Evetifator

 

Evetifator

CAS 2278265-85-1

MF C20H19ClF3N3O4 MW457.8 g/mol

2-(4-chlorophenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide

2-(4-chlorophenoxy)-N-(3-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo [1.1.1]pentan-1-yl)acetamide
eukaryotic translation initiation factor 2B (eIF2B) activator, DNL-343, DNL 343, FYL3Y9D7SK

Evetifator (also known as DNL343) is a potent, selective, and brain-penetrant small molecule activator of eukaryotic initiation factor 2B (eIF2B). As of 2026, it is primarily being investigated for the treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). 

Key Characteristics and Function 

• Mechanism of Action: It acts as an eIF2B activator. eIF2B is a critical regulator of protein synthesis; by activating it, the drug aims to address the Integrated Stress Response (ISR) which, when chronically activated, leads to neurodegeneration.
• Pharmacological Profile:
  • Potency: It shows an IC50cap I cap C sub 50𝐼𝐶50 of 3.2 nM in cellular reporter assays.
  • Brain Penetration: It is specifically designed to cross the blood-brain barrier to target the central nervous system (CNS).

• A Study to Evaluate the Bioavailability and Safety of DNL343 in Healthy VolunteersCTID: NCT04581772Phase: Phase 1Status: CompletedDate: 2021-06-11
• A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL343 in Healthy VolunteersCTID: NCT04268784Phase: Phase 1Status: CompletedDate: 2022-02-07
• HEALEY ALS Platform Trial - Regimen G DNL343CTID: NCT05842941Phase: Phase 2/Phase 3Status: CompletedDate: 2025-02-04
• A Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL343 in Participants With Amyotrophic Lateral SclerosisCTID: NCT05006352Phase: Phase 1Status: CompletedDate: 2024-09-19
• HEALEY ALS Platform Trial - Master ProtocolCTID: NCT04297683Phase: Phase 2/Phase 3Status: Active, not recruitingDate: 2025-12-31

SYN

WO 2019/032743

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019032743&_cid=P10-MKOU1U-66006-1

EXAMPLE 3

2-(4-chlorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1- bicyclo[1.1.1]pentanyl]acetamide

[0257] 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (200 mg, 0.65 mmol), 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid (131 mg, 0.71 mmol; 8:1 to 10:1 ratio of cis- to trans-) and triethylamine (NEt₃) (0.45 mL, 3.23 mmol) were dissolved in EtOAc (2.6 mL) and T3P solution (0.58 mL, 1.94 mmol, 50 % in EtOAc) was added. The resulting reaction mixture was heated to 100 °C overnight, cooled to rt and was diluted with sat. aq. NaHCO₃ solution (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified employing reverse-phase prep-HPLC to deliver the desired product as a clear oil. ¹H-NMR (400 MHz; CDCl₃): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.76-4.69 (m, 1H), 4.44 (s, 2H), 3.39-3.30 (m, 1H), 2.92-2.84 (m, 2H), 2.74-2.68 (m, 2H), 2.67 (s, 6H). LC-MS m/z: = 458.20 [M+H]⁺.

[0258] Alternatively, a mixture of 2-(4-chlorophenoxy)acetic acid (50 mg, 0.27 mmol), 2-(4-chlorophenoxy)acetic acid (50 mg, 0.27 mmol), NEt₃ (123 mg, 1.21 mmol) and T3P (185 mg, 0.29 mmol, 50% purity) in DCM (1 mL) was stirred at 0 °C for 1 h. To the mixture was added 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine HCl salt (8:1 to 10:1 favoring the cis- diastereomer) (70 mg, 0.24 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. To the reaction was added sat. aq. NaHCO₃ (4 mL). The aqueous phase was extracted with DCM (5 mL, 3 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to provide the title compound.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022133236&_cid=P10-MKOTTO-58939-1

2-(4-chlorophenoxy)-N-[3-[5-[cA-3-(trifluoromethoxy)cyclobutyl]-l,3,4-oxadiazol-2-yl]-l-bicyclo[l.l.l]pentanyl]acetamide, designated herein as Compound I, has the following formula:

Example 1. Synthesis of Compound I

2-(4-chlorophenoxy)-/V-[l-(hydrazinecarbonyl)-3-bicyclo[l.l.l]pentanyl]acetamide

[0131] To a suspension of methyl 3-[[2-(4-chlorophenoxy)acetyl]amino]bicyclo[l.l.l]pentane-l-carboxylate (270 mg, 0.87 mmol) in EtOH (0.25-0.1M) was added hydrazine hydrate (131 mg, 2.6 mmol) in EtOH (3.5 mL) and the reaction mixture was heated at 90 °C overnight. The reaction mixture

was cooled to rt often causing the product to crystallize out of solution. This solid was collected by removal of the supernatant. If the product did not crystallize, the solution was concentrated, and the crude product was sufficiently pure to use in subsequent steps.

