Palacaparib

 

Palacaparib

CAS 2756333-39-6

MFC21H22F2N6O2 MW428.4 g/mol

6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide

2-Pyridinecarboxamide, 6-fluoro-5-(4-((5-fluoro-3,4-dihydro-2-methyl-3-oxo-6-quinoxalinyl)methyl)-1-piperazinyl)-N-methyl-

6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide
poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, AZD 9574, 9UG32UQW48

Palacaparib is an investigational new drug that is being evaluated by AstraZeneca for the treatment of prostate cancer.^[1] It is a selective PARP1 inhibitor.^[2][3]

Palacaparib (also known as AZD9574) is an investigational, orally bioavailable cancer drug developed by AstraZeneca. It belongs to a class of medications called PARP inhibitors.

Key Characteristics

• High Selectivity: It selectively targets the PARP1 enzyme. It features an 8,000-fold greater selectivity for PARP1 over other PARP forms like PARP2. This targeted approach aims to lower typical bone marrow toxicities linked with older, non-selective PARP inhibitors.
• Brain Penetrance: Unlike many earlier options, it successfully crosses the blood-brain barrier. This trait makes it a prime candidate for managing primary brain tumors and central nervous system (CNS) metastases.

Mechanism of Action

1. Enzyme Binding: Palacaparib tightly binds to the PARP1 enzyme at single-strand DNA break locations.
2. DNA Trapping: It traps the enzyme on the damaged DNA, blocking the base excision repair pathway.
3. Synthetic Lethality: This stalling stalls replication forks and forces single-strand breaks to progress into double-strand breaks.
4. Cell Death: In tumors with homologous recombination deficiency (HRD)—such as BRCA1/2 mutations—cells cannot fix these severe breaks, triggering apoptosis (programmed cell death).

Clinical Research and Targets

According to active registries from the National Cancer Institute (NCI), Palacaparib is undergoing early-phase human trials both as a single agent and alongside other treatments. Researchers are testing its efficacy across several oncological areas:

• Advanced Solid Malignancies: Studies focus heavily on HRD-positive tumors, including specific types of breast, ovarian, and pancreatic cancers.
• Prostate Cancer: Active monotherapy and combination trials target metastatic prostate cancer.
• CNS Malignancies: Preclinical designs show promise in treating gliomas when paired with radiation or alkylating agents like temozolomide.

• OriginatorAstraZeneca
• ClassAntineoplastics; Carbamates; Fluorinated hydrocarbons; Ketones; Piperazines; Pyridines; Quinoxalines; Small molecules
• Mechanism of ActionPoly(ADP-ribose) polymerase-1 inhibitors
• Phase I/IIProstate cancer; Solid tumours
• 03 Jun 2026Phase-I/II clinical trials in Prostate cancer (Combination therapy, Hormone refractory, Second-line therapy or greater, Metastatic disease) in USA (PO) (NCT07590934)
• 14 May 2026AstraZeneca plans a phase I/II trial for Prostate cancer (Metastatic disease, Combination therapy, Second-line therapy or greater, Hormone-refractory) in USA, Australia, Germany, Italy, South Korea, Spain, United Kingdom (PO) in May 2026 (NCT07590934) (EudraCT2025-524920-23)
• 19 Feb 2026Chemical structure information added.

Palacaparib is an orally bioavailable central nervous system (CNS) penetrant and inhibitor of nuclear enzyme poly(ADP-ribose) polymerase (PARP) 1, with potential antineoplastic activity. Upon oral administration, palacaparib selectively binds to PARP1, thereby preventing repair of damaged DNA via the base excision repair (BER) pathway. This agent enhances the accumulation of DNA strand breaks and promotes genomic instability eventually leading to apoptosis. Palacaparib may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell chemo- and radioresistance. PARP1 catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and plays a key role in the repair of single strand DNA (ssDNA) breaks and double-strand break (DSBs). Palacaparib is able to penetrate the blood-brain barrier (BBB).

