Tacaciclib

2768774-66-7

AUR-102

• Tacaciclib
• SCHEMBL24548621
• GTPL12880
• 528.6 g/mol
• C₃₀H₃₆N₆O₃

INN 12755

UNI D3G4JKK1MA

(2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-2-[3-[6-[[(E)-4-morpholin-4-ylbut-2-enoyl]amino]pyridin-3-yl]phenyl]butanamide

(αS)-N-(5-Cyclopropyl-1H-pyrazol-3-yl)-α-(1-methylethyl)-3-[6-[[(2E)-4-(4-morpholinyl)-1-oxo-2-buten-1-yl]amino]-3-pyridinyl]benzeneacetamide

Benzeneacetamide, N-(5-cyclopropyl-1H-pyrazol-3-yl)-α-(1-methylethyl)-3-[6-[[(2E)-4-(4-morpholinyl)-1-oxo-2-buten-1-yl]amino]-3-pyridinyl]-, (αS)-

Tacaciclib is a CDK inhibitor, antineoplastic effect.

The present invention is directed to methods of preparation of compound of formula (I) that is useful for inhibiting Cyclin-dependent kinase 7 (CDK7) and for treating diseases or disorders mediated thereby.

CDK7, which complexes with cyclin H and RING-finger protein MAT1, phosphorylates the cell cycle CDKs in the activation of T-loop, to promote their activities (Fisher et al., Cell., Aug 26;78(4):713- 24, 1994). As such, it has been proposed that inhibiting CDK7 would provide a potent means of inhibiting cell cycle progression, which may be especially relevant given that there is compelling evidence from gene knockout studies in mice for lack of an absolute requirement for CDK2, CDK4 and CDK6 for the cell cycle at least in most cell types (M alumbres et al., Nature Cell Biology, 11, 1275 – 1276, 2009), whilst different tumors appear to require some, but they are independent of other interphase CDKs (CDK2, CDK4 , CDK6). Recent genetic and biochemical studies have confirmed the importance of CDK7 for cell cycle progression (Larochelle. et al., Mol Cell., Mar 23;25(6):839-50. 2007; Ganuza et al., EM BO J., May 30; 31(11): 2498-510, 2012).

Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general Transcription factor II Human (TFIIH). CDK7 also plays a role in transcription and possibly in DNA repair. The trimeric Cak complex CDK7/CyclinH/MATl is also a component of TFIIH, the general transcription/DNA repair factor IIH (Morgan, DO., Annu.Rev. Cell Dev. Biol. 13, 261-91, 1997). As a TFIIH subunit, CDK7 phosphorylates the CTD (Carboxy-Terminal-Domain) of the largest subunit of RNA polymerase II (pol II). The CTD of mammalian pol (II) consists of 52 heptad repeats with the consensus sequence 1 YSPTSPS 7 and the phosphorylation status of the Ser residues at positions 2 and 5 has been shown to be

important in the activation of RNAP-II indicating that it is likely to have a crucial role in the function of the CTD. CDK7, which primarily phosphorylates Ser-5 (PSS) of RNAP-II at the promoter as part of transcriptional initiation (Gomes et ah, Genes Dev. 2006 Mar 1; 20(5):601-12, 2006), in contrast with CDK9, which phosphorylates both Ser-2 and Ser-5 of the CTD heptad (Pinhero et al., Eur. J. Biochem., 271, pp. 1004-1014, 2004).

In addition to CDK7, other CDKs have been reported to phosphorylate and regulate RNA pol (II) CTD. The other CDKs include, Cdk9/ Cyclin T1 or T2 that constitute the active form of the positive transcription elongation factor (P-TEFb) (Peterlin and Price, Mol Cell., Aug 4; 23(3): 297-305,2006) and Cdkl2/Cyclin K and Cdkl3/Cyclin K as the latest members of RNAPII CTD kinases (Bartkowiak et al., Genes Dev., Oct 1 5;24(20):2303-16, 2010; Blazek et al., Genes Dev .Oct 15;25(20):2158-72, 2011).

Disruption of RNAP II CTD phosphorylation has been shown to preferentially effect proteins with short half-lives, including those of the anti-apoptotic BCL-2 family. (Konig et al., Blood, 1, 4307-4312, 1997; The transcriptional non-selective cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1; (Gojoet al., Clin. Cancer Res. 8, 3527-3538, 2002).

This suggests that the CDK7 enzyme complexes are involved in multiple functions in the cell: cell cycle control, transcription regulation and DNA repair. It is surprising to find one kinase involved in such diverse cellular processes, some of which are even mutually exclusive. It also is puzzling that multiple attempts to find cell cycle dependent changes in CDK7 kinase activity remained unsuccessful. This is unexpected since activity and phosphorylation state of its substrate, CDC2, fluctuate during the cell cycle. In fact, it is shown that cdk7 activity is required for the activation of both Cdc2/Cyclin A and Cdc2/Cyclin B complexes, and for cell division. (Larochelle, S. et al. Genes Dev 12,370-81, 1998). Indeed, flavopiridol, a non-selective pan-CDK inhibitor that targets CTD kinases, has demonstrated efficacy for the treatment of chronic lymphocytic leukemia (CLL), but suffers from a poor toxicity profile (Lin et al.,). 27, 6012-6018, 2009; Christian et al., Clin. Lymphoma Myeloma, 9, Suppl.

3, S179-S185, 2009).

International publication WO2016193939, which is incorporated herein by reference for all purposes describes CDK7 inhibitors and processes for the preparation thereof. Inhibitors of CDK7 are currently being developed for the treatment of cancer. For drug development, it is typically advantageous to employ individual stereoisomers as they exhibit marked differences in pharmacodynamic, pharmacokinetic, and toxicological properties.

PATENT

WO 2016/193939 COMPD 44

https://patents.google.com/patent/WO2016193939A1/en

InventorSusanta SamajdarRamulu PoddutooriChetan PanditSubhendu MUKHERJEERajeev Goswami

AURIGENE DISCOVERY TECHNOLOGIES LIMITED [IN]/[IN]

Inventors

• SAMAJDAR, Susanta
• PODDUTOORI, Ramulu
• PANDIT, Chetan
• MUKHERJEE, Subhendu
• GOSWAMI, Rajeev

PATENT

Applicants

• AURIGENE ONCOLOGY LIMITED [IN]/[IN]

Inventors

• PODDUTOORI, Ramulu
• VIJAYKUMAR BHAT, Uday
• THIMMASANDRA SEETHAPPA, Devaraja

WO2022229835

Example- 1: Preparation of compound of formula (I)

Scheme-1: Preparation of KRM-A

Step-4

KRM-A 4

Step-1: Preparation of 2-(3-bromophenyl)-3-methylbutanoic acid (1)

2M LDA (698 mL, 1.38mol) was added to a solution of 2-(3-bromophenyl) acetic acid (XA, 150 g, 0.69 mol) in THF (700mL) at -78 °C over a period of 30 min. The reaction mixture was stirred for 2h at -78 °C followed by a drop wise addition of isopropyl bromide (X _B , 255 g, 2.07 mol) over a period of 30 min. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was quenched with IN HC1 (pH 2) and the obtained product was extracted to ethyl acetate (500 mL x 3). The combined organic layer was washed with water followed by brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound which was purified by silica column by eluting with 0-10% ethyl acetate-hexane system to afford the title compound (150 g, 83% yield) , HPLC purity-96%. The compound of formula (1) can also be prepared by the procedure described in CN 110590747.

Step-2: Preparation of Compound 3

2-(3-bromophenyl)-3-methylbutanoic acid (1, 510 g, 1.98 mol) was dissolved in 30% of IP A in water (10.2 L; 3.06 L of IPA-7.14 L of water) and ( 1L\ 2i ?)-cyclohexane-1,2-diamine (2, 113 g, 0.9 mol) was added. The reaction mixture was stirred at room temperature for 10 min until the precipitation was observed, then was heated to 100 °C until the solution became clear and stirred at the same temperature for another 30 min. The reaction mixture was allowed to slowly reach room temperature for 8-12h. The obtained solid was filtered and washed with 500 mL of 30% IPA-water mixture and dried under vacuum to afford the compound 3 (620 g, wet).

Work up (for Chiral purity): Small portion (100 mg) of compound 3 was taken in DCM (2-3 mL) and was added IN HC1 (pH 2) at 0 °C until the clear solution was observed. The compound was extracted into DCM, dried over NaiSCL and the solvent was evaporated to afford the title compound as white solid (20 mg). Chiral HPLC was recorded for this sample and 20.6% of undesired isomer was observed in chiral HPLC.

In order to improve the chiral purity of the title compound, the recrystallization method was performed as described below.

Step-3: Recrystallization

The compound 3 (619.90 g) was taken in 30% of IP A in water (12.4 L), then the mixture was heated to 100 °C until the solution became clear and was stirred at the same temperature for another 30min. The reaction mixture was allowed to reach room temperature slowly for 8-12h.

The obtained solid was filtered and washed with 500mL 30% IPA-water and dried under vacuum to afford a desired compound (360g, wet).

Work up for analysis (for Chiral purity): Small portion (100 mg) from above compound was taken in DCM (2-3mL), was added IN HC1 (pH 2) at 0 °C until the clear solution was observed and the compound was extracted to DCM, dried over NaiSCL and the solvent was evaporated to afford title compound as white solid (35 mg). Chiral HPLC was recorded for this sample and 10.3% of undesired isomer was observed in chiral HPLC.

The recrystallization method was repeated for three more times by using 30% of IPA in water as per the aforesaid procedure to obtain the purity of greater than 98.50% ee along with 0.27% other isomer to afford 286 g of compound 4.

Step-4: Preparation of (S)-2-(3-bromophenyl)-3-methylbutanoic acid (KRM-A)

The compound 4 (286 g) was taken in DCM (1.3 L), then was added IN HC1 at 0 °C until the clear solution was observed, and the compound was extracted to DCM (500 mL x 2). The organic layer was separated, washed with brine solution (500 mL) and dried over NaiSCL. The solvent was evaporated from the reaction mixture to afford title compound as white solid (148 g, 60% yield). Chiral HPLC: 98.50%

*H NMR (400MHz, DMSO-de): d 12.5 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.26 (m, 2H), 3.16 (d, 1H), 2.23-2.11 (m, 1H), 0.98 (d, 3H), 0.63 (d, 3H); Chiral HPLC: 98.50% retention time: 4,588 min.

Scheme-2: Preparation of compound of formula (I)

Step-1: Synthesis of (S)-2-(3-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbutanamide

Step-la: Preparation ofKRM-D

To a stirred solution of KRM-A (lOOg, O.388mol) in dry DCM (600 mL, 6 vol), a catalytic amount of DMF (10 mL) was added followed by oxalyl chloride (45 mL, 0.525 mol) dropwise at 0°C over a period of 30 min. After completion of addition, the reaction mixture was stirred for 15 min at the same temperature. The reaction mixture was allowed to reach room temperature and stirred for 2 to 4h. After completion of the reaction (reaction was monitored by TLC, acid chloride formation was checked by quenching an aliquot of reaction mixture with MeOH), the reaction mixture was concentrated under vacuum at 40°C-45°C to afford crude (S)- 2-(3-bromophenyl)-3-methylbutanoyl chloride (KRM-D). The crude KRM-D was dissolved in toluene (500mL) and used for next step.

Step-lb: Preparation of compound of formula (II)

(5)-2-(3-bromophcnyl)-3-mcthylbutanoyl chloride in toluene was added slowly to a pre-cooled solution (0 to 5 °C) of ieri-butyl 3-amino-5-cyclopropyl-1H-pyrazole- l-carboxylate (KRM-B, 95.5g, 0.427 mol) and N, N-diisopropylethyl amine (100 mL, 0.583 mol) in toluene (1.2 L) at 0 °C for the period of l-2h. The reaction mixture was allowed to reach RT and stirred overnight. The reaction mixture was then cooled to 0-5°C and washed with ice-cold 1.5N HC1 (3 x 500 mL). The organic layer was washed with sodium bicarbonate solution (500 mL), brine solution (500 mL), dried over anhydrous NaiSCL _, filtered and concentrated under vacuum at 45-50°C to afford crude tert-butyl (S)-5-( 2-(3-bromophenyl)-3-methylbutanamido)-3-

cyclopropyl- lH-pyrazole- 1-carboxylate (compound of formula (IG)) as light brown oil (~180g, LCMS: m/z= 461.9 (M+H) ⁺ , HPLC: 80.80%, retention time:15.89 min) . The crude product was taken as such for next step without further purification.