LC-MS m/z: = 310.1 [M+H]⁺.

2-(4-chlorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide

[0132] 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (200 mg, 0.65 mmol), 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid (131 mg, 0.71 mmol; 8:1 to 10:1 ratio of cis- to trans-) and triethylamine (NEt₃) (0.45 mL, 3.23 mmol) were dissolved in EtOAc (2.6 mL) and T3P solution (0.58 mL, 1.94 mmol, 50 % in EtOAc) was added. The resulting reaction mixture was heated to 100 ºC overnight, cooled to rt and was diluted with sat. aq. NaHCO₃ solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified employing reverse-phase prep-HPLC to deliver the desired product as a clear oil.¹H-NMR (400 MHz; CDCl₃): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.76-4.69 (m, 1H), 4.44 (s, 2H), 3.39-3.30 (m, 1H), 2.92-2.84 (m, 2H), 2.74-2.68 (m, 2H), 2.67 (s, 6H). LC-MS m/z: = 458.20 [M+H]⁺.

[0133] Alternatively, a mixture of 2-(4-chlorophenoxy)acetic acid (50 mg, 0.27 mmol), NEt3 (123 mg, 1.21 mmol) and T3P (185 mg, 0.29 mmol, 50% purity) in DCM (1 mL) was stirred at 0 °C for 1 h. To the mixture was added 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine HCl salt (8:1 to 10:1 favoring the cis- diastereomer) (70 mg, 0.24 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. To the reaction was added sat. aq. NaHCO3 (4 mL). The aqueous phase was extracted with DCM (5 mL, 3 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023250107&_cid=P10-MKOTXL-62392-1

Example 14: Preparation of 2-(4-chlorophenoxy)-N-(3-(5-((ls,3s)-3-(trifluoromethoxy)cyclobutyl)- l,3,4-oxadiazol-2-yl)bicyclo[l.l.l]pentan-l-yl)acetamide (I)

[0377] XI- la, 2-(4-chlorophenoxy)acetic acid (XII- la), and 2-MeTHF were charged to a reactor under N2 condition and cooled to 0 ~ 5 °C. TEA was added while maintaining an internal temperature of not more than about 10 °C under N2 condition and rinsed with 2-methyltetrahydrafuran (2-MeTHF). The contents were agitated at about 0 ~ 5 °C for not less than about 20 minutes. Diphenylphosphinic chloride in 2-MeTHF solution is added slowly while maintaining an internal temperature of not more than about 10 °C under N2 condition and rinsed with 2-MeTHF. The contents were warmed to about 20 ~ 25 °C and then agitated for not less than about 1 hour until the reaction was completed. The contents were cooled to about 0 ~ 5 °C and then aqueous 10% K2CO3 was added while maintaining an internal temperature of not more than about 10 °C. After phase separation, the organic layer was successively washed with aqueous 10% K2CO3 and 5% K2CO3. The organic layer was concentrated to a target volume 3 V. 2-MeTHF was added and then the contents were concentrated to a target volume 3 V to control the water content to not more than about 0.3 w/w%. IPA was added and then the contents were heated to about 60 ~ 70 °C to

dissolve all solids. The contents were filtered at about 60 ~ 70 °C through cartridge filter and rinsed with pre-heated IPA (60 ~ 70 °C). The filtrate was concentrated to a target volume 4 V. IPA was added and concentrated to a target volume 4 V to control the residual 2-MeTHF relative to IPA to not more than 1 % by GC. The contents were adjusted to about 20 ~25 °C. n-Heptane was added and then heated to about 60 ~ 80 °C to dissolve all solids. The contents were adjusted to about 62 ~ 70 °C. Seed crystal was charged and agitated for not less than about 0.5 hour. n-Heptane was added while maintaining an internal temperature of about 60 ~ 65 °C. The contents were cooled to about 0 ~ 5 °C over 12 hour (5 °C per hour). The slurry was agitated for not less than 2 hours. The slurry was filtered and washed with precooled IPA/n-heptane mixture. The wet cake was dried at 25 °C under vacuum. If any individual impurity except 2-(4-chlorophenoxy)-N-(3-(5-(trans-3-(trifluoromethoxy)cyclobutyl)-l,3,4-oxadiazol-2-yl)bicyclo[l.l.l]pentan-l-yl)acetamide was more than 0.12%, recrystallization was performed.

