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Girocitinib

October 25, 2025 2:44 am / Leave a comment

Girocitinib

CAS 2222137-79-1

MFC17H18N4O3 MW 326.36

2-[(2R,5S)-5-[4-[(1R)-1-hydroxyethyl]-12-oxa-3,5,8-triazatricyclo[7.3.0.0^2,6]dodeca-1,4,6,8,10-pentaen-3-yl]oxan-2-yl]acetonitrile

[(2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl}oxan-2-yl]acetonitrile

2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile
Janus kinase inhibitor, anti-inflammatory, A0IES9T8GO

In an era where targeted therapies are redefining the landscape of medical treatment, Girocitinib emerges as a beacon of hope for many. This innovative drug, developed by leading pharmaceutical research institutions, primarily targets specific proteins involved in disease progression. Classified as a tyrosine kinase inhibitor (TKI), Girocitinib has shown significant promise in the treatment of various cancers, particularly non-small cell lung cancer (NSCLC). The drug is currently in the advanced stages of clinical trials, with researchers optimistic about its potential to provide a more effective and less toxic treatment option compared to conventional therapies.

Girocitinib is designed to interfere with the signaling pathways that promote cancer cell growth and survival. It does this by inhibiting the activity of tyrosine kinases, enzymes that play a key role in the activation of many proteins by signaling pathways within the cell. Tyrosine kinases are often overactive in cancer cells, leading to unchecked proliferation and survival. By targeting these enzymes, Girocitinib effectively disrupts these malign processes, thereby slowing down or even halting the progression of the disease.

The primary indication for Girocitinib is non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases. NSCLC is notoriously difficult to treat, especially in its advanced stages, and current treatments often come with significant side effects. Clinical trials have shown that Girocitinib can significantly improve progression-free survival in patients with specific genetic mutations that make them more responsive to TKI therapy. These mutations can be identified through genetic testing, allowing for a more personalized treatment approach that increases the likelihood of success.

In addition to NSCLC, researchers are exploring the potential of Girocitinib to treat other types of cancer, including colorectal cancer and certain forms of leukemia. Early-stage trials have shown encouraging results, suggesting that Girocitinib could become a versatile tool in the oncology arsenal. Its ability to target specific molecular pathways makes it a promising candidate for combination therapies, which aim to enhance treatment efficacy while minimizing resistance and adverse effects.

The development of Girocitinib is a testament to the power of modern science and technology in addressing some of the most challenging health issues of our time. The drug’s journey from the laboratory to clinical trials has been marked by rigorous research and collaboration among scientists, healthcare professionals, and patients. As we await the results of ongoing studies, there is a palpable sense of anticipation in the medical community, as Girocitinib holds the promise of transforming cancer treatment for many patients.

In conclusion, Girocitinib represents a significant advancement in the field of targeted cancer therapy. Its mechanism of action, which involves the inhibition of tyrosine kinases, offers a more precise and potentially less harmful treatment option for patients with NSCLC and possibly other cancers. As research progresses, Girocitinib may well become a cornerstone in the fight against cancer, providing hope and improved outcomes for countless individuals around the world.

PDT PAT

WO2018067422

SYN

US10738060]

https://patents.google.com/patent/US10738060B2/en?oq=US10738060

Example 4: Synthesis of 2-[(2R,5S)-5-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl] acetonitrile (4)

Step 1. In a round bottom flask, triethylamine (188 g, 1.86 mol, 1.0 eq) was added dropwise to a stirred solution of di-tert-butyl dicarbonate (162 g, 0.744 mol, 1.2 eq) and compound A4-1 (100 g, 0.62 mol, 1.0 eq) in water (500 mL) and 1,4-dioxane (500 mL). After stirring for 18 hrs at room temperature, the solution was extracted with MTBE (500 mL*2) and the aqueous phase was cooled on ice and carefully acidified to pH 3 by slow addition of 10% citric acid solution. The urethane was then extracted twice with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give compound A4-2 as clear viscous oil (180 g, yield 100%). MS-ESI:[M+1]⁺: 262.1

Step 2. A solution of compound A4-2 (40 g, 0.153 mmol, 1.0 eq) in THF (600 mL) was treated with 4-methylmorpholine (17 g, 0.168, 1.1 eq) at room temperature. The resulting mixture was cooled to 0° C. before being treated with isobutyl chloroformate (22.7 g, 0.166 mmol, 1.08 eq) dropwise. The resulting reaction mixture was stirred at 0° C. for an addition 20 mins before being filtered and washed with THF. Then the clear filtrate solution was cooed to 0° C., and treated with a solution of NaBH₄(11.2 g, 0.295 mol, 1.93 eq) in water (100 mL). The resulting mixture was stirred overnight at room temperature, and then quenched with an aqueous HCl solution (1.0 mol/L,200 mL) dropwise, The mixture was extracted with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-3 as a yellow oil (25 g, yield 66%). MS-ESI:[M+1]⁺: 248.1

Step 3. A solution of compound of A4-3 (25 g, 0.1 mol, 1.0 eq) in toluene (300 mL) and acetic acid (150 mL) was heated to reflux for 5 hrs and then cooled, concentrated under vacuum. The residual was added saturated sodium bicarbonate solution to pH 7-8 in ice-bath. Then the mixture was extracted three times with ethyl acetate, and the combined extracts was washed with brine, dried over anhydrous sodium sulfate, concentrated and recrystallized by ethyl acetate and PE to give compound A4-4 as a white powder (8.0 g, yield 37.2%). GC-MS: 215

Step 4. A solution of tributyl phosphine (72.9 g, 0.36 mol, 1.0 eq) in nitromethane (500 mL), was added dropwise chloroacetonitrile (27.2 g, 0.36 mol, 1.0 eq) in nitrogen atmosphere. The resulting reaction mixture was stirred for 16 hrs at room temperature, then concentrated. The residual oil solidified when a small amount of ethyl acetate was added. The solid was recrystallized by ethyl acetate and DCM to afford compound A4-5 as a white powder (95 g, yield 95%).

Step 5. To a solution of dry compound A4-5 (8.3 g, 30 mmol, 3.0 eq) in N,N-dimethylacetamide (30 mL) in nitrogen atmosphere, was added solid Potassium tert-butoxide (3.1 g, 28 mmol, 2.8 eq) in portions at 0° C. The resulting mixture was gradually warmed to 30° C. and stirred for 2 hrs. The resulting ylide solution was then treated with compound A4-4 (2.15 g, 10 mmol, 1.0 eq), and stirred overnight at 70° C. After cooled to room temperature, the resulting slurry was poured into the mixture of ice-water (100 mL) and saturated sodium bicarbonate solution (100 mL). The mixture was extracted twice with ethyl acetate, and the combined extracts was washed three times with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-6 as yellow oil without purification (7.5 g, yield 100%). MS-ESI:[M+1]⁺: 239.1

Step 6. To a solution of compound A4-6 (7.5 g, 10 mmol, 1.0 eq) in methanol (200 mL), was added 10% Pd/C (0.5 g,50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrates was concentrated under vacuum, and purified by silica gel column chromatography to give compound A4-7 as off-white powder (1.6 g, yield 66.7%). MS-ESI:[M+1]⁺: 241.1

Step 7. To a solution of compound A4-7 (1.6 g, 6.67 mmol, 1.0 eq) in DCM (20 mL), was added TFA (10 g, 88.5 mmol, 13.2 eq). The reaction mixture was stirred for 2 hrs at room temperature until TLC showed the reaction was complete, then concentrated under vacuum. Water (20 mL) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/L) to pH 10. Then the aqueous phase was extracted six times with DCM/methanol (10/1). The combined extracts was dried over anhydrous sodium sulfate, concentrated to give compound A4-8 as light-brown oil (950 mg, yield 100%). MS-ESI:[M+1]⁺: 141.1

Step 8. To a solution of compound A1-14 (prepared as step 4 to 12 in example 1) (600 mg, 3.0 mmol, 1.0 eq) in n-butanol (15 mL), was added compound A4-8 (950 mg, 6.7 mmol, 2.26 eq) and DIPEA (1.36 g, 10.5 mmol, 3.5 eq). The reaction mixture was stirred for 1 hr at 135° C., concentrated and purified by silica gel column chromatography to give compound A4-9 (2R,5S) as light-yellow powder (254 mg, yield 28.0%).MS-ESI: [M+1]⁺: 303.1.

¹H NMR (300 MHz, d₆-DMSO): 9.063 (s, 1H), 8.503 (d, 1H), 9.326 (d, 1H), 7.176 (d, 1H), 4.431-4.513 (m, 1H), 4.128-4.156 (m, 1H), 3.633-3.659 (m, 1H), 3.448-3.518 (m, 1H), 2.775-2.841 (m, 2H), 2.205-2.312 (m, 1H), 1.829-1.859 (m, 2H), 1.501-1.521 (m, 1H).

Step 9. To a solution of compound A4-9 (254 g, 0.84 mmol, 1.0 eq) in methanol (20 mL), was added 10% Pd/C (0.15 g,50% wet). Hydrogenation was carried out under atmospheric pressure at room temperature until hydrogen uptake ceased. The catalyst was filtered and washed by methanol. The filtrates was concentrated under vacuum, and compound A4-10 was obtained as yellow oil (230 mg, yield 100%). MS-ESI:[M+1]⁺: 273.1

Step 10. A solution of D-Lactamide (388 mg, 4.2 mmol, 5.0 eq) and Et3O—BF₄(1.3 g, 6.72 mmol, 8.0 eq) in THF (10 mL) was stirred for 30 mins at room temperature in nitrogen atmosphere. Then the above solution was added to the mixture of compound A4-10 (230 mg, 0.84 mmol, 1.0 eq) in ethanol (10 mL). After stirring for 3 hrs at 85° C. until HPLC showed the reaction was complete, the mixture was concentrated, added water and extracted four times with ethyl acetate. The organic phases was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution to pH 8, extracted twice with ethyl acetate. The second organic phases was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as light-yellow powder (120 mg, yield 43.8%). MS-ESI: [M+1]⁺: 327.6,

¹H NMR (300 MHz, CDCl₃): 9.039 (s, 1H), 7.939 (d, 1H), 7.196 (d, 1H), 5.235-5.336 (m, 1H), 4.806-4.973 (m, 1H), 4.403-4.483 (t, 1H), 4.096-6.116 (m, 2H), 2.700-2.807 (m, 4H), 2.105-2.312 (m, 2H), 1.830-1.852 (d, 3H).

SYN

US2022227777

https://patents.google.com/patent/US20220227777A1

International patent application WO2018067422A1 discloses 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives as selective JAK1 kinase inhibitors and preparation methods thereof, wherein compound I and its preparation method is disclosed.