Step-1 c: Preparation of compound of formula (I)

To a suspension of tert-butyl (S)-5-(2-(3-bromophenyl)-3-methylbutanamido)-3-cyclopropyl-1H-pyrazole-1-carboxylate (180 g, 1,731 mol) in dioxane (360 mL ) was added 2N aqueous HC1 (360 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, dioxane was concentrated, and the reaction mixture was diluted with water (500 mL) and basified with solid sodium bicarbonate (until pH-8). The obtained compound was extracted with DCM (700 mL x 3). The combined organic layers were washed with water (300 mL), brine solution (300 mL), and dried over anhydrous NaiSCL _. The organic layer was concentrated to obtain a crude (S)-2-(3-bromophenyl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-3-methylbutanamide (Compound of formula (G)) as a semi-solid. The crude was dissolved in toluene (500 mL) and the solution was stirred for 18 h. The obtained solid was filtered and washed with toluene (100 mL) and n-heptane (200 mL). The solid was further dried under vacuum at 45-50°C for 6 h to afford a title compound (1 lOg, Yield: 78% over two steps). LCMS: m/z= 362 (M+H) ⁺ , HPLC: 97.66%, retention time: 24.10 min

Step-2: Preparation of (S, E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl) amino)-3-methyl-l-oxobutan-2- yl) phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide (Compound of formula (I))

To a degassed solution of (5)-2-(3-bromophcnyl)-N-(5-cyclopropyl-1 H-pyrazol-3-yl)-3-methylbutanamide (50 g, 0.138 mol) and (E)-4 -morpholino-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)but-2-enamide (KRM-C, 56.6 g, 0.151 mol, 1.1 eq) (prepared according to the procedure described in W02020202001) in 1,4-dioxane (500 mL, 10 vol) and water (100 mL, 2 vol) was added K3PO4 tribasic (73.2 g, 0.345 mol, 2.5 eq) at room temperature The reaction mass was stirred for 20 min with argon purging (degassing). Pd(dppf)Ch.DCM (3.38 g, 0.0042 mol, and 0.03eq) was added to the reaction mixture and the reaction mixture was heated to 90°C for 1-2 h (The reaction was monitored by TLC using 10% methanol in DCM as solvent system).

After completion of the reaction, the reaction mass was cooled to room temperature and filtered through Celite ^® bed. The bed was washed with 1, 4-dioxane (200 mL) and the filtrate was concentrated to get crude compound. The crude compound was dissolved in 5% methanol in DCM (400 mL) and washed with water (200 mL x 2). The aqueous layer was separated and

extracted with DCM (100 mL x 2). The combined organic layer was washed with brine solution, filtered and dried over sodium sulfate. The organic layer was concentrated under vacuum at 35-40°C to obtain crude title compound (~80g).

The crude compound of formula (I), (80 g) was dissolved in 700 mL of ethyl acetate. The reaction mixture was cooled to 15°C and 2N HC1 was slowly added (until pH ~1). The reaction mixture was then stirred at room temperature for 20 min and the layers were separated. The aqueous layer (containing the product) was washed with ethyl acetate (300 mL x 3). The aqueous layer was cooled to 0°C and adjusted the pH to ~8 using 20% aqueous NaiCCL solution. The product was extracted with 10% methanol in DCM (300 mL x 3). The combined organic layer was washed with water (300 mL), dried over sodium sulfate and filtered. The filtrate was treated with activated charcoal (16 g, 20% w/w with respect to crude input of 80 g), then the reaction mixture was stirred overnight at room temperature and filtered through Celite ^® bed. The bed was washed with 5% methanol in DCM (~ 20 vol, until absence of product by TLC). The filtrate was concentrated under vacuum at 35°C – 40°C to afford compound of formula (I) (70g, HPLC purity: 92.70%, retention time: 15.65 min).

Work-up for improved chiral purity: The above compound of formula (I) was dissolved in ethylacetate (~30 vol, 2L) and washed with aqueous citric acid (2 times, 400 mL x 1 and 200mL x 1), aqueous NaHCCL solution (2%, 500 mL x 1) and aqueous NaCl solution (10%, 500 mL x 1). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum at 35°C – 40°C to afford compound of formula (I) (~60g).

*H NMR (400MHz, DMSO-rfe): d: 10.79 (s, 1H), 10.46 (s, 1H), 8.61 (d, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.39 (m, 2H), 6.84-6.77 (m, 1H), 6.62 (s, 2H), 6.51 (d, 1H), 6.13 (s, 1H) , 3.62-3.59 (m, 4H), 3.35 (d, 1H), 3.15-3.13 (m, 2H), 2.42-2.39 (m, 5H), 1.80-1.77 (m, 1H), 0.98 (d, 3H) , 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H); LCMS: m/z= 529.25-free base (M+H) ⁺ , HPLC: 98.98%, retention time: 15.40 min.

Patent

 WO-2022130304

PATENT

 WO2023107861

In some embodiments, the compound of formula (I) is (E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt or a stereoisomer thereof (Compound 44).

Compound 44 is disclosed in WO 2016/193939 Al, published December 8, 2016, entitled “Substituted heterocyclyl derivatives as cdk inhibitors,” the entire contents of which are incorporated herein by reference. Compound 44A can be in the form of a fumaric acid salt or cocrystal as described in WO 2022/130304 Al, published June 23, 2022, entitled “Cocrystal of a cdk inhibitor,” the entire contents of which are incorporated herein by reference.

Example 3: Synthesis of Compounds 44A & 44B via Chiral Separation

Scheme-1

Step-1: Synthesis of 2-(3-bromophenyl)-3-methylbutanoic acid

[0352] 2M LDA (698 mL, 1.38mol) was added to a solution of 2-(3 -bromophenyl) acetic acid (reagent-1, 150g, 0.69mol) in THF (700mL) at -78 °C over a period of 30 min. The reaction mass was stirred for 2h at -78 °C followed by the drop wise addition of Isopropyl bromide (255 g, 2.07mol) over a period of 30 min at -78 °C. The reaction mass was stirred at room temperature for overnight. The reaction mass was quenched with IN HC1 (pH 2) and product extracted to ethyl acetate (500mL x 3). The combined organic layer washed with water followed by brine, dried and concentrated under reduced pressure to afford the title crude compound which was purified by silica column by eluting with 0-10% ethyl acetate -hexane system to afford the title compound 2 (150g, 83% yield). LCMS: m/z = 254.80 (M-2H)’

Step-2: Synthesis of tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5-cyclopropyl-lH-pyrazole-1 -carboxylate

[0353] 2-(3-bromophenyl)-3-methylbutanoic acid (intermediate-2, 70g, 0.0.27mol) was dissolved in dry DCM (500 mL) and added oxalyl chloride (68 mL, 0.78mol) dropwise at 0 °C followed by addition of catalytic amount of DMF (0.8mL) and maintained reaction mass at same temperature for 30min. The reaction mass was allowed to room temperature and stirred for 4h, distilled off the solvent and excess oxalyl chloride under vacuum. Re-dissolved the residue in DCM (250 mL) and added slowly to the cooled solution of tert-butyl 3 -amino-5 -cyclopropyl- 1H-pyrazole-1 -carboxylate (intermediate-3, 49g, 0.218mol) and TEA (55 mL, 0.546mol) in THF (250 mL) at 0 °C for 30min, The reaction was stirred at room temperature for 12h then the reaction mass was concentrated under reduced pressure and the residue was dissolved in DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography by eluting with 15% ethyl acetate-hexane to afford the title compound 4 (90g, 71% ) LCMS: m/z = 363.80 (M-Boc+2).

Step-3: Synthesis of tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)butanamido)-l H -pyr azole- 1 -carboxylate

[0354] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)-3-methylbutanamido)-5-cyclopropyl-lH-pyrazole-1 -carboxylate (intermediate-4, 90g, 0.193mol) and 4, 4, 4′, 4′, 5, 5, 5′, 5′-octamethyl-2,2′-bi(l,3,2-dioxaborolane) (62g, 0.25 Imol) in 1,4-Dioxane (500 mL) was added potassium acetate (37.80g, 0.386mol). The reaction mass was allowed to stir for 10 min with degassing at RT and added PdC12(dppf).DCM complex (12.5g, 0.015mol). The reaction mass was heated for 3-4 h at 100 °C. Reaction mixture cooled to RT and filtered on celite bed, filtrate evaporated to get dark brown liquid. The crude material was purified by silica column chromatography by eluting with 20% ethyl acetate in hexane to afford the compound 5 (90g, 86%). LCMS: m/z = 410 (M-Boc+1)+.

Step-4: Synthesis of (E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl)amino)-3-methyl-l-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide

[0355] To a degassed solution of tert-butyl 5-cyclopropyl-3-(3-methyl-2-(3-(4, 4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)butanamido)- 1 H-pyrazole- 1 -carboxylate, 5 (10g, 0.019mol) and (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide (7.7g, 0.023mol) in

1,4-Dioxane (lOOmL) and water (40mL) followed by Cs2CO3 (14.5g, 0.045mol) were added. The reaction mass was allowed to stir for 10 min with degassing and added Pd(PPh3)4 (1.1g, 0.00095mol), heated the reaction mass for 4 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with brine solution. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layer was evaporated to dryness and crude material was purified by silica column chromatography by eluting with 10%-l 5 % methanol in DCM to get desired pure compound 44 (4.5g, 44%). LCMS: m/z = 529.15 (M+H)+; HPLC: 95.17%, rt: 6.34 min.

[0356] Racemic (E)-N-(5 -(3 -( 1 -((5 -cyclopropyl- 1 H-pyrazol-3 -yl)amino)-3 -methyl- 1 -oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide was separated by using chiral preparative HPLC column (Method: Column: Chiral Pak IA (20mm X 250 mm, 5 micron), Elution: isocratic (50:50), A=ACN, B= MeOH, Flow: 20mL/min ) to afford the pure Isomer- 1 and Isomer-2.

Isomer-1 (Compound 44-A):

[0357] 1HNMR (DMSO-d6, 400MHz): 5 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.41-2.32 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.59 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.72%, rt: 6.39 min; Chiral HPLC: 97.68%, rt: 14.47.

Isomer-2 (Compound 44B):

[0358] 1HNMR (DMSO-d6, 400MHz): 5 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.04 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.50 (d, 1H), 6.14 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.40-2.39 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.24%, rt: 6.39 min; Chiral HPLC: 97.92%, rt: 8.80.

Example 4: Preparation of Compound 44-A via Chiral Synthesis

Preparation of KRM-A (chemical precursor to Compound 44-A)

Step-4

KRM-A 

Step-1: Preparation of 2-(3-bromophenyl)-3-methylbutanoic acid (1)

[0359] 2M LDA (698 mL, 1.38mol) was added to a solution of 2-(3 -bromophenyl) acetic acid (150 g, 0.69 mol) in THF (700mL) at -78 °C over a period of 30 min. The reaction mixture was stirred for 2h at -78 °C followed by drop wise addition of isopropyl bromide (XB, 255 g, 2.07 mol) over a period of 30 min at -78 °C. The reaction mass was stirred at room temperature overnight. The reaction mass was quenched with IN HC1 (pH 2) and the obtained product was extracted to ethyl acetate (500 mL x 3). The combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title crude compound which was purified by silica column by eluting with 0-10% ethyl acetate -hexane system to afford the title compound (150 g, 83% yield), HPLC purity-96%. The compound of formula (1) can also be prepared by the procedure described in CN110590747.

Step-2: Preparation of Compound 3

[0360] 2-(3-bromophenyl)-3-methylbutanoic acid (1, 510 g, 1.98 mol) was dissolved in 30% of IPA in water (10.2 L; 3.06 L of IPA-7.14 L of water) and (1R, 27?)-cyclohexane-l,2-diamine (2, 113 g, 0.9 mol) was added. The reaction mixture was stirred at room temperature for 10 min until the precipitation was observed, then heated to 100 °C till the solution becomes clear and was stirred at same temperature for another 30 min. The reaction mixture was allowed to attain room temperature slowly for 8-12h. The obtained solid was filtered and washed with 500 mL of 30% IPA-water mixture and dried under vacuum to afford the compound 3 (620 g, wet).

[0361] Work up for analysis (for Chiral purity): Small portion (100 mg) of compound 3 was taken in DCM (2-3 mL) and was added IN HC1 (pH 2) at 0 °C till the clear solution was observed. The compound was extracted into DCM, dried over Na2SC>4 and the solvent was evaporated to afford the title compound as white solid (20 mg). Chiral HPLC was recorded for this sample and 20.6% of undesired isomer was observed in chiral HPLC.

[0362] In order to improve the chiral purity of the title compound, the recrystallization method was performed as described below.

Step-3: Recrystallization

[0363] The compound 3 (619.90 g) was taken in 30% of IPA in water (12.4 L), then the mixture was heated to 100 °C till the solution becomes clear and stirred at same temperature for another 30min. The reaction mixture was allowed to attain room temperature slowly for 8-12h. The obtained solid was filtered and washed with 500mL 30% IP A- water and dried under vacuum to afford a desired compound (360g, wet).

[0364] Work up for analysis (for Chiral purity): Small portion (100 mg) from above compound was taken in DCM (2-3mL), was added IN HC1 (pH 2) at 0 °C till the clear solution was observed and the compound was extracted to DCM, dried over Na2SCL and the solvent was evaporated to afford title compound as white solid (35 mg). Chiral HPLC was recorded for this sample and 10.3% of undesired isomer was observed in chiral HPLC.

[0365] The recrystallization method was repeated for three more times by using 30% of IPA in water as described above to get the purity >98.50% ee along with 0.27% other isomer to afford 286 g of compound 4.

