Bosmolisib

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Bosmolisib

CAS 2055765-77-8

MF 2055765-77-8 MW478.3 g/mol

4-{[(1S)-1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one

Pyrido[2,3-d]pyrimidin-5(8H)-one, 4-[[(1S)-1-(4,8-dichloro-1,2-dihydro-1-oxo-2-phenyl-3-isoquinolinyl)ethyl]amino]-

4-[[(1S)-1-(4,8-dichloro-1-oxo-2-phenylisoquinolin-3-yl)ethyl]amino]-8H-pyrido[2,3-d]pyrimidin-5-one
phosphatidylinositol 3-kinase (PI3K) inhibitor, antineoplastic, BR 101801, FJ5CTS1VNJ

A Study of Bosmolisib (BR101801) in Participants With R/R PTCL.CTID: NCT07180771Phase: Phase 2Status: Not yet recruitingDate: 2025-09-18
BR101801 in Adult Patients With Advanced Hematologic Malignancies(Phase I)CTID: NCT04018248Phase: Phase 1Status: CompletedDate: 2025-09-10

Bosmolisib is an orally bioavailable inhibitor of phosphoinositide 3-kinase delta (PI3-kinase subunit delta; PI3K-delta; PI3Kdelta) and DNA-dependent protein kinase (DNA-PK), with potential antineoplastic and immunomodulating activities. Upon oral administration, bosmolisib inhibits the activity of both PI3K-delta and DNA-PK. This prevents PI3K-mediated signaling pathways and may lead to the inhibition of cancer cell growth in PI3K-overexpressing tumor cells. Specifically, since PI3K regulates c-myc expression, inhibition of PI3K signaling may lead to a decrease in proliferation of c-myc-expressing tumor cells. Also, by inhibiting the activity of DNA-PK, bosmolisib interferes with the non-homologous end joining (NHEJ) process and prevents the repair of DNA double strand breaks (DSBs) caused by ionizing radiation or chemotherapeutic treatment. This increases chemo- and radiotherapy cytotoxicity by inhibiting the ability of tumor cells to repair damaged DNA. The PI3K pathway is upregulated in a variety of tumors and plays an important role in regulating cancer cell proliferation, growth, and survival. DNA-PK is activated upon DNA damage and plays a key role in repairing double-stranded DNA breaks. The enhanced ability of tumor cells to repair DSBs plays a major role in the resistance of tumor cells to chemo- and radiotherapy. In addition, bosmolisib is able to decrease Tregs and increase CD8 lymphocytes.

OriginatorBoryung Pharmaceutical
ClassAntineoplastics; Small molecules
Mechanism of ActionDNA-activated protein kinase inhibitors; Phosphatidylinositol 3 kinase delta inhibitors; Phosphatidylinositol 3 kinase gamma inhibitors
Phase IHaematological malignancies
PreclinicalColorectal cancer
18 Sep 2025Boryung Pharmaceutical plans a phase II trial for Peripheral T Cell Lymphoma and Nodal T-follicular helper cell lymphoma (Second-line therapy or greater) in September 2025 (PO, Capsule) (NCT07180771)
06 Jan 2025Chemical structure information added.
09 Dec 2023Updated efficacy and adverse event data from a phase I trial in Hematological malignancies presented at the 65^th American Society of Hematology Annual Meeting and Exposition (ASH-2023

SYN

WO 2016/204429.

SYN

[WO2019139399A1]

xample 1. Preparation of (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one

[116](S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one (4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one) represented by the chemical formula 3 above was prepared by the same method as that described in Example 10 of International Patent Publication No.

WO 2016/204429.

SYN

[WO2016204429]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016204429&_cid=P22-MK6A2W-95428-1

<Example 10> Preparation of (S)-4-((l-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido [2,3-d]pyrimidin-5(8H)-one

In Example 5, 50 mg (0.113 vol) of (S)-4— ((1-(8-chloro-1—oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido [2, 3-d]pyrimidin-5(8H)-one prepared was dissolved in 2 mL of acetic acid, and then 17 mg (0.124 vol) of N—chlorosuccinimide (NCS) was added. The mixture was stirred at 50 ^° C for 15 hours, filtered under reduced pressure, neutralized using an aqueous sodium bicarbonate solution, and then the organic layer extracted by adding dichloromethane and water was dried (Na ₂ SO ₄ ), filtered, concentrated under reduced pressure, and separated by column chromatography (SiO ₂ , eluent: dichloromethane/methanol, 30/1 -> dichloromethane/methanol, 10/1) to afford 25 mg (0.052 mmol, 46% yield) of compound (S)— 4-((1— (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2, 3-d]pyramidin-5(8H)-one as a pale yellow solid.

^LH NMR (300 MHz, CDC1₃) δ 10.99 (d, J = 4.8 Hz, 1Ή)， 8.25 (s, 1H) , 7.95(dd, ^JJ = 1.9 Hz, J = 7.5 Hz, 1H)， 7.75 (d, J = 7.8 Hz, 1H) , 7.46-7.62 (m, 6H), 7.20 (d, J = 6.7 Hz, 1H) , 6.3 (d, J = 7.5 Hz, 1H), 5.04 (t , J = 67.2 Hz, 1H) , 1.67 (d, J = 7.2 Hz, 3H) .

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US214732247&_cid=P22-MK69S5-86256-1

Example 10: Preparation of (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidine-5(8H)-one

50 mg (0.113 mmol) of (S)-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidine-5(8H)-one prepared in Example 5 was dissolved in 2 mL of acetic acid, to which 17 mg (0.124 mmol) of N-chlorosuccinimide (NCS) was added, followed by stirring at 50° C. for 15 hours. The reaction mixture was filtered under reduced pressure. Saturated sodiumbicarbonate aqueous solution was added thereto, followed by neutralization. Dichloromethane and water were added thereto, followed by extraction. The extracted organic layer was dried (Na ₂SO ₄), filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (SiO ₂, eluent: dichloromethane/methanol, 30/1→dichloromethane/methanol, 10/1) to give 25 mg of the target compound (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidine-5(8H)-one as a pale yellow solid (0.052 mmol, yield: 46%).

¹H NMR (300 MHz, CDCl ₃) δ 10.99 (d, J=4.8 Hz, 1H), 8.25 (s, 1H), 7.95 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.46-7.62 (m, 6H), 7.20 (d, J=6.7 Hz, 1H), 6.3 (d, J=7.5 Hz, 1H), 5.04 (t, J=67.2 Hz, 1H), 1.67 (d, J=7.2 Hz, 3H).

PAT