Preparation of a Compound of Formula I

[0204]THF (60 mL, 12 V), (R)-lactamide (6.6 g, 4.0 eq) and Et₃O—BF₄(13.9 g, 4.0 eq) were added to a 250 mL three-necked flask #1, the system was stirred; the materials in three-necked flask #1 were stirred under nitrogen protection for later use; a compound of formula II (5.0 g, 1.0 eq) and ethanol (80 mL, 16 V) were added to another 250 mL three-necked flask #2; the system was heated to 70±5° C. under nitrogen protection; the materials in three-necked flask #1 were added to three-necked flask #2 with a syringe dropwise within 10-20 minutes; the system was heated to 85±5° C. (internal temperature was in the range of 72-75° C.) under nitrogen protection for reacting for 2 hours; the system was cooled to room temperature; the reaction liquid was concentrated with a rotary evaporator until there was basically no fraction flowing out; 1M HCl (80 mL) was added to the residual concentrated liquid, the pH was about 1 (determined with a pH test paper); the system was extracted four times with DCM (50 mL×4); the pH of the aqueous phase was adjusted to 7-8 with saturated sodium bicarbonate solution; the system was stirred at room temperature for 0.5 hour, then was filtered, the filter cake was washed with water (60 mL) and EA (10 mL), respectively; the filter cake was dried under vacuum at 50° C. for 16 hours; 4.3 g of faint yellow solid was obtained, with a purity of 95.0%; the solid was dissolved with methanol (30 mL); 4.1 g of silicon based metal eliminator and 1.0 g of activated carbon were added, the system was heated to 50° C. and stirred for 1 hour, then was cooled, filtered, washed with methanol (30 mL); the filtrate was concentrated with rotary evaporator until there was basically no fraction flowing out; methanol (10 mL) and MTBE (25 mL) were added to the residue, the system was heated to 50° C., and was stirred for 0.5 hour, then was cooled, the system was cooled to 10±5° C. and stirred for 0.5 hour; filtered, the filter cake was washed with MTBE (25 mL); the filter cake was dried under vacuum at 50° C. for 16 hours, 3.2 g of faint yellow solid was obtained, with a purity of 97.9%.
[0205]MS-ESI: [M+1]+: 327.6
[0206]¹H NMR (400 MHz, CDCl₃): 8.988 (s, 1H), 7.922 (d, 1H), 7.175 (d, 1H), 5.200-5.265 (m, 1H), 4.859-4.942 (m, 1H), 4.350-4.406 (t, 1H), 4.020-4.108 (m, 2H), 3.067 (d, 1H), 2.619-2.779 (m, 3H), 2.108-2.269 (m, 2H), 1.790-1.895 (m, 3H).
[0207]THF (650 mL, 12 V), (R)-lactamide (70.6 g, 4.0 eq) and Et₃O—BF₄(150.6 g, 4.0 eq) were added to a 1000 mL three-necked flask #1, the system was stirred; the materials in three-necked flask #1 were stirred under nitrogen protection for later use; a compound of formula II (54 g, 1.0 eq) and ethanol (860 mL, 16 V) were added to another 2000 mL three-necked flask #2; the system was heated to 70±5° C. under nitrogen protection; the materials in three-necked flask #1 were slowly added to three-necked flask #2 dropwise within 1 hour; the system was heated to 85±5° C. (internal temperature was in the range of 72-75° C.) under nitrogen protection for reacting for 2 hours; the system was cooled to room temperature; the reaction liquid was concentrated with a rotary evaporator until there was basically no fraction flowing out; 1M HCl (450 mL) was added to the residual concentrated liquid, the pH was about 1 (determined with a pH test paper); the system was extracted four times with DCM (270 mL×4); the pH of the aqueous phase was adjusted to 7-8 with saturated sodium bicarbonate solution; the system was stirred at room temperature for 0.5 hour, then was filtered, the filter cake was washed with water (540 mL); MTBE (270 mL) was added to the filter cake, the system was stirred at room temperature for 0.5 hour, filtered, the filter cake was washed with MTBE (108 mL); the filter cake was dried under vacuum at 50° C. for 16 hours; 49.2 g of light yellow solid was obtained, with an HPLC purity of 94.2%; the solid was dissolved with methanol (380 mL); silicon based metal eliminator (44 g) and activated carbon (5.4 g) were added, the system was heated to 50° C. and stirred for 1 hour, then was cooled, filtered, washed with methanol (430 mL); the filtrate was concentrated with a rotary evaporator to (80-110 mL, 1.5 V-2 V); MTBE (540 mL) was added to the residue, the system was heated to 50° C., and was stirred for 1 hour, then was cooled to 10±5° C. and stirred for 0.5 hour; filtered, the filter cake was washed with MTBE (270 mL); 42.4 g of filter cake was obtained, with an HPLC purity of 96.9%; the filter cake was dried under vacuum at 50° C. for 16 hours, 41.0 g of light yellow solid was obtained, with an HPLC purity of 96.7%, a yield of 63.3%.
[0208]Purification of a Compound of Formula I:
[0209]A compound of formula I (41 g) was dissolved with methanol; silica gel (50 g) was added to the solution, the system was concentrated to dryness for later use; silica gel (200 g) was added to the chromatographic column, the column was compacted with an air pump; a compound of formula I mixed with silica gel was added to the chromatographic column, the column was compacted with an air pump; the chromatographic column was eluted with an eluent (V_MeOH:V_DCM=1:100-1:30); qualified components were collected, concentrated to dryness; the product was dried under vacuum at 50° C. for 16 hours; 36 g of off-white solid was obtained, with an HPLC purity of 98.5%.
[0210]The MS-ESI and ¹H NMR data are consistent with example 21.
[0211]THF (60 mL, 6 V), (R)-lactamide (13.2 g, 4.0 eq) and Et₃O—BF₄(27.9 g, 4.0 eq) were added to a 100 mL three-necked flask #1, the system was stirred; the materials in #1 were stirred under nitrogen protection for later use; a compound of formula II (10 g, 1.0 eq) and ethanol (100 mL, 10 V) were added to another 250 mL three-necked flask #2; the system was heated to 70±5° C. under nitrogen protection; the materials in three-necked flask #1 were slowly added to three-necked flask #2 dropwise within 20 minutes; the system was heated to 80±5° C. (internal temperature was in the range of 72-75° C.) under nitrogen protection for reacting for 0.5 hour; the system was cooled to room temperature 20-30° C.; the reaction liquid was concentrated to about 50-80 mL with a rotary evaporator between 30-40° C.; water (100 mL, 10 V) was added to the system, then the system was concentrated with a rotary evaporator between 30-40° C. until there was basically no fraction flowing out; the system was cooled to 20-30° C.; the temperature of the system was controlled at 20-30° C., 12M HCl (5.5 g) was used to adjust the pH of the system to 2-3, the system was extracted with ethyl acetate (50 mL×2, 5V×2); the organic phase was discarded, and the aqueous phase was transferred to a flask; the temperature of the system was controlled at 20-30° C., the pH of the system was adjusted to 8-9 with saturated potassium carbonate solution (23 g); the temperature of the system was controlled at 20-25° C., the system was stirred for 2 hours, then was filtered, the filter cake was washed with water (50 mL) and MTBE (50 mL); the filter cake was dried with an air blower at 50° C. for 24 hours, 18 g of earth yellow solid was obtained, with an HPLC purity of 93.5%.
[0212]The MS-ESI and ¹H NMR data are consistent with example 21.
[0213]THF (120 mL, 12 V), (R)-lactamide (13.2 g, 4.0 eq) and Et₃O—BF₄(27.8 g, 4.0 eq) were added to a 250 mL three-necked flask #1, the system was stirred; the materials in #1 were stirred under nitrogen protection for later use; a compound of formula II (10 g, 1.0 eq) and ethanol (140 mL, 14 V) were added to another 500 mL three-necked flask #2; the system was heated to 40-45° C. (internal temperature) under nitrogen protection; the materials in three-necked flask #1 were added to three-necked flask #2 dropwise within 1 hour; the system was maintained at 40-45° C. (internal temperature) under nitrogen protection for reacting for 4.5 hours; the system was cooled to room temperature, and water (20 mL, 2V) was added; the system was concentrated with a rotary evaporator at 30-40° C. until there was basically no fraction flowing out; the system was cooled to 20-30° C.; the temperature of the system was controlled at 20-30° C., 12M HCl (3 mL) was used to adjust the pH of the system to 2-3, the system was extracted with ethyl acetate (50 mL×2, 5V×2); the organic phase was discarded, and the aqueous phase was transferred to a flask; the temperature of the system was controlled at 20-30° C., the pH of the system was adjusted to 8-9 with 50% potassium carbonate solution (15 mL); the temperature of the system was controlled at 20-25° C., the system was stirred for 2 hours, then was filtered, the filter cake was washed with water (50 mL) and acetone (50 mL); the crude product was triturated and stirred with water (50 mL) at 20-25° C. for 1 hour; the system was filtered, the filter cake was washed with water (50 mL) and acetone (50 mL); the filter cake was dried with an air blower at 50° C. for 24 hours, 17.8 g of khaki solid was obtained, with an HPLC purity of 95.3%.
[0214]The MS-ESI and ¹H NMR data are consistent with example 21.
[0215]THF (60 mL, 12 V), (R)-lactamide (6.6 g, 4.0 eq) and Et₃O—BF₄(13.9 g, 4.0 eq) were added to a 250 mL three-necked flask #1, the system was stirred; the materials in three-necked flask #1 were stirred under nitrogen protection for later use; a compound of formula II (5 g, 1.0 eq) and ethanol (70 mL, 14 V) were added to another 250 mL three-necked flask #2; the system was heated to 40-45° C. (internal temperature) under nitrogen protection; the materials in three-necked flask #1 were added to three-necked flask #2 dropwise within 20 minutes; the system was maintained at 40-45° C. (internal temperature) under nitrogen protection for reacting for 3 hours; the system was cooled to room temperature and was filtered, the filter cake was washed with THF (10 mL); water (10 mL, 2V) was added to the filtrate; the filtrate was concentrated with a rotary evaporator to 10-20 mL (2V-4V), the concentrated residue was exchanged with ethyl acetate (25 mL×2) and concentrated to 10-20 mL (2V-4V); water (50 mL, 10V) was added to the concentrated residue; the internal temperature was controlled at 20-25° C., 12M HCl (4.1 g) was used to adjust the pH of the system to 1-2; activated carbon (0.5 g) was added to the system, and the system was stirred at room temperature for 2 hours, and was filtered, the filter cake was washed with water (10 mL) and 1M HCl (10 mL); the combined filtrate was extracted with ethyl acetate (25 mL×2), the organic phase was discarded; the internal temperature was controlled at 20-25° C., the pH of the system was adjusted to 9-10 with saturated potassium carbonate solution (15 g); the internal temperature was controlled at 15-20° C., the system was stirred for 1 hour, and was filtered, the filter cake was washed with water (10 mL); the filter cake was triturated with acetone aqueous solution (50 mL, V/V=1:1) for 1 hour; the system was filtered, the filter cake was washed with acetone aqueous solution (10 mL, V/V=1:1); the filter cake was dried with an air blower at 50° C. for 24 hours; 5.0 g of pale gray solid was obtained, with an HPLC purity of 95.6%, and a yield of 83.5%;
[0216]Purification of a Compound of Formula I:
[0217]5.0 g of the obtained solid and methanol (40 mL) were added to a flask, and were stirred for 10 minutes at room temperature, the materials were basically dissolved and the solution was clear; activated carbon (0.5 g) and silica gel (4.0 g) were added to the system; the system was heated to 50-55° C., the temperature was maintained and the system was stirred for 2 hours, then was filtered with silica gel (5 g), the filter cake was washed with methanol (50 mL); the filtrate was concentrated with a rotary evaporator to 5-10 mL; MTBE (50 mL) was added to the concentrated residue; the system was heated to reflux, and was allowed for reflux for 1 hour; the system was cooled to 5-10° C., the temperature was maintained and the system was stirred for 1 hour and was filtered, the filter cake was washed with MTBE; the filter cake was dried with a drying oven under vacuum at 50° C. for 16 hours; 3.0 g of off-white solid was obtained, with a yield of 60% and a purity of 97.9%; the filtrate was concentrated to dryness to obtain 1.4 g of yellow solid.
[0218]The MS-ESI and ¹H NMR data are consistent with example 21.

PAT

NEW SELECTIVE JAK1 INHIBITORS AND THEIR USEPublication Number: HR-P20211965-T1Priority Date: 2016-10-03
Novel JAK1 selective inhibitors and uses thereofPublication Number: KR-102399848-B1Priority Date: 2016-10-03Grant Date: 2022-05-19
Novel Jak1-selective inhibitors and their usesPublication Number: CN-113214278-BPriority Date: 2016-10-03Grant Date: 2022-10-28
Jak1 selective inhibitors and uses thereofPublication Number: US-RE49834-EPriority Date: 2016-10-03Grant Date: 2024-02-13
Novel jak1 selective inhibitors and uses thereofPublication Number: US-2019256523-A1Priority Date: 2016-10-03
JAK1 selective inhibitors and uses thereofPublication Number: US-10738060-B2Priority Date: 2016-10-03Grant Date: 2020-08-11
Novel Jak1-selective inhibitors and their usesPublication Number: CN-108366994-BPriority Date: 2016-10-03Grant Date: 2021-10-01
Novel Jak1-selective inhibitors and their usesPublication Number: CN-113214278-APriority Date: 2016-10-03
Novel jak1 selective inhibitors and uses thereofPublication Number: EP-3509591-B1Priority Date: 2016-10-03Grant Date: 2021-11-17
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereof.Publication Number: MX-2024006688-APriority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: US-12195476-B2Priority Date: 2019-06-06Grant Date: 2025-01-14
Novel jak1 selective inhibitors and uses thereofPublication Number: CA-3039178-A1Priority Date: 2016-10-03
Novel jak1 selective inhibitors and uses thereofPublication Number: EP-3509591-A1Priority Date: 2016-10-03
Novel JAK1 selective inhibitors and uses thereofPublication Number: JP-2019537559-APriority Date: 2016-10-03
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: EP-4248967-A3Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: JP-2023089169-APriority Date: 2019-06-06
Synthesis method of furoimidazopyridine compounds, crystal forms of furoimidazopyridine compounds and crystal forms of their saltsPublication Number: CN-113906035-BPriority Date: 2019-06-06Grant Date: 2023-11-10
Synthesis method of furoimidazopyridine compounds, crystal forms of furoimidazopyridine compounds and crystal forms of their saltsPublication Number: CN-117327083-APriority Date: 2019-06-06
METHOD OF SYNTHESIS OF FUROIMIDAZOPYRIDINE COMPOUND, CRYSTAL FORM OF FUROIMIDAZOPYRIDINE COMPOUND, AND CRYSTAL FORM OF ITS SALT.Publication Number: MX-2024004146-APriority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: US-2022227777-A1Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: AU-2020289149-B2Priority Date: 2019-06-06Grant Date: 2023-05-11
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: EP-4248966-A2Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: EP-4248966-A3Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: EP-4248967-A2Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: WO-2020244348-A1Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: AU-2020289149-A1Priority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound and crystal form of salt thereofPublication Number: CN-113906035-APriority Date: 2019-06-06
Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereofPublication Number: EP-3981771-A1Priority Date: 2019-06-06

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///////////Girocitinib, Janus kinase inhibitor, anti-inflammatory, A0IES9T8GO

Gildeuretinol

October 24, 2025 2:27 am / Leave a comment

Gildeuretinol

Retin-20,20,20-d3-ol

CAS118139-35-8

MF C20H272H3O, MW 289.5 g/mol

(2E,4E,6E,8E)-3-(2H3)methyl-7-methyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol; (20,20,20-2H3)retinol

(2E,4E,6E,8E)-7-methyl-3-(trideuteriomethyl)-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraen-1-ol
vitamin A analogue, Orphan Drug, Stargardt disease, breakthrough therapy, Pediatric Rare Disease designations, ALK-001, KL-49, ALK 001, KL 49

OriginatorColumbia University
DeveloperAlkeus Pharmaceuticals
ClassEye disorder therapies; Retinoids; Vitamins
Mechanism of ActionDimerisation inhibitors; Vitamin A replacements
Orphan Drug StatusYes – Stargardt disease
Phase II/IIIDry age-related macular degeneration
Phase IIStargardt disease
No development reportedRetinal dystrophies
08 Sep 2025Gildeuretinol – Alkeus Pharmaceuticals receives Orphan Drug status for Stargardt disease in European Union
09 Jan 2025Alkeus Pharmaceuticals announces intention to submit an NDA to US FDA for Stargardt disease in 2025
09 Jan 2025Efficacy and adverse event data from phase II trial for Stargardt disease released by Alkeus Pharmaceuticals

Gildeuretinol is an investigational new drug being developed by Alkeus Pharmaceuticals, Inc. for the treatment of retinal diseases, particularly Stargardt disease and geographic atrophy secondary to age-related macular degeneration (AMD). Stargardt disease is caused by a defect in the ABCA4 gene that clears toxic byproducts resulting from the dimerization of vitamin A. Gildeuretinol is new molecular entity designed to reduce the dimerization of vitamin A in the eye without affecting the visual cycle.^[1]

Gildeuretinol has received breakthrough therapy, orphan drug and Pediatric Rare Disease designations from the U.S. Food and Drug Administration.^[2]

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References

Zaydon YA, Tsang SH (July 2024). “The ABCs of Stargardt disease: the latest advances in precision medicine”. Cell & Bioscience. 14 (1) 98. doi:10.1186/s13578-024-01272-y. PMC 11282698. PMID 39060921.
Fitch J (22 November 2024). “Gildeuretinol for Stargardt disease receives Rare Pediatric Disease, Fast Track Designations”. Contemporary Pediatrics.