Step-4: Preparation of (S)-2-(3-bromophenyl)-3-methylbutanoic acid (KRM-A)

[0366] The compound 4 (286 g) was taken in DCM (1.3 L), then was added IN HC1 at 0 °C until the clear solution was observed, and the compound was extracted to DCM (500 mL x 2). The organic layer was separated and washed brine solution (500 mL) and dried over Na2SO4, the solvent was evaporated to afford title compound as white solid (148 g, 60% yield). Chiral HPLC: 98.50%

[0367] ‘H NMR (400MHz, DMSO-d₆): 8 12.5 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.26 (m, 2H), 3.16 (d, 1H), 2.23-2.11 (m, 1H), 0.98 (d, 3H), 0.63 (d, 3H); Chiral HPLC: 98.50% retention time: 4.588 min.

Preparation of Compound 44-A

Step-1: Synthesis of (S)-2-(3-bromophenyl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-3-methylhutanamide

Step- la: Preparation of KRM-D

[0368] To a stirred solution of KRM-A (100g, 0.388mol) in dry DCM (600 mL, 6 vol), a catalytic amount of DMF (10 mL) was added followed by oxalyl chloride (45 mL, 0.525 mol) dropwise at 0 °C over a period of 30 min. After completion of addition, the reaction mixture was stirred for 15 min at the same temperature. The reaction mixture was allowed to reach room temperature and stirred for 2 to 4h. After completion of the reaction (reaction was monitored by TLC, acid chloride formation was checked by quenching an aliquot of reaction mixture with MeOH), the reaction mixture was concentrated under vacuum at 40°C-45°C to afford crude 2-(3-bromophenyl)-3 -methylbutanoyl chloride (KRM-D). The crude KRM-D was dissolved in toluene (500mL) and used for next step.

Step- lb: Preparation of compound of formula Z

[0369] (S)-2-(3-bromophenyl)-3 -methylbutanoyl chloride in toluene was added slowly to a pre-cooled solution (0 to 5 °C) of te/7-butyl 3 -amino-5 -cyclopropyl- IH-pyrazole-l -carboxylate (KRM-B, 95.5g, 0.427 mol) and N, N-diisopropylethyl amine (100 mL, 0.583 mol) in toluene (1.2 L) at 0 °C for the period of l-2h. The reaction mixture was allowed to attain RT and stirred for overnight. The reaction mixture was then cooled to 0-5°C and washed with ice-cold 1.5N HCI (3 x 500 mL). The organic layer was washed with sodium bicarbonate solution (500 mL),

brine solution (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum at 45-50°C to afford crude tert-butyl (5)-5-(2-(3-bromophenyl)-3-methylbutanamido)-3-cyclopropyl-lH-pyrazole-1 -carboxylate (compound of formula Z) as light brown oil (~180g, LCMS: m/z= 461.9 (M+H)⁺, HPLC: 80.80%, retention time: 15.89 min). The crude product was taken as such for next step without further purification.

Step-lc: Preparation of compound of formula Y

[0370] To a suspension of tert-butyl (S)-5-(2-(3-bromophenyl)-3-methylbutanamido)-3-cyclopropyl-lH-pyrazole-1 -carboxylate (180 g, 1.731 mol) in dioxane (360 mL) was added 2N aqueous HC1 (360 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature.

[0371] After completion of the reaction, dioxane was concentrated, and the reaction mixture was diluted with water (500 mL) and basified with solid sodium bicarbonate (until pH-8). The resulted compound was extracted with DCM (700 mL x 3). The combined organic layers were washed with water (300 mL) and brine solution (300 mL), and dried over anhydrous Na2SO4. The organic layer was concentrated to get a crude (<S)-2-(3-bromophenyl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-3-methylbutanamide (Compound of formula Y) as a semi solid. The crude was dissolved in toluene (500 mL) and the solution was stirred for 18 h. The solid formed was filtered and washed with toluene (100 mL) and n-heptane (200 mL). The solid was further dried under vacuum at 45-50°C for 6 h to afford a title compound (110g, Yield: 78% over two steps). LCMS: m/z= 362 (M+H)⁺, HPLC: 97.66%, retention time: 24.10 min

[0372] Step-2: Preparation of (S, E)-N-(5-(3-(l-((5-cyclopropyl-lH-pyrazol-3-yl) amino)-3-methyl-l-oxobutan-2-yl) phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide (Compound 44A)

[0373] To a degassed solution of (<S)-2-(3-bromophenyl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-3-methylbutanamide (50 g, 0.138 mol) and (£)-4-morpholino-N-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)but-2-enamide (KRM-C, 56.6 g, 0.151 mol, 1.1 eq) (prepared according to the procedure described in W02020202001) in 1,4-dioxane (500 mL, 10 vol) and water (100 mL, 2 vol) was added K3PO4 tribasic (73.2 g, 0.345 mol, 2.5 eq) at room temperature The reaction mass was stirred for 20 min with argon purging (degassing). Pd(dppf)C12.DCM [l,l’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane] (3.38 g, 0.0042 mol, and 0.03eq) was added and the reaction mixture was heated to 90°C for 1-2 h (The reaction was monitored by TLC using 10% methanol in DCM as solvent system).

[0374] After completion of the reaction, the reaction mass was cooled to room temperature and filtered through Celite® bed. The bed was washed with 1, 4-dioxane (200 mL) and the filtrate was concentrated to get crude compound. The crude compound was dissolved in 5% methanol in DCM (400 mL) and washed with water (200 mL x 2). The aqueous layer was separated and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine solution, filtered and dried over sodium sulphate. The organic layer was concentrated under vacuum at 35-40°C to get crude title compound (~80g).

[0375] The crude compound 44A, (80 g) was dissolved in 700 mL of ethyl acetate. The reaction mixture was cooled to 15°C and 2N HC1 was slowly added (until pH ~1). The reaction mixture was then stirred at room temperature for 20 min and the layers were separated. The aqueous layer (containing the product) was washed with ethyl acetate (300 mL x 3). The aqueous layer was cooled to 0°C and adjusted the pH to ~8 using 20 % aqueous Na2COs solution. The product was extracted with 10% methanol in DCM (300 mL x 3). The combined organic layer was washed with water (300 mL), dried over sodium sulphate and filtered. The filtrate was treated with activated charcoal (16 g, 20% w/w with respect to crude input of 80 g), stirred overnight at room temperature and filtered through Celite® bed. The bed was washed with 5% methanol in DCM (~ 20 vol, till absence of product by TLC). The filtrate was concentrated under vacuum at 35°C – 40°C to afford compound 44A (70g, HPLC purity: 92.70%, retention time: 15.65 min).

[0376] ‘ H NMR (400MHz, DMSO-^): <5: 10.79 (s, 1H), 10.46 (s, 1H), 8.61 (d, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.39 (m, 2H), 6.84-6.77 (m, 1H), 6.62 (s, 2H), 6.51 (d, 1H), 6.13 (s, 1H), 3.62-3.59 (m, 4H), 3.35 (d, 1H), 3.15-3.13 (m, 2H), 2.42-2.39 (m, 5H), 1.80-1.77 (m, 1H), 0.98 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H);

LCMS: m/z= 529.25-free base (M+H)⁺, HPLC: 98.98%, retention time: 15.40 min.

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REF

POSTER SESSION: Molecular Targeted Agents| Volume 138, SUPPLEMENT 2, S47, October 01, 2020

//////Tacaciclib, GTPL12880, AUR-102

CC(C)C(C1=CC=CC(=C1)C2=CN=C(C=C2)NC(=O)C=CCN3CCOCC3)C(=O)NC4=NNC(=C4)C5CC5

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Sotuletinib HCl

CAS: 2222138-31-8 (HCl)
Chemical Formula: C20H23ClN4O3S

Molecular Weight: 434.939

7W3V82OQ0P

Synonym: Sotuletinib HCl; Sotuletinib hydrochloride, Sotuletinib monohydrochloride, BLZ945; BLZ 945; BLZ-945;

IUPAC/Chemical Name: 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide hydrochloride

Sotuletinib, also known as BLZ945, is a potent and selective CSF-1R kinase inhibitor. BLZ945 showed effects of CSF1R inhibition on other tumor-infiltrating immune cells. BLZ945 attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. BLZ945 decreases the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis.

Sotuletinib (BLZ945) is an experimental drug in development for the treatment of amyotrophic lateral sclerosis (ALS). It works as a colony-stimulating factor 1 (CSF1) receptor inhibitor.^[1][2][3]

• OriginatorCelgene Corporation; Novartis
• ClassAmides; Amines; Antineoplastics; Benzothiazoles; Cyclohexanols; Ethers; Pyridines; Small molecules
• Mechanism of ActionMacrophage colony stimulating factor receptor antagonists

• Phase IIAmyotrophic lateral sclerosis
• Phase I/IISolid tumours

• 05 Dec 2022Novartis Pharmaceuticals terminates a phase I/II trials in Solid tumours (Combination therapy, Late-stage disease, Metastatic disease) in Taiwan, Japan, Israel (PO) in US, Israel, Italy, Japan, Singapore, Spain, Taiwan and Switzerland (EudraCT2015-005806-12) (NCT02829723)
• 14 Feb 2022Adverse events and pharmacodynamics data from preclinical macaque model study in brain disorders presented at the 29th Conference on Retroviruses and Opportunistic Infections
• 03 Dec 2020Chemical structure information added

An orally bioavailable inhibitor of colony stimulating factor 1 receptor (CSF-1R; CSF1R), with potential antineoplastic activity. CSF1R inhibitor BLZ945 selectively binds to CSF1R expressed on tumor-associated macrophages (TAMs), blocks the activity of CSF1R, and inhibits CSF1R-mediated signal transduction pathways. This inhibits the activity and proliferation of TAMs, and reprograms the immunosuppressive nature of existing TAMs. Altogether, this reduces TAM-mediated immune suppression in the tumor microenvironment, re-activates the immune system, and improves anti-tumor cell responses mediated by T-cells. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor for its ligand, colony stimulating factor 1 (CSF1); this receptor is overexpressed by TAMs in the tumor microenvironment, and plays a major role in both immune suppression and the induction of tumor cell proliferation.

PATENT

The free base and salts of the compound of formula (I) may be prepared for example, according to the procedures given in International Patent Application No. PCT/US2007/066898 filed on Apr. 18, 2007 and published as WO2007/121484 on Oct. 25, 2007. The compound of formula (I) has the chemical name: 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide and is also known as BLZ945.

Step 1. Preparation of 4-(2-((lR,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (lR,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105°c for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give 4-(2-((lR,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1(MH⁺).

PATENT

 US-2020093801

https://patents.google.com/patent/US20200093801A1

PATENT

CN116139135

PATENT

US20200190057

PATENT

CN110475555

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References

1. ^ Pognan, François; Buono, Chiara; Couttet, Philippe; Galarneau, Jean-René; Timsit, Yoav; Wolf, Armin (29 October 2022). “Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib”. Current Research in Toxicology. 3: 100091. doi:10.1016/j.crtox.2022.100091. ISSN 2666-027X.
2. ^ Thongchot, Suyanee; Duangkaew, Supani; Yotchai, Wasan; Maungsomboon, Sorranart; Phimolsarnti, Rapin; Asavamongkolkul, Apichat; Thuwajit, Peti; Thuwajit, Chanitra; Chandhanayingyong, Chandhanarat (2 December 2022). “Novel CSF1R-positive tenosynovial giant cell tumor cell lines and their pexidartinib (PLX3397) and sotuletinib (BLZ945)-induced apoptosis”. Human Cell. 36 (1): 456–467. doi:10.1007/s13577-022-00823-0.
3. ^ Martinez-Gonzalez, Loreto; Martinez, Ana (1 February 2023). “Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis”. Expert Opinion on Investigational Drugs. 32 (2): 141–160. doi:10.1080/13543784.2023.2178416.

////////Sotuletinib HCl, BLZ945,  BLZ 945, BLZ-945,

O=C(NC)C1=NC=CC(OC2=CC=C3N=C(N[C@H]4[C@H](O)CCCC4)SC3=C2)=C1.[H]Cl

Opevesostat

• ODM208

2231294-96-3
Chemical Formula: C21H26N2O5S

Molecular Weight: 418.508

2-[(1,3-dihydro-2H-isoindol-2-yl)methyl]-5-{[1-(methanesulfonyl)piperidin-4-yl]methoxy}-4H-pyran-4-one

2832831-08-8

4H-Pyran-4-one, 2-[(1,3-dihydro-2H-isoindol-2-yl)methyl]-5-[[1-(methylsulfonyl)-4-piperidinyl]methoxy]-, 4-methylbenzenesulfonate (1:1)

2-((1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHYL)-5-((1-(METHYLSULFONYL)-4-PIPERIDINYL)METHOXY)-4H-PYRAN-4-ONE, TOSYLATE

useful in the treatment of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases, and to pharmaceutical compositions containing such compounds.

Prostate cancer is worldwide the most common cancer in men. Even though the 5-year survival rate of patients with localized prostate cancer is high, the prognosis for those patients, who develop castration-resistant prostate cancer (CRPC) within that 5-year follow-up period, is poor.

