330477-A1Priority Date:2014-08-21
• Aminopyrimidinyl compoundsPublication Number:US-11197867-B2Priority Date:2014-08-21Grant Date:2021-12-14
• Aminopyrimidinyl compoundsPublication Number:TW-201609706-APriority Date:2014-08-21

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References

References

1.  Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, et al. (October 2018). “Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)”. Journal of Medicinal Chemistry. 61 (19): 8597–8612. doi:10.1021/acs.jmedchem.8b00917. PMID 30113844.
2.  Forman SB, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, et al. (December 2020). “TYK2/JAK1 Inhibitor PF-06700841 in Patients with Plaque Psoriasis: Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial”. The Journal of Investigative Dermatology. 140 (12): 2359–2370.e5. doi:10.1016/j.jid.2020.03.962. PMID 32311398.
3.  Martin G (February 2023). “Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors”. Dermatology and Therapy. 13 (2): 417–435. doi:10.1007/s13555-022-00878-9. PMC 9884727. PMID 36592300.
4.  Caso F, Costa L, Triggianese P, Maione F, Bertolini N, Vastarella M, et al. (May 2023). “Recent developments for new investigational JAK inhibitors in psoriatic arthritis”. Expert Opinion on Investigational Drugs. 32 (5): 361–371. doi:10.1080/13543784.2023.2207737. PMID 37096862.

Clinical data
Trade names	Lisraya
Other names	PF-06700841
Identifiers
IUPAC name
CAS Number	1883299-62-4
PubChem CID	118878093
DrugBank	DB15003
ChemSpider	72380129
UNII	3X8387Q25N
ChEMBL	ChEMBL4297477
Chemical and physical data
Formula	C18H21F2N7O
Molar mass	389.411 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

///////////brepocitinib, anax labs, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841, dermatomyositis

#brepocitinib, #anax labs, #APPROVALS 2026, #FDA 2026, #Lisraya, #PF 06700841, #3X8387Q25N, #PF-06700841, #dermatomyositis