Clinical data

Other names	ALK-001, KL-49
Identifiers
IUPAC name
CAS Number	118139-35-8
PubChem CID	169490774
UNII	PSZ7W5NR24
KEGG	D12713
ChEMBL	ChEMBL5314606
Chemical and physical data
Formula	C₂₀H₃₀D₃O
Molar mass	292.500 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

/////////Gildeuretinol, vitamin A analogue, Orphan Drug, Stargardt disease, breakthrough therapy, Pediatric Rare Disease designations, ALK-001, KL-49, ALK 001, KL 49, PSZ7W5NR24

Frevecitinib

October 23, 2025 3:02 am / Leave a comment

Frevecitinib

CAS 1299417-07-4

MF C22H21N7O2 MW 415.4 g/mol

3-[(3S)-3-(1-methyl-2-oxo-5-pyrazolo[1,5-a]pyridin-3-ylimidazo[4,5-b]pyridin-3-yl)piperidin-1-yl]-3-oxopropanenitrile

3-{(3S)-3-[1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-
yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]piperidin1-yl}-3-oxopropanenitrile
Janus kinase inhibitor, anti-inflammatory, 5N5L287M8T, KN 002, KN-002

Single and Multiple Ascending Dose Study of KN-002

CTID: NCT05006521

Phase: Phase 1

Status: Completed

Date: 2024-08-07

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011157397&_cid=P11-MH2TVG-48083-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US210080653&_cid=P11-MH2U9I-58146-1

It has now been found that a drug substance disclosed in WO2011/051452, namely the compound (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile having the structure shown below and known herein as compound (I) can be prepared in different polymorphic forms. Surprisingly one form exists as a polymorph with particularly advantageous stability properties. Compound (I) as prepared following the process in WO2011/051452 is known as Form I herein.

SYN

US8501735]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US76222175&_cid=P11-MH2U0A-51623-1

PAT

N-containing heteroaryl derivatives as jak3 kinase inhibitorsPublication Number: KR-101675614-B1Priority Date: 2009-10-29Grant Date: 2016-11-11
N-containing heteroaryl derivatives as jak3 kinase inhibitorsPublication Number: US-2012245140-A1Priority Date: 2009-10-29
N-containing heteroaryl derivatives as jak3 kinase inhibitorsPublication Number: US-2013131038-A9Priority Date: 2009-10-29
N-containing heteroaryl derivatives as JAK3 kinase inhibitorsPublication Number: US-8501735-B2Priority Date: 2009-10-29Grant Date: 2013-08-06
N-containing heteroaryl derivatives as JAK3 kinase inhibitorsPublication Number: US-8946257-B2Priority Date: 2009-10-29Grant Date: 2015-02-03
Heteroaryl imidazolone derivatives as jak inhibitorsPublication Number: EP-2582703-A1Priority Date: 2010-06-15
Heteroaryl Imidazolone Derivatives as Jap InhibitorsPublication Number: KR-20130113331-APriority Date: 2010-06-15
Heteroaryl imidazolone derivatives as jak inhibitorsPublication Number: US-2013089512-A1Priority Date: 2010-06-15
Heteroaryl imidazolone derivatives as jak inhibitorsPublication Number: WO-2011157397-A1Priority Date: 2010-06-15
N-containing heteroaryl derivatives as jak3 kinase inhibitorsPublication Number: EP-2493895-B1Priority Date: 2009-10-29Grant Date: 2017-04-26
Novel polymorphsPublication Number: US-2018016284-A1Priority Date: 2015-02-05
Novel polymorphsPublication Number: US-2019031687-A1Priority Date: 2015-02-05
Novel polymorphsPublication Number: WO-2016124464-A1Priority Date: 2015-02-05
Heteroaryl imidazolone derivatives as jak inhibitorsPublication Number: CA-2802588-A1Priority Date: 2010-06-15
Heteroaryl imidazolone derivatives as JAK inhibitorsPublication Number: CN-102933583-APriority Date: 2010-06-15
Novel polymorphsPublication Number: EP-3053927-A1Priority Date: 2015-02-05
Novel polymorphsPublication Number: EP-3253769-B1Priority Date: 2015-02-05Grant Date: 2019-03-13
New polymorphPublication Number: JP-2018502929-APriority Date: 2015-02-05
New polymorphPublication Number: JP-6685326-B2Priority Date: 2015-02-05Grant Date: 2020-04-22
PolymorphsPublication Number: US-10087196-B2Priority Date: 2015-02-05Grant Date: 2018-10-02
Crystalline form of a JAK3 kinase inhibitorPublication Number: US-10155757-B2Priority Date: 2015-03-10Grant Date: 2018-12-18
Crystalline form of a jak3 kinase inhibitorPublication Number: US-2018044336-A1Priority Date: 2015-03-10
Crystalline form of a jak3 kinase inhibitorPublication Number: WO-2016142201-A1Priority Date: 2015-03-10
Polymorphic forms of (s)-3-(3(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3(2h)-yl)piperidin-1-yl)-3-oxopropanenitrilePublication Number: CA-2972977-CPriority Date: 2015-02-05Grant Date: 2019-04-09
polymorphPublication Number: CN-107207533-BPriority Date: 2015-02-05Grant Date: 2019-04-16
Formulation of a pan-jak inhibitorPublication Number: TW-202440105-APriority Date: 2022-12-02
Formulation of a pan-jak inhibitorPublication Number: US-2024261224-A1Priority Date: 2022-12-02
Formulation of a pan-jak inhibitorPublication Number: WO-2024119058-A2Priority Date: 2022-12-02
Formulation of a pan-jak inhibitorPublication Number: WO-2024119058-A3Priority Date: 2022-12-02
Crystalline form of a jak3 kinase inhibitorPublication Number: EP-3268364-A1Priority Date: 2015-03-10

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///////////Frevecitinib, Janus kinase inhibitor, anti-inflammatory, 5N5L287M8T, KN 002, KN-002

Remibrutinib

October 22, 2025 8:52 am / Leave a comment

Remibrutinib

CAS 1787294-07-8

N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide

MW 507.5 g/mol, MF C₂₇H₂₇F₂N₅O₃

LOU064
NVP-LOU064-NXA
LOU064-NXA
I7MVZ8HDNU
WHO 11062

APPROVALS 2025, FDA 2025, 9/30/2025, To treat chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment

Remibrutinib, sold under the brand name Rhapsido, is a medication used for the treatment of chronic spontaneous urticaria.^[1] Remibrutinib is an oral, small molecule kinase inhibitor that inhibits Bruton’s tyrosine kinase (BTK).^[1] It is taken by mouth.^[1]

SYN

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01916

SYN

Example 6

N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide

(1) tert-Butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 8

To a solution of 4-amino-6-chloropyrimidin-5-ol (content 90%, 2.00 g, 12.37 mmol) in THF (120 mL) was added N-Boc-N-methyl-2-hydroxyethylamine (6.07 g, 34.64 mmol) followed by SMOPEX-301 (1 mmol/g, 30.90 g, 30.90 mmol). Then, a solution of DIAD (6.01 mL, 30.52 mmol) in THF (20 mL) was added slowly. The reaction mixture was stirred at 60 °C for 3 hr. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford an oil which was triturated with EtOAc and a white precipitate was formed. The solid was filtered off to afford INT 8. The mother liquor was concentrated and the residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0- 100%) to afford more INT 8 as a beige solid.

UPLC-MS: MS (ESI): [M+H]⁺ 303.1, rt = 0.86 min. ¹H NMR (DMSO-d₆): δ (ppm) 7.97 (s, 1H), 7.26 (s, br, 2H), 4.02-3.93 (m, 2H), 3.54 (t, 2H), 2.89 (s, br, 3H), 1.39 (s, 9H).

(2) tert-Butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2- methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 9

To a solution of INT 8 (447 mg, 1.48 mmol) in DME (7.0 mL) and water (1.0 mL) was added INT 5 (638 mg, 1.54 mmol) followed by aqueous sodium carbonate solution (1 M, 4.21 mL, 4.21 mmol). The mixture was degassed with argon for 10 min and bis(triphenylphosphine)palladium(II) dichloride (49.2 mg, 0.070 mmol) was added. The reaction mixture was stirred at 110 °C for 10 min in a microwave reactor. More INT 5 (232 mg, 0.56 mmol) was added and the reaction mixture was stirred at 110 °C for an additional 15 min in a microwave reactor. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0-100%) to afford INT 9 as an off-white solid.

UPLC-MS: MS (ESI): [M+H]⁺ 554.3, rt = 1.21 min. ¹H NMR (DMSO-d₆): δ (ppm) rotamers 9.76 (s, 1H), 8.19 (s, 1H), 7.74-7.53 (m, 2H) 7.20-6.85 (m, 5H), 3.57-3.48 (m, 2H), 3.29- 3.15 (m, 2H), 2.58 (s, 3H), 2.08-1.99 (overlapping s, 3H and m, 1H), 1.34 and 1.28 (s, 9H), 1.10-1.02 (m, 2H), 0.84-0.77 (m, 2H).

(3) N-(3-(6-Amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide, INT 10

To a solution of INT 9 (335 mg, 0.61 mmol) in DCM (5.0 mL) was added TFA (0.47 mL, 6.05 mmol). The reaction mixture was stirred at RT for 15 hr. The mixture was concentrated under reduced pressure. The residue was dried in vacuum to afford INT 10 as theTFA salt as a brown oil.

UPLC-MS: MS (ESI): [M+H]⁺ 454.3, rt = 0.73 min. ¹H NMR (DMSO-d₆): δ (ppm) 10.02 (s, 1H), 9.07-8.13 (s, v br, number of H cannot be assigned), 8.58 (s, 1H), 8.51 (s, br, 2H), 7.71-7.61 (m, 2H), 7.29-7.22 (m, 1H), 7.14-7.05 (m, 2H), 3.75-3.65 (m, 2H), 3.16-3.07 (m, 2H), 2.48 (s, 3H, overlapping with solvent peak), 2.12 (s, 3H), 2.10-1.99 (m, 1H), 1.11-1.03 (m, 2H), 0.83-0.76 (m, 2H).

(4) N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide

To a solution of acrylic acid (62 mg, 0.87 mmol) in DMF (4.0 mL) was added DIPEA (0.302 mL, 1.73 mmol) followed by T3P solution (50% in DMF) (0.438 mL, 0.750 mmol). The mixture was stirred at RT for 30 min. To a solution of INT 10 (containing 3.0 eq TFA, content 90%, 510 mg, 0.577 mmol) and DIPEA (0.302 mL, 1.731 mmol) in DMF (2.0 mL) at 0 °C was added dropwise the above solution. The reaction mixture was stirred at 0 °C for 30 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water (2x) and brine (2x), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica;

DCM/(MeOH with 2% aqueous ammonium hydroxide) gradient, 0-9%) to afford the title compound Example 6 as a white solid.

UPLC-MS: MS (ESI): [M+H]⁺ 508.3, rt = 0.95 min. ¹H NMR (DMSO-d₆): δ (ppm) rotamers 9.77 and 9.56 (s, total 1H), 8.25-8.14 (m, 1H), 7.79-7.50 (m, 2H), 7.17-6.93 (m, 5H), 6.70-6.55 (m, 1H), 6.06 (t, 1H), 5.59 (d, 1H), 3.63-3.40 (m, 4H), 2.80 and 2.49 (s, total 3H, peak at 2.49 overlapping with solvent peak), 2.09-1.93 (m, 4H), 1.11-1.00 (m, 2H), 0.85-0.76 (m, 2H).

PAT

SYN

Synthesis of Remibrutinib

DOI: 10.1055/s-0040-1707094

Publication Date: 2020

Publication Name: Synfacts

PAT

Amino Pyrimidine DerivativesPublication Number: US-2023312483-A1Priority Date: 2013-11-29
A complex of bisphenol and a phosphorus compound and heat-developable image-recording material containing the samePublication Number: DE-60121375-T2Priority Date: 2000-01-11Grant Date: 2007-07-05
Photothermographic materialPublication Number: DE-60011207-T2Priority Date: 1999-10-26Grant Date: 2005-06-23
CD19 binding molecules and uses thereofPublication Number: US-12221481-B2Grant Date: 2025-02-11

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Medical uses

Remibrutinib is indicated for the treatment of chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment^[1]

Society and culture

Legal status

Remibrutinib was approved for medical use in the United States in September 2025.^[2]

Names

Remibrutinib is the international nonproprietary name.^[3]

Remibrutinib is sold under the brand name Rhapsido.^[2]

References

https://www.novartis.com/us-en/sites/novartis_us/files/rhapsido.pdf
“Novartis receives FDA approval for Rhapsido (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU)” (Press release). Novartis Pharmaceuticals. 30 September 2025. Retrieved 1 October 2025 – via PR Newswire.
World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 34 (1). hdl:10665/339768.