The androgen receptor (AR) signalling axis is critical in all stages of prostate cancer. In the CPRC stage, disease is characterized by high AR expression, AR amplification and persistent activation of the AR signalling axis by residual tissue/tumor androgens and by other steroid hormones and intermediates of steroid biosynthesis. Thus, treatment of advanced prostate cancer involves androgen deprivation therapy (ADT) such as hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists/antagonists or surgical castration, AR antagonists or CYP17A1 inhibitors (such as abiraterone acetate in combination with prednisone).

Although therapies can initially lead to disease regression, eventually majority of the patients develop a disease that is refractory to currently available therapies. Increased progesterone levels in patients treated with abiraterone acetate has been hypothesized to be one of the resistance mechanisms. Several nonclinical and clinical studies have indicated upregulation of enzymes that catalyse steroid biosynthesis at the late stage of CRPC. Very recently it has been published that 11β-OH androstenedione can be

metabolized into 11-ketotestosterone (11-K-T) and 11-ketodehydrotestosterone (11-K-DHT) which can bind and activate AR as efficiently as testosterone and dihydrotestosterone. It has been shown that these steroids are found in high levels in plasma and tissue in prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been addressed that prostate cancer resistance to CYP17A1 inhibition may still remain steroid dependent and responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1, such as by CYP11A1 inhibition therapy (Cai, C. et al, Cancer Res., 71(20), 6503-6513, 2011).

Cytochrome P450 monooxygenase 11A1 (CYP11A1), also called cholesterol side chain cleavage enzyme, is a mitochondrial monooxygenase which catalyses the conversion of cholesterol to pregnenolone, the precursor of all steroid hormones. By inhibiting CYP11A1, the key enzyme of steroid biosynthesis upstream of CYP17A1, the total block of the whole steroid biosynthesis can be achieved. CYP11A1 inhibitors may therefore have a great potential for treating steroid hormone dependent cancers, such as prostate cancer, even in advanced stages of the disease, and especially in those patients who appear to be hormone refractory. It has been recently shown that a compound having CYP11A1 inhibitory effect significantly inhibited tumor growth in vivo in a murine CRPC xenograft model (Oksala, R. et al, Annals of Oncology, (2017) 28 (suppl.

PATENT

WO2018115591

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018115591&_cid=P20-LQXJT7-60871-1

Example 4. SIMILAR

N-((4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclohexyl)- methyl)methanesulfonamide (Compound 173)

To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.10 g, 0.41 mmol) in DMF (2 ml) were added (4-(methylsulfonamidomethyl)cyclohexyl)methyl methanesulfonate (0.14 g, 0.45 mmol) and K₂CO₃ (0.12 g, 0.8 mmol). The reaction mixture was heated at 80 °C for 2 h. The mixture was cooled to RT, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried with Na₂SO₄, filtered and evaporated. The crude product was purified by column chromatography to afford the title compound (0.06 g). ¹H NMR (400 MHz, Chloroform-d) δ ppm 0.92 – 1.11 (m, 4 H) 1.40 – 1.63 (m, 2 H) 1.78 – 2.00 (m, 4 H) 2.91 – 2.99 (m, 5 H) 3.65 (d, J=6.46 Hz, 2 H) 3.77 (s, 2 H) 4.03 (s, 4 H) 5.04 (br t, J=6.31 Hz, 1 H) 6.49 (s, 1 H) 7.20 (s, 4 H) 7.59 (s, 1 H).

ntermediate 58: 5-Hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

To a stirred solution of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (2.0 g, 12.5 mmol) in acetonitrile (50 mL) were added DIPEA (3.22 mL, 25.0 mmol) and isoindoline (1.78 g, 25.0 mmol) at RT. When the reaction was complete, the precipitated solid was filtered and washed with EtOAc. The title compound was collected as pale brown solid (1.1 g). LC-MS: m/z 244.1 (M+H)⁺.

///////////////////

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/////////Opevesostat, ODM 208

 O=C1C=C(CN2CC3=C(C=CC=C3)C2)OC=C1OCC4CCN(S(=O)(C)=O)CC4

ORZILOBEN,

CAS 1555822-28-0

 2-methyl-3-(pentyloxy)benzoic acid

Orziloben is a medium chain fatty acid (MCFA) analogue^[1].

Patent

WO2020074964

The rising global epidemic of obesity and its comorbidities, e.g., type 2 diabetes mellitus and hyperlipidemia, is placing an enormous burden both on public health (mortality and morbidity) and on the available public health resources required to treat these conditions.

Current drugs that treat hyperlipidemia (e.g., statins, omega-3 fatty acids, fibrates) have mostly neutral effects on glycemic control, whilst drugs targeting glycemic control e.g., insulin, thiazolidinediones (TZDs), have adverse effects upon bodyweight and (for TZDs) other unwanted side-effects restricting their use.

In addition to hyperlipidemia and type 2 diabetes, a marked increase in the prevalence of non-alcoholic fatty liver disease (NAFLD) has occurred. NAFLD has become the most common chronic liver condition in Western populations in relation to the obesity and type 2 diabetes epidemics. The prevalence of non-alcoholic steatohepatitis (NASH), a form of NAFLD that is associated with hepatic inflammation and ballooning of hepatocytes, is expected to increase by 63% between 2015 and 2030 in the United States (Estes, Hepatology, 2018; 67(1): 123-133), where NASH is expected to become the leading cause of liver transplantation by 2020. As liver fibrosis, but not inflammation, is associated with mortality and morbidity in NASH patients, drugs which prevent progression/induce regression of fibrosis are also a focus of biomedical research.

The development of novel compounds that simultaneously target both hyperlipidemia and glycemic control, without the adverse side-effects (e.g., weight gain) typically associated with insulin sensitising drugs is thus a desirable goal. Such compounds would be even more attractive if they could additionally prevent the progression/reverse hepatic fibrosis and reduce hepatic steatosis. The present invention addresses these needs for new treatment methods, compounds, and pharmaceutical compositions.

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[1]. Skjaeret, et al. Preparation of benzoic acid derivatives for treatment of metabolic and liver diseases. World Intellectual Property Organization, WO2020074964 A1 2020-04-16.

/////////ORZILOBEN, 1555822-28-0, OBESITY

O=C(C1=C(C)C(OCCCCC)=CC=C1)O

Oditrasertib

• UNII-I1YQT8HC89
• I1YQT8HC89
• cas 2252271-93-3
• 4-(3,3-Difluoro-2,2-dimethylpropanoyl)-3,5-dihydro-2H-pyrido(3,4-F)(1,4)oxazepine-9-carbonitrile

PYRIDO(3,4-F)-1,4-OXAZEPINE-9-CARBONITRILE, 4-(3,3-DIFLUORO-2,2-DIMETHYL-1-OXOPROPYL)-2,3,4,5-TETRAHYDRO-

Oditrasertib is a serine/threonine kinase (STK) inhibitor.

PATENT

[WO2018213632A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018213632

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///////////Oditrasertib,

CC(C)(C(F)F)C(=O)N1CCOC2=C(C=NC=C2C1)C#N

Obeldesivir,

2647441-36-7

361.35 g/mol

C₁₆H₁₉N₅O₅

[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methyl 2-methylpropanoate

Q55KCM7PXB; ATV006; UNII-Q55KCM7PXB

Obeldesivir (GS-5245, ATV006) is an isobutyric ester prodrug of GS-441524 made by Gilead Sciences that is currently in Phase III trials for the outpatient treatment of COVID-19 in high risk patients.^[1][2] The purpose of the isobutyric ester modification on obeldesivir is to improve the oral bioavailability of the parent nucleoside, GS-441524. Obeldesivir is hydrolyzed to its parent nucleoside, GS-441524, which is in turn converted to remdesivir-triphosphate (GS-443902) by a nucleoside kinase, adenylate kinase and nucleotide diphosphate kinase.^[3][4]

GS-443902 is a bioactive ATP analogue with broad-spectrum antiviral activity ^[5] and is the same compound formed by remdesivir, though by a different enzymatic pathway. Unlike remdesivir, which is metabolized by enzymes that are highly expressed in the liver, GS-441524 released by obeldesivir is metabolized by enzymes that are evenly expressed throughout the body. Due to their different metabolic pathways, obeldesivir can be administered orally, whereas remdesivir must be administered intravenously for COVID-19 treatment.^{[citation needed]}

The pharmacokinetic properties of obeldesivir and improved was first published by Chinese researchers in May 2022. The Chinese group pursued investigation of obeldesivir independently from Gilead Sciences. Compared to IV administered GS-441524 in rats at 5 mg/kg, orally administered obeldesivir at 25 mg/kg (referred to as “ATV006”) yielded approximately 22% bioavailability.^[6] Treatment with obdeldesivir reduced viral load and prevents lung pathology in KI-hACE2 and Ad5-hACE2 mouse models of SARS-CoV-2. A patent filed by Gilead Sciences with a priority date of August 27, 2020,^[7] found the bioavailability of GS-441524 after oral administration of obdeldesivir (compound 15) in mice, rats, ferrets, dogs, and cynomolgus macaques to be 41%, 63.9%, 154%, 94%, and 38%, respectively. Across all species evaluated, obeldesivir showed improved oral bioavailability compared to oral administration of the parent nucleoside, GS-441524

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00750

Abstract

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3–7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350–400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment.

Synthesis of ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl Isobutyrate (3)

To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 4 (2000 mg, 6.0 mmol) (30) and isobutyric acid (638 mg, 7.2 mmol) in DMF (5 mL), N,N′-diisopropylcarbodiimide (914 mg, 7.2 mmol) was slowly added followed by 4-(dimethylamino)pyridine (737 mg, 6.0 mmol). The reaction mixture was stirred for 4 h and then diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20% MeOH in CH₂Cl₂ to provide the intermediate ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate. LCMS m/z = 402.2 (M + 1). To a solution of the intermediate (1500 mg) in THF (10 mL), conc. HCl (2 mL) was added, and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with CH₂Cl₂, washed with water, saturated aqueous bicarbonate, and brine, dried over sodium sulfate, concentrated, and subjected to silica gel chromatography, eluting with 30% MeOH in CH₂Cl₂ to afford the title compound (660 mg, 50%). ¹H NMR (400 MHz, MeOH-d₄) δ 7.88 (s, 1H), 6.96–6.85 (m, 2H), 4.50–4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H). LCMS m/z: 362.1 (M + 1). ¹³C NMR (400 MHz, CHCl₃–d₃) δ 175.9, 155.6, 147.9, 123.5, 110.2, 100.8, 116.9, 116.6, 81.3, 79.0, 74.0, 70.2, 62.9, 33.2, 18.7, 18.6. HRMS m/z: 362.14615, C₁₆H₂₀N₅O₅ 362.14644.

PATENT

WO-2022047065-A2

PATENT

PATENT

WO2023167938

To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, Intermediate 1 (2000 mg, 6.0 mmol) (Siegel et. al. J. Med. Chem.2017, 60, 1648-1661) in tetrahydrofuran (THF) was added N,N-dimethylaminopyridine (DMAP) (0.03 eq). To the reaction mixture, isobutyric anhydride (1.1 eq) was added slowly. After the completion of the staring material, the reaction mixture was concentrated and purified by flash chromatography using 20% methanol in DCM as an eluant to give ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate, Intermediate 1a. LCMS: MS m/z: 402.2 (M+1).

Concentrated HCl (5 eq, 1mL) was added to a solution of Intermediate 1a (1000 mg) in acetonitrile (10 mL), which was then stirred at room temperature for 2 hours. LCMS showed the product formation. The reaction was stopped after 4 hours. The reaction mixture was diluted with ethyl acetate and quenched with saturated bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulphate, and concentrated. The residue was purified by flash chromatography using 30% methanol DCM as an eluant. The collected fractions were concentrated to give Intermediate 2.¹H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 6.96 – 6.85 (m, 2H), 4.50 – 4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H); LCMS: MS m/z: 362.1 (M+1).

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References

1. ^ “Clinical Trials Register”.
2. ^ “Gilead touts Veklury resilience against mutated coronavirus, plots phase 3 for new COVID oral antiviral”. 19 October 2022.
3. ^ Cho, A.; Saunders, O. L.; Butler, T.; Zhang, L.; Xu, J.; Vela, J. E.; Feng, J. Y.; Ray, A. S.; Kim, C. U. (2012). “Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides”. Bioorganic & Medicinal Chemistry Letters. 22 (8): 2705–2707. doi:10.1016/j.bmcl.2012.02.105. PMC 7126871. PMID 22446091.
4. ^ Yan, Victoria C.; Muller, Florian L. (2020). “Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment”. ACS Medicinal Chemistry Letters. 11 (7): 1361–1366. doi:10.1021/acsmedchemlett.0c00316. PMC 7315846. PMID 32665809.
5. ^ Gordon, C. J.; Tchesnokov, E. P.; Woolner, E.; Perry, J. K.; Feng, J. Y.; Porter, D. P.; Götte, M. (2020). “Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency”. The Journal of Biological Chemistry. 295 (20): 6785–6797. doi:10.1074/jbc.RA120.013679. PMC 7242698. PMID 32284326.
6. ^ Cao, Liu; et al. (2022). “The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants”. Science Translational Medicine. 14 (661): eabm7621. doi:10.1126/scitranslmed.abm7621. PMC 9161374. PMID 35579533.
7. ^ “Espacenet – search results”.