SYN

[WO2021260092A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021260092&_cid=P22-MS178J-58931-1

Example 20: 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-ciuinoxalin-6-yl)methvnDiDerazin-1-vn-N-methyl-pyridine-2-carboxamide

Triethylphosphane (20.90 ml, 145.06 mmol) was added dropwise with an addition funnel to a stirred suspension of 8-fluoro-7-(hydroxymethyl)-3-methyl-1 H-quinoxalin-2-one (intermediate 17) (15.1 g, 72.53 mmol) and 1 ,2-dibromo-1 ,1 ,2,2-tetrachloroethane (52.0 g, 159.56 mmol) in DCM (400 mL) at 0°C under nitrogen. The mixture was stirred at r.t for 3 h gave a light-yellow suspension. Crude LCMS indicated full conversion. DCM was removed under vacuum; the residue was slurry in 300 mL diethyl ether at rt and the light yellow ppt was filtered and washed with 200 ml ether. The solid was taken into 300 ml of water, stirred at rt for 10 min, the solid was collected by filtration, thorough wash (200 ml) with water to remove the salts. The solid was dried under vacuum for overnight (no heat). The solid was washed with hexanes and dried in vacuum in a bushel funnel to give 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1 H)-one (intermediate 59) (22.76 g, 116 %, likely contains some inorganic salts) as an off white solid. Used as such for next reaction. 1 H NMR (500 MHz, DMSO-c/6) 2.42 (3H, s), 4.65 - 4.93 (2H, m), 7.28 - 7.42 (1 H, m), 7.51 (1 H, d), 12.53 (1 H, br s); m/z (ES⁺) [M+H]⁺ = 271 , 273.

To a flask charged with 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1 H)-one (intermediate 59) (22.76 g) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide, 2HCI ( intermediate 32) (24.24 g, 77.9 mmol) in acetonitrile (350 ml), was added DIPEA (38.0 ml, 217.59 mmol) at rt and the resulting mixture was stirred at 70°C for 4 h. Reaction was not complete. To the mixture was added 5 g of Kl and 2 g of Nal and the mixture was stirred at 50°C for 20 h. More 540 mgs (~0.03eq) of 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (intermediate 32) was added to the mixture and the stirring continued at 50°C for 2 h. The solid from the reaction suspension was collected by filtration, washed with acetonitrile and dried. The resulting material was then suspended in water (~400 ml), slurred at rt for 20 min, filtered and dried (97% purity by LCMS). The solid was then dissolved into a mixture of DCM/MeOH (3/1) (about 1.5 L) at reflux, filtered through a pad of silica gel, removed most of the DCM until solid precipitate out and the mixture was kept at rt for 20 min. The solid was collected by filtration and repeated the procedure for the filtrate, and the solids were combined to yield the product 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (example 20) (26 g, 84%) as a light yellow solid. 1 H NMR (500 MHz, DMSO-c/6) 2.41 (3H, s), 2.57 - 2.69 (4H, m), 2.76 (3H, d), 3.16 (4H, br s), 3.70 (2H, s), 7.29 (1 H, br t), 7.40 - 7.60 (2H, m), 7.83 (1 H, d), 8.38 (1 H, br d), 12.44 (1 H, br s); m/z (ES⁺) [M+H]⁺ = 429.

PAT

• Chemical compoundsPublication Number:US-12421208-B2Priority Date:2020-06-25Grant Date:2025-09-23
• Chemical compoundsPublication Number:US-11795158-B2Priority Date:2020-06-25Grant Date:2023-10-24
• Chemical compoundsPublication Number:US-2022009901-A1Priority Date:2020-06-25
• Combining ATR inhibitors and PARP inhibitors for cancer treatmentPublication Number:IL-309388-APriority Date:2021-06-16
• Use of ATR inhibitors in combination with PARP inhibitors to treat cancerPublication Number:KR-20240021884-APriority Date:2021-06-16
• Quinoxaline derivatives as anticancer drugsPublication Number:CN-115768760-APriority Date:2020-06-25
• Quinoxaline derivatives as anti-cancer drugsPublication Number:WO-2021260092-A1Priority Date:2020-06-25
• Quinoxaline derivatives as anti-cancer drugsPublication Number:EP-4172152-A1Priority Date:2020-06-25

SYN

• Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective InhibitorPublication Name:Journal of Medicinal ChemistryPublication Date:2024-12-10PMID:39655996DOI:10.1021/acs.jmedchem.4c01725
• New Horizons of Synthetic Lethality in Cancer: Current Development and Future PerspectivesPublication Name:Journal of Medicinal ChemistryPublication Date:2024-07-02PMCID:PMC11284803PMID:38955347DOI:10.1021/acs.jmedchem.4c00113