[0378] ’H NMR (600 MHz, MeCN-d₃): 7.65 (s, 1H), 7.3

PAT

• Compounds, compositions and methodsPublication Number: JP-2023052166-APriority Date: 2017-08-09
• Compounds, compositions, and methodsPublication Number: CN-111094233-BPriority Date: 2017-08-09Grant Date: 2024-03-15
• Modulators of eukaryotic initiation factor 2B, compositions and methodsPublication Number: US-11236100-B2Priority Date: 2017-08-09Grant Date: 2022-02-01
• Compounds, compositions, and methodsPublication Number: CN-118239938-APriority Date: 2017-08-09
• Solid forms of a compoundPublication Number: US-2024059662-A1Priority Date: 2020-12-18
• Modulators of eukaryotic initiation factor 2B, compositions and methodsPublication Number: US-2022411433-A1Priority Date: 2017-08-09
• COMPOUNDS, COMPOSITIONS AND METHODSPublication Number: WO-2019032743-A1Priority Date: 2017-08-09
• Modulators of eukaryotic initiation factor 2B, compositions and methodsPublication Number: US-11851440-B2Priority Date: 2017-08-09Grant Date: 2023-12-26
• Compounds, compositions and methodsPublication Number: US-2021147435-A1Priority Date: 2017-08-09

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Fanregratinib

 

Fanregratinib

CAS 1628537-44-9

MF C27H33ClN6O2, 509.0 g/mol

4-chloro-3-[2-[2-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]pyrimidin-5-yl]ethyl]-5-methoxy-N-methylbenzamide

• 4-Chloro-3-(2-(2-((4-((3s,5r)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide
• 4-chloro-3-(2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide
• 4-chloro-3-[2-[2-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]pyrimidin-5-yl]ethyl]-5-methoxy-N-methylbenzamide
• Benzamide, 4-chloro-3-[2-[2-[[4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]phenyl]amino]-5-pyrimidinyl]ethyl]-5-methoxy-N-methyl-, cis-
• Benzamide, 4-chloro-3-[2-[2-[[4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]phenyl]amino]-5-pyrimidinyl]ethyl]-5-methoxy-N-methyl-, rel-
• cis-4-Chloro-3-[2-[2-[[4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]phenyl]amino]-5-pyrimidinyl]ethyl]-5-methoxy-N-methylbenzamide
• rel-4-Chloro-3-[2-[2-[[4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]phenyl]amino]-5-pyrimidinyl]ethyl]-5-methoxy-N-methylbenzamide

fibroblast growth factor receptor tyrosine kinase inhibitor, antineoplastic, 8RWL2B2CLS

• OriginatorHutchison MediPharma
• DeveloperHutchison MediPharma; HUTCHMED
• ClassAntineoplastics; Small molecules
• Mechanism of ActionType 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
• PreregistrationCholangiocarcinoma
• Phase IIMesothelioma
• Phase I/IISolid tumours
• 29 Dec 2025Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Inoperable/Unresectable) in China (PO)
• 29 Dec 2025Updated efficacy data from a phase II trial in Cholangiocarcinoma released by HUTCHMED
• 03 Nov 2025HUTCHMED announces intention to submit new drug application to NMPA for Cholangiocarcinoma in first half of 2026

FANREGRATINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
Fanregratinib is a small molecule drug. The usage of the INN stem '-gratinib' in the name indicates that Fanregratinib is a fibroblast growth factor receptor (FGFR) inhibitor. Fanregratinib has a monoisotopic molecular weight of 508.24 Da.

Fanregratinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. Upon administration, fanregratinib binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells. FGFR, a family of receptor tyrosine kinases (RTKs) upregulated in many tumor cell types, plays a key role in cellular proliferation, migration and survival.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159751913&_cid=P10-MKQ98D-55657-1

Example 9

Synthesis of Compounds 79-91, 146-155

Compound 79

4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide

(C) 4-chloro-3-(2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide

A mixture of 4-chloro-3-((E)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)vinyl)-5-methoxy-N-methylbenzamide (120 mg, 0.237 mmol), 4-methylbenzenesulfonohydrazide (528 mg, 2.84 mmol) and sodium acetate (233 mg, 2.84 mmol) in THF (6 mL) and water (6 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was concentrated. The residue was partitioned between 2N HCl (15 mL) and EA (15 mL). The aqueous layer was then adjusted to pH=8 with 30% NaOH and extracted with DCM (2*15 mL). The combined extracts were concentrated and the residue was purified via ISCO (eluted with MeOH in H 2O 0˜100%) to afford the title compound as a yellow solid (50 mg, 41.5% yield). MS (m/z): 509.0 (M+H) +. 1H NMR (400 MHz, CD 3OD) δ 8.11 (s, 2H), 7.44 (d, J=9.1 Hz, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 3.93 (s, 3H), 3.53-3.44 (m, 2H), 3.10-2.99 (m, 4H), 2.90 (s, 3H), 2.82 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H), 1.16 (d, J=6.4 Hz, 6H).