//////////Obeldesivir, GS-5245, ATV006

 CC(C)C(OC[C@H]1O[C@@](C#N)(C2=CC=C3C(N)=NC=NN32)[C@H](O)[C@@H]1O)=O

Igermetostat

C32H46N4O4. 550.73

2409538-60-7

2KES6YSH8D

INN 12655

BENZAMIDE, N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-3-(ETHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO)-2-METHYL-5-((TRANS-3-(1-PIPERIDINYL)CYCLOBUTYL)OXY)-
IGERMETOSTAT
IGERMETOSTAT [INN]
N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-3-(ETHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO)-2-METHYL-5-((TRANS-3-(1-PIPERIDINYL)CYCLOBUTYL)OXY)BENZAMIDE
N-((4,6-DIMETHYL-2-OXO-1,2-DIHYDROPYRIDIN-3-YL)METHYL)-3-(ETHYL(OXAN-4-YL)AMINO)-2-METHYL-5-(((1R,3R)-3-(PIPERIDIN-1-YL)CYCLOBUTYL)OXY)BENZAMIDE

PATENT

PATENT

US20230382898

The compound has been disclosed in patent WO2020020374A1. It is an enhancer of Zeste homolog 2 (EZH2) inhibitor, and can be used for preventing or treating EZH2-mediated diseases, including brain cancer, thyroid cancer, cardiac sarcoma, lung cancer, oral cancer, stomach cancer and various other cancers.

PATENT

US20210308141

Example 4: Preparation of the Compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(trans-3-morpholinylcyclobutoxy)benzamide (4)

[1]. Peng, et al. Polysubstituted benzene compound and preparation method and use thereof.

World Intellectual Property Organization, WO2020020374 A1. 2020-01-30.

//////////Igermetostat

CCN(C1CCOCC1)c2cc(O[C@H]3C[C@@H](C3)N4CCCCC4)cc(C(=O)NCc5c(C)cc(C)[nH]c5=O)c2C

Golcadomide (CC-99282)

(S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione

2-[(3S)-2,6-dioxopiperidin-3-yl]-4-[[2-fluoro-4-[(3-morpholin-4-ylazetidin-1-yl)methyl]phenyl]methylamino]isoindole-1,3-dione

• 2-[(3S)-2,6-Dioxo-3-piperidinyl]-4-[[[2-fluoro-4-[[3-(4-morpholinyl)-1-azetidinyl]methyl]phenyl]methyl]amino]-1H-isoindole-1,3(2H)-dione (ACI)
• (S)-2-(2,6-Dioxopiperidin-3-yl)-4-[[2-fluoro-4-[(3-morpholinoazetidin-1-yl)methyl]benzyl]amino]isoindoline-1,3-dione
• CC 1007548
• CC 99282
• CC-99282
• CC1007548
• Golcadomide
• WHO 12305

Golcadomide HCl, 2639939-36-7

Chemical Name: CC-99282 Hydrochloride; 2-[(3S)-2,6-Dioxopiperidin-3-yl]-4-[[2-fluoro-4-[(3-morpholin-4-ylazetidin-1-yl)methyl]phenyl]methylamino]isoindole-1,3-dione hydrochloride

Novel potent and orally active cereblon (CRBN) E3 ligase modulator

Ref: https://www.sciencedirect.com/science/article/abs/pii/S0268960X22000686

Golcadomide is a modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and antineoplastic activities. Upon administration, golcadomide specifically binds to cereblon (CRBN), thereby affecting the ubiquitin E3 ligase activity, and targeting certain substrate proteins for ubiquitination. This induces proteasome-mediated degradation of certain transcription factors, some of which are transcriptional repressors in T-cells. This leads to modulation of the immune system, including activation of T-lymphocytes, and downregulation of the activity of other proteins, some of which play key roles in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins.

PATENT

US20220324855

Example 1: Synthesis of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (Compound 1)

PATENT

WO2022271557

Example 1: Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3- morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione

[00242] Synthesis of Ethyl 4-nitro-1,3-dioxo-isoindoline-2-carboxylate (Compound 10): To a solution of 4-nitroisoindoline-1,3-dione (Compound 11, 440 g, 2.29 mol) and TEA (262 g, 2.59 mol, 359 mL) in dry DMF (2.2 L) was cooled to 0 °C and ethyl chloroformate (313 g, 2.89 mol, 275 mL) was added dropwise over 5 minutes. The reaction mixture was stirred at 22 °C for 10 hours. The mixture was slowly added to chilled water (10 L) and the resulting suspension stirred for 5 minutes. The suspension was filtered and the filter cake was washed with water (1 L). The solid was dissolved with ethyl acetate (5 L) and the organic phase was washed with aqueous HCl (1 M, 1 L), water (2 L) and brine (2 L). The organic phase was dried over sodium sulfate , filtered and concentrated to give Compound 10 (360 g, 59%) as a white solid. ¹ H NMR (400 MHz CDCl ₃ ) δ ppm 8.24 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.06-8.02 (m, 1H), 4.49 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H).

[00243] Synthesis of tert-Butyl (4S)-5-amino-4-(4-nitro-1,3-dioxo-isoindolin-2-yl)-5-oxo-pentanoate (Compound 6): To a solution of Compound 10 (165 g, 625 mmol) and DIEA (113 g, 874 mmol, 153 mL) in dry THF (1700 mL) was added tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate hydrochloride ( 149 g, 625 mmol) and heated at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with methyl tert-butyl ether (5 L) and stirred at 20 °C for 1 hour. The suspension was filtered and the filter cake was dissolved with DCM (4 L). The organic phase was washed with water (1.5 L x 3), brine (1.5 L) and dried over sodium sulfate . The organic phase was filtered and concentrated under reduced pressure to give a light yellow oil. The oil was diluted with hexane / ethyl acetate (10/1, 2 L) and stirred until a light yellow suspension formed. The suspension was filtered and the filter cake was triturated and concentrated in vacuum to give Compound 6 (175 g, 74%) as a light yellow solid. ¹ H NMR (400 MHz CDCl3) δ ppm 8.12 (d, J = 8.0 Hz, 2H), 7.94 (t, J = 8.0 Hz, 1H), 6.48 (s, 1H), 5.99 (s, 1H), 4.84- 4.80 (m, 1H), 2.49-2.44 (m, 2H), 2.32-2.27 (m, 2H), 1.38 (s, 9H).

[00244] Synthesis of tert-Butyl (S)-5-amino-4-(4-amino-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 5): To a suspension of Compound 6 (170.0 g, 450.5 mmol, 1.00 eq) in DMA (1.00 L) was added palladium on carbon (50.0 g, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen gas (50 psi) at 25 °C for 16 hours. The mixture was filtered and the filtrate was poured into cooled water (3.0 L). The mixture was stirred at 10 °C for 1 hour and filtered. The filter cake was washed with water (700 mL) and dissolved in DCM (1.00 L). The organic phase was dried over sodium sulfate , filtered and concentrated under reduced pressure to give Compound 5 (107 g, 68%) as a green solid. ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 7.52 (s, 1H), 7.43 (dd, J = 8.4, 7.2 Hz, 1H), 7.13 (s, 1H), 6.95-6.99 (m, 2H), 6.42 (s, 2H), 5.75 (s, 1H), 4.47-4.51 (m, 1H), 2.32-2.33 (m, 1H), 2.14-2.20 (m, 3H), 1.32 (s, 9H); HPLC purity, 100.0%; SFC purity, 100.0% ee.

[00245] Synthesis of 2-fluoro-4-(hydroxymethyl)benzaldehyde (Compound 8): To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzaldehyde (370.0 g, 1.38 mol, 1.00 eq ) in THF (1.85 L) was added a solution of p-toluenesulfonic acid monohydrate (78.7 g, 413.6 mmol, 0.30 eq) in water (1.85 L) drop-wise at 10 °C. The mixture was stirred at 27 °C for 16 hours. TEA (80 mL) was added drop-wise and stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (600 mL × 4). The combined

organic phase was washed with brine (1.50 L), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 8 (137.5 g, 76%) as a yellow oil. ¹ H NMR (400 MHz CDCl ₃ ) δ ppm 10.34 (s, 1H), 7.86 (dd, J = 8.0, 7.2 Hz, 1H), 7.25 (s, 1H), 7.22 (d, J = 4.4 Hz, 1H) , 4.79 (d, J = 6.0 Hz, 2H), 1.91 (t, J = 6.0 Hz, 1H).

[00246] Synthesis of tert-Butyl (S)-5-amino-4-(4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)-1,3-dioxoisoindolin-2-yl)-5- oxopentanoate (Compound 2-b): To a solution of Compound 5 (100.0 g, 287.9 mmol, 1.00 eq) and Compound 8 (57.7 g, 374.3 mmol, 1.30 eq) in dry DCM (1.00 L) was added TFA (164.1 g , 1.44 mol, 5.00 eq) at 0 °C. The reaction mixture was stirred at 28 °C for 2 hours. To the solution was added sodium cyanoborohydride (27.1 g, 431.8 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 28 °C for 30 minutes. The reaction mixture was quenched by addition of MeOH (600 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 2-b (110.0 g, 74.0%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.56 (s, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.02-7.18 ( m, 4H), 6.94-7.01 (m, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.47-4.53 (m, 3H), 2.31-2.35 (m, 1H), 2.15-2.22 (m, 3H), 1.31 (s, 9H); HPLC purity, 94.0%; SFC purity, 100.0% ee.

[00247] Synthesis of tert-butyl (S)-5-amino-4-(4-((4-(chloromethyl)-2-fluorobenzyl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 2-a): To a solution of Compound 2-b (100.0 g, 206.0 mmol, 1.00 eq) in NMP (430.0 mL) was added DIEA (79.9 g, 617.9 mmol, 3.00 eq) and MsCl (47.2 g, 411.9 mmol, 2.00 eq) at 0 °C. The ice bath was removed, and the reaction was stirred at 28°C for 10 hours. The reaction was poured into cooled water (<10°C, 2.0 L) and stirred for 10 minutes. The mixture was extracted with methyl tert-butyl ether (750 mL x 3). The combined organic layer was washed with brine (1.25 L), dried over sodium sulfate , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 2-a (86.0 g, 81.2%) as a yellow solid.

¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 7.55 (s, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.38 (t, J = 8.0Hz, 1H), 7.31 (dd, J = 10.8, 1.6 Hz, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (s, 1H), 7.11 (t, J = 6.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 4.61 (d, J = 6.4 Hz, 2H), 4.49-4.53 (m, 1H), 2.29-2.38 (m , 1H), 2.16-2.25 (m, 3H), 1.30 (s, 9H); HPLC purity, 98.0%; SFC purity, 100.0% ee.

[00248] Synthesis of tert-butyl (S)-5-amino-4-(4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)-1,3- dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 2): To a solution of 4-(azetidin-3-yl)morpholine hydrochloride (Compound 7 HCl, 30.5 g, 170.7 mmol, 1.00 eq) and DIEA (66.2 g, 512.0 mmol, 3.00 eq) in DMSO (350.0 mL) was added to a solution of Compound 2-a (86 g, 170.65 mmol, 1.00 eq) in DMSO (350.0 mL) drop-wise at 15 °C. The reaction mixture was stirred at 28 °C for 16 hours. The reaction mixture was poured into cold half saturated brine (<10°C, 2.5 L) and extracted with ethyl acetate (1.50 L, 1.00 L, 800.0 mL). The combined organic phase was washed with saturated brine (1.50 L), dried over sodium sulfate , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 2 (68.3 g, 65.7%) as a yellow solid. ¹ H NMR (400 MHz DMSO-d ₆ ) δ ppm 7.55 (s, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.94-7.10 (m, 5H), 4.56 (d, J = 6.4 Hz, 2H), 4.49-4.52 (m, 1H), 3.54-3.55 (m, 6H) 3.31-3.32 (m, 3H), 2.81-2.88 (m, 3H), 2.29-2.38 (m, 1H), 2.15-2.25 (m, 7H), 1.30 (s, 9H); HPLC purity, 100.0%; SFC purity, 100.0% ee.

[00249] Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione (Compound 1): A solution of Compound 2 (30.0 g, 49.2 mmol, 1.00 eq) and benzenesulfonic acid (31.1 g, 196.8 mmol, 4.00 eq) in acetonitrile (480.0 mL) was stirred at reflux for 3 hours. The reaction was cooled to 20 °C, poured into cold brine:saturated sodium bicarbonate solution (1:1, <10 °C, 2.0 L) and extracted with ethyl acetate (1.0 L). The organic phase was washed with cold brine:saturated sodium bicarbonate solution (1:1, <10°C, 1.00 L) once more. The combined aqueous phase was extracted with ethyl acetate (500.0 mL x 2). The combined organic phase was washed with cold brine (<10°C, 1.0 L), dried over sodium sulfate , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give Compound 1 (17.5 g, 66.0%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.10 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.04-7.10 (m , 4H), 7.00 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.58 (d, J = 6.4 Hz, 2H), 3.53-3.55 (m, 6H) , 3.30-3.32 (m, 2H), 2.81-2.89 (m, 4H), 2.54-2.61 (m, 2H), 2.20 (m, 4H) 2.03-2.06 (m, 1H); HPLC purity, 100.0%; SFC purity, 97.2% ee; LCMS (ESI) m/z 536.1 [M+H] ⁺ .