External links

Clinical trial number NCT05030311 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1 Antihistamines (REMIX-1)” at ClinicalTrials.gov
Clinical trial number NCT05032157 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1-antihistamines (REMIX-2)” at ClinicalTrials.gov

Clinical data

Trade names	Rhapsido
License data	US DailyMed: Remibrutinib
Routes of administration	By mouth
ATC code	L04AA60 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	1787294-07-8
PubChem CID	118107483
IUPHAR/BPS	10457
DrugBank	DB16852
ChemSpider	78317000
UNII	I7MVZ8HDNU
KEGG	D12285
ChEMBL	ChEMBL4483575
PDB ligand	N6Z (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₇H₂₇F₂N₅O₃
Molar mass	507.542 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

Maurer M, Berger W, Gimenez-Arnau A, Hayama K, Jain V, Reich A, Haemmerle S, Lheritier K, Walsh P, Xia S, Storim J: Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. J Allergy Clin Immunol. 2022 Dec;150(6):1498-1506.e2. doi: 10.1016/j.jaci.2022.08.027. Epub 2022 Sep 9. [Article]
Nuesslein-Hildesheim B, Ferrero E, Schmid C, Huck C, Smith P, Tisserand S, Rubert J, Bornancin F, Eichlisberger D, Cenni B: Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. J Neuroinflammation. 2023 Aug 26;20(1):194. doi: 10.1186/s12974-023-02877-9. [Article]
Bozek A, Reich A: Evaluating remibrutinib in the treatment of chronic spontaneous urticaria. Immunotherapy. 2025 May;17(7):479-484. doi: 10.1080/1750743X.2025.2510892. Epub 2025 Jun 2. [Article]
Kaul M, End P, Cabanski M, Schuhler C, Jakab A, Kistowska M, Kinhikar A, Maiolica A, Sinn A, Fuhr R, Cenni B: Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial. Clin Transl Sci. 2021 Sep;14(5):1756-1768. doi: 10.1111/cts.13005. Epub 2021 Apr 9. [Article]
Gimeno R, Ribas-Llaurado C, Pesque D, Andrades E, Cenni B, Ambros B, Pujol R, Gimenez-Arnau AM: Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcepsilonR1 expression level and omalizumab clinical response. Clin Transl Allergy. 2023 Mar;13(3):e12227. doi: 10.1002/clt2.12227. [Article]
Dorner T, Kaul M, Szanto A, Tseng JC, Papas AS, Pylvaenaeinen I, Hanser M, Abdallah N, Grioni A, Santos Da Costa A, Ferrero E, Gergely P, Hillenbrand R, Avrameas A, Cenni B, Siegel RM: Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjogren’s syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial. Ann Rheum Dis. 2024 Feb 15;83(3):360-371. doi: 10.1136/ard-2023-224691. [Article]
FDA Approved Drug Products: RHAPSIDO (remibrutinib) tablets, for oral use [Link]
Novartis: Novartis receives FDA approval for Rhapsido® (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU) [Link]

//////////Remibrutinib, APPROVALS 2025, FDA 2025, Rhapsido, LOU064, NVP-LOU064-NXA, LOU064-NXA, I7MVZ8HDNU, WHO 11062

Fovinaciclib

October 15, 2025 2:33 am / Leave a comment

Fovinaciclib

CAS 2146171-49-3

MF C29H40N8OS

Exact Mass: 548.3046

Molecular Weight: 548.75

7-cyclopentyl-N,N-dimethyl-2-({5-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-2-yl}amino) thieno[3,2-d]pyrimidine-6-carboxamide

7-cyclopentyl-N,N-dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide

7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide

7-Cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino Thieno[3,2-d]pyrimidine-6-carboxamide
cyclin dependent kinase inhibitor, antineoplastic, Fovinaciclibum, LPW3H579X8, inzhou Aohong Pharmaceutical Co

OriginatorChongqing Fochon Pharmaceutical
DeveloperAhon Pharmaceutical; Chongqing Fochon Pharmaceutical; Shanghai Fosun Pharmaceutical
Class2 ring heterocyclic compounds; Amides; Amines; Antineoplastics; Cyclopentanes; Piperazines; Piperidines; Pyridines; Pyrimidines; Small molecules; Thiophenes
Mechanism of ActionCyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors
MarketedHER2 negative breast cancer
No development reportedSolid tumours
04 Sep 2025Chemical structure information added.
02 Sep 2025Launched for HER2-negative-breast-cancer (Late-stage disease, Second-line therapy or greater) in China (PO) (Shanghai Henlius Biotech pipeline, September 2025)
26 Aug 2025Registered for HER2-negative-breast-cancer (Late-stage disease, Second-line therapy or greater) in China (PO) prior to August 2025

Fovinaciclib is an orally bioavailable inhibitor of cyclin-dependent kinase (CDK) types 4 (CDK4) and 6 (CDK6), with potential antineoplastic activity. Upon administration, fovinaciclib selectively inhibits CDK4 and CDK6, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1/S transition and leads to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play key roles in the regulation of both cell cycle progression from the G1-phase into the S-phase and cell proliferation.

On May 29, 2025, China’s National Medical Products Administration (NMPA) approved the Class 1 innovative drug Fovinaciclib (CDK4&6 inhibitor), developed by Jinzhou Aohong Pharmaceutical Co., Ltd. This medication, in combination with fulvestrant, is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative recurrent or metastatic breast cancer, who have experienced disease progression following prior endocrine therapy.

Notably, Fovinaciclib represents an excellent example of scaffold hopping—its design replaces the pyrrolo-pyrimidine core of Ribociclib (first approved on March 13, 2017) with a thieno-pyrimidine ring.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN236278427&_cid=P21-MGRD95-18783-1

Example 3

7-Cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino Thieno[3,2-d]pyrimidine-6-carboxamide (3)

According to the synthesis method of Example 2, CH
₃CHO replaced by CH
₂O, to prepare the title compound 7-cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide (3). MS-ESI (m/z): 549 [M+1] ⁺ .

PAT

WO2017193872

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017193872&_cid=P21-MGRDEF-24321-1

Example 5

[0266]

7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridi n-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (5)

[0267]

To a solution of 7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (4) (1.5 g, 2.8 mmol) in DCM (45 mL) was added NaBH (OAc) ₃(3.56 mg, 16.8 mmol) followed by CH ₂O (40％in water, 252 mg, 3.4 mmol) . The mixture was stirred at r.t. for 30 min. The mixture was diluted with saturated aqueous NaHCO ₃(100 mL) and extracted with DCM (2 × 30 mL) . The extracts were dried over Na ₂SO ₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 96: 3: 1 DCM/methanol/ammonia to give 7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (5) . MS-ESI (m/z) : 549 [M + 1] ⁺.

PAT

Certain protein kinase inhibitorsPublication Number: JP-2019516790-APriority Date: 2016-05-07
Certain protein kinase inhibitorsPublication Number: US-2019209566-A1Priority Date: 2016-05-07
Certain protein kinase inhibitorsPublication Number: WO-2017193872-A1Priority Date: 2016-05-07
Certain protein kinase inhibitorsPublication Number: US-10835535-B2Priority Date: 2016-05-07Grant Date: 2020-11-17
A class of protein kinase inhibitorsPublication Number: CN-109153686-BPriority Date: 2016-05-07Grant Date: 2021-04-30
specific protein kinase inhibitorsPublication Number: KR-102374033-B1Priority Date: 2016-05-07Grant Date: 2022-03-14
Certain protein kinase inhibitorsPublication Number: EP-3452484-B1Priority Date: 2016-05-07Grant Date: 2023-07-05
Certain protein kinase inhibitorsPublication Number: ES-2954148-T3Priority Date: 2016-05-07Grant Date: 2023-11-20

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//////////Fovinaciclib, CHINA 2025, APPROVALS 2025, cyclin dependent kinase inhibitor, antineoplastic, Fovinaciclibum, LPW3H579X8, inzhou Aohong Pharmaceutical Co

Foselutoclax

October 14, 2025 2:31 am / Leave a comment

Foselutoclax

CAS 2271269-01-1

MF C53H59ClF3N6O10PS3 MW 1159.7 g/mol

(10R)-14-chloro-25-methyl-7,7-dioxo-10-[(phenylsulfanyl)methyl]-134-(phosphonooxy)-21-(propan-2-yl)-83-(trifluoromethanesulfonyl)-21H-7λ6-thia-6,9-diaza-4(1,4)-piperazina-13(1)-piperidina-2(2,3)-pyrrola-1(1),3(1,3),5,8(1,4)-tetrabenzenatridecaphane-24-carboxylic acid

5-(4-chlorophenyl)-2-methyl-4-[3-[4-[4-[[4-[[(2R)-1-phenylsulfanyl-4-(4-phosphonooxypiperidin-1-yl)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]-1-propan-2-ylpyrrole-3-carboxylic acid
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, VT53CL5GES, UBX 1325

Foselutoclax is an investigational new drug that is being evaluated for the treatment of age-related eye diseases, particularly diabetic macular edema (DME) and wet age-related macular degeneration (AMD). Developed by Unity Biotechnology, this senolytic compound acts as a potent inhibitor of Bcl-xL, a protein that senescent cells rely on for survival.^[1] Foselutoclax is designed to selectively eliminate senescent cells in the retina, potentially addressing the underlying causes of vision loss in these conditions.^[2]

Assess the Efficacy and Safety of Repeat Intravitreal Injections of Foselutoclax (UBX1325) in Patients With DME (ASPIRE)CTID: NCT06011798Phase: Phase 2Status: CompletedDate: 2025-08-05
Safety, Tolerability and Evidence of Activity Study of UBX1325 in Patients With Diabetic Macular Edema (BEHOLD)CTID: NCT04857996Phase: Phase 2Status: CompletedDate: 2024-05-16
Safety and Tolerability Study of UBX1325 in Patients With Diabetic Macular Edema or Neovascular Age-Related Macular DegenerationCTID: NCT04537884Phase: Phase 1Status: CompletedDate: 2022-03-10

REF

Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial resultsPublication Name: Nature MedicinePublication Date: 2024-02PMID: 38321220DOI: 10.1038/s41591-024-02802-4
Senolytics in the treatment of diabetic retinopathyPublication Name: Frontiers in PharmacologyPublication Date: 2022-08-26PMCID: PMC9462063PMID: 36091769DOI: 10.3389/fphar.2022.896907
Senolytic drugs: from discovery to translationPublication Name: Journal of Internal MedicinePublication Date: 2020-08-04PMCID: PMC7405395PMID: 32686219DOI: 10.1111/joim.13141
bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell deathPublication Name: CellPublication Date: 1993-08-27PMID: 8358789DOI: 10.1016/0092-8674(93)90508-n

PAT

Treatment of Lung Diseases Using Pharmaceutical Agents that Eliminate Senescent Cells

Publication Number: US-2020354336-A9

Priority Date: 2017-08-11

Senescent Cells and for Treating CancerPublication Number: US-2022017485-A1Priority Date: 2018-06-13
Acyl sulfonamides that are bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancerPublication Number: EP-4335516-A2Priority Date: 2018-06-13
Methods of Inhibiting Pathological AngiogenesisPublication Number: US-2020253991-A1Priority Date: 2017-10-31
Methods of inhibiting pathological angiogenesisPublication Number: US-11129838-B2Priority Date: 2017-10-31Grant Date: 2021-09-28
Treatment of Lung Diseases Using Pharmaceutical Agents that Eliminate Senescent CellsPublication Number: US-2020199103-A1Priority Date: 2017-08-11

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US279621490&_cid=P21-MGPXU3-15237-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US421382898&_cid=P21-MGPXWE-19244-1

A crystalline solid meglumine salt of of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, the compound of Formula I:

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US348024244&_cid=P21-MGPXWE-19244-1

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Clinical data

Other names	UBX1325
Identifiers
IUPAC name
CAS Number	2271269-01-1
PubChem CID	147562879
IUPHAR/BPS	13366
ChemSpider	115277082
UNII	VT53CL5GES
Chemical and physical data
Formula	C₅₃H₅₉ClF₃N₆O₁₀PS₃
Molar mass	1159.69 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

Crago SM (22 June 2023). “Design for Phase 2B ASPIRE Study of UBX1325 for DME announced by UNITY”. Modern Retina. Archived from the original on 13 August 2024.
Macha N, Yu M, Sapieha P, Klier S, Ghosh A, White L, et al. (September 2024). “Multifocal Electroretinography Changes after UBX1325 (Foselutoclax) Treatment in Neovascular Age-Related Macular Degeneration”. Journal of Clinical Medicine. 13 (18): 5540. doi:10.3390/jcm13185540. PMC 11433175. PMID 39337030.

//////////foselutoclax, antineoplastic, VT53CL5GES, UBX 1325

Fosdesdenosine sipalabenamide

October 13, 2025 2:34 am / Leave a comment

Fosdesdenosine sipalabenamide

CAS 2348493-39-8

MF C26H29N6O7P, MW=568.5 g/mol

benzyl N-(P-ambo-3′-deoxy-OP-phenyl-5′-adenylyl)-Lalaninate

benzyl (2S)-2-[[[(2S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-L-alaninyl)-phosphatenucleoside analogue, antineoplastic, NUC 7738, Y7BFN2M72F

Fosdesdenosine sipalabenamide is an investigational new drug that is being evaluated for the treatment of advanced solid tumors and lymphoma.^[1] This compound is a phosphoramidate derivative of cordycepin (3′-deoxyadenosine), an adenosine analog originally isolated from the fungus Cordyceps.^[2][3] As a nucleoside analog with potential antineoplastic properties, Fosdesdenosine sipalabenamide is designed to inhibit RNA synthesis and act as an RNA inhibitor.^[1] The drug is being developed by NuCana Plc.^[1]

Fosdesdenosine Sipalabenamide is a phosphoramidate derivative of the monophosphate form of cordycepin (3′-deoxyadenosine; 3′-dA), an adenosine derivative first isolated from Cordyceps sinensis, with potential antineoplastic, antioxidant, and anti-inflammatory activities. Upon administration and cellular uptake of fosdesdenosine sipalabenamide by passive diffusion, cordycepin monophosphate (3′-dAMP) is converted into its active anti-cancer metabolite 3′-deoxyadenosine triphosphate (3′-dATP). 3′-dATP functions as a ribonucleoside analogue and competes with ATP during transcription. Therefore, this agent causes RNA synthesis inhibition, inhibits cellular proliferation, and induces apoptosis. Also, 3′-dAMP activates AMP-activated protein kinase (AMPK) and reduces mammalian target of rapamycin (mTOR) signaling. This prevents the hyperphosphorylation of the translation repressor protein 4E-BP1. This results in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family, plays an important role in the PI3K/AKT/mTOR signaling pathway that regulates cell growth and proliferation, and its expression or activity is frequently dysregulated in human cancers. Compared to cordycepin alone, the addition of the phosphoramidate moiety may overcome cancer resistance and allow for greater cytotoxicity as fosdesdenosine sipalabenamide does not require a nucleoside transporter for cellular uptake, is independent of enzymatic activation by adenosine kinase (AK) and is not susceptible to enzymatic degradation by adenosine deaminase (ADA). Altogether, this may help overcome cancer resistance to cordycepin.