SYN

[WO2014139465]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014139465&_cid=P10-MKQ9F3-62190-1

Example 9: Synthesis of Compounds 78-103

Compound 78

4-chloro-3-(2-(2-((4-((3S,5/f)-3,5-dimethylpiperazin-l-yl)phenyl)amino)pyrimidin-5

-yl)ethyl)-5-methoxy-N-methylbenzamide

(A) Methyl 4-chloro-3-((_JE)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)

phenylamino)pyrimidin-5-yl)vinyl)-5-methoxybenzoate

A mixture of (E)-methyl 4-chloro-3-(2-(2-chloropyrimidin-5-yl)vinyl)-5-methoxy benzoate (150mg, 0.442 mmol), 4-((35',5i?)-3,5-dimethylpiperazin-l-yl)aniline (109 mg, 0.531 mmol) and TFA (0.1 mL, 1.326 mmol) in propan~2-oi (5 mL) was stirred at 150 ^°C for 1 h under microwave. The resulting mixture was concentrated, basified with ammonia water, purified via ISCO (DCM/MeOH) to afford the title compound as a

yellow solid (130 mg, 57.9% yield). MS (m/z): 508.2(M+H)⁺.

(B) 4-chloro-3-((£)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)phenylamino)pyrim idin-5-yl)vinyl)-5-methoxy-N-methylbenzamide

A mixture of methyl 4-chloro-3-((E)-2-(2-(4-((35',5i?)-3,5-dimethylpiperazin-l-yl) phenylamino)pyrimidin-5-yl)vinyl)-5-methoxybenzoate (250 mg, 0.492 mmol) and methylamine (6 mL, 35% solution in ethanol) was stirred at 145 ^°C for 22 min under microwave. The resulting mixture was concentrated, purified via ISCO (DCM/MeOH) to afford the title compound as a yellow solid (145 mg, 58.1%> yield). MS (m/z):

506.9(M+H)⁺.

(C) 4-chloro-3-(2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)phenylamino)pyrimidin -5-yl)ethyl)-5-methoxy-N-methylbenzamide

A mixture of 4-chloro-3-((E)-2-(2-(4-((35^*,5i?)-3,5-dimethylpiperazin-l-yl)

phenylamino)pyrimidin-5-yl)vinyl)-5-methoxy-N-methylbenzamide (120 mg, 0.237 mmol), 4-methylbenzenesulfonohydrazide (528 mg, 2.84 mmol) and sodium acetate (233 mg, 2.84 mmol) in THF (6mL) and water (6mL) was stirred overnight at 100 ^°C under nitrogen atmosphere. The resulting mixture was concentrated. The residue was partitioned between 2N HC1 (15 mL) and EA (15 mL). The aqueous layer was then adjusted to pH=8 with 30% NaOH and extracted with DCM (2* 15 mL). The combined extracts were concentrated and the residue was purified via ISCO (eluted with MeOH in H₂0 0-100%) to afford the title compound as a yellow solid (50 mg, 41.5% yield). MS (m/z): 509.0(M+H)⁺. 1H NM (400 MHz, CD₃OD) δ 8.1 1 (s, 2H), 7.44 (d, J = 9.1 Hz, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 9.1 Hz, 2H), 3.93 (s, 3H), 3.53 - 3.44 (m, 2H), 3.10 - 2.99 (m, 4H), 2.90 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.25 (t, J = 7.5 Hz, 2H), 1.16 (d, J = 6.4 Hz, 6H).

PAT

• Novel pyrimidine and pyridine compounds and their usagePublication Number: WO-2014139465-A1Priority Date: 2013-03-15
• Novel pyrimidine and pyridine compounds and usage thereofPublication Number: WO-2014139145-A1Priority Date: 2013-03-15
• Pyrimidine and pyridine compounds and their usePublication Number: BR-112015020772-B1Priority Date: 2013-03-15
• Pyrimidine and pyridine compounds and their usagePublication Number: US-9701680-B2Priority Date: 2013-03-15Grant Date: 2017-07-11
• Novel pyrimidine and pyridine compounds and usage thereofPublication Number: US-2016052926-A1Priority Date: 2013-03-15
• Novel pyrimidine and pyridine compounds and their usagePublication Number: EP-2970120-A1Priority Date: 2013-03-15
• Novel pyrimidine and pyridine compounds and their usagePublication Number: EP-2970120-B1Priority Date: 2013-03-15Grant Date: 2018-09-12
• Novel pyrimidine and pyridine compounds and their usagePublication Number: US-2016024021-A1Priority Date: 2013-03-15
• The salts of a compound and the crystalline forms thereofPublication Number: WO-2021073494-A1Priority Date: 2019-10-14
• The salts of a compound and the crystalline forms thereofPublication Number: US-2023121346-A1Priority Date: 2019-10-14
• The salts of a compound and the crystalline forms thereofPublication Number: TW-202128669-APriority Date: 2019-10-14
• Salts of compounds and crystalline forms thereofPublication Number: CN-114555558-APriority Date: 2019-10-14
• SALTS OF THE COMPOUND 4-CHLORO-3-(2-(2-((4-((3S,5R)-3,5-DIMETHYLPIPERAZIN-1-YL)PHENYL)AMINO)PYRIMIDIN-5-YL)ETHYL)-5 -METHOXY-N-METHYLBENZAMIDE AND CRYSTALLINE FORMS THEREOFPublication Number: AR-120202-A1Priority Date: 2019-10-14