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References

Clinical data
Other names	AZD-9574
Identifiers
IUPAC name
CAS Number	2756333-39-6
PubChem CID	162524593
IUPHAR/BPS	11946
ChemSpider	115008044
UNII	9UG32UQW48
ChEMBL	ChEMBL5095223
PDB ligand	A1H64 (PDBe, RCSB PDB)
Chemical and physical data
Formula	C21H22F2N6O2
Molar mass	428.444 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  "Palacaparib". AdisInsight. Springer Nature Switzerland AG. Retrieved 5 July 2026.
2.  Johannes JW, Balazs AY, Barratt D, Bista M, Chuba MD, Cosulich S, et al. (December 2024). "Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor". Journal of Medicinal Chemistry. 67 (24): 21717–21728. doi:10.1021/acs.jmedchem.4c01725. PMID 39655996.
3.  Shkil DO, Chesnokova NA, Ivashchenko AA, Petersen EV, Maximov PY (May 2026). "Structural Determinants of PARP1 Selectivity from Molecular Dynamics Analysis of PARP1 and PARP2 Complexes". Molecules. 31 (10). Basel, Switzerland: 1592. doi:10.3390/molecules31101592. PMC 13210057. PMID 42197145.

///////////palacaparib, ANAX LABS, poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, AZD 9574, 9UG32UQW48

#palacaparib, #ANAX LABS, #poly (ADP-ribose) polymerase (PARP) inhibitor, #antineoplastic, #AZD 9574, #9UG32UQW48

Pariceract

 

Pariceract

CAS 1919820-28-2

MFC20H30N4O2 MW358.5 g/mol

• 5,7-dimethyl-N-((1r,4r)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
• 5,7-Dimethyl-N-(4-pentoxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
• Pyrazolo(1,5-a)pyrimidine-3-carboxamide, 5,7-dimethyl-N-(trans-4-(pentyloxy)cyclohexyl)-

5,7-dimethyl-N-[trans-4-(pentyloxy)cyclohexyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
beta-glucocerebrosidase activator, antiparkinsonian, BIA 28-6156, LTI-291, LIT291, LTI-00291, BIA28-6156, LTI- 91, LIT 291, LTI 00291, Gcase activator 1, V9WUN9UUU8

Pariceract (INNTooltip International Nonproprietary Name; developmental code name BIA 28-6156 or LTI-291) is a β-glucocerebrosidase (GCase) activator or positive allosteric modulator which is under development for the treatment of Parkinson's disease.^{[1][2][3][4][5]} It is taken orally.^[1] GCase is a lysosomal enzyme encoded by the gene GBA1.^[4][5] Loss-of-function mutations in this gene are thought to promote α-synuclein accumulation and are among the leading genetic risk factors for Parkinson's disease.^[4][5][6] As such, activation of GCase might provide a disease-modifying therapy for treatment of Parkinson's disease.^[4][5] Pariceract was first described in the scientific literature by 2017.^[6] It was originated by Lysosomal Therapeutics and is under development by Lysosomal Therapeutics and Bial.^[1][2][3] As of October 2025, it is in phase 2 clinical trials.^[1][2][3]

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=F663B00AA9F0AD415A4FD77C12CCF971.wapp1nC?docId=US467040657&_cid=P12-MS418O-86059-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025198486&_cid=P12-MS41BL-88178-1

Example 3 - Preparation of 5,7-dimethyl-/V-((l/?,4/?)-4- (pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[00168] Part 1 : Under nitrogen atmosphere, purified water (41.32 L, 2.0 V) and NaOH (5.99 kg, 1.4 eq.) were charged to a reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was added to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[00169] Part 2: Under nitrogen atmosphere, purified water (30.99 L, 1.5 V) and NaCI

(2.27 kg, 0.11 wt.%) were charged to the reactor at 20 °C; after this, purified water (10.33 L, 0.5 V) was charged to wash the walls and the solution was left stirring for 0.5-3 hours until the solid was dissolved; the solution was transferred from the reactor to a clean drum.

[00170] Part 3: Under nitrogen atmosphere, purified water (62 L, 3.0 V) and the compound of Formula (IV) in HCI salt form (27.84 kg, 1.15 eq.), from step 3 of Example 1, were charged to the reactor at 25 °C; after this, purified water (16.5 L, 0.8 V) was charged to wash the walls and then MTBE (165.28 L, 8.0 V) was charged to the reactor and the solution was left stirring for 0.5-1 hour; after this, the solution was cooled down to 5 °C and the NaOH (5.99 kg, 1.4 eq.) aqueous solution (prepared in advance in part 1) was charged in 0.5-2 hours; then, the temperature of the reaction mixture was increased to 25 °C and it was left stirring for 1-3 hours. The agitation was stopped, and the phases were separated. The organic phase was washed two times: the first with 5% NaCI aqueous (41.32 L, 2.0 V) prepared in advance in part 2 and the second with purified water (41.32 L, 2.0 V). Then, the organic phase was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V). MTBE (62 L, 3.0 V) was charged to the reactor and the solution was concentrated under vacuum until the total volume was 51.65 L - 72.31 L (2.5-3.5 V).