SYN

Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3′-Deoxyadenosine, as a Potential Anticancer Agent

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2022-11-23

PMCID: PMC9743095

PMID: 36417756

DOI: 10.1021/acs.jmedchem.2c01348

R_p)- and (S_p)-3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-l-alaninyl)-phosphate (7a)

Prepared according to general procedure C using 3′-deoxyadenosine (1) (0.05 g, 0.20 mmol) in anhydrous THF (4 mL), N-methyl imidazole (0.080 μL, 1.0 mmol), and phenyl(benzyloxy-l-alaninyl) phosphorochloridate (4a) (0.021 g, 0.6 mmol) in THF (2.4 mL) Purification by Biotage Isolera One (cartridge SNAP 25 g, 25 mL/min, CH₃OH/CH₂Cl₂ 1–8% 10 CV, 8% 5 CV) and preparative TLC (1000 μM, eluent system CH₃OH/CH₂Cl₂ 5/95) afforded the title compound 7a as a white solid (0.032 g, 28%). ³¹P NMR (202 MHz, CD₃OD) δ_P 3.91, 3.73. ¹H NMR (500 MHz, CDCl₃) δ_H 8.26 (s, 0.5H, H-8), 8.24 (s, 0.5H, H-8), 8.22 (s, 0.5H, H-2), 8.21 (s, 0.5H, H-2), 7.34–7.25 (m, 7H, Ar), 7.21–7.13 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 0.5H, H-1′), 6.00 (d, J = 1.5 Hz, 0.5H, H-1′), 5.15–5.04 (m, 2H, CH₂Ph), 4.73–4.63 (m, 2H, H-2′, H-4′), 4.43–4.35 (m, 1H, H-5′), 4.27–4.20 (m, 1H, H-5′), 4.03–3.91 (m, 1H, CHCH₃), 2.35–2.28 (m, 1H, H-3′), 2.09–2.02 (m, 1H, H-3′), 1.32 (d, J = 7.4 Hz, 1.5 H, CHCH₃), 1.28 (d, J = 7.4 Hz, 1.5 H, CHCH₃). ¹³C NMR (125 MHz, CD₃OD) δ_C 174.84 (d, ³J_C-P = 4.5 Hz, C=O), 174.63 (d, ³J_C-P = 4.5 Hz, C═O), 157.32 (C-6), 157.31 (C-6), 153.86 (C-2), 153.84 (C-2), 152.13 (C-4), 152.07 (C-4), 150.20 (C-Ar), 150.18 (C-Ar), 140.47 (C-8), 137.26 (C-Ar), 137.19 (C-Ar), 130.76 (CH-Ar), 130.74 (CH-Ar), 129.57 (CH-Ar), 129.32 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 129.26 (CH-Ar), 126.16 (CH-Ar), 126.14 (CH-Ar), 121.46 (d, ³J_C-P = 4.7 Hz, CH-Ar), 121.38 (d, ³J_C-P = 4.7 Hz, CH-Ar) 120.54 (C-5), 120.53 (C-5), 93.24 (C-1′), 93.18 (C-1′), 80.43 (d, ³J_C-P = 3.6 Hz, C-4′), 80.36 (d, ³J_C-P = 3.6 Hz, C-4′), 76.62 (C-2′), 68.62 (d, ²J_C-P = 5.3 Hz, C-5′), 68.30 (d, ²J_C-P = 5.3 Hz, C-5′), 67.95 (CH₂Ph), 67.92 (CH₂Ph), 51.74 (CHCH₃), 51.60 (CHCH₃), 34.91 (C-3′), 34.70 (C-3′), 20.45 (d, ³J_C-P = 7.0 Hz, CHCH₃), 20.28 (d, ³J_C-P = 7.0 Hz, CHCH₃). Reversed-phase HPLC eluting with H₂O/CH₃CN from 100/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, t_R 13.56 and 13.75 min. C₂₆H₂₉N₆O₇P required m/z 568.2 [M]. MS (ES+) found m/z 569.2 [M + H]⁺, 591.2 [M + Na]⁺, 1159.4 [2M+Na]⁺.

The two diastereoisomers 7a-R_p and 7a-S_p were separated via Biotage Isolera One (cartridge SNAP-Ultra C18 12 g, F: 12 mL/min, isocratic eluent system: H₂O/CH₃OH 45/55 in 30 min, 150 mg sample) to obtain:

7a-R_p as Fast Eluting Isomer (76 mg)

³¹P NMR (202 MHz, CD₃OD) δ_P 3.91. ¹H NMR (500 MHz, CDCl₃) δ_H 8.26 (s, 1H, H-8), 8.22 (s, 1H, H-2), 7.37–7.25 (m, 7H, Ar), 7.22–7.12 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 1H, H-1′), 5.12 (AB q, J_AB = 12.0 Hz, 2H, CH₂Ph), 4.74–4.70 (m, 1H, H-2′), 4.69–4.62 (m, 1H, H-4′), 4.44–4.38 (m, 1H, H-5′), 4.28–4.21 (m, 1H, H-5′), 3.99–3.90 (m, 1H, CHCH₃), 2.35–2.27 (m, 1H, H-3′), 2.09–2.02 (m, 1H, H-3′), 1.29 (d, J = 7.0 Hz, 3H, CHCH₃). HPLC reversed-phase HPLC eluting with H₂O/CH₃CN from 90/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, showed one peak with t_R 13.56 min.

7a-S_p as Slow-Eluting Isomer (61 mg)

³¹P NMR (202 MHz, CD₃OD) δ_P 3.73. ¹H NMR (500 MHz, CDCl₃) δ_H 8.24 (s, 1H, H-8), 8.22 (s, 1H, H-2), 7.36–7.26 (m, 7H, Ar), 7.22–7.13 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 1H, H-1′), 5.08 (AB q, J_AB = 12.0 Hz, 2H, CH₂Ph), 4.70–4.67 (m, 1H, H-2′), 4.66–4.60 (m, 1H, H-4′), 4.41–4.35 (m, 1H, H-5′), 4.26–4.19 (m, 1H, H-5′), 4.02–3.94 (m, 1H, CHCH₃), 2.36–2.27 (m, 1H, H-3′), 2.08–2.01 (m, 1H, H-3′), 1.34–1.30 (m, 3H, CHCH₃). HPLC reversed-phase HPLC eluting with H₂O/CH₃CN from 90/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, t_R 13.75 min.

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Clinical data

Other names	NUC-7738
Identifiers
IUPAC name
CAS Number	2348493-39-8
PubChem CID	166177279
DrugBank	DB19148
UNII	Y7BFN2M72F
ChEMBL	ChEMBL5277528
Chemical and physical data
Formula	C₂₆H₂₉N₆O₇P
Molar mass	568.527 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

“Fosdesdenosine sipalabenamide”. PatSnap.
“Fosdesdenosine Sipalabenamide”. PubChem. U.S. National Library of Medicine.
Serpi M, Ferrari V, McGuigan C, Ghazaly E, Pepper C (December 2022). “Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3′-Deoxyadenosine, as a Potential Anticancer Agent”. Journal of Medicinal Chemistry. 65 (23): 15789–15804. doi:10.1021/acs.jmedchem.2c01348. PMC 9743095. PMID 36417756.

….///////Fosdesdenosine sipalabenamide, antineoplastic, NUC 7738, Y7BFN2M72F

Flezurafenib

October 12, 2025 2:42 am / Leave a comment

Flezurafenib

CAS 2760321-00-2

MF C26H21FN4O3 MW456.5 g/mol, P26TTM6U27

5-({(3S)-3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl}oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

5-[[(3S)-3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-chromen-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one
rapidly accelerated fibrosarcoma (Raf) kinase inhibitor,
antineoplastic

Flezurafenib is an investigational new drug designed as a rapidly accelerated fibrosarcoma (RAF) kinase inhibitor which is being evaluated for the treatment of cancer. Developed by Jazz Pharmaceuticals, this novel therapeutic agent is currently being explored for its efficacy against solid tumors and hematological malignancies harboring oncogenic mutations that activate the RAS-RAF-MAPK signaling pathway.^[1][2] As of January 2025, flezurafenib has reached Phase 1 clinical trials, where it is being evaluated for the treatment of advanced cancers and advanced malignant solid neoplasms.^[1]

PAT

WO2022023450]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022023450&_cid=P11-MGN3DV-58095-1

[0402] Example 3. Chiral Synthesis of Compounds A-l and A-2

[0403] A. Synthesis of P2

[0404] Step 1: To a solution of 2,5-dihydroxybenzaldehyde (200 g, 1448 mmol) and pyridinium p-toluenesulfonate (18.2 g, 72.4 mmol) in DCM (3.75 L) was added 3,4-dihydro-2H-pyran (165 mL, 1810 mmol) dropwise over 10 minutes and the reaction temperature warmed to 30 °C. The reaction was stirred for 2 hours and checked by UPLC-MS which indicated the reaction was 92% complete (~5% starting material and ~3% later running unknown). The reaction was stopped. The reaction was washed with water (1.5 L) and the DCM solution was passed through a 750g silica pad and followed through by DCM (2.5 L). The DCM solution was reduced in-vacuo and the crude product was then slowly diluted with Pet. Ether to ~1L total volume, stirred and cooled to -10° C to afford a thick yellow slurry. The product was filtered and washed with Pet. Ether (2 x 150 mL) and pulled dry for 3 hours to afford 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (265g, 1192 mmol, 82% yield) as a bright yellow solid. ¾ NMR (400 MHz, DMSO-d6) d/ppm: 10.35 (s, 1H), 10.23 (s, 1H), 7.32 – 7.19 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 5.36 (t, J = 3.3 Hz, 1H), 3.77 (ddd, J = 11.2, 8.8, 3.6 Hz, 1H), 3.59 – 3.49 (m, 1H), 1.94 – 1.45 (m, 6H). UPLC-MS (ES+, Short acidic): 1.64 min, m/z 223.0 [M+H]⁺ (100%).

[0405] Step 2: 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (107 g, 481 mmol) was dissolved in diglyme (750 mL) and K2CO3 (133 g, 963 mmol) was added on one portion with stirring to afford a bright yellow suspension. The reaction was then heated to 140°C and tert-butyl acrylate (155 mL, 1059 mmol) in DMF (75 mL) was added over 10 minutes starting at ~110°C and up to 130°C. Maintained this temperature for a further 1 hour. UPLC-MS indicated that the

reaction had progressed 75%. After a further hour this showed clean conversion to 85% product and little or no side-products. After another 3 hours UPLC-MS showed 88% product (previous reactions had showed that further heating did not afford more conversion). The dark brown reaction was cooled to room temperature overnight and filtered to remove inorganics. The reaction was suspended in EtOAc (2.5 L) and water (2.5 L) and the phases separated. The aqueous was re-extracted with EtOAc (2.5 L) and the combined organics were washed with brine (2 x 1.5 L) and the organics were reduced in-vacuo. The crude product was then purified on silica (2Kg) loading in a minimum volume of DCM. A gradient of EtOAc in Pet. Ether (10 – 25%) was run and clean product fractions combined and reduced in-vacuo to afford tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (93.5 g, 281 mmol, 58% yield) as a yellow solid. ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 7.37 (q, J = 1.2 Hz, 1H), 7.05 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (dd, J = 8.7, 0.7 Hz, 1H), 5.35 (t, J = 3.3 Hz, 1H), 4.82 (d, J = 1.4 Hz, 2H), 3.77 (ddt, J = 13.3, 8.3, 4.2 Hz, 1H), 3.59 – 3.48 (m, 1H), 1.93 – 1.49 (m, 6H), 1.49 (s, 9H). UPLC-MS (ES+, Short acidic): 2.18 min, m/z ([M+H]⁺) not detected (100%).

[0406] Step 3: tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (215 g, 647 mmol) was suspended in MeOH (1.6 L) at room temperature (did not dissolve immediately) and pyridinium p-toluenesulfonate (16.3 g, 64.7 mmol) added. The reaction was warmed to 40°C with a hot water bath and checked by UPLC-MS for progress after 1 hour which indicated the reaction was complete and was a clear orange solution. The reaction was reduced in-vacuo and the crude product dissolved in DCM (2 L) and washed with water (1 L). The organic layer was dried (MgSC>4), filtered and reduced in-vacuo to afford the crude product as a yellow solid. This was suspended in Pet. Ether and stirred in an ice bath before filtering, to afford a bright yellow solid. This was dried under high vac at 50°C for 2 hours to afford tert-butyl 6-hydroxy-2H-chromene-3-carboxylate (144.4 g, 582 mmol, 90% yield). ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 9.17 (s, 1H), 7.33 (s, 1H), 6.76 – 6.64 (m, 3H), 4.77 (d, J = 1.4 Hz, 2H), 1.49 (s, 9H). UPLC-MS (ES+, Short acidic): 1.71 min, m/z 247.2 [M-H]- (100%).

[0407] Step 4: tert-Butyl 6-hydroxy-2H-chromene-3-carboxylate (84. g, 338.34mmol) was dissolved in DCM (500mL) and trifluoroacetic acid (177.72mL, 2320.9mmol) added at room temperature and the reaction stirred to give a brown solution. Initially gas evolution was noted and the reaction was stirred over several days at room temperature. DCM and TFA were removed in-vacuo and finally azeotroped with 200ml of toluene before slurrying with diethyl ether and filtering to give the crude product 6-hydroxy-2H-chromene-3-carboxylic acid (53.15g, 276.58mmol, 81.745% yield) as a cream solid. ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 12.77 (s, 1H), 9.14 (s, 1H), 7.37 (t, J = 1.4 Hz, 1H), 6.72 (dd, J = 2.4, 0.9 Hz, 1H), 6.70 – 6.64 (m, 2H), 4.78 (d, J = 1.4 Hz, 2H).

[0408] Step 5: (R)-Phanephos and [RuCl₂(p-cym)]₂ (1.2: 1 eq., 6.6 mg, 3.0 mg respectively) were weighed into a 50 mL glass lined Parr vessel followed by the substrate (1.845 g, 9.6 mmol). Methanol (16 mL, 0.6 M substrate concentration) was added to the vessel followed by triethylamine (135 μL, 0.96 mmol, 0.1 eq.). A PTFE stirrer bar was added and the thermocouple was covered with PTFE tape. The vessel was sealed and purged with nitrogen 5 times (at ~2 bar) and 5 times with stirring (~500 rpm). The vessel was then purged with hydrogen 5 times (at -10 bar) and 5 times with stirring (~500 rpm). The vessel was then pressurised to 5 bar hydrogen pressure and heated to 40 °C (with 1500 rpm stirring speed). The pressure was kept constant but with venting and refilling to 5 bar after sampling. After 21.5 hours, the vessel was allowed to cool. After 22.5 hours, the vessel was vented and purged with nitrogen. Each -0.1 mL sample was diluted to -1 mL with MeOH for SFC analysis. Work-up procedure: MeOH removed by concentrating under vacuum, followed by addition of EtOAc (10 mL) and 1 M HC1 (10 mL). The layers were mixed before separating. The EtOAc layer was washed with a further portion of 1 M HC1 (4 mL) before removing the aqueous layer to leave the EtOAc organic phase. The aqueous layer was then washed with a further portion of EtOAc (4 mL) and the organic layers were combined. EtOAc was then removed under vacuum to leave behind the product as a greyish solid (See Table 29). P2 is the first eluting product with a retention time of 5.8 min and PI is the second eluting product with a retention time of 6.1 min using the SFC method as described in Example 1.

