Prifetrastat

CAS 2569008-99-5

MFC19H18N4O5S MW414.4 g/mol

N-(6-((1H-Pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide

2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide
antineoplastic, PF-07248144, PF 07248144, Solid tumours, CANCER, KAT6-IN-1, GN6DU4ZE30

Prifetrastat is an inhibitor of MYST histone acetyltransferase (HAT) KAT6, with potential antineoplastic activity. Upon administration, prifetrastat targets and binds to KAT6, and inhibits the acetylation of histones and other nonhistone substrates. This may disrupt gene expression and inhibit the proliferation of tumors that overexpress KAT6. KAT6A (MOZ; MYST3) and KAT6B (MORF; MOZ2; MYST4), commonly amplified genes in solid tumors, play key roles in cell cycle regulation and in tumorigenesis.

Prifetrastat (also known as PF-07248144) is an investigational, first-in-class small molecule drug that acts as a selective inhibitor of the epigenetic modifiers KAT6A and KAT6B. It is primarily studied as an antineoplastic agent for hormone receptor-positive (ER+/HER2–) advanced or metastatic breast cancer.

Mechanism of Action

• Inhibits KAT6A and KAT6B histone acetyltransferases to block abnormal tumor cell growth.
• Suppresses lineage-specific gene expression tied to estrogen receptor signaling and drug resistance.
• Induces cell cycle arrest and tumor senescence.

Clinical Development

• Evaluated in clinical trials (such as phase 1/2 and phase 3 evaluations) for patients whose breast cancer progressed after prior endocrine therapy and CDK4/6 inhibitors.
• Commonly tested in combination regimens alongside anti-estrogen therapies like fulvestrant

Prifetrastat (also known as PF-07248144) is an investigational, first-in-class small molecule drug that acts as a selective inhibitor of the epigenetic modifiers KAT6A and KAT6B. It is primarily studied as an antineoplastic agent for hormone receptor-positive (ER+/HER2–) advanced or metastatic breast cancer.

Mechanism of Action

• Inhibits KAT6A and KAT6B histone acetyltransferases to block abnormal tumor cell growth.
• Suppresses lineage-specific gene expression tied to estrogen receptor signaling and drug resistance.
• Induces cell cycle arrest and tumor senescence.

Clinical Development

• Evaluated in clinical trials (such as phase 1/2 and phase 3 evaluations) for patients whose breast cancer progressed after prior endocrine therapy and CDK4/6 inhibitors.
• Commonly tested in combination regimens alongside anti-estrogen therapies like fulvestrant
• Phase IIIHER2 negative breast cancer
• Phase IISolid tumours
• No development reportedBreast cancer
• 07 Aug 2026Prifetrastat is still in phase II development in Solid-tumours (Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Australia, Japan, China, South Korea (PO, Tablet) (NCT04606446)
• 07 Aug 2026Prifetrastat is still in phase II development in Solid-tumours (Monotherapy, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Australia, Japan, China, South Korea (PO, Tablet) (NCT04606446)
• 28 Jul 2026No recent reports of development identified for phase-I development in Breast-cancer(Metastatic disease) in USA (PO)

PAT

[WO2020254946]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020254946&_cid=P12-MSO1IP-41527-1

Example 45: Preparation of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide according to Scheme C (Route A).

To a suspension of 4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (A-2) (2.5 g, 10 mmol) in pyridine (8.0 mL) was added 2-methoxybenzene-1-sulfonyl chloride (3.17 g, 15.4 mmol). The reaction was stirred at 120 °C for 1.5 h. The mixture was cooled to room temperature and diluted with MeOH. The resulting suspension was filtered. and the filter cake was washed with MeOH (30 mL). The solids were dissolved in DCM (50 mL) and MeOH (30 mL) was added. The DCM was removed under vacuum

and the precipitate was collected by filtration. The filter cake was dried by lyophilization to provide 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (2.5 g, 59% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) d 10.18 (s, 1H), 7.87 (d, J= 2.0 Hz, 1H), 7.80 (dd, J=1.6, 7.9 Hz, 1H), 7.66– 7.59 (m, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.74 (s, 1H), 6.30 (t, J=2.0 Hz, 1H), 5.44 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H); m/z (ESI+) 415.0 (M+H) ⁺ .

Example 45: Alternative preparation of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide according to Scheme D.

A 100 mL reactor equipped with an overhead stirrer was charged with 4-methoxy-6-(1H-pyrazol-1-ylmethyl)-1,2-benzoxazol-3-amine (A-2) (10.00 g, 40.94 mmol), 2-methoxybenzenesulfonyl chloride (10.15 g, 49.13 mmol), and acetonitrile (100 mL). The resulting suspension was stirred at 25 °C for 55 minutes. Via pipette, dimethylsulfoxide (0.36 mL, 4.09 mmol) was added in one portion. Via syringe, 3,5-lutidine (14.8 mL, 122.82 mmol) was added dropwise over 15 minutes. The resulting light-yellow suspension was stirred at 25 °C for 18 hours to reach >98% conversion as judged by LCMS. The reaction mixture was acidified with 1 M aq. HCl (100 mL), then

concentrated to ~80 mL (rotary evaporator, 40 °C, 85 mbar). The slurry was treated with additional 1 M aq. HCl (40 mL) to rinse down the walls of the vessel, then stirred at 20 °C for 2.5 hours. The resulting precipitate was collected by suction filtration. The filter cake was washed with water (2 x 50 mL), then dried under vacuum at 35 °C for 48 hours, affording crude 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (15.2 g, 90% yield, 98% purity by LCMS) as a solid. m/z 415.1 (M+H) ⁺ .

