Pasodacigib

Cas 2648721-77-9

MFC24H23FN4O3 mw 434.5 g/mol

3-Quinolinecarboxamide, 6-fluoro-1,2-dihydro-1-methyl-4-[4-(5-methyl-2-benzoxazolyl)-1-piperidinyl]-2-oxo-

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide
diacylglycerol kinase inhibitor, antineoplastic, BAY 2862789, BAY-2862789, XM6U88YE6H

Pasodacigib (also known by its developmental code BAY 2862789 or BAY-2862789) is an investigational small-molecule drug developed by Bayer AG. It functions as a potent and selective diacylglycerol kinase alpha (DGKα) inhibitor designed for cancer immunotherapy.

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🧪 Mechanism of Action

• Targeting DGKα: Diacylglycerol kinase alpha (DGKα) is an enzyme that converts diacylglycerol (DAG) into phosphatidic acid (PA) within cells.
• T-Cell Reactivation: In the tumor microenvironment, overactive DGKα metabolises DAG, which depletes the signaling required for T-cell activation. By blocking this enzyme, pasodacigib aims to restore DAG levels, reactivating the patient’s own T-cells to mount a clinically beneficial anti-tumor immune response.

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📋 Key Details & Chemical Properties

• Developer: Bayer AG
• CAS Registry Number: 2648721-77-9
• Molecular Formula: C₂₄H₂₃FN₄O₃
• Molecular Weight: 434.46 g/mol
• Research Status: It is an investigational drug that has entered clinical trial assessment (such as the Bayer-led study NCT05858164) to evaluate its safety and efficacy in treating advanced malignancies.

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⚠️ Important Medical Disclaimer

Pasodacigib is strictly an investigational compound undergoing clinical development and laboratory research. It is not approved by the FDA or any other global regulatory authority for prescription, public medical use, or patient purchase.

If you are looking into this molecule for scientific research or a clinical study, please let me know if you need specific details regarding its chemical structure, information on related DGK inhibitors, or updates on active oncology clinical trials

Pat

US11998539,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US400268899&_cid=P22-MS6W4B-66581-1

Example 298

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

68 mg 6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile (160 μmol, example 217), 9 mg palladium(II)acetate (40 μmol) and 142 mg acetaldoxime (2.4 mmol) were stirred in 1.5 mL ethanol for 5 h at 80° C. The reaction mixture was diluted with water, extracted with ethyl acetate two times, the combined organic layers were filtered through a waterresistant filter and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 41.4 mg of the title compound (100% purity, 60% yield).

1H NMR (400 MHz, DMSO-d 6) δ ppm 2.02-2.15 (m, 2H) 2.17-2.26 (m, 2H) 2.44 (s, 3H) 3.13-3.25 (m, 3H) 3.35-3.43 (m, 2H) 3.59 (s, 3H) 7.18 (d, 1H) 7.47-7.63 (m, 6H) 7.73 (br s, 1H).

LC-MS (Method 2): R t=1.17 min; MS (ESIpos): m/z=435.4 [M+H] +

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021105117&_cid=P22-MS6W2Y-65422-1

Intermediate 101

6-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1 H)-dione

To a solution of 5.00 g 6-fluoro-2H-3,1-benzoxazine-2,4(1 H)-dione (26.8 mmol, CAS 321-69-7) and 9.3 ml. N,N-diisopropylethylamine (54 mmol) in 40 ml. dimethylformamide was added 5.1 ml. iodomethane (80 mmol) at rt and the mixture was stirred overnight. The reaction mixture was diluted with 1000 ml. water and the resulting solid was collected by filtration, the filter cake was washed with water and dried in vacuum to give 4.93 g of the title compound (99 % purity, 93 % yield).