[0409] B. Synthesis of 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one

0410] Step 1: 2-Amino-4-fluoropyridine (400 g, 3568 mmol) was charged into a 10 L fixed reactor vessel and then taken up in DCM (4 L) as a slurry under nitrogen atmosphere. To this was added DMAP (43.6 g, 357 mmol) and cooled to 10°C. Di-tert-butyldicarbonate (934 g, 4282 mmol) was added, as a solution in DCM (1 L), over the space of 1.5 hours. The reaction was stirred at room temperature for 2 hours after which time the complete consumption of the starting material was evident by NMR. To the reaction was added N,N-dimethylethylenediamine (390 mL, 3568 mmol) and the reaction warmed to 40°C overnight (converting any di-BOC material back to the mono-BOC desired product). Allowed to cool to room temperature and then diluted with further DCM (2 L) and washed with water (2 L). Extracted with further DCM (2 L), washed with water

(1 L), brine (1.2 L) and dried (MgSO₄) before filtering. The solvents were removed in-vacuo and the resultant product was slurried in DCM/Pet. Ether (1:1) (500 mL). Filtered, washed with further Pet. Ether and pulled dry to afford tert- butyl N-(4-fluoro-2-pyridyl)carbamate (505 g, 2380 mmol, 67% yield) as a cream solid product. A second crop of material was isolated from the mother liquors after passing through a short pad of silica followed by trituration with DCM/Pet. Ether (1:1) (-200 mL) to afford tert-butyl N-(4-fluoro-2-pyridyl)carbamate (46.7 g, 220 mmol, 6% yield). ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 10.13 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 9.4, 5.7 Hz, 1H), 7.60 (dd, J = 12.3, 2.4 Hz, 1H), 6.94 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 1.47 (s, 9H). UPLC-MS (ES+, Short acidic): 1.64 min, m/z 213.1 [M+H]+ (98%).

[0411] Step 2: tert-butyl-N-(4-fluoro-2-pyridyl)carbamate (126 g, 594 mmol) and TMEDA (223 mL, 1484 mmol) were taken up in dry THF (1.7 L) and then cooled to -78°C under nitrogen atmosphere. To this solution was added n-butyllithium solution (2.5M solution in hexanes) (285 mL, 713 mmol) and then allowed to stir for a further 10 minutes. sec-Butyllithium solution (1.2M in cyclohexane) (509 mL, 713 mmol) was added keeping the reaction temperature below -70°C whilst stirred for 1 hour. After this time, Iodine (226 g, 891 mmol) in THF (300 mL) was added slowly and dropwise over 30 minutes to keep the temp below -65°C. Stirred at -70°C for another 10 minutes and then quenched by the addition of sat. aq. NH4CI solution (400 mL) and then a solution of sodium thiosulphate (134 g, 848 mmol) dissolved in water (600 mL). This addition raised the temperature to — 25°C. The reaction was warmed to room temperature then transferred to the 5L separator and extracted with EtOAc (2 x 1.5 L) and then washed with brine (500 mL), dried (MgSCL) and then evaporated in vacuo to afford crude material (~200g). This was taken up in hot DCM (500 mL) (slurry added to the silica pad) and then passed through a 2Kg silica pad. Washed through with DCM (10 x 1 L fractions) and then the product was eluted from the column with EtOAc in Pet. Ether (10% to 100%), (1 L at each 10% increase, with 1 L fractions). This gave 2 mixed fractions and clean product containing fractions, which were combined and evaporated in vacuo to afford tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (113.4 g, 335.4 mmol, 57% yield) as a white solid. Clean by UPLC-MS and NMR. The mixed fractions were combined with previous crude material to afford 190g in total of a cream solid that was composed of -50% of the desired product. This was re-columned as above to afford a combined second crop from all 4 batches as a cream solid tert-butyl N-(4-fluoro-3-iodo-2-pyridyl) carbamate (107.5 g, 318 mmol, 54% yield). ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 9.47 (s, 1H), 8.33 (dd, J = 8.7, 5.5 Hz, 1H), 7.19 (dd, J = 7.3, 5.5 Hz, 1H), 1.46 (s, 9H). UPLC-MS (ES+, Short acidic): 1.60 mm, m/z 339.1 [M+H]+ (100%).

[0412] Step 3: tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (300 g, 887 mmol), 3,3-dimethoxyprop- 1 -ene (137 mL, 1153 mmol) and DIPEA (325 mL, 1863 mmol) were suspended in DMF (2 L) and water (440 mL) to give a yellow slurry. This was degassed for 20 minutes at 30°C. To this mixture was then added Palladium (II) acetate (19.92 g, 89 mmol) in one portion and degassed again for a further 15mins. The reaction was slowly and carefully heated to 100°C. Gas evolution at around 85°C (large volumes of off gassing, presumably due to the loss of Boc group as CO2 and isobutylene). The reaction became darker once off gassing finished and full solubility achieved. The reaction was then heated at 100°C for 3 hours and checked by UPLC-MS (70% desired product, 18% un-cyclised intermediate and 7% des-iodo BOC). The reaction was heated for a further 2 hours and this showed 81% desired product, 12% un-cyclised intermediate and 8% des-iodo BOC. After 7 hours the reaction showed 89% desired product, 4% un-cyclised

intermediate and 7% des-iodo BOC. The reaction was heated overnight. The reaction solution was cooled and filtered through celite and evaporated in-vacuo to a thick dark orange slurry which was then suspended in water (1 L) and acidified to pH~l-2 with aq. HC1 (4N) solution. This was then basified to pH~9 with sat. aq. Na₂CO₃ solution. Extracted with DCM (2 x 2L) and washed with brine and dried (MgS04). EtOAc (2 L) was added to the solution and then the organics were passed through a 500g silica plug. This was then followed by DCM/EtOAc (1 : 1) (2 L) and finally EtOAc (2 L) (the final wash through contained only baseline). The product containing fractions were combined and reduced in-vacuo to give an orange slurry and then suspended in hot diethyl ether (300 mL), cooled back to ~10°C in an ice bath with stirring before being filtered and washed with 150 mL of ice cold diethyl ether. Pulled dry to afford 5-fluoro-3,4-dihydro-lH-l,8-naphthyridin- 2-one (58.4 g, 351.5 mmol, 39.6 % yield) as a cream fluffy solid. ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 10.69 (s, 1H), 8.29 – 7.90 (m, 1H), 6.92 (dd, J = 8.8, 5.7 Hz, 1H), 2.88 (dd, J= 8.3, 7.1 Hz, 2H), 2.57 – 2.47 (m, 2H). UPLC-MS (ES+, Short acidic): 1.04 mm, m/z 167.0 [M+H]+ (100%).

[0413] C. Synthesis of Compounds A-l and A-2

[0414] Step 1: Potassium carbonate (832mg, 6.02mmol) was added to a stirred solution of 5- fluoro-3,4-dihydro-lH-l,8-naphthyridin-2-one (250mg, 1.5mmol), P2 (see step A, 292mg, 1.5mmol; 85% ee) and DMSO (2mL) at room temperature. The reaction was degassed and flushed with nitrogen 3 times before being stirred under a nitrogen atmosphere for 18 hours at 100°C. The reaction mixture was cooled to room temperature and diluted with water (20mL) and the resulting mixture extracted with EtOAc (20mL). A solution of citric acid (1156.3mg, 6.02mmol) in water (lOmL) was then added to the aqueous layer resulting in a solid precipitate which was filtered and dried in vacuo to give (S)- or (R)-6-[(7-oxo-6, 8-dihydro- 5H-1 ,8-naphthyridin-4-yl)oxy]chromane-3 -carboxylic acid (345mg, 1.01 mmol, 67% yield) as a white solid. UPLC-MS (ES+, Short acidic): 1.29 mm, m/z 341.1 [M+H]+. ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 12.71 (lH, br s), 10.47 (1H, s), 7.95 (1H, d, J = 6.0Hz), 6.97 (1H, d, J = 2.4Hz), 6.89 (1H, dd, J = 8.4Hz, 2.4Hz), 6.83 (1H, d, J = 8.4Hz), 6.24 (1H, d, J = 6.0Hz), 4.33 (1H, dd, J = 11.2Hz, 3.2Hz), 4.15 (1H, dd, J = 11.2Hz, 7.2Hz), 3.05-2.89 (5H, m), 2.53 (2H, t, J = 7.6Hz).

[0415] Step 2: Propylphosphonic anhydride (0.91mL, 1.52mmol) was added to a stirred solution of (S)-6-[(7-oxo-6,8-dihydro-5H-l,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (345mg, 1.01 mmol), 2-amino- l-(4-fluorophenyl)ethanone hydrochloride (288mg, 1.52mmol), N,N-diisopropylethylamine (0.88mL, 5.07mmol) andDCM (lOmL) at room temperature. After stirring for 2 hours the reaction was complete by LCMS. Water (50mL) and DCM (50mL) were added and the organic layer separated and washed with sat. aq. Na₂CO₃ (50mL). The organic layer was dried over sodium sulfate and solvent removed in vacuo. The residue was purified by column chromatography using an eluent of 0-5% MeOH in DCM to give (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-l,8-naphthyridin-4-yl)oxy]chromane-3-carboxamide (300mg, 0.63mmol, 62% yield) as a yellow solid. UPLC-MS (ES+, Short acidic): 1.52 mm, m/z 476.4 [M+H]+. ¾ NMR (400 MHz, DMSO-d₆) d/ppm: 10.47 (1H, s), 8.60-8.54 (1H, m), 8.08 (1H, dd, J = 8.8Hz, 5.6Hz), 7.95 (1H, d, J = 5.6Hz), 7.41-7.37 (2H, m), 7.01-6.97 (1H, m), 6.90 (1H, dd, J = 8.8Hz, 3.2Hz), 6.86 (1H, d, J = 8.8Hz), 6.25 (1H, d, J = 5.6Hz), 4.65 (2H, d, J = 6.0Hz), 4.42-4.35 (1H, m), 3.96 (1H, t, J = 9.6Hz), 3.03-2.87 (5H, m), 2.55-2.52 (2H, m), 1 exchangeable proton not seen.

[0416] Step 3: (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6, 8-dihydro- 5H-1, 8-naphthyridin-4-yl)oxy]chromane-3 -carboxamide (300mg, 0.63mmol), ammonium acetate

(1216mg, 15.77mmol) and acetic acid (5mL) were combined in a sealable vial, the vial sealed and the reaction stirred and heated to 130°C for 18 hours after which time the reaction was complete by LCMS. The reaction was cooled to room temperature and AcOH removed in vacuo. DCM (50mL) was added to the residue and sat. aq. Na₂CO₃ (50mL) added. The organic layer was separated and washed with brine, dried over sodium sulfate and solvent removed in vacuo. The residue was purified by column chromatography using an eluent of 0-10% MeOH in DCM to give (R)- or (S)-5 – [3 – [4-(4-fluorophenyl)- 1 H-imidazol-2-y 1] chroman-6-yl] oxy-3 ,4-dihydro- 1 H- 1 , 8-naphthyridin-2-one (141mg, 0.31mmol, 49% yield) as a yellow solid.

[0417] Chiral LCMS of the product, together with chiral LCMS’s of Compounds A-l and A-2 showed that this product is predominantly Compounds A-l (Fig. 7), with a similar ee to that of the starting acid (85% ee), however accurate analysis cannot be done due to overlap of the peaks. UPLC-MS (ES+, Short acidic): 1.36 mm, m/z 457.2 [M+H]+. Ή NMR (400 MHz, DMSO-d₆) d/ppm: 12.31 (0.2H, s), 12.10 (0.8H, s), 10.47 (1H, s), 7.96 (1H, d, J = 6.0Hz), 7.80-7.75 (1.8H, m), 7.69-7.65 (0.2H, m), 7.59-7.78 (0.8H, m), 7.29-7.23 (0.4H, m), 7.19-7.13 (1.8H, m), 7.03-7.00 (1H, m), 6.92 (1H, dd, J = 8.8Hz, 2.8Hz), 6.89 (1H, d, J = 8.8Hz), 6.27 (1H, d, J = 6.0Hz), 4.55-4.48 (1H, m), 4.16-4.09 (1H, m), 3.44-3.36 (1H, m), 3.30-3.21 (1H, m), 3.16-3.09 (1H, m), 2.94 (2H, t, J = 7.2Hz), 2.54 (2H, t, J = 7.2Hz).

[0439] A. Synthesis of P2

[0440] Step 1: 2,5-Dihydroxybenzaldehyde (13.6 kg, 98.18 mol) was dried using 2 x azeotropic concentrations with 2 x 125-130 kg of THF at up to 35 °C, concentrating under vacuum to 27-41 kg each time. The THF was then removed using 4 x azeotropic concentrations with 4 x 179-187 kg of DCM at up to 35 °C, concentrating under vacuum to 27-41 kg each time. The concentrate was diluted with DCM (284 kg) and pyridine p-toluenesulfonate (PPTS; 1.25 kg, 4.97 mol) was added. 3,4-dihydro-2H-pyran (10.4 kg, 123.63 mol) was added slowly at between 25-35 °C and the reaction was stirred at 30 °C for 90 minutes. The mixture was added to a solution of Na₂CO₃ (7.1 kg) in water (138 kg) at -15 °C and allowed to warm to 25 °C and then stirred for 6 h. The mixture was filtered through Celite® (33 kg), washing with DCM (92.5 kg). The filtrate was allowed to stand for 1 h and then the organic phase was separated and concentrated to 27-41 kg.

The DCM was then removed using 3 x azeotropic concentrations with 3 x 105 kg n-heptane at up to 35 °C, concentrating under vacuum to 27-41 kg each time. The concentrate was diluted with n- heptane (210 kg) and the heated to 30-40 °C and stirred for 6 h. The solution was then cooled to – 5 to -15 °C over 4 h, stirred for 9 h and filtered, washing the filter cake with n-heptane (39.5 kg).