Example 2: Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3- morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione

[00250] Synthesis of tert-butyl (S)-5-amino-4-(4-nitro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 6): Ethyl acetate (245 mL, 5 V ), 3-nitrophthalic anhydride (49.1 g, 0.25 mol, 1 eq), and tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (59.2 g, 0.25 mol,

1 eq) were charged into a reactor and cooled to 15-20°C. A premade solution of CDI (66.7 g,

0.41 mol, 1.5 eq) in DMF (245 mL, 5 V) was charged and the mixture was stirred at 20-25°C for

1 hour. The reaction was quenched with 15% (wt/wt) aqueous citric acid solution (10 V).

EtOAc (5 V) was added, the mixture was agitated and the phases split and separated. Tea

aqueous layer was extracted with EtOAc (5 V) and the combined organic layers were washed

twice with a 5% (wt/wt) aqueous citric acid solution (5 V each wash). The organic layer was

distilled at reduced pressure to 5 V and further continuously distilled at reduced pressure with the addition of iPrOH (10 V), maintaining a constant volume at 5 V. The final distillate was diluted to 13 V with iPrOH and used in the next step without further handling. 91% solution yield. [00251] Synthesis of tert-butyl (S)-5-amino-4-(4-amino-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 5): The solution of Compound 6 in iPrOH was charged to a hydrogenation reactor. 10% palladium on carbon (50% wet, 4.65g 5 wt%) was charged. The reaction mixture was stirred under 50-60 psi H2 at 40-50 ^o C for 16 hrs. The reaction mixture was filtered and the filter cake was washed three times with iPrOH (1 V each wash). The solution was distilled at reduced pressure to 5 V, cooled to ambient temperature and seeded (1 wt%). Water (20 V) was charged at 20-25 ^o C. The resulting slurry was cooled to 3-8 ^o C for 4-8 hrs. The solids were collected by filtration and washed three times with cold water (1.5 V each wash). The solids were dried at 35-45 ^o C under reduced pressure to give Compound 5 in 87% yield. ¹ H NMR (500 MHz DMSO-d ₆ ) δ (ppm): 7.52 (s, 1H), 7.43 (dd, J = 8.4, 7.0 Hz, 1H), 7.13 (s, 1H), 6.97 (ddd, J = 10.9, 7.7, 0.61 Hz, 2H), 6.43 (s, 2H), 4.49 (m, 1H), 2.33 (m, 1H), 2.17 (m, 3H), 1.32 (s, 9H); HPLC purity, 99.2%; Chiral purity, 99.9% ee; LCMS (ESI) m/z 348.2, [M+H] ⁺ , 292.2 [Mt-Bu+H] ⁺ . Residual IPA: 0.7 mol% by ¹ H NMR.

[00252] Synthesis of 4-(1-(4-bromo-3-fluorobenzyl)azetidin-3-yl)morpholine (Compound 4): A mixture of 4-bromo-3-flurobenzaldehyde (Compound 14, 82 g, 396 mmol ) and 4-(azetidin-3-yl)-morpholine hydrochloride (Compound 7 HCl, 72 g, 396 mmol) in acetonitrile (820 ml) was agitated at 25±5°C for at least 3 hours. The mixture was cooled to 10±5°C and sodium triacetoxyborohydride (130 g, 594 mmol) was added in four portions while maintaining the temperature of the mixture below 30°C. The temperature of the mixture was adjusted to 25±5°C and stirred for at least 30 min until reaction completion. The mixture was transferred to a precooled (10-15°C) solution of aqueous citric acid (152 g in 400 ml water, 792 mmol) while maintaining the temperature below 30°C. Once the quenching process was complete, the mixture was concentrated to ~ 560 ml (7 volumes) while keeping the temperature at or below 45°C. The mixture was then washed with toluene (320 ml). To the aqueous phase was added THF and the pH was adjusted to above 12 with aqueous NaOH solution (320 ml, 10 N). The phases were separated, and the aqueous phase was removed. The organic phase was washed with brine and subsequently concentrated with addition of THF (~ 3L) until KF ≤ 0.10%. The mixture was filtered to remove any inorganics and the product Compound 4 was isolated as a solution in THF with 95% yield.

[00253] Synthesis of sodium (2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)phenyl) (hydroxy)methanesulfonate (Compound 13): A solution of Compound 4 (520 g, 1.58 mol) in

THF (380 ml) was cooled to −15 ± 5 °C. A solution of iPrMgCl ^. LiCl (1.3 M, 1823 ml, 2.37 mol) in THF was added over the course of at least 1 hour while maintaining the temperature below −10 °C. After addition was complete, the temperature of the reaction mixture was adjusted to 0 ± 5 °C and stirred for at least 1 hour. Once magnesiation was complete, the mixture was cooled to −15 ± 5 °C (target −15 °C to −20 °C) and a solution of DMF (245 ml g, 3.16 mol) in THF (260 ml) was added slowly over the course of at least 1 hour while maintaining the temperature below −10 °C. The temperature of the mixture was then adjusted to −15 ± 5 °C and agitated for at least 4 hours.

[00254] Upon reaction completion, the reaction mixture was charged into an aqueous 3 N HCl solution (2600 ml) over the course of at least 1 hour while maintaining the temperature below −5 °C. The temperature of the mixture was then adjusted to 5 ± 5 °C and agitation was stopped, letting the mixture settle for at least 15 minutes. The layers were separated. The lower aqueous layer containing the product was washed with 2-MeTHF (2600 ml). The aqueous layer was then charged with 2-MeTHF (2600 ml) and the temperature of the batch was adjusted to −10 ± 5 °C. To the cooled mixture, an aqueous 5 N NaOH (728 ml, 3.64 mol) solution was added while maintaining the temperature below −5 °C until the pH of the mixture was between 10 and 11. The temperature of the mixture was adjusted to 5 ± 5 °C and agitated for at least 15 minutes. The agitation of the mixture was stopped and the mixture allowed to settle for at least 15 minutes. The layers were separated, and the lower aqueous layer was back extracted two times with 2-MeTHF (2600 ml). The combined organic layer was washed with water (1040 mL) and the organic solution was evaporated to dryness, affording 372 g of crude Compound 3 freebase as an oil (yield 85%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.18 (s, 1H), 7.78 (t, J =7.7 Hz, 1H), 7.23-7.35 (m, 2H), 3.66 (s, 2H), 3.51 -3.60 (m, 4H), 3.26-3.47 (m, 2H), 2.72-2.97 (m, 3H), 2.12-2.32 (m, 4H).

[00255] The crude Compound 3 freebase (4.3 kg) was adsorbed onto silica gel (8.6 kg) with 100% DCM, loaded onto a 60 L column containing 12.9 kg silica gel (packed with 100% DCM), and eluted with DCM ( 86 L), followed successively by 1% MeOH/DCM (40 L), 3% MeOH/DCM (80 L) and 10% MeOH/DCM (40 L). The fractions were collected and concentrated at or below 38˚C to give Compound 3 as a purified oil (3.345 kg, yield 66%).

[00256] A portion of Compound 3 (1.0 kg, 3.59 mol) was dissolved in ethanol (16.0 L, 16

vol) at 20±5 °C and the mixture heated to 40 °C. A solution of Na2S2O5 (622.0 g, 3.27 mol; 0.91 eq) in water (2 L, 2 vol) was prepared at 20±5 °C and added to the freebase solution at 40 °C to obtain an off-white suspension. The batch was agitated and maintained at 40 °C for 2 hrs, then cooled to 20±5 °C and agitated for 1 to 2 hrs. The batch was filtered and washed with ethanol (2×2.0 L, 2×2 vol) to obtain an off-white solid. The wet cake was dried under vacuum at 40 °C for 18 hrs to afford about 1.88 kg of Compound 13.

[00257] Synthesis of 2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzaldehyde (Compound 3): Compound 13 (1.88 kg) was dissolved in ethyl acetate (15.0 L) at 20±5 °C . A 2 M Na ₂ CO ₃ solution (total 15.0 L used) was added to adjust the pH to 10.0. The batch was agitated for 1 to 1.5 hrs at 20±5 °C. After the reaction was complete, the phases were separated and the organic layer was washed with brine (2.0 L). The organic layer was concentrated to dryness at 35-38 °C to afford 852.0 g of Compound 3 as a colorless oil (yield 81%).

[00258] Synthesis of 2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzaldehyde bis-oxalic acid salt (Compound 3 bis-oxalic acid salt): A portion of the Compound 3 oil (187 g, 0.67 mol) was dissolved in isopropanol (1125 ml) and water (375 ml). A first portion (~30%) of this freebase mixture (480 ml) was slowly added over the course of at least 30 minutes to a solution of oxalic acid (125 g, 1.38 mol) in IPA (1125 ml)/water (375 ml) at 60 ± 5 °C. A second portion (~20%) of the freebase mixture (320 ml) was slowly added over the course of at least 30 minutes to the reaction mixture at 60 ± 5 °C. The reaction mixture was agitated at 60 ± 5 °C for at least 90 minutes. A third portion (~25%) of the freebase mixture (~ 400 ml) was slowly added over the course of at least 30 minutes to the reaction mixture at 60 ± 5 °C and the reaction mixture was agitated at 60 ± 5 °C for at least 90 minutes. The remaining freebase solution (400 ml) was slowly added over the course of at least 30 minutes to the reaction mixture at 60 ± 5 °C and the reaction mixture was agitated at 60 ± 5 °C for at least 90 minutes. The temperature of the mixture was adjusted to 20 ± 5 °C (target 20 °C) over the course of at least 1 hour and the mixture was agitated for at least 16 hours at 20 ± 5 °C and then filtered. The cake was washed three times with IPA (2 x 375 ml) and dried in the drying oven at ≤ 40 °C with a slow bleed of nitrogen to afford 261 g of Compound 3 bis-oxalic acid salt (yield 85%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.21 (s, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.42-7.56 (m, 2H), 4.31 (s, 2H), 3.89 -4.03 (m, 2H), 3.75-3.89 (m, 2H), 3.60 (br t, J = 4.3 Hz, 4H), 3.26 (br t, J = 6.9 Hz, 1H), 2.37 (br s, 4H) .

[00259] Synthesis of tert-butyl (S)-5-amino-4-(4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)-1,3- dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 2):

Acetonitrile (6.8 L, 8.0 X Vol) was added to a 30 L jacketed cylindrical reactor. Compound 5 (0.845 kg, 1.00 X Wt) and Compound 3 bis-oxalic acid salt (1.35 kg, 1.60 The contents of the reactor were equilibrated with agitation at 20 ± 5 °C. Trifluoroacetic acid (0.19 L, 0.22 X Vol) was added dropwise, maintaining the batch temperature at 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for no less than 5 minutes and then sodium triacetoxyborohydride (0.13 kg, 015 X Wt) was added as a solid, maintaining the batch temperature at 20 ± 5 °C. The process of adding trifluoroacetic acid and then sodium triacetoxyborohydride was repeated an additional 5 times. After the last addition, the reaction mixture was sampled to determine the reaction progress. The reaction was held at 20 ± 5 °C overnight. The reaction mixture was then quenched with water (3.4 L, 4.0 X Vol), maintaining the batch temperature at 20 ± 5 °C. The mixture was then stirred at 20 ± 5 °C for no less than 30 minutes and the resulting slurry filtered through a 3 L sintered glass filter, directing the filtrates to clean containers. The reactor was rinsed with acetonitrile (0.4 L, 0.5 X Vol) and the rinse passed through the contents of the 3 L sintered glass filter, directing the filtrate to the containers containing the main batch. The contents of the containers were concentrated to ~5 X Vol under reduced pressure at a bath temperature of no more than 30 °C. The residue was transferred to a clean reactor, was rinsing with 2-MeTHF (2.5 L, 3.0 X Vol) to complete the transfer. Additional 2-MeTHF (10.1 L, 12.0 X Vol) was added to the reactor, followed by water (3.4 L, 4.0 X Vol). The mixture was agitated for no less than 15 minutes at 20 ± 5 °C, then allowed to settle for no less than 10 minutes at 20 ± 5 °C before transferring the bottom aqueous layer to new containers. An aqueous sodium bicarbonate solution (5.3 L, 6.3 X Vol, 9% wt/wt) was added to the reactor with stirring over 30 minutes, maintaining batch temperature no more than 25 °C. The mixture was agitated for no more than 15 minutes at 20 ± 5 °C, then allowed to settle for no less than 10 minutes at 20 ± 5 °C before the bottom aqueous layer was transferred to new containers. The aqueous sodium bicarbonate wash was repeated an additional 2 times to reach a pH of about 6.6 for the spent aqueous layer. A saturated aqueous solution of NaCl(0.85 L, 1.0 X Vol) was then added to reactor with agitation. The mixture was agitated for no less than 15 minutes at 20 ± 5 °C, then allowed to settle for no less than 10 minutes before the bottom aqueous layer was transferred to new containers. The remaining organics were concentrated under reduced pressure to a batch volume of ~5 X Vol at a bath temperature of about 40 °C. Acetonitrile (5.1 L, 6.0 X Vol) was added to the residual volume and the resulting solution concentrated to a batch volume of ~ 5 X Vol under reduced pressure at bath temperature of about 40 °C. The process of adding acetonitrile and concentrating under vacuum was repeated two more times to reach the distillation endpoint with a water content of about 1%. The acetonitrile solution was transferred to a clean container along with two 1.7 L (2.0 X Vol) rinses and held at 5 °C overnight. The acetonitrile solution was then filtered through a 3 L sintered glass filter, followed by a 1.7 L (2.0 X Vol) acetonitrile rinse, directing the filtrates to a clean container. The filtrate was transferred to a clean reactor and the container rinsed twice with 1.7 L (2.0 X Vol) of acetonitrile to complete the transfer. Enough acetonitrile (roughly 0.6 L) was added to adjust the total volume in the reactor to about 14 L. A solution assay of the contents of the reactor was obtained to calculate the amount of Compound 2 present for use in the next step (result = 1.3 kg = 1.00 X Wt for remainder of process).

