Camibirstat

Camibirstat

CAS 2671128-05-3

N-{(2S)-1-[(4-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-yl}-1,3-thiazol-2-yl)amino]-3-methoxy-1-oxopropan-2-yl}-1-(methanesulfonyl)-1H-pyrrole-3-carboxamide
ATPase inhibitor, antineoplastic

MW C24H30N6O6S2 MF 562.7 g/mol

• 1H-Pyrrole-3-carboxamide, N-((1S)-2-((4-(6-((2R,6S)-2,6-dimethyl-4-morpholinyl)-2-pyridinyl)-2-thiazolyl)amino)-1-(methoxymethyl)-2-oxoethyl)-1-(methylsulfonyl)-
• N-[(2S)-1-[[4-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-2-yl]-1,3-thiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylsulfonylpyrrole-3-carboxamide
• FHD 286

Camibirstat is an investigational new drug that is being evaluated for the treatment of cancer. It is a small molecule that acts as a selective inhibitor of SMARCA2 and SMARCA4, which are key components of the SWI/SNF chromatin remodeling complex.^[1]

It is being developed by Foghorn Therapeutics.^[2]

Camibirstat is an orally bioavailable, allosteric, small molecule inhibitor of transcription activator BRG1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4; SMARCA4) and BRM (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2; SMARCA2), with potential antineoplastic activity. Upon oral administration, camibirstat targets, binds to, and inhibits the activity of BRG1 and/or BRM, the primary ATPase components and mutually exclusive subunits of the BRG1/BRM-associated factor (BAF) complexes. This may lead to the inhibition of the SWI/SNF chromatin remodeling complex, disrupt chromatin remodeling and gene expression, and result in the downregulation of oncogenic pathways and the inhibition of tumor cell proliferation. BAF is an important regulator of transcriptional programs and gene expression. Mutations in BAF or its transcription factor partners are found in certain diseases including cancers.

PAT

• Compounds and uses thereofPublication Number: US-2024101550-A1Priority Date: 2020-01-29
• Compounds and their usesPublication Number: JP-7561195-B2Priority Date: 2020-01-29Grant Date: 2024-10-03
• Compounds and uses thereofPublication Number: TW-I859406-BPriority Date: 2020-01-29Grant Date: 2024-10-21
• Compounds and uses thereofPublication Number: IL-295100-APriority Date: 2020-01-29
• Compounds and uses thereofPublication Number: KR-20220133258-APriority Date: 2020-01-29
• Compounds and uses thereofPublication Number: US-11485732-B2Priority Date: 2020-01-29Grant Date: 2022-11-01
• Compounds and uses thereofPublication Number: JP-2023512039-APriority Date: 2020-01-29
• Compounds and uses thereofPublication Number: US-2023129003-A1Priority Date: 2020-01-29
• Compounds and uses thereofPublication Number: WO-2021155262-A1Priority Date: 2020-01-29
• Compounds and uses thereofPublication Number: TW-202136252-APriority Date: 2020-01-29
• Compounds and uses thereofPublication Number: AU-2021213811-A1Priority Date: 2020-01-29
• Compound and use thereofPublication Number: CN-115023226-APriority Date: 2020-01-29
• Compounds and uses thereofPublication Number: EP-4096664-A1Priority Date: 2020-01-29
• Methods of treating cancersPublication Number: WO-2021236080-A1Priority Date: 2020-05-20
• Methods of treating cancersPublication Number: EP-4153176-A1Priority Date: 2020-05-20
• ways to treat cancerPublication Number: CN-115867314-APriority Date: 2020-05-20
• how to treat cancerPublication Number: JP-2023535124-APriority Date: 2020-05-20
• Compounds and uses thereofPublication Number: US-2021230154-A1Priority Date: 2020-01-29
• Treatment options with inhibitors of BRG1 and BRM enzyme activityPublication Number: CN-117337179-APriority Date: 2021-03-19
• Therapeutic regimens of an inhibitor of the enzymatic activity of brg1 and brmPublication Number: EP-4308124-A1Priority Date: 2021-03-19
• Treatment regimens for inhibitors of BRG1 and BRM enzymatic activityPublication Number: JP-2024511383-APriority Date: 2021-03-19
• Therapeutic regimens of an inhibitor of the enzymatic activity of brg1 and brmPublication Number: US-2024189318-A1Priority Date: 2021-03-19
• Methods of treating cancersPublication Number: US-2022079940-A1Priority Date: 2020-05-20

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US331910582&_cid=P11-MG1TKU-39131-1

Example 1. Preparation of N—((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide

N—((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide was synthesized as shown in Scheme 1 below.

Step 7: Preparation of N—((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-O-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide

To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid (Intermediate K) (2.43 g, 12.9 mmol), EDCI (2.69 g, 14.0 mmol), HOBt (1.89 g, 14.0 mmol), and DIPEA (10.2 mL, 58.4 mmol) in dichloromethane (50 mL) was added Intermediate J (5.00 g, 11.7 mmol). After stirring at room temperature for 4 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with saturated aqueous NH 4Cl, once with brine, dried over Na 2SO 4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 1:2). The residue was triturated with methyl tert-butyl ether. After 0.5 h, the suspension was filtered, the filter cake was washed with methyl tert-butyl ether, and dried in vacuo. The solid was dissolved in dimethyl sulfoxide (12 mL) and added dropwise to water (800 mL). The suspension was filtered to give wet filter cake. The filter cake was suspended in water and stirred at room temperature. After 1 hour, the solid was collected by filtration, washed three times with water and dried in vacuo to give N—((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (3.9 g, 6.93 mmol, 59.3% yield) as a white solid.

LCMS (ESI) m/z: [M+H] +=563.1.

1H NMR (400 MHz, DMSO-d6) δ 12.49 (br s, 1H), 8.51 (d, J=7.2 Hz, 1H), 7.98-7.97 (m, 1H), 7.78 (s, 1H), 7.67-7.57 (m, 1H), 7.29-7.27 (m, 1H), 7.26 (d, J=7.2 Hz, 1H), 6.88-6.74 (m, 2H), 4.94-4.91 (m, 1H), 4.25 (d, J=11.6 Hz, 2H), 3.77-3.67 (m, 2H), 3.63-3.62 (m, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 2.44-2.38 (m, 2H), 1.18 (d, J=6.0 Hz, 6H).

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Clinical data
Other names	FHD286
Identifiers
IUPAC name
CAS Number	2671128-05-3
PubChem CID	156818030
ChemSpider	115010237
UNII	QHA5XLA4SA
ChEMBL	ChEMBL5095181
Chemical and physical data
Formula	C24H30N6O6S2
Molar mass	562.66 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  Yu L, Wu D (July 2024). “SMARCA2 and SMARCA4 Participate in DNA Damage Repair”. Frontiers in Bioscience (Landmark Edition). 29 (7): 262. doi:10.31083/j.fbl2907262. PMID 39082357.
2.  “Camibirstat”. PatSnap.

/////////////Camibirstat, ATPase inhibitor, antineoplastic, Foghorn Therapeutics, FHD 286