[00171] Part 4: Under nitrogen atmosphere, DMF (92.97 L, 4.5 V), the compound of Formula (VII) (20.66 kg, 1.0 eq.), from step 2 of Example 2, and l,l'-carbonyldiimidazole (21.07 kg, 1.2 eq.) were charged to the reactor at 25 °C; DMF (10.33 L, 0.5 V) was added to wash the walls. The temperature of the reaction mixture was increased to 28 °C, and it was left stirring for 2-5 hours. If necessary, charge additional l,l'-carbonyldiimidazole (1.76 kg, 0.1 eq.) to the reactor at 28 °C and leave it stirring for 2-5 hours. After this, purified water (1.178 kg, 0.6 eq.) was charged to the reactor and it was left stirring for 1-4 hours. Under nitrogen atmosphere, the compound of Formula (IV) Free Base in MTBE solution (27.84 kg ,1.15 eq.), from Part 3, was charged to the reactor in 1-2 hours; MTBE (4.132 L, 0.2 V) was charged to rinse the drum and then it was transferred to the reactor. The solution was left stirring for 16-24 hours and then DMF (20.66 L, 1.0 V) was charged to the reactor. The solution was concentrated under vacuum until the total volume was 123.96 L - 165.28 L (6.0-8.0 V).

[00172] Part 5: The reaction mixture temperature was increased to 40 °C and purified water (41.32 L, 2.0 V) was added dropwise to the reactor in 1-2 hours; the reaction mixture was left stirring for 2-5 hours before cooling down to 20 °C; the slurry was left stirring for 10-15 hours and then purified water (82.64 L, 4.0 V) was added dropwise in 1-3 hours to the reactor; the slurry was left stirring for 3-6 hours. After this, the solid was centrifuged and the cake was washed with DMF:H2O (1: 1, 20.66 L, 1.0 V x 2) two times and then washed with purified water (41.32 L, 2.0 V) one time*. The cake was dried under vacuum at 55 °C for 15-24 hours and 32.35 kg were obtained (83.3% yield and 100% purity by HPLC).

* In one campaign, at this stage the wet cake was dissolved in acetonitrile (25.5 V), the temperature adjusted to 27°C and stirred for 2-6 hours. The solution was filtered via a polish filter (0.22 pirn). The solution was concentrated under vacuum to 5.0 - 7.0 V at a temperature below 35°C. The temperature was adjusted to 20°C and purified water was added (14.0 V) in 2-4 hours. The slurry was stirred for 4-8 hours at 20°C, and afterwards filtered and washed with purified water (4.0 V).

Example 4 - Recrystallisation of 5,7-dimethyl-/V-((l/?,4R)-4- (pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound of Formula (A))

[00173] Under nitrogen atmosphere, MEK (192 L, 6.0 V) and the compound of Formula (A) from Example 3 in crude (32 kg, 1.0 eq.) were charged to a reactor at 25 °C; MEK (160 L, 5.0 V) was added to wash the walls. The solution was left stirring for 1-3 hours until the solid was dissolved. After this, the solution from the reactor was transferred to a clean drum.

[00174] Under nitrogen atmosphere, the crude compound of Formula (A) in MEK solution was transferred to another reactor via a polish filter. The temperature was set at 17 °C and n-heptane (115.2 kg, 3.6 V) was charged in 2-4 hours. The solution was concentrated under vacuum until the total volume was 320 L - 352 L (10-11 V). In the event that there is no solid precipitation, proceed to the 2^nd concentration directly; if there is solid precipitation, take a solid sample for XRPD test, and ensure that the crystal form is polymorph form B; if it is not form B, proceed to the 2^nd concentration (and repeat if required). The reactor temperature was kept at 17 °C before cooling down to 0 °C and it was left stirring for 6-12 hours. A solid sample was taken for XRPD test to make sure that the crystal form is form B; if not form B, keep at 0 °C and stir for 6-12 hours; sample solid every 6-10 hours for XRPD until the crystal form is form B. The solid was centrifuged and washed with MEK:n-heptane (1 : 10, 57.6 L, 1.8 V ) and then with n-heptane (57.6 L, 1.8

V). The cake was dried under vacuum at 30 °C for 16-24 hours and 30.67 kg were obtained (95% yield and purity of 100% by HPLC).