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Filricianine

 

Filricianine

CAS 2140857-94-7

MF C45H52N2O12S3, 909.1

3H-Indolium, 3-(3-carboxypropyl)-2-[2-[3-[2-[1,3-dihydro-3,3-dimethyl-1-(3-sulfopropyl)-2H-indol-2-ylidene]ethylidene]-2-(4-sulfophenoxy)-1-cyclohexen-1-yl]ethenyl]-3-methyl-1-(3-sulfopropyl)-, inner salt

3-[(2Z)-3-(3-carboxypropyl)-2-[(2E)-2-[3-[(E)-2-[3,3-dimethyl-1-(3-sulfopropyl)indol-1-ium-2-yl]ethenyl]-2-(4-sulfophenoxy)cyclohex-2-en-1-ylidene]ethylidene]-3-methylindol-1-yl]propane-1-sulfonate

3-[(3RS)-3-(3-carboxypropyl)-2-{(1Ξ)-2-[(3Ξ)-3-{(2Ξ)-2-[3,3-dimethyl-1-(3-sulfopropyl)- 1,3-dihydro-2H-indol-2-ylidene]ethylidene}-2-(4-sulfophenoxy)cyclohex-1-en-1-yl]ethen-1-yl}-3-methyl-3H-indol-1-ium-1-yl]propane-1-sulfonate
diagnostic imaging agent, CI4MD9KLX8

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Fosrolapitant

 

Fosrolapitant

CAS 2573694-38-7

MF C27H29F6N2O8P MW654.5 g/mol

phosphonooxymethyl (5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-2-oxo-8-phenyl-1,9-diazaspiro[4.5]decane-9-carboxylate

(phosphonooxy)methyl (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-2-oxo-8-phenyl-1,7-diazaspiro[4.5]decane-7-carboxylate
neurokinin 1 (NK1) receptor antagonist, HR20013, HR 20013, M5QGY92X8B

Fosrolapitant (HR20013) is a novel, intravenous, highly selective neurokinin-1 (NK-1) receptor antagonist used for the prevention of chemotherapy-induced nausea and vomiting (CINV), particularly for cisplatin-based regimens. As a prodrug, it is rapidly converted to rolapitant, offering a long half-life (~180 h). It is often combined with palonosetron and dexamethasone for high efficacy. 

Fosrolapitant is a small molecule drug. The usage of the INN stem '-pitant' in the name indicates that Fosrolapitant is a neurokinin NK1​ (substance P) receptor antagonist. Fosrolapitant has a monoisotopic molecular weight of 654.16 Da.

Key Aspects of Fosrolapitant:

• Mechanism: Acts as an NK-1 receptor antagonist to prevent nausea/vomiting.
• Administration: Intravenous (IV) formula, often combined as a fixed-dose with palonosetron (HR20013).
• Metabolism: Completely converted to rolapitant in the body, which has a prolonged half-life of approximately 180 hours.
• Clinical Efficacy: In trials (e.g., PROFIT trial), it demonstrated high effectiveness in preventing CINV in patients receiving highly emetogenic chemotherapy.
• Safety Profile: Common adverse events in trials included constipation (22.7%), increased blood pressure (18.2%), abdominal distension (13.6%), and injection site reactions (9.1%). 

Fosrolapitant is designed to improve convenience and patient compliance in managing acute and delayed nausea and vomiting associated with cancer treatments. 

HR20013 for Nausea and Vomiting Associated With Moderate Emetic Risk Anticancer Agents

CTID: NCT06554184

Phase: Phase 3

Status: Completed

Date: 2025-11-17

SYN

WO-2020259675-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020259675&_cid=P20-MKT4GS-85082-1

Under N2 protection, compound 3 (1.95 g, 2.543 mmol, 1 eq) dissolved in dichloromethane (40 mL) was added to a 100 

_mL single-necked flask. Trifluoroacetic acid (1.45 mL, 19.52 mmol, 8 eq) was slowly added under ice water cooling. The mixture was stirred until the reaction was complete, concentrated, and 2.29 g of oil was obtained. After separation and purification, 1.39 g of white foamy solid was obtained, with a yield of 83.5%. 

