Tigozertinib

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Tigozertinib

CAS 2660250-10-0

MF C28H37FN6O3S MW 556.7

3-Isoquinolinamine, N-[2-[(3S,4R)-3-fluoro-4-methoxy-1-piperidinyl]-4-pyrimidinyl]-5-(1-methylethyl)-8-[(2R,3S)-2-methyl-3- [(methylsulfonyl)methyl]-1-azetidinyl]-

N-{2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl}-8-{(2R,3S)-3-[(methanesulfonyl)methyl]-2-methylazetidin-1-yl}-5-(propan-2-yl)isoquinolin-3-amine

N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine

N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-l-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-l-yl)isoquinolin-3-amine

epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, antineoplastic, PA4PTH5HL9, BLU 945

Tigozertinib (BLU-945) is currently under investigation in clinical trial NCT04862780 (Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC) for the treatment of NSCLC.

Tigozertinib is a fourth-generation, orally bioavailable, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, tigozertinib targets, binds to and inhibits the activity of EGFR with C797S triple mutations including ex19del/T790M/C797S and L858R/T790M/C797S, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. BLU-945 inhibits mutated forms of EGFR with C797S mutation, which prevents covalent bond formation with third-generation EGFR inhibitors leading to drug resistance. BLU-945 may have enhanced anti-tumor effects in tumors with C797S-mediated resistance when compared to other EGFR tyrosine kinase inhibitors.Tigozertinib is a fourth-generation, orally bioavailable, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, tigozertinib targets, binds to and inhibits the activity of EGFR with C797S triple mutations including ex19del/T790M/C797S and L858R/T790M/C797S, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. BLU-945 inhibits mutated forms of EGFR with C797S mutation, which prevents covalent bond formation with third-generation EGFR inhibitors leading to drug resistance. BLU-945 may have enhanced anti-tumor effects in tumors with C797S-mediated resistance when compared to other EGFR tyrosine kinase inhibitors.

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REF

Synthesis of BLU-945, an EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung CancerPublication Name: SynfactsPublication Date: 2022-09-20DOI: 10.1055/s-0041-1738705
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung CancerPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-07-15PMCID: PMC9340769PMID: 35838760DOI: 10.1021/acs.jmedchem.2c00704
Effects of antithymocyte serum on lymph node cells participating in the graft-vs-host reactionPublication Name: Cellular ImmunologyPublication Date: 1976-06-01PMID: 7359DOI: 10.1016/0008-8749(76)90132-5

SYN

WO2021133809

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021133809&_cid=P11-MJ29N8-15768-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021133809&_cid=P11-MJ292P-02302-1

Example 5, Compound 117: Synthesis of (3S,4R)-3-fluoro-l-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-l-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

To a solution of 3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-l-yl]-5-(propan-2-yl)isoquinoline(28 g,76.3mmol, from step 1 of Example 3), (3R,4S)-l-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol(17.2g,76.3mmol, peak 1 from Example B12), CS2CO3 (49.8 g, 152 mmol),C-phos (4.27 g, 9.15mmol, 2-dicyclohexylphosphino-2’,6’-bis(N,N-dimethylamino)biphenyl) and Pd2(dba)3 (3.94 g, 3.81 mmol) in dioxane (400 mL) was heated to 100 °C for 16 h under N2 atmosphere. The mixture reaction was filtered and the filtrate was concentration under vacuum. The residue was applied onto a silica gel column with EA/PE (2: 1) to give product 28.8 g (67%) as a light-yellow solid.

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