Perzebertinib, Bizrolertinib

Perzebertinib, Bizrolertinib

CAS 2414056-31-6

MFC27H26F2N8O3 MW548.5 g/mol

5-[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]oxy-6-methoxy-N-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)phenyl]quinazolin-4-amine

• 4-Quinazolinamine, 5-[[(4R)-3,3-difluoro-1-methyl-4-piperidinyl]oxy]-6-methoxy-N-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)phenyl]-
• 5-[[(4R)-3,3-Difluoro-1-methyl-4-piperidinyl]oxy]-6-methoxy-N-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)phenyl]-4-quinazolinamine

5-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]oxy}-6-methoxy-N-{3-methyl-4-[([1,2,4]triazolo[1,5-c]pyrimidin-7-yl)oxy]phenyl}quinazolin4-amine
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, ZN-A-1041, ZN 1041, RG 6596, Bizrolertinib, UN8TM5120C

Perzebertinib (also known as bizrolertinib or by developmental codes ZN-A-1041, ZN-1041, and RG6596) is an orally active, potent, and highly selective HER2 (ERBB2) tyrosine kinase inhibitor (TKI) designed to treat advanced solid tumors, primarily HER2-positive breast cancer.

Mechanism of Action

Perzebertinib functions as a selective, irreversible inhibitor of the HER2 tyrosine kinase. It blocks the ATP-binding site of the receptor to stop autophosphorylation. This action shuts down downstream signaling via the PI3K/AKT and MAPK pathways, successfully suppressing the growth, survival, and migration of tumor cells overexpressing HER2.

Key Clinical Advantages

• Blood-Brain Barrier (BBB) Penetration: The drug is designed to cross the blood-brain barrier effectively. This makes it highly valuable for treating brain metastases, a common and aggressive complication in advanced HER2-positive breast cancers.
• EGFR Sparing: Unlike older pan-EGFR/HER2 inhibitors, perzebertinib is engineered to spare wild-type EGFR. Sparing EGFR helps minimise common on-target side effects like severe skin rash and diarrhea.
• Efflux Resistance: It is not a substrate for P-gp or BCRP efflux pumps, allowing it to maintain high concentrations within central nervous system (CNS) tissues.

Development and Clinical Status

Initially discovered and developed by Suzhou Zanrong Pharmaceutical Technology (Zion Pharma), the asset is being co-developed in partnership with Roche and Genentech.

The drug has progressed through Phase 1 clinical studies evaluating its safety and pharmacokinetics in advanced solid tumors, moving forward into Phase 2/3 evaluations for HER2-positive advanced or locally advanced metastatic breast cancer. It is frequently evaluated as a monotherapy or in combination regimens alongside established therapies like capecitabine, trastuzumab, or pertuzumab

PAT

US11723908, Example 37, EG 77

https://patentscope.wipo.int/search/en/detail.jsf?docId=US344952565&_cid=P10-MS9QYW-06569-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=34DD4AB27E9264643AB08F2936B38B1B.wapp1nA?docId=EP476958262&_cid=P10-MS9QXM-05913-1

 International Patent Publication No. WO 2020/057511 A1, which is incorporated herein by reference in its entirety, discloses quinazoline compounds that inhibit type I receptor tyrosine kinases, demonstrate good brain penetration in animals, and possess favorable toxicity profiles (for example a decreased activity against hERG), and thus particularly useful in the treatment of type I receptor tyrosine kinases mediated diseases or conditions, in particular ErbB2-associated disease or conditions, including cancer (e.g., metastatic cancer, such as brain metastases). A specific compound, which is identified as (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (also referred to as compound (I) herein),

PAT

WO2020057511

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020057511&_cid=P10-MS9R3W-09545-1

Example 32

[0681]

(S) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine

Step 5: (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine and

[0696]

(S) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine

[0697]

[0698]

To a solution of 4-chloro-5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazoline (410 mg, 1.19 mmol) in Propan-2-ol (60 mL) was added TsOH. H ₂O (68 mg, 0.36 mmol) and 4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylaniline (259 mg, 1.07 mmol) . The resulting mixture was stirred at 100℃ under Ar ₂protection and concentrated. The residue was dissolved in H ₂O (100 mL) , basified with aq. NaHCO ₃to pH =7-8, extracted with DCM: MeOH = 20: 1 (100 mLx3) . The combined organic layers were dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH=30/1) to give product (300 mg, 46%yield) as white solid. The racemic material was subsequently separated by chiral SFC to give two isomers:

[0699]

(R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine (Peak 1, retention time 6.241 min, ee: >99%) (100 mg, 67%) as a white solid. MS (ESI) m/z: 549.2 (M+H) ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 10.04 (s, 1H) , 9.20 (s, 1H) , 8.61 (s, 1H) , 8.33 (s, 1H) , 7.88 (d, J = 2.0 Hz, 1H) , 7.79-7.76 (m, 1H) 7.69 (d, J = 9.2 Hz, 1H) , 7.53 (d, J = 9.2 Hz, 1H) , 7.11 (d, J = 8.8 Hz, 1H) , 6.90 (s, 1H) , 4.84-4.79 (m, 1H) , 4.03 (s, 3H) , 3.22-3.21 (m, 1H) , 2.93 (d, J = 7.2 Hz, 1H) , 2.38 (s, 3H) , 2.41-2.34 (m, 1H) , 2.34-2.27 (m, 1H) , 2.19 (s, 3H) , 2.16-2.10 (m, 2H) .

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References

• Quinazoline derivatives as antitumor agentsPublication Number:US-2023293533-A1Priority Date:2018-09-18
• Quinazoline derivatives as antitumor agentsPublication Number:ES-2971927-T3Priority Date:2018-09-18Grant Date:2024-06-10
• Quinazoline derivatives as antitumor agentsPublication Number:EP-4360713-B1Priority Date:2018-09-18Grant Date:2024-10-30
• Quinazoline derivatives as antitumor agentsPublication Number:ES-3007082-T3Priority Date:2018-09-18Grant Date:2025-03-19
• Quinazoline derivatives as antitumor agentsPublication Number:EP-4360713-A2Priority Date:2018-09-18
• Quinazoline derivatives as antitumor agentsPublication Number:EP-3853220-B1Priority Date:2018-09-18Grant Date:2024-01-03
• Quinazoline derivatives as antitumor agentsPublication Number:EP-3853220-A1Priority Date:2018-09-18
• Quinazoline derivatives as antitumor agentsPublication Number:US-2021386742-A1Priority Date:2018-09-18
• Quinazoline derivatives as antitumor agentsPublication Number:US-11723908-B2Priority Date:2018-09-18Grant Date:2023-08-15
• Crystalline forms of quinazoline derivatives, preparation, compositions and uses thereofPublication Number:CN-120623183-APriority Date:2021-10-20
• Crystalline forms of quinazoline derivatives, preparation, compositions and uses thereofPublication Number:CN-120309621-APriority Date:2021-10-20
• Quinazoline derivatives as antitumor agentsPublication Number:WO-2020057511-A1Priority Date:2018-09-18
• Quinazoline Derivatives as Antitumor AgentsPublication Number:JP-7546550-B2Priority Date:2018-09-18Grant Date:2024-09-06
• Quinazoline derivatives as antitumor agentsPublication Number:CA-3099776-A1Priority Date:2018-09-18

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