[0129]

¹H-NMR(400MHz，CD ₃OD):δ(ppm)7.89(s，2H)，7.86(s，1H)，7.41-7.27(m，5H)，5.66(d，J＝12Hz，1H)，5.50-5.47(m，1H)，4.60(d，J＝8Hz，1H)，4.20-3.88(m，3H)，2.51-2.10(m，5H)，1.86-1.66(m，3H)，1.44-1.31(m，4H).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US380158929&_cid=P20-MKT480-75882-1

Example 1

STEP 1

Compound 1 (2.43 g, 4.86 mmol, 1 eq) was weighed and dissolved in dichloromethane (36 mL) in a 100 mL three-necked flask under N ₂ atmosphere. Diisopropylethylamine (5 g, 38.76 mmol, 8 eq) was added and the mixture was cooled to −30° C. Trimethylchlorosilane (1.36 g, 12.52 mmol, 2.6 eq) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to −25° C. A solution of chloromethyl chloroformate (0.77 g, 6 mmol, 1.23 eq) in dichloromethane was added dropwise and the mixture was stirred under controlled temperature at −20° C.˜−5° C. until completion of the reaction. The reaction solution was poured into ice water, put to separation, and extracted with dichloromethane. Water and 1 N hydrochloric acid solution were added and put to separation. The organic layer was then successively washed with brine, saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3.0 g yellow jelly with a yield of 104%.

Compound 3 (1.95 g, 2.543 mmol, 1 eq) was added into a 100 mL single-necked flask and dissolved in dichloromethane (40 mL) under N 2 atmosphere. Trifluoroacetic acid (1.45 mL, 19.52 mmol, 8 eq) was added slowly under ice water cooling. The reaction mixture was stirred until completion of the reaction, and then concentrated to give 2.29 g oil which was then purified purified to give 1.39 g white foamy solid with a yield of 83.5%.

1H-NMR (400 MHz, CD 3OD): δ(ppm) 7.89 (s, 2H), 7.86 (s, 1H), 7.41-7.27 (m, 5H), 5.66 (d, J=12 Hz, 1H), 5.50-5.47 (m, 1H), 4.60 (d, J=8 Hz, 1H), 4.20-3.88 (m, 3H), 2.51-2.10 (m, 5H), 1.86-1.66 (m, 3H), 1.44-1.31 (m, 4H).

PAT

• Use of nk1 antagonist prodrug compound in combination with 5-ht3 receptor antagonistPublication Number: US-2024016822-A1Priority Date: 2020-12-25
• Use of nk1 antagonist prodrug compound in combination with 5-ht3 receptor antagonistPublication Number: EP-4268818-A1Priority Date: 2020-12-25
• Neurokinin-1 antagonistPublication Number: EP-3991730-A1Priority Date: 2019-06-28
• Neurokinin-1 antagonistPublication Number: WO-2020259675-A1Priority Date: 2019-06-28
• Neurokinin-1 antagonistsPublication Number: TW-202115064-APriority Date: 2019-06-28

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/////fosrolapitant, neurokinin 1 (NK1) receptor antagonist, HR20013, HR 20013, M5QGY92X8B

#fosrolapitant, #neurokinin 1 (NK1) receptor antagonist, #HR20013, #HR 20013, #M5QGY92X8B

Frespaciguat

 

Frespaciguat

CAS 2101645-33-2

MF C27H22ClF5N6O3 MW 608.9 g/mol

3-[4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)indazol-3-yl]-5-methyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanoic acid

3-{4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic acid
guanylate cyclase activator, MK5475, MK 5475, sGC activator 1, 6DXN080KGB

Frespaciguat (development code MK-5475) is an experimental inhaled soluble guanylate cyclase stimulator developed by Merck for pulmonary arterial hypertension.^[1][2][3][4]

Frespaciguat is a small molecule drug. The usage of the INN stem '-ciguat' in the name indicates that Frespaciguat is a guanylate cyclase activator and stimulator. Frespaciguat is under investigation in clinical trial NCT05612035 (Frespaciguat (MK-5475) INSIGNIA-PH-COPD: A Study of the Efficacy and Safety of Frespaciguat (an Inhaled sGC Stimulator) in Adults With PH-COPD). Frespaciguat has a monoisotopic molecular weight of 608.14 Da.

• Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006)CTID: NCT04370873Phase: Phase 1Status: CompletedDate: 2025-05-28
• A Study of the Efficacy and Safety of Frespaciguat (MK-5475) in Participants With Pulmonary Arterial Hypertension (INSIGNIA-PAH: Phase 2/3 Study of an Inhaled sGC Stimulator in PAH) (MK-5475-007)CTID: NCT04732221Phase: Phase 2/Phase 3Status: CompletedDate: 2025-05-25
• Frespaciguat (MK-5475) in Participants With Hypoxemia Due to COVID-19 Pneumonia (MK-5475-009)CTID: NCT04425733Phase: Phase 1Status: WithdrawnDate: 2025-05-15
• Frespaciguat (MK-5475) INSIGNIA-PH-COPD: A Study of the Efficacy and Safety of Frespaciguat (an Inhaled sGC Stimulator) in Adults With PH-COPDCTID: NCT05612035Phase: Phase 2Status: Active, not recruitingDate: 2025-10-07
• A Study of Single Doses of Frespaciguat (MK-5475) on Pulmonary Vascular Resistance (MK-5475-002)CTID: NCT03744637Phase: Phase 1Status: CompletedDate: 2025-06-04

SYN

US10030027,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US199416000&_cid=P12-MKUJSJ-89968-1

Example 10B

(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid

Step A—(S)-Methyl 3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate

In a flask containing I-A1 (91 mg, 0.27 mmol), I-11B (80 mg, 0.24 mmol) and potassium bicarbonate (73.2 mg, 0.73 mmol) in t-BuOH (2.4 mL) was stirred at 80° C. for 16 h. The reaction was cooled to RT, diluted with EtOAc and water, and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over anhydr. Na 2SO 4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography with (EtOAc:EtOH 3:1):hexane (0-40%) to afford the title compound. m/z=623 (M+1).

Step B—(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid

In a flask containing (S)-methyl 3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate (120 mg, 0.19 mmol) in dioxane (8.7 mL) was added LiOH (46 mg, 1.93 mmol) in water (1 mL). The reaction was stirred 2 h at 50° C. The reaction was cooled to RT, concentrated in vacuo and diluted with EtOAc. Acetic acid (132 μl, 2.31 mmol) was added and the mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine (2×), dried over anhydr. MgSO 4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with (EtOAc:EtOH 3:1):hexane (0-100%) to afford the title compound Ex-10B. 1H NMR (400 MHz, DMSO-d 6) δ 12.12 (s, 1H), 11.09 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.26 (dd, J=8.7, 1.7 Hz, 1H), 7.22-7.11 (m, 4H), 6.54 (s, 2H), 4.82 (t, J=6.8 Hz, 2H), 2.90 (tt, J=19.4, 6.9 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.52-2.49 (m, 2H), 1.76 (s, 3H); m/z=609 (M+1).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025006295&_cid=P12-MKUJNS-84717-1

EXAMPLE 2

[0038] To an autoclave was charged anisole (12.78 L), indazole ester (IV) (2.13 kg, 5.64 mol), and hexamethyldisilazane (4.55 kg, 28.2 mol). The mixture was cooled to 0-5 ^oC and the vessel was placed under slight positive pressure with no N₂ sweeping. A solution of H₂O (203.21 g, 11.27 mol) in sulfolane (6.39 L) was added while keeping at < 10 ^oC in order to minimize NH3 gas escaping. The resulting mixture was cooled to -10 ^oC, then TfOH (1.692 kg, 11.27 mol) was slowly added at < 22 ^oC. The vessel was sealed and the mixture was heated at 120-130 °C for 24 h. The upper vessel was kept warm so that solid ammonium triflate did not deposit there.

[0039] After cooling the mixture to rt, the batch (biphasic) was further cooled to 0-10 ^oC.2.4 equiv 1N KOH (13.53 L, 14.207 kg, 13.53 mol) was slowly added at < 25 ^oC. After agitating for 30 min, and letting settle at rt, the bottom aqueous layer was removed (pH~14). The organic layer was washed with 18% brine (10.5 L). The aqueous layer was removed (pH ~12). To the organic phase was added ¼ (101 mL, 149 g) of 1.1 equiv methanesulfonic acid (402 mL, 595 g, 6.20 mol), then seeded with 0.2 wt% amidine MSA type A (8.5 g). The rest of MSA (447 g, 302 mL) was then slowly added over 1 h. During MSA addition, the temperature was controlled at < 25 ^oC. The resulting slurry, after aging at 22 ^oC for 15 h, was filtered, then displacement washed with 2 x 3 vol 2-MeTHF (2 x 6.4 L), and vacuum dried under N₂ at < 30 °C for 24 h. The product (III) was obtained (4.62 kg, 10.58 mol, 93 % yield) as an off-white to light beige solid.