[00260] Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione bis-besylate salt (Compound 1 bis-besylate salt): The solution of Compound 2 in acetonitrile from the previous step was diluted with acetonitrile (roughly 2 L) such that the total volume in the reactor was about 16 L. The solution was cooled with stirring to 10 ± 5 °C and held within that range for 96 hours. Benzenesulfonic acid (1.86 kg, 1.43 X Wt) was added while sparging the reaction mixture with nitrogen gas and maintaining the batch temperature at 10 ± 10 °C. The temperature of the reactor was then adjusted to 20 ± 5 °C and the mixture stirred at that temperature for 60 minutes. The total volume of reaction mixture was adjusted back to 16 L to account for solvent lost during sparging by the addition of acetonitrile (roughly 0.4 L). The reaction mixture was then heated to 55 ± 5 °C over the course of about 30 minutes and held in that range for 15 to 16 hours for reaction completion. The mixture was then cooled to 50 ± 5 °C and MTBE (3.9 L, 3.0 X Vol) was added, maintaining the batch temperature at 50 ± 5 °C. The mixture was allowed to stir at 50 ± 5 °C for about 1.5 hours to establish a self-seeded slurry. Additional MTBE (3.9 L, 3.0 X Vol) was added to the reactor over the course of about 1.75 hours at 50 ± 5 °C. The slurry was cooled to 20 ± 5 °C over the course of about 1.75 hours and held in that temperature range overnight. The slurry was filtered using a Buchner funnel. The reactor was rinsed twice with

MTBE (3.9 L each, 3.0 X Vol) and the rinse was used to wash the solids in the Buchner funnel. The solids were dried on drying trays for about 23 hours at 40 °C under reduced pressure (15-150 mbar), yielding 1.62 kg (77.9%) of Compound 1 bis-besylate salt.

[00261] Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione hydrochloride salt (Compound 1 HCl): A suspension of Compound 1 bis-besylate salt (120 g, 1 equiv.) in 2-MeTHF (25 L/kg) was added to a reactor and agitated at 10 °C. A solution of KHCO ₃ (32.5 g, 2.4 equiv) in water (1.8 L, 6 L/kg) was added to the slurry over the course of 40 minutes. The mixture was stirred for an additional 30 minutes. The batch was then allowed to settle, at which point the aqueous (bottom) layer was separated and discarded. An aqueous solution of NaCl (5%, 5 L/kg, 575 ml) was added to the organic layer and the mixture was agitated for 10 minutes, after which point the temperature was raised to 20 °C. The batch was allowed to settle, at which point the aqueous (bottom) layer was discarded. The brine was repeated a second time.

Additional 2-MeTHF (500 ml) was added to dilute the organic layer, resulting in a concentration of about 20 mg product per ml. A solution of HCl (total 0.98 eq.) in 2-MeTHF was prepared and a portion (20% of total, corresponding to ~0.2 eq.) then added to the reaction mixture over the course of about 10 min. Seeds of Compound 1 hydrochloride (~5% wt) were added, but did not dissolve. The batch was held under vigorous agitation for one hour. To the slurry, the remaining portion of the HCl solution (~0.78 eq.) was added over the course of 3 hours at a constant rate. Vigorous agitation was maintained. After addition was complete, the batch was held for one hour, after which the batch was filtered, washed three times with 3 L/kg of 2-MeTHF . The filter cake was placed in a vacuum oven at 22 °C for 12 hours, at which point the temperature was raised to 40 °C. Dry cake of Compound 1 hydrochloride (58g, 75% yield) was obtained and packaged. Achiral HPLC purity: 98.91%; chiral HPLC purity: 99.68%.

Example 4: Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3- morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione

[00264] Synthesis of tert-butyl (S)-5-amino-4-(4-nitro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 6): To a solution of 3-nitrophthalic anhydride (Compound 12,

35.15 g, 176.6 mmol, 1.00 eq) in ethyl acetate (350 mL) was added tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate hydrochloride (Compound 9 HCl, 43.22 g, 181.1 mmol, 1.025 eq) ), DMF (70

mL) and 2-MeTHF (110 mL) at 25°C. 2,6-Lutidine (23.4 mL, 201 mmol, 1.14 eq) was added

slowly to maintain the temperature at or below 25°C. The mixture was aged at 25°C for 1 hour before being cooled to 5°C. CDI (4.17 g, 25.7 mmol, 0.146 eq) was added and stirred until the temperature returned to 5°C. Another portion of CDI (4.62 g, 28.5 mmol, 0.161 eq) was added and stirred until temperature returned to 5°C. CDI (8.87 g, 54.7 mmol, 0.310 eq) was added and stirred until the temperature returned to 5°C. CDI (8.91 g, 54.9 mmol, 0.311 eq) was added and stirred until the temperature returned to 5°C. The mixture was warmed to 20°C and CDI (16.4 g, 101.1 mmol, 0.573 eq) was added, and the mixture was aged at 20°C for 16 hours. The mixture was cooled to 5°C and a solution of 30 wt% citric acid and 5 wt% NaCl (350 mL) was added slowly while maintaining the temperature. The mixture was warmed to 20°C and aged for 30 minutes. The phases were split and separated. The organic phase was diluted with EtOAc (175 mL) and washed with a solution of 5 wt% citric acid (175 mL), and concentrated by distillation (75 torr, 50°C) to a volume of 175 mL EtOAc. The solvent was changed to iPrOH by constant volume distillation (75 torr, 50°C) with 350 mL iPrOH to a final volume of 175 mL. The distillate was diluted with 200 mL iPrOH to afford Compound 6 as a solution for use in the next step. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.18 – 8.13 (m, 2H), 7.96 (t, J = 7.8 Hz, 1H), 6.34 (s, 1H), 5.59 (s, 1H), 4.90 (dd, J = 10.1, 4.6 Hz, 1H), 2.61 (ddt, J = 14.6, 10.1, 6.1 Hz, 1H), 2.49 (ddt, J = 14.2, 8.7, 5.2 Hz, 1H), 2.44 – 2.29 ( m, 2H), 1.44 (s, 9H).

[00265] Synthesis of tert-butyl (S)-5-amino-4-(4-amino-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 5): To a solution of Compound 6 in iPrOH (375 mL) was added 5% palladium on carbon (1.23 g, 3.5 wt%, wet). The mixture was purged with nitrogen five times and with hydrogen three times. The mixture was pressurized with hydrogen (50 psi) and aged at 50°C for 16 hours. The mixture was cooled to room temperature and purged with nitrogen three times, filtered to remove catalyst, and the filter cake was washed with iPrOH (20mL) three times. The filtrate was concentrated to 200 mL, seeded (0.454 g, 1.3 wt%) at 22 °C, and aged for 45 minutes. Water (1325 mL) was added over 3 hours at 22°C. After the addition of water, the mixture was cooled to 8°C over 2 hours and aged for 1 hour at 8°C. The slurry was filtered, and the cake was rinsed with cold water (200 mL) three times and dried under vacuum at 50°C to yield Compound 5 as a yellow solid (47.97 g, 80.6% yield, 99.62% LC purity, 103% ¹ H NMR potency). ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.46 (dd, J = 8.3, 7.0 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.28 (s, 1H), 5.41 (s, 1H), 5.28 (s, 2H), 4.83 (dd, J = 9.3, 6.0 Hz, 1H), 2.52 (p, J = 7.0 Hz, 2H), 2.36 – 2.29 (m, 2H), 1.44 (s, 9H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ (ppm): 171.80, 171.12, 169.64, 168.27, 145.70, 135.50, 132.20, 121.43, 112.98, 80.99, 53.04, 32.23, 28.02 , 24.36. LCMS (ESI): m/z 291.9 [M+H – tBu]

[00266] Synthesis of 4-(1-(4-bromo-3-fluorobenzyl)azetidin-3-yl)morpholine bis-methanesulfonic acid salt (Compound 4 bis-methanesulfonic acid salt): A mixture of 4-bromo-3- fluorobenzaldehyde (Compound 14, 102 g, 493 mmol) and 4-(azetidin-3-yl)morpholine hydrochloride (Compound 7 HCl, 90 g, 493 mmol) in acetonitrile (1000 ml) was agitated at a temperature of about 20 to 25 °C for 2 to 3 hours. The slurry was cooled to temperature of about 10 to 15 °C and sodium triacetoxyborohydride (STAB, 162 g, 739 mmol) was added in 4 portions over the course of about 45 minutes while maintaining the batch temperature at no more than 30 °C. The slurry was stirred at a temperature of about 20 to 25 °C for at least 30 minutes and then quenched by an aqueous citric acid solution (191 g, 986 mmol in 500 ml of water) at a temperature of about 40 to 45 °C over the course of 2 hours. Upon completion of the quenching process, the batch volume was reduced by vacuum distillation to about 700 ml at a temperature of no more than 45 °C. Cyclopentylmethylether (CPME, 400 ml) was added to the aqueous solution to afford a final volume of about 1100 ml. The pH was adjusted to about 8 to 9 by addition of an aqueous solution of 10 N NaOH (added volume about 430 ml). The phases were separated, and the aqueous phase discarded. The organic phase was washed with brine (100 ml) twice such that the pH was no more than 8 and the volume was adjusted to about 1000 ml with addition of extra CPME. The batch was distilled at constant volume under reduced pressure with addition of CPME until KF was no more than 0.15%. CPME was added (if needed) to adjust the batch to a volume of 1000 ml at the end of distillation. The dry CPME solution was seeded (500 to 750 mg) at ambient temperature. The seeded, dry CPME slurry was heated to a temperature of 50 to 60 °C and then charged with methanesulfonic acid in 200 ml of CPME over the course of 4 to 5 hours. The slurry was then cooled to 20 °C over the course of 4 to 5 hours and kept at 20 °C for 3 to 4 hours, filtered, rinsed with CPME and dried in a vacuum oven at 35 to 40 °C over 16 hours to give Compound 4 bis-methanesulfonic acid salt as a white solid. ¹ H NMR (500 MHz DMSO-d ₆ ) δ (ppm): 10.62 (br s, 1-2H), 7.85 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 9.5 Hz, 1.9 Hz, 1H), 7.34 (dd, J = 8.2 Hz, 1.8 Hz, 1H), 4.55-4.24 (m, 7H), 3.84 (br s, 4H), 3.14 (m, 4H); HPLC purity, 99.8%, LCMS (ESI) m/z 329.1 /331.1[M/M+2] ⁺ . XRPD pattern of the product is shown in FIG.10. DSC thermogram of the product is shown in FIG.11.

[00267] Preparation of 4-(1-(4-bromo-3-fluorobenzyl)azetidin-3-yl)morpholine (Compound 4): A slurry of Compound 4 bis-methanesulfonic acid salt (70 g, 134 mmol) in t -butyl methyl ether was cooled to 10±5°C. An aqueous solution of NaOH (2 N, 201 ml, 403 mmol) was added over the course of at least 30 minutes while maintaining the batch temperature at about 15 °C. After the addition of NaOH , the batch temperature was raised to 20±5°C and agitated over the course of about 20 minutes. The organic layer was separated and washed with water (210 ml) three times. The organic layer was subsequently concentrated with addition of THF (~ 1.05L) until KF ≤ 0.10%. The product Compound 4 was isolated as a solution in THF

with 95% solution yield.