¹H NMR (400 MHz, DMSO-cfe) d ppm 3.47 (s, 3H), 7.40-7.61 (m, 1 H), 7.69-7.93 (m, 2H).Intermediate 102

6-fluoro-4-hydroxy-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile

4.85 g 6-fluoro-1 -methyl-2H-3,1 -benzoxazine-2,4(1 H)-dione (intermediate 101 , 24.6 mmol,) was solubilised in 50 ml. tetrahydrofurane, 34 ml. triethylamine (250 mmol) and then 15.1 ml. ethyl cyanoacetate (133 mmol) were added carefully and the suspension was stirred 72 h at 900. The reaction mixture was cooled down to rt, concentrated under reduced pressure, the residue was diluted with water and ethyl acetate (1 :1) and the mixture was adjusted to pH = 1 with hydrogen chloride solution (2 M in water). The resulting solid was filtered and the filter cake was washed with less water and ethyl acetate to give 4.40 g of the title compound (100 % purity, 82 % yield).

¹H NMR (400 MHz, DMSO-cfe) d ppm 3.34 (br s, 3H), 7.01 -7.44 (m, 2H), 7.51 -7.70 (m, 1 H).

Intermediate 103

4-chloro-6-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

A mixture of 4.40 g 6-fluoro-4-hydroxy-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (intermediate 102, 20.0 mmol) and 19 ml. phosphoric trichloride (200 mmol) was stirred overnight at 900. The reaction mixture was cooled down to rt, diluted with hexane and the resulting solid was filtered. The filter cake was carefully added to a half saturated solution of sodium bicarbonate, the resulting suspension was filtered, the solid was washed with water, ethyl acetate and then with ethanol and dried in vacuum to give 4.17 g of the title compound (100 % purity, 88 % yield).

¹H NMR (400 MHz, DMSO-cfe) d ppm 3.67 (s, 3H); 7.58 – 8.09 (m, 3H).

Example 217

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)pipendin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

80 mg 4-chloro-6-fluoro-1-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (338 pmol, intermediate 103) was suspended in 2.5 ml. 2-propanol, 180 mI_ N,N-diisopropylethylamine (1.0 mmol) and 87.7 mg 5-methyl-2-(piperidin-4-yl)-1 ,3-benzoxazole (406 pmol, CAS 199292-77-8) were added and the mixture was stirred for 2 h at 900. The reaction mixture was cooled down to rt and the suspension was diluted with water and stirred for 15 min. The solid was filtered off and washed with water and ethanol to give 127 mg of the title compound (98 % purity, 88 % yield).

¹H NMR (400 MHz, DMSO-cfe) d ppm 2.07 – 2.19 (m, 2 H) 2.27 – 2.35 (m, 2 H) 2.44 (s, 3 H) 3.43 (tt, 1 H) 3.55 – 3.64 (m, 5 H) 3.81 (br d, 2 H) 7.18 (dd, 1 H) 7.53 (d, 1 H) 7.54 – 7.61 (m, 2 H) 7.61 – 7.70 (m, 2 H).

LC-MS (Method 2): R, = 1.32 min; MS (ESIpos): m/z = 417.4 [M+H]⁺

Example 298

6-fluoro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)pipendin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

68 mg 6-fluoro-1 -methyl-4-[4-(5-methyl-1 ,3-benzoxazol-2-yl)piperidin-1-yl]-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (160 pmol, example 217), 9 mg palladium(ll)acetate (40 pmol) and 142 mg acetaldoxime (2.4 mmol) were stirred in 1 .5 ml. ethanol for 5 h at 80TT The reaction mixture was diluted with water, extracted with ethyl acetate two times, the combined organic layers were filtered through a waterresistant filter and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5pm 100x30mm, mobile phase: acetonitrile / water (0.2 vol. % ammonia 32 %)-gradient) to give 41 .4 mg of the title compound (100 % purity, 60 % yield).

¹H NMR (400 MHz, DMSO-cfe) d ppm 2.02 – 2.15 (m, 2 H) 2.17 – 2.26 (m, 2 H) 2.44 (s, 3 H) 3.13 – 3.25 (m, 3 H) 3.35 – 3.43 (m, 2 H) 3.59 (s, 3 H) 7.18 (d, 1 H) 7.47 – 7.63 (m, 6 H) 7.73 (br s, 1 H).

LC-MS (Method 2): R, = 1 .17 min; MS (ESIpos): m/z = 435.4 [M+H]

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