PAT

• 4-amino-2-(1h-pyrazolo[3,4-b]pyridin-3-yl)-6-oxo-6,7-dihydro-5h-pyrrolo[2,3-d]pyrimidine derivatives and the respective (1h-indazol-3-yl) derivatives as cgmp modulators for treating cardiovascular diseasesPublication Number: EP-3394067-B1Priority Date: 2015-12-22Grant Date: 2020-04-01
• Soluble guanylate cyclase stimulatorPublication Number: TW-201734017-APriority Date: 2015-12-22
• 4-Amino-2- (1h-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5h-pyrrolo [2,3-d] pyrimidine derivatives and respectively (1h- indazol-3-yl) are derived as cgmp activators for the treatment of cardiovascular diseasePublication Number: IL-260020-APriority Date: 2015-12-22
• Soluble guanylate cyclase stimulatorsPublication Number: TW-I724079-BPriority Date: 2015-12-22Grant Date: 2021-04-11
• cGMP modulators for the treatment of cardiovascular diseasePublication Number: CN-108738320-BPriority Date: 2015-12-22Grant Date: 2021-11-19
• 4-Amino-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivatives and their respective (1H-indazol-3-yl) derivativesPublication Number: CN-108738320-APriority Date: 2015-12-22
• 4-amino-2-(1H-pyrazolo[3,4-B]pyridin-3-yl)-6-oxo-6,7-dihydro-5H-pyrrolo[ as a cGMP modulator for the treatment of cardiovascular disease 2,3-D]pyridine derivatives and respective (1H-indazol-3-yl) derivativesPublication Number: KR-102191312-B1Priority Date: 2015-12-22Grant Date: 2020-12-15
• Soluble guanylate cyclase stimulatorsPublication Number: US-10030027-B2Priority Date: 2015-12-22Grant Date: 2018-07-24
• 4-Amino-2- (1H-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine derivatives and cardiovascular disease (1H-indazol-3-yl) derivatives as cGMP modulators for treatingPublication Number: JP-2018538333-APriority Date: 2015-12-22
• Soluble guanylate cyclase stimulatorsPublication Number: US-2018305366-A1Priority Date: 2015-12-22
• Processes for preparing crystalline soluble guanylate cyclase stimulatorsPublication Number: WO-2025006294-A2Priority Date: 2023-06-26
• Processes for preparing soluble guanylate cyclase stimulatorsPublication Number: WO-2025006295-A1Priority Date: 2023-06-26
• 4-Amino-2- (1H-pyrazolo [3,4-b] pyridin-3-yl) -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine derivatives and cardiovascular disease (1H-indazol-3-yl) derivatives as cGMP modulators for treatingPublication Number: JP-6454448-B2Priority Date: 2015-12-22Grant Date: 2019-01-16
• Soluble guanylate cyclase stimulatorsPublication Number: US-10428076-B2Priority Date: 2015-12-22Grant Date: 2019-10-01
• Soluble guanylate cyclase stimulatorsPublication Number: US-2017174693-A1Priority Date: 2015-12-22

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Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	2101645-33-2
PubChem CID	129242560
ChemSpider	129394387
UNII	6DXN080KGB
ChEMBL	ChEMBL5944803
Chemical and physical data
Formula	C27H22ClF5N6O3
Molar mass	608.95 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  Bajwa, Ednan K.; Cislak, Dawn; Palcza, John; Feng, Hwa-ping; Messina, Eric J.; Reynders, Tom; Denef, Jean-François; Corcea, Vasile; Lai, Eseng; Stoch, S. Aubrey (January 2023). "Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH)". Respiratory Medicine. 206 107065. doi:10.1016/j.rmed.2022.107065. PMID 36521262.
2.  Patel, Mahesh J.; Bajwa, Ednan K.; Cislak, Dawn; Palcza, John; Reynders, Tom; Barthson, Jenny; Lai, Eseng; Stoch, S. Aubrey (9 September 2023). "A randomized study to evaluate the effects of single-dose MK-5475 co-administered with sildenafil on systemic hemodynamics". European Respiratory Journal PA1208. doi:10.1183/13993003.congress-2023.PA1208.
3.  El-Kersh, Karim; Jalil, Bilal A. (July 2023). "Pulmonary hypertension inhaled therapies: An updated review". The American Journal of the Medical Sciences. 366 (1): 3–15. doi:10.1016/j.amjms.2023.03.002. PMID 36921672.
4.  Tawa, Masashi; Okamura, Tomio (August 2022). "Factors influencing the soluble guanylate cyclase heme redox state in blood vessels". Vascular Pharmacology. 145 107023. doi:10.1016/j.vph.2022.107023. PMID 35718342.

/////////frespaciguat, ANAX, ADVECT, guanylate cyclase activator, MK5475, MK 5475, sGC activator 1, 6DXN080KGB

#frespaciguat, #ANAX, #ADVECT, #guanylate cyclase activator, #MK5475, #MK 5475, #sGC activator 1, #6DXN080KGB