To purify the crude product, a suspension of crude 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (14.00 g, 33.78 mmol) in dichloromethane (210 mL) was heated in a 40 °C bath until a clear solution was obtained (10 minutes). The mixture was filtered, and the filtrate returned to a clean reaction vessel, using additional dichloromethane (70 mL) to quantitate the transfer. Ethyl acetate (140 mL) was added to the solution over 2 minutes, then the mixture stirred for 2.5 hours. No crystallization was observed, so the solution was concentrated under reduced pressure (200 mbar) to remove dichloromethane (volume was reduced by about 70 mL). More ethyl acetate (140 mL) was added to the residue, and the mixture stirred at room temperature for 21 hours. The resulting suspension was concentrated under reduced pressure (40 °C, 200 mbar) to about 280 mL, then stirred at room temperature for 3 hours. The solids were collected by filtration, with additional ethyl acetate (70 mL) used to rinse the reaction vessel and filter cake. The filter cake was dried in a vacuum oven at 35 °C for 23 hours, affording 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (12.0 g, 85% yield, 97.9% purity by UPLC, no single impurity larger than 0.5%) as a solid. m/z 415.1 (M+H) ⁺ .

To purify further, a suspension of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (2.0 g, 4.73 mmol) in acetone (80 mL) was heated to reflux (bath temperature 55 °C) with stirring for 2 hours. While the mixture was still heated, ethyl acetate (30 mL) was added slowly, so that the internal temperature remained above 45 °C. The resulting slurry was concentrated to about 30 mL under mild vacuum (bath temp 65 °C), then cooled slowly at a rate of 1 °C/min to 20 °C (~31 minutes). The resulting precipitate was collected by suction filtration. The filter cake dried under vacuum at 50 °C for 22 hours, yielding 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Example 45) (1.825 g, 93% yield, 99.5% purity by UPLC) as a crystalline solid. ¹ hour

NMR (400 MHz, CHLOROFORM-d) d 8.14 (dd, J=1.7, 7.8 Hz, 1H), 8.04 (s, 1H), 7.59 -7.51 (m, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.78 (d, J=0.6 Hz, 1H), 6.45 (s, 1H), 6.32 (t, J=2.1 Hz, 1H), 5.38 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H).

PAT

US20250122182, Example 45,

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=EB10EA12C4409E47C6165613EF765C49.wapp1nC?docId=WO2026003716&_cid=P12-MSO1HW-40533-1

Scheme 1

Step 2

In an inerted reactor were added 6-((1 H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (lnt-4, 27.5 Kg, 112.6 mol, 1 equiv.), 2-methoxybenzenesulfonyl chloride (lnt-5, 33.9 Kg, 168.9 mol, 1.5 equiv.) and THF (248 L, 9-L/Kg). A solution of sodium te/Y-butoxide in THF (2 M, 197 L, 394.1 mol, 3.5 eq.) was added to the stirred mixture at 20 °C over 4 h. At the end of the addition the line was rinsed with THF (27.5 L, 1 L/Kg) and the mixture stirred for a further 1 h. Following reaction completion water (413 L, 15 L/Kg) was added at once followed by slow addition of aq. HCI (2 M, 197 L, 394.1 mol, 3.5 equiv.). The mixture was left stirring overnight, then the slurry was filtered, washed twice with CH3OH (82.5 L, 3 L/Kg) and dried to afford the title compound as a white solid (42.32 Kg, 90.6% yield).

¹H NMR (400 MHz, DMSO) 5 10.09 (s, 1 H), 7.87 (dd, J = 2.3, 0.7 Hz, 1 H), 7.81 (dd, J = 7.8, 1.7 Hz, 1 H), 7.63 (ddd, J = 8.4, 7.4, 1.7 Hz, 1 H), 7.50 (dd, J = 1.8, 0.7 Hz, 1 H), 7.10 (td, J = 7.6, 1 .0 Hz, 1 H), 6.84 (d, J = 1 .0 Hz, 1 H), 6.30 (t, J = 2.1 Hz, 1 H), 5.44 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H). ¹³C NMR (101 MHz, DMSO) 5 164.82, 156.92, 154.39, 151.76, 144.13, 139.80, 135.73, 131.03, 130.43, 127.66, 120.52, 113.34, 106.25, 106.17, 104.42, 101.33, 56.51, 56.42, 55.01. HRMS: Ci9Hi₈N₄O5S⁺ [M+1 ]⁺ calculated:

415.1072; measured: 415.1071.

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