PAT

• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-2017334916-A1Priority Date:2014-11-06
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-2025066364-A1Priority Date:2014-11-06
• SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERSPublication Number:US-2017183354-A1Priority Date:2014-11-06
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-9732089-B2Priority Date:2014-11-06Grant Date:2017-08-15
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-11091492-B2Priority Date:2014-11-06Grant Date:2021-08-17
• Substituted pyrazolo[1,5-a]pyrimidines and their use in treating medical disorders - Patents.comPublication Number:JP-7519221-B2Priority Date:2014-11-06Grant Date:2024-07-19
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-2022169652-A1Priority Date:2014-11-06
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-11932645-B2Priority Date:2014-11-06Grant Date:2024-03-19
• Substituted pyrazolo(1,5-a)pyrimidines and their use in the treatment of medical disordersPublication Number:WO-2016073895-A1Priority Date:2014-11-06
• Substituted pyrazolo[1,5-A]pyrimidines and their use in the treatment of medical disordersPublication Number:US-10570135-B2Priority Date:2014-11-06Grant Date:2020-02-25
• Substituted pyrazolo(1,5-a)pyrimidines and their use in the treatment of medical disordersPublication Number:EP-4406616-A2Priority Date:2014-11-06
• Substituted pyrazolo[1,5-a]pyrimidines and their use in the treatment of medical disordersPublication Number:US-2020385390-A1Priority Date:2014-11-06

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References

References

1.  "LTI 291". AdisInsight. Springer Nature Switzerland AG. 15 October 2025. Retrieved 19 February 2026.
2.  "Delving into the Latest Updates on Pariceract with Synapse". Synapse. 8 May 2025. Retrieved 19 February 2026.
3.  "Pariceract Drug Profile". Ozmosi. 1 January 1900. Retrieved 19 February 2026.
4.  den Heijer JM, Kruithof AC, Moerland M, Walker M, Dudgeon L, Justman C, et al. (July 2023). "A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator". Movement Disorders. 38 (7): 1197–1208. doi:10.1002/mds.29346. hdl:1887/3722043. PMID 37195859.
5.  den Heijer JM, Kruithof AC, van Amerongen G, de Kam ML, Thijssen E, Grievink HW, et al. (September 2021). "A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator". British Journal of Clinical Pharmacology. 87 (9): 3561–3573. doi:10.1111/bcp.14772. PMC 8451761. PMID 33576113.
6.  Ellis JM, Fell MJ (September 2017). "Current approaches to the treatment of Parkinson's Disease". Bioorganic & Medicinal Chemistry Letters. 27 (18): 4247–4255. doi:10.1016/j.bmcl.2017.07.075. PMID 28869077. Increased degradation of a-synuclein is another potential mechanism explored in the clinic. Currently, the leading candidates for this approach center on modulating the activity of the Glucocerebrosidase (GBA) pathway. Mutations in GBA are the leading genetic risk factor for sporadic PD and reductions in GBA activity are thought to lead to an accumulation of a-synuclein. Lysosomal Therapeutics is currently developing a brain penetrant, small molecule enhancer of GBA activity called LTI-291 (structure not reported) which is expected to enter Phase 1 testing in 2017.

External links

• BIA 28-6156 - Pariceract (INN) - Bial
• LTI-291 - AlzForum

Clinical data
Other names	BIA 28-6156; LTI-291; LIT291; LTI-00291
Routes of administration	Oral[1]
Drug class	β-Glucocerebrosidase (GCase) activator or positive allosteric modulator
Identifiers
IUPAC name
CAS Number	1919820-28-2
PubChem CID	121327414
ChemSpider	68028144
UNII	V9WUN9UUU8
Chemical and physical data
Formula	C20H30N4O2
Molar mass	358.486 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

////////pariceract, ANAX LABS, beta-glucocerebrosidase activator, antiparkinsonian, BIA 28-6156, LTI-291, LIT291, LTI-00291, BIA28-6156, LTI- 91, LIT 291, LTI 00291, Gcase activator 1, V9WUN9UUU8

#pariceract, #ANAX LABS, #beta-glucocerebrosidase activator, #antiparkinsonian, #BIA 28-6156, #LTI-291, #LIT291, #LTI-00291, #BIA28-6156, #LTI- 91, #LIT 291, #LTI 00291, #Gcase activator 1, #V9WUN9UUU8

Pasodacigib

 

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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