The wet cake was dried at 30-40 °C for 24 h in vacuo to give 2-hydroxy-5-(oxan-2- yloxy)benzaldehyde (9.38 kg, 40.6%). Additional product (8.00 kg, 34.3%) was recovered by dissolving solid attached to the walls of the reaction vessel with 42 kg DCM and concentrating the resultant solution in vacuo to give a further 8.00 kg (34.3% yield ) of product to give a total yield of 74.9% (17.38 kg). LCMS (ES-): 15.18 mm, m/z 221.12 [M-H]-.

[0441] Step 2: To a stirring solution of 2-hydroxy-5-(oxan-2-yloxy)benzaldehyde (16.95 kg, 76.27 mol) in diglyme (113.4 kg) was added K₂CO₃ (21.4 kg, 154.83 mol) and the mixture was heated to between 80-90 °C. Tert-butyl prop-2-enoate (20.0 kg, 156.04 mol) was added, and the mixture was heated to between 120-130 °C and stirred for 18 hr. The mixture was cooled and

filtered, and the filter cake washed with EtOAc (80.0 kg). The filtrate was diluted with EtOAc (238.0 kg) and water (338.0 kg) and stirred for 1 hr at 20-30 °C, then stood for 2 hr. The mixture was filtered through Celite® (40.0 kg), and the filter cake washed with EtOAc (84.0 kg). The filtrate was left to stand for 2 hr and the aqueous layer was extracted with EtOAc (312.0 kg), stirring for 1 hr at 0-30 °C and standing for 2 hr. The organic layers were combined and washed with 2 x 345 kg water, stirring at between 20-30 °C for 1 hr and standing for 2 hr for each wash. The combined organics were then concentrated to 182.4 kg maintaining the temperature below 50 °C under vacuum. This gave the product tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylate as a 9.3% solution in diglyme/EtOAc (66.9% yield) and was used in the next stage without further isolation. LCMS (ES-): 20.26 mm, m/z 247.12 [M-THP]-.

[0442] Step 3: Tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylate (16.9 kg, 50.84 mol) as a 181.8 kg solution in diglyme/EtOAc was concentrated to 68 kg under vacuum at 50 °C. TFA (110.3 kg, 1002.46 mol) was added and the reaction was warmed to 40 °C under nitrogen flow and then stirred for 8 hrs. The mixture was then diluted with DCM (222.0 kg) and cooled to between -5 and -15 °C, and then stirred for 7 hrs. The solid was filtered and the filter cake washed with DCM (67.0 kg). The wet cake was dried for 24 hr under vacuum at between 30-40 °C to give 6-hydroxy-2H-chromene-3-carboxylic acid (8.75 kg, 78.5% yield). LCMS (ES-): 0.85 min, m/z 191.11 [M-H]-.

[0443] Step 4: To a stirring solution of 6-hydroxy-2H-chromene-3-carboxylic acid (7.19 kg, 37.4 mol) in N2-degassed EtOH (60 kg) was added (R)-Phanephos (131 g, 0.227 mol), [RuCl₂(p-cym)]₂ (70 g, 0.114 mol), and Et₃N (5.6 kg, 55.3 mol). The reaction atmosphere was replaced with 3 x N2 and then 3 x H₂, adjusting the H₂ pressure to between 0.5-0.6 MPa, and then stirred for 18 hrs at 40 °C. The atmosphere was then replaced with 3 x N2 and then 3 x H₂, adjusting the H₂ pressure to between 0.5-0.6 MPa again and the mixture was stirred for a further 18 hrs.

[0444] The mixture was concentrated in vacuo to ca. 30 kg at no more than 40 °C. The reaction was diluted with MTBE (53 kg) and cooled to between 15-25 °C. 5% Na₂CO₃ (80 kg) was added dropwise, and the mixture was stirred for 2 hrs and stood for 2 hrs at between 15-25 °C. The aqueous layer was collected and 5% Na₂CO₃ (48 kg) was added to the organic layer, then stirred for 2 hrs at 15-25 °C and filtered through Celite® (10.0 kg). The wet cake was washed with water (20 kg) and the combined aqueous filtrate and aqueous layer were diluted with IP Ac (129.0 kg). The pH of the mixture was adjusted to 1-3 with dropwise addition of 6 N HC1 (29 kg) at 15-25 °C and stirred for 2 hrs. The mixture was filtered through Celite® (10 kg), washing the filter cake with IP Ac (34 kg) and the filtrate was left to stand for 2 hrs at 15-25 °C. The aqueous layer was then extracted with IP Ac (34 kg) and the combined organic layers were concentrated to ca. 35 kg under vacuum at no more than 40 °C. Me-cyclohexane (21 kg) was added dropwise at 15-25 °C and concentrated to ca. 35 kg under vacuum at no more than 40 °C. Further Me-cyclohexane (20 kg) was added dropwise at 15-25 °C and stirred for 3 hrs. The mixture was then stirred at 40-50 °C for 4 hrs and cooled to 15-25 °C over 3 hrs and then stirred for a further 2 hrs.

[0445] The mixture was then filtered, washing the filter cake with 16.4 kg of IPAc/Me-cyclohexane (1/4, v/v). The wet cake was dried for 24 hrs at 35-45 °C under vacuum to give (3R)-6-hydroxy-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (5.2 kg, 68.6% yield, chiral purity 95.5%). Further product was isolated by rinsing solid from the reaction vessel wall with EtOH (42 kg) and concentrating to dryness. The resulting solid was suspended in IP Ac (875mL) and Me-cyclohexane (2625mL) and stirred for 5 h at 40 °C and then cooled to 20 °C over 2 h and stirred for 16 h and filtered. The filter cake was then split into 2 equal batches and each batch suspended in IP Ac (912mL) and Me-cyclohexane (2737mL). The resulting mixtures were stirred at 45 °C for 18 h and then filtered and the filter cake dried at 45 °C to give (3R)-6-hydroxy-3,4-dihydro-2H-l-benzopyran-3 -carboxylic acid (1.27 kg, 17% yield, chiral purity 96.2%). LCMS (ES-): 1.74 min, m/z 193.03 [M-H]-.

[0446] Chiral resolution to improve chiral purity:

[0447] (3R)-6-Hydroxy-3,4-dihydro-2H-l-benzopyran-3-carboxylicacid (P2; 5.94 kg, 30.59 mol) (chiral purity =95.5%) was dissolved in IP Ac (138.2 kg) and stirred for 2 hrs at 20-30 °C. The solution obtained was filtered through Celite® (12 kg), washing through with IP Ac (25 kg). In a separate vessel, (S)-(+)-2-phenylglycinol (4.4 kg, 32.07 mol) was dissolved in IP Ac (56 kg), stirring for 1 hr at 40-50 °C. The filtrate was added to this solution over 4 hrs at 40-50 °C, and stirred for 1 hr. The mixture was then stirred for 1 hr at 15-25 °C, and concentrated to ca. 120 kg under vacuum at no more than 40 °C. The concentrate was stirred for 3 hrs at 15-25 °C and filtered, washing through with IP Ac (12 kg) (chiral purity = 96.2%).

[0448] The wet cake was redissolved in EtOH (29 kg), heated to 40-50 °C and diluted with IP Ac (64 kg). 30 g of dry product was added and stirred for 30 min at 15-25 °C. The mixture was concentrated to ca. 42 kg under vacuum at no more than 40 °C, and rediluted with IP Ac (64 kg). This step was repeated two additional times, then stirred at 40-50 °C for 8 hrs. The mixture was filtered, washing through with IP Ac (13 kg) (chiral purity = 97.7%). This recrystallisation process was repeated two further times, for a total of 3 recrystallisation rounds to give material with 98.9% chiral purity.

[0449] The wet cake (10.7 kg) was then dissolved in IN HC1 (45.4 kg) and stirred for 1 hr at 20-30 °C. The mixture was filtered through Celite® (11.5 kg), washing through with IP Ac (28 kg). The aqueous layer was extracted with IP Ac (28.8 kg) and the combined organic layers were washed with water (30 kg), then concentrated to ca. 24 kg at 40 °C under vacuum. Me-cyclohexane (19 kg) was added at 20 °C and the mixture was concentrated to ca. 24 kg at 40 °C under vacuum. This step was repeated twice more. The concentrate was diluted with Me-cyclohexane (29 kg) and stirred for 1 hr at 15-25 °C. The mixture was filtered, and the wet cake was rinsed with Me-Cyclohexane (59 kg). The wet cake was dried under vacuum at 35-45 °C for 16 hrs to give (3R)-6-hydroxy-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (3.02 kg, 50.2% yield).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US350349340&_cid=P11-MGN37Z-55206-1

PAT

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Other names	JZP-815
Identifiers
IUPAC name
CAS Number	2760321-00-2
PubChem CID	162772363
IUPHAR/BPS	13233
UNII	P26TTM6U27
KEGG	D13132
Chemical and physical data
Formula	C₂₆H₂₁FN₄O₃
Molar mass	456.477 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

“JZP-815”. PatSnap.
Riaud M, Maxwell J, Soria-Bretones I, Dankner M, Li M, Rose AA (February 2024). “The role of CRAF in cancer progression: from molecular mechanisms to precision therapies”. Nature Reviews. Cancer. 24 (2): 105–122. doi:10.1038/s41568-023-00650-x. PMID 38195917.

///////////flezurafenib, JZP-815, JZP 815, P26TTM6U27, ANTINEOPLASTIC, CANCER

Ezobresib

October 11, 2025 2:35 am / Leave a comment

Ezobresib

CAS 1800340-40-2

MF C30H33N5O2 MW 495.6 g/mol

2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol
bromodomain and extra-terminal motif (BET) inhibitor,
antineoplastic, BMS-986158, BMS 986158, Bristol Myers Squibb, antineoplastic, UNII-X8BW0MQ5PI

2-[3-(3,5-dimethyltriazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]pyrido[3,2-b]indol-7-yl]propan-2-ol

Ezobresib is an investigational new drug that has been evaluated for the treatment of cancer. It inhibits Bromodomain and Extra-Terminal domain (BET) proteins, with potential antineoplastic activity.^[1] Developed by Bristol Myers Squibb, this therapeutic agent has been studied for its efficacy in treating various cancers, including solid tumors and hematological malignancies.^[2] Despite showing promise in early-phase clinical trials, recent developments suggest that Bristol Myers Squibb has decided to discontinue further development of ezobresib.^[3]

BMS-986158 is under investigation in clinical trial NCT02419417 (Study of BMS-986158 in Subjects With Select Advanced Cancers).

Ezobresib is an inhibitor of the Bromodomain (BRD) and Extra-Terminal domain (BET) family of proteins, with potential antineoplastic activity. Upon administration, ezobresib binds to the acetyl-lysine binding site in the BRD of BET proteins, thereby preventing the interaction between BET proteins and acetylated histones. This disrupts chromatin remodeling and prevents the expression of certain growth-promoting genes, resulting in an inhibition of tumor cell growth. BET proteins (BRD2, BRD3, BRD4 and BRDT) are transcriptional regulators that bind to acetylated lysines on the tails of histones H3 and H4, and regulate chromatin structure and function; they play an important role in the modulation of gene expression during development and cellular growth

SYN

US10112941,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US206490064&_cid=P21-MGLNPO-16484-1

Examples 54 & 55

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

To a 100 mL round bottom flask containing 5-bromo-2-chloropyridin-3-amine (2.90 g, 14.0 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (2.70 g, 6.99 mmol) [Seefeld, M. A. et al. PCT Int. Appl., 2008, WO2008098104] and Pd(PPh ₃) ₄(0.61 g, 0.52 mmol) in DMF (20 mL) was added cuprous iodide (0.20 g, 1.05 mmol) and Et ₃N (1.9 mL, 14.0 mmol). The reaction mixture was purged with N ₂for 3 min and then heated at 100° C. for 1 h. After cooling to room temperature, the mixture was diluted with 10% LiCl solution and extracted with EtOAc (2×). The combined organics were washed with sat. NaCl, dried over MgSO ₄, filtered and concentrated. CH ₂Cl ₂was added, and the resulting precipitate was collected by filtration. The mother liquor was concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 100% EtOAc/CH ₂Cl ₂). The resulting solid was combined with the precipitate and triturated with cold EtOAc to give the title compound (740 mg, 47%) as a light tan solid. LCMS (M+H)=224.1; HPLC RT=1.03 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2: Methyl 3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Following a procedure analogous to that described in Step 2 of Example 1, 2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine (740 mg, 3.31 mmol) was converted to the title compound (644 mg, 54%). ¹H NMR (400 MHz, CDCl ₃) δ 7.94 (t, J=1.9 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.83 (dt, J=7.8, 1.3 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.36 (ddd, J=8.0, 2.3, 0.9 Hz, 1H), 6.38 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.34 (s, 3H); LCMS (M+H)=358.2; HPLC RT=2.34 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 3 of Example 1, methyl 3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate (2.82 g, 7.88 mmol) was converted to the title compound (1.58 g, 62%). ¹H NMR (500 MHz, DMSO-d ₆) δ 11.93 (s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.36 (dd, J=8.2, 0.6 Hz, 1H), 8.29-8.22 (m, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 2.31 (s, 3H); LCMS (M+H)=322.3; HPLC RT=1.98 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Alternate synthesis of Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (Step 2 of Example 40, 3.000 g, 9.83 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (4.18 g, 10.82 mmol), copper (I) iodide (0.281 g, 1.475 mmol), Pd(Ph ₃P) ₄(0.738 g, 0.639 mmol) and triethylamine (2.74 mL, 19.66 mmol) in DMF (25 mL) was purged under a nitrogen stream and then heated in a heating block at 95° C. for 2 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted into ethyl acetate. Washed with water, NH ₄OH, brine and concentrated. The residue was triturated with 100 mL CHCl ₃, filtered off the solid and rinsed with CHCl ₃to give. 1.6 g of product. The filtrate was loaded unto the ISCO column (330 g column, A: DCM; B: 10% MeOH/DCM, 0 to 100% gradient) and chromatographed to give an additional 0.7 g. of methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (2.30 g total, 7.16 mmol, 72.8% yield).

Step 4: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 4 of Example 1, methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (80 mg, 0.25 mmol) was converted to the title compound (65 mg, 53%) after purification by prep HPLC (Column: Phen Luna C18, 30×100 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 10-100% B over 14 min, then a 2-min hold at 100% B; Flow: 40 mL/min). ¹H NMR (400 MHz, CDCl ₃) δ 8.51 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.40-7.30 (m, 3H), 5.62 (d, J=10.6 Hz, 1H), 4.11-4.03 (m, 4H), 3.92-3.83 (m, 4H), 3.56 (td, J=11.9, 1.8 Hz, 1H), 3.35 (td, J=11.9, 1.9 Hz, 1H), 3.18-3.05 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.0 Hz, 1H), 1.71-1.58 (m, 1H), 1.50-1.37 (m, 1H), 1.09 (d, J=12.8 Hz, 1H); LCMS (M+H)=496.3; HPLC RT=2.93 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 5: 2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Following a procedure analogous to that described in Step 5 of Example 1, methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (65 mg, 0.13 mmol) was converted to racemic 2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol, which was separated by chiral prep SFC (Column: Chiralpak IB 25×2 cm, 5 μm; Mobile Phase: 70/30 CO ₂/MeOH; Flow: 50 mL/min); to give Enantiomer A (24 mg, 36%) and Enantiomer B (26 mg, 38%). Enantiomer A: ¹H NMR (500 MHz, CDCl ₃) δ 8.44 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.47-7.41 (m, 3H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 5.59 (d, J=10.5 Hz, 1H), 4.06 (dd, J=11.8, 2.8 Hz, 1H), 3.90-3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, 1H), 3.35 (td, J=11.9, 2.0 Hz, 1H), 3.15-3.04 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, 1H), 1.92 (s, 1H), 1.75 (s, 6H), 1.69-1.58 (m, 1H), 1.47-1.38 (m, 1H), 1.12 (d, J=13.4 Hz, 1H); LCMS (M+H)=496.4; HPLC RT=2.46 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). SFC RT=5.50 min (Column: Chiralpak IB 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO ₂/MeOH; Flow: 2 mL/min); SFC RT=1.06 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 50/50 CO ₂/(1:1 MeOH/CH ₃CN); Flow: 2 mL/min); [α] _D ²⁰=−117.23 (c=0.08, CHCl ₃). Enantiomer B: ¹H NMR (500 MHz, CDCl ₃) δ 8.44 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.47-7.41 (m, 3H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 5.59 (d, J=10.5 Hz, 1H), 4.06 (dd, J=11.8, 2.8 Hz, 1H), 3.90-3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, 1H), 3.35 (td, J=11.9, 2.0 Hz, 1H), 3.15-3.04 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, 1H), 1.92 (s, 1H), 1.75 (s, 6H), 1.69-1.58 (m, 1H), 1.47-1.38 (m, 1H), 1.12 (d, J=13.4 Hz, 1H); LCMS (M+H)=496.4; HPLC RT=2.46 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). SFC RT=8.30 min (Column: Chiralpak IB 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO ₂/MeOH; Flow: 2 mL/min); SFC RT=2.83 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 50/50 CO ₂/(1:1 MeOH/CH ₃CN); Flow: 2 mL/min); [α] _D ²⁰=+88.78 (c=0.10, CHCl ₃).

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

Step 2: Methyl 3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Step 3: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Alternate synthesis of Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 4: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 5: 2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (S)-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

The enantiomers of phenyl(tetrahydro-2H-pyran-4-yl)methanol (2.0 g, 10.4 mmol) [Orjales, A. et al. J. Med. Chem. 2003, 46, 5512-5532], were separated on preparative SFC. (Column: Chiralpak AD 5×25 cm, 5 μm; Mobile Phase: 74/26 CO ₂/MeOH; Flow: 270 mL/min; Temperature 30° C.). The separated peaks were concentrated and dried under vacuum to give white solids. Enantiomer A: (S)-phenyl(tetrahydro-2H-pyran-4-yl)methanol: (0.91 g, 45.5%) SFC RT=2.32 min (Column: Chiralpac AD 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO ₂/MeOH; Flow: 3 mL/min); Temperature 40° C. Enantiomer B: (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol. (0.92 g, 46%) SFC RT=3.09 min (Column: Chiralpac AD 250×4.6 mm, 5 μm; Mobile Phase: 70/30 CO ₂/MeOH; Flow: 3 mL/min); Temperature 40° C.

Following a procedure analogous to that described in Step 4 of Example 1 except using toluene (120 mL) as the solvent, methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (4 g, 12.45 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (Enantiomer B above, 5.86 g, 30.5 mmol) was converted to the title compound (5.0 g, 81%). HPLC RT=2.91 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2. (S)-2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

A 500 mL round bottom flask containing (S)-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (5.0 g, 10.09 mmol) in THF (150 mL) was cooled in an ice/MeOH bath. MeMgBr, (3M in Et ₂O, 17.0 mL, 51.0 mmol) was added slowly over 4 min. The resulting solution was stirred for 2 h and then quenched carefully with sat. NH ₄Cl. The reaction mixture was diluted with 10% LiCl solution extracted with EtOAc. The organic layer was dried over MgSO ₄, filtered and concentrated. The crude material was purified using ISCO silica gel chromatography (120 g column, gradient from 0% to 6% MeOH/CH ₂Cl ₂). The product was collected and concentrated then dissolved in hot MeOH (35 mL). To the mixture was added 15 mL water and the mixture was cooled to room temperature. The resulting white precipitate was collected by filtration with 2:1 MeOH/water rinse then dried under vacuum to give the title compound (3.2 g, 62%). ¹H NMR (500 MHz, CDCl ₃) δ 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37-7.31 (m, 2H), 7.30-7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 4.06 (d, J=8.9 Hz, 1H), 3.89-3.83 (m, 1H), 3.55 (td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9, 2.1 Hz, 1H), 3.10 (q, J=10.8 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03 (d, J=14.2 Hz, 1H), 1.89 (s, 1H), 1.74 (s, 6H), 1.68-1.59 (m, 1H), 1.46-1.36 (m, 1H), 1.12 (d, J=12.2 Hz, 1H); LCMS (M+H)=496.3; HPLC RT=2.44 min (Column: Chromolith ODS S5 4.6×50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT=2.01 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 60/40 CO ₂/(1:1 MeOH/CH ₃CN); Flow: 2 mL/min). SFC RT=1.06 min (Column: Chiralcel OD-H 250×4.6 mm, 5 μm; Mobile Phase: 50/50 CO ₂/(1:1 MeOH/CH ₃CN); Flow: 2 mL/min).

Step 1: (S)-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 2. (S)-2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

PATENT

CN-108558871

WO-2015100282

LIT

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancerPublication Name: Science Translational MedicinePublication Date: 2023-06-21PMCID: PMC10758289PMID: 37343085DOI: 10.1126/scitranslmed.add7872
Recent updates on 1,2,3-triazole-containing hybrids with in vivo therapeutic potential against cancers: A mini-reviewPublication Name: European Journal of Medicinal ChemistryPublication Date: 2023-05-05PMID: 36893627DOI: 10.1016/j.ejmech.2023.115254
Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic PropertiesPublication Name: ACS Medicinal Chemistry LettersPublication Date: 2022-07-05PMCID: PMC9290009PMID: 35859878DOI: 10.1021/acsmedchemlett.2c00219
Synthesis of BMS-986158Publication Name: SynfactsPublication Date: 2021-11-17DOI: 10.1055/s-0041-1737090
Development of BET inhibitors as potential treatments for cancer: A new carboline chemotypePublication Name: Bioorganic & Medicinal Chemistry LettersPublication Date: 2021-11-01PMID: 34560263DOI: 10.1016/j.bmcl.2021.128376
Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug DesignPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-09-20PMID: 34543572DOI: 10.1021/acs.jmedchem.1c00625
Retrospective assessment of rat liver microsomal stability at NCATS: data and QSAR modelsPublication Name: Scientific ReportsPublication Date: 2020-11-26PMCID: PMC7693334PMID: 33244000DOI: 10.1038/s41598-020-77327-0
High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
Predictive models of aqueous solubility of organic compounds built on A large dataset of high integrityPublication Name: Bioorganic & Medicinal ChemistryPublication Date: 2019-07-15PMCID: PMC8274818PMID: 31176566DOI: 10.1016/j.bmc.2019.05.037
Highly predictive and interpretable models for PAMPA permeabilityPublication Name: Bioorganic & Medicinal ChemistryPublication Date: 2017-02-01PMCID: PMC5291813PMID: 28082071DOI: 10.1016/j.bmc.2016.12.049
BET inhibitor resistance emerges from leukaemia stem cellsPublication Name: NaturePublication Date: 2015-09-14PMCID: PMC6069604PMID: 26367796DOI: 10.1038/nature14888
Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung CancerPublication Name: Clinical cancer research : an official journal of the American Association for Cancer ResearchPublication Date: 2013-11-14PMCID: PMC3838895PMID: 24045185DOI: 10.1158/1078-0432.ccr-12-3904
Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 KinasesPublication Name: Journal of Medicinal ChemistryPublication Date: 2009-10-12PMID: 19821562DOI: 10.1021/jm9010065
[Statistical analysis of cerebrospinal fluid acid-base equilibrium and cerebrospinal fluid lactate concentration in cases of brain tumors, cerebrocranial injuries and meningoencephalitis]Publication Name: Neurologia i neurochirurgia polskaPublication Date: 1976-07PMID: 8740

PAT

Tricyclic compounds as anticancer agentsPublication Number: WO-2015100282-A1Priority Date: 2013-12-24
Tricyclic compound as anticancer agentsPublication Number: EP-3466949-B1Priority Date: 2013-12-24Grant Date: 2020-12-23
Novel tricyclic compounds as anticancer agentsPublication Number: TW-202028203-APriority Date: 2013-12-24
Novel tricyclic compounds as anticancer agentsPublication Number: TW-I726544-BPriority Date: 2013-12-24Grant Date: 2021-05-01
Tricyclic compounds as anticancer agentsPublication Number: CN-108558871-BPriority Date: 2013-12-24Grant Date: 2022-02-18

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Clinical data

Other names	BMS-986158
Identifiers
IUPAC name
CAS Number	1800340-40-2
PubChem CID	118196485
DrugBank	DB15435
ChemSpider	58828664
UNII	X8BW0MQ5PI
KEGG	D12710
ChEMBL	ChEMBL4297458
Chemical and physical data
Formula	C₃₀H₃₃N₅O₂
Molar mass	495.627 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

Ma Z, Zhang C, Bolinger AA, Zhou J (October 2024). “An updated patent review of BRD4 degraders”. Expert Opinion on Therapeutic Patents. 34 (10): 929–951. doi:10.1080/13543776.2024.2400166. PMC 11427152. PMID 39219068.
“Clinical Trials Using Ezobresib”. National Cancer Institute.
Brown A. “Bristol backs out of BET inhibition”. ApexOnco.

////////////Ezobresib, antineoplastic, BMS-986158, BMS 986158, Bristol Myers Squibb, antineoplastic, UNII-X8BW0MQ5PI

Epsametostat

October 10, 2025 2:31 am / Leave a comment

Epsametostat

CAS 2202678-06-4

MF C31H36F3N7O3 MW611.7 g/mol

N-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-1-(6-methylpyridazin-3-yl)-5-{(1R)-1-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}indolizine-7-carboxamide

N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-6-methyl-1-(6-methylpyridazin-3-yl)-5-[(1R)-1-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl]indolizine-7-carboxamide
histone N-methyltransferase inhibitor, antineoplastic, Shanghai Haihe Pharmaceutical, HH 2853, (R)-HH2853

Epsametostat is an investigational new drug that is being evaluated for the treatment of peripheral T-cell lymphoma. It is a EZH1/EZH2 inhibitor developed by Shanghai Haihe Pharmaceutical Research & Development Co., Ltd.^[1][2][3]

PAT

Pyrido five-element aromatic ring compound, preparation method therefor and use thereofPublication Number: EP-3524602-A1Priority Date: 2016-09-07
Pyrido five-element aromatic ring compound, preparation method therefor and use thereofPublication Number: US-2019211010-A1Priority Date: 2016-09-07
Pyrido five-element aromatic ring compound, preparation method therefor and use thereofPublication Number: WO-2018045971-A1Priority Date: 2016-09-07
Pyrido five-element aromatic ring compound, preparation method therefor and use thereofPublication Number: US-10968215-B2Priority Date: 2016-09-07Grant Date: 2021-04-06

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018045971&_cid=P22-MGK809-27208-1

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References

An R, Li YQ, Lin YL, Xu F, Li MM, Liu Z (February 2023). “EZH1/2 as targets for cancer therapy”. Cancer Gene Therapy. 30 (2): 221–235. doi:10.1038/s41417-022-00555-1. PMID 36369341.
Wei L, Mei D, Hu S, Du S (August 2024). “Dual-target EZH2 inhibitor: latest advances in medicinal chemistry”. Future Medicinal Chemistry. 16 (15): 1561–1582. doi:10.1080/17568919.2024.2380243. PMC 11370917. PMID 39082677.
“Epsametostat”. PatSnap.

Clinical data

Other names	HH2853
Identifiers
IUPAC name
CAS Number	2202678-06-4
PubChem CID	134340937
ChemSpider	115010245
UNII	P8U5JF6NBY
Chemical and physical data
Formula	C₃₁H₃₆F₃N₇O₃
Molar mass	611.670 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////Epsametostat, histone N-methyltransferase inhibitor, antineoplastic, Shanghai Haihe Pharmaceutical, HH 2853, (R)-HH2853

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Rp)- and (Sp)-3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-l-alaninyl)-phosphate (7a)

7a-Rp as Fast Eluting Isomer (76 mg)

7a-Sp as Slow-Eluting Isomer (61 mg)

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Examples 54 & 55

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

Step 2: Methyl 3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Step 3: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Alternate synthesis of Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 4: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 5: 2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: 2-Chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

Step 2: Methyl 3-((2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Step 3: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Alternate synthesis of Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 4: Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 5: 2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (S)-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 2. (S)-2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

Step 1: (S)-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Step 2. (S)-2-[3-(Dimethyl-1H-1,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol

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R_p)- and (S_p)-3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-l-alaninyl)-phosphate (7a)

7a-R_p as Fast Eluting Isomer (76 mg)

7a-S_p as Slow-Eluting Isomer (61 mg)