[00268] Preparation of 2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzaldehyde dihydrochloride (Compound 3 di-HCl): A solution of Compound 4 (44 g, 134 mmol) in THF (total volume ~ 350 ml) was then cooled to −20 ± 5 °C. A solution of iPrMgCl ^. LiCl (1.3 M, 176 ml, 228 mmol) in THF was added over the course of half an hour while maintaining the temperature below −10 °C. After the addition was complete, the batch was stirred at −20 ± 5 °C for 16 to 22 hours. DMF (21 ml, 268 mmol) was then added slowly over the course of 30 minutes while maintaining the batch temperature no more than -15 °C. The batch was stirred at −20 ± 5 °C for 6 to 24 hours. 2-MeTHF (350 ml) was then added to the batch over the course of 30 minutes, followed by slow addition of 3 N HCl (235 ml, 704 mmol) while keeping the batch temperature no more than -10 °C. After the addition of aqueous HCl, the batch was warmed to 0 ± 5 °C and 2 N aqueous NaOH (154 ml, 309 mmol) was added slowly to adjust the solution pH to about 8 to 9. The batch was stirred for about 30 minutes and then warmed to 20 ± 5 °C. The organic layer was separated and washed with 15% aqueous NaCl (3 x 140 ml). The organic layer was subsequently concentrated with addition of 2-MeTHF until KF ≤ 0.10%.

[00269] A portion of the free base of 2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzaldehyde (37.4 g, 134 mmol) so obtained was dissolved in 2-MeTHF (total ~ 420 ml) , to which isopropanol (420 ml) and water (21 ml) were added at 20 ± 5 °C. The batch was then heated to 50 ± 5 °C and a solution of HCl in IPA (5 to 6 N, 28 ml, half of total HCl volume) was added over the course of 1 hour. The batch was seeded with 2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzaldehyde dihydrochloride (700 mg) and aged for 1 hour. The remaining HCl (28 ml) was then added over the course of 1 hour. The batch was agitated at 50 ± 5 °C for 4 hours and then cooled to 20 ± 5 °C for 8 hours. The slurry was filtered, washed with IPA (210 ml), and the filter cake dried under vacuum at 50 ± 5 °C to afford Compound 3 dihydrochloride salt (36 g, yield 75%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 12.32-12.55 (m, 1H), 10.23 (s, 1H), 7.93 (t, J =7.6 Hz, 1H), 7.66 (d, J = 10.5 Hz , 1H), 7.58 (d, J = 7.9 Hz, 1H), 4.80 (br s, 2H), 4.48-4.70 (m, 2H), 4.30 (br s, 4H), 3.78-4.00 (m, 5H), 2.93-3.15 (m, 2H). Two polymorphic forms were obtained. XRPD pattern and DSC thermogram of Form A (anhydrous) are shown in FIG.5 and FIG.6, respectively. XRPD pattern, TGA thermogram and DSC thermogram of Form B (hydrate) are shown in FIG.7, FIG.8, and FIG.9, respectively.

[00270] Synthesis of tert-butyl (S)-5-amino-4-(4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)-1,3- dioxoisoindolin-2-yl)-5-oxopentanoate (Compound 2): A mixture of Compound 5 (12 g, 34.5 mmol, 1.0 eq) and Compound 3 dihydrochloride (14.56 g, 41.5 mmol, 1.2 eq) in MeCN (96 ml) was cooled to 0-5 °C. Trifluoroacetic acid (TFA, 2.0 ml, 26 mmol, 0.75 eq) was added, followed by sodium triacetoxyborohydride (STAB, 2.75 g, 12.95 mmol, 0.375 eq) while maintaining the internal temperature below 10 °C. The addition of TFA and STAB was repeated three additional times. After a total of four additions of TFA and STAB, the reaction was aged at 0-5°C for 1 hour. A 10% brine solution (108 ml) was then added to the reaction mixture over the course of 1 hour and partitioned with IPAc (96 ml). The mixture was warmed to 20-25 °C and aged for 30 minutes. The layers were then separated and the organic layer was washed with 2.0 M K3PO4 (114 ml). The pH of the spent aqueous layer should have a pH of about 8.5 – 9.0. The layers were separated again and the organic phase was washed with 8.5% NaHCO ₃ (2 x 60 ml), with 30 minutes between each wash, followed by 24% brine (60 ml). The organic fraction was distilled to 72 ml at an internal temperature near 50°C. Toluene (72 ml) was added to bring the volume to 144 ml and distillation continued at constant volume at 50°C with feed and bleed until water content < 0.1. The mixture was heated to 50°C and acetonitrile (48 ml) was added, followed by slow addition of heptane (144 ml) while maintaining the internal temperature above 45 °C. The reaction was held at 50 °C for 2 hours. Once complete, the reaction was slowly cooled to 20-25°C over the course of 4 hours and held at 20-25°C overnight (16 hour). The yellow slurry was then filtered and the yellow cake displacement washed with 1:3:3 mixture of acetonitrile/heptane/toluene (3 x 48 ml). The final cake was then dried under reduced pressure at 50 °C under nitrogen to provide Compound 2 (87.7% isolated molar yield) with >99.0% LCAP. HPLC purity, 99.85%; Chiral purity, >99.9% ee. ¹ H NMR (DMSO-d6, 500 MHz) δ (ppm) 7.55 (s, 1H), 7.51 (dd, J = 7.2, 8.4 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.16 ( s, 1H), 7.0-7.1 (m, 5H), 4.57 (d, J = 6.3 Hz, 2H), 4.5-4.5 (m, 1H), 3.5-3.6 (m, 6H), 3.3-3.4 (m, 3H), 2.8-2.9 (m, 3H), 2.3-2.4 (m, 1H), 2.1-2.3 (m, 7H), 1.31 (s, 9H); LCMS m/z 610.3 [M+H] ⁺ .

[00271] Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione bis-besylate salt (Compound 1 bis-besylate): To a suspension of Compound 2 (130 g, 1.0 equiv.) in MeCN (1.56 L, 12 L/kg) agitated at 55 °C was added a solution of benzene sulfonic acid (185 g, 5.5

equiv.) in MeCN (0.39 L, 3 L/kg) and water (0.01 L, 2.0 equiv.). The mixture was stirred at 55 °C for 16 hours. After the reaction age, crystalline seeds (1.3 g, 1 wt%) of bis-besylate salt of Compound 1 were charged into the batch, resulting in formation of a yellow slurry. The slurry was then cooled to 20 °C over the course of 90 minutes. 2-MeTHF (1.3 L, 10 L/kg) was added to the batch slowly over 2 hours at 20 °C. The batch was agitated for an additional 4 hours at 20°C. The yellow slurry was then filtered and the yellow cake re-slurried with MeTHF (1.3 L, 10 L/kg) followed by a displacement MeTHF (0.65 L, 5 L/kg) wash. The final cake was then dried under reduced pressure at 50 °C under nitrogen to give Compound 1 bis-besylate salt (160 g, 88.4% yield). HPLC purity: 98.39%; chiral HPLC purity: 100%. XRPD pattern, TGA thermogram and DSC thermogram of the product are shown in FIG.1, FIG.2, and FIG.3, respectively.

[00272] Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline -1,3-dione hydrochloride salt (Compound 1 HCl): A suspension of Compound 1 bis-besylate salt (300 g, 1 equiv.) in EtOAc (4.68 L, 15.6 L/kg) and 2-propanol (0.12 L, 0.4 L/kg) was agitated at 15 °C. To the suspension was added a solution of KHCO ₃ (82.4 g, 2.5 equiv) in water (1.8 L, 6 L/kg) over 30 minutes. The mixture was heated to 20 °C over 30-60 minutes and then agitated for 30 minutes. The batch was allowed to settle for 30 minutes, at which point the aqueous (bottom) layer was discarded. To the rich organic layer was added water (1.2 L, 4 L/kg) and the reactor contents were agitated for 30 minutes. The batch was allowed to settle for 30 minutes, at which point the aqueous (bottom) layer was discarded. To the rich organic stream was added 2-propanol (2.375 L, 7.9 L/kg) and the stream was then filtered. Water was added to the filtrate to adjust the water content to 8≤KF≤8.2. To the above agitated solution at 20 °C was added 0.2 N HCl (38 mL, 0.025 equiv prepared in EtOAC/IPA 2:1, v/v with 8wt% water) over 10 minutes. To the mixture was added crystalline seeds of Compound 1 hydrochloride salt (1.6 g, 0.5wt%) and the contents of the reactor were agitated at 20 °C for 30 minutes. To the suspension was added 0.2 N HCl (1.44 L, 0.945 equiv. prepared in EtOAC/IPA 2:1, v/v with 8 wt% water) over 4.5 hours. The slurry was agitated for 14 hours, then filtered and washed with EtOAC/IPA (750 mL, 2.5 L/kg, 2:1 v/v with 8 wt% water) followed by IPA (750 mL, 2.5 L/kg). The solids were dried under vacuum at 40 °C to afford Compound 1 hydrochloride salt (170 g, 90% yield). Achiral HPLC purity: 99.91%; chiral HPLC purity: 99.58%. XRPD analysis (FIG.4) confirmed the product (a)

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//////////Golcadomide, CC 99282, CC 1007548, WHO 12305

C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)NCC4=C(C=C(C=C4)CN5CC(C5)N6CCOCC6)F

INAXAPLIN, 2446816-88-0

• 2446816-88-0
• S2SJ2RVZ6Y
• UNII-S2SJ2RVZ6Y
• C₂₁H₁₈F₃N₃O₃

3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide

Inaxaplin (VX-147) is a small-molecule apolipoprotein L1 inhibitor developed by Vertex Pharmaceuticals for APOL1-mediated kidney disease. In preliminary studies the drug has shown promise in treating people with kidney disease and multiple gain of function mutations on the APOL1 gene.^[1][2]

    FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetics support a causal role for the G1 and G2 APOL1 variants in inducing kidney disease. Individuals with 2 APOL1 risk alleles are at increased risk of developing primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, and NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids. Corticosteroids induce remission in a minority of patients and are associated with numerous side effects. These patients, in particular individuals of recent sub-Saharan African ancestry with 2 APOL1 risk alleles, experience rapid disease progression leading to end-stage renal disease (ESRD). Thus, there is an unmet medical need for treatment for FSGS and NDKD.

PATENT

US20230271945, Compound 2

Compound 2

3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (2)

Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (2)

Alternative Procedure for Synthesis of Compound (2)

Step 1. Synthesis of Methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51)

Step 2. Synthesis of Methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic Acid (S12)

Step 4. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (2)

Re-Crystallization of Compound 2

Form A of Compound 2

Hydrate Form A of Compound 2

PATENT

US20230271945, Compound 88

PATENT

US20230271945, Compound 89

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//////////

References

1. ^ Gbadegesin, Rasheed; Lane, Brandon (August 2023). “Inaxaplin for the treatment of APOL1-associated kidney disease”. Nature Reviews Nephrology. 19 (8): 479–480. doi:10.1038/s41581-023-00721-0. PMC 10461697. PMID 37106136.
2. ^ Egbuna, Ogo; Zimmerman, Brandon; Manos, George; Fortier, Anne; Chirieac, Madalina C.; Dakin, Leslie A.; Friedman, David J.; Bramham, Kate; Campbell, Kirk; Knebelmann, Bertrand; Barisoni, Laura; Falk, Ronald J.; Gipson, Debbie S.; Lipkowitz, Michael S.; Ojo, Akinlolu; Bunnage, Mark E.; Pollak, Martin R.; Altshuler, David; Chertow, Glenn M. (16 March 2023). “Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants”. New England Journal of Medicine. 388 (11): 969–979. doi:10.1056/NEJMoa2202396. PMID 36920755. S2CID 257534251.

………///////INAXAPLIN

Danicopan

USFDA 3/29/2024, To treat extravascular hemolysis with paroxysmal nocturnal hemoglobinuria, Voydeya

C₂₆H₂₃BrFN₇O₃

580.418

• 1903768-17-1

(2S,4R)-1-[2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl]-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide

• ACH 0144471
• ACH-4471
• ACH0144471
• ALXN 2040
• ALXN-2040
• ALXN2040

Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.^[2] It is a complement inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated hemolysis and deposition of complement C3 proteins on red blood cells.^[2]

Danicopan was approved for medical use in Japan in January 2024, and in the United States in March 2024.^[3][4]

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematologic disease characterized by hemolysis, thrombophilia, and bone marrow dysfunction.^1,7 Both hemolysis and thrombophilia are mediated primarily by the complement system.¹ Standard therapy for PNH involves the use of complement C5 inhibitors (e.g. eculizumab, ravulizumab) which are effective in mitigating complement-mediated intravascular hemolysis and thromboembolism.¹ Unfortunately, complement C5 inhibition does not address C3-mediated extravascular hemolysis, which occurs earlier in the complement cascade within the alternative pathway.^1,5

Danicopan is a small molecule complement factor D inhibitor that selectively blocks the alternative pathway, thereby working to address extravascular hemolysis when used in conjunction with C5 inhibitors.³ It was first approved in January 2024 in Japan for patients with PNH,^2,6 shortly after which the EMA adopted a positive opinion and recommended granting it marketing authorization.² It was subsequently approved by the FDA in March 2024.⁴

SYN

WO2015130795

SYN

https://patents.google.com/patent/US9796741

SYN

PAT

https://patents.google.com/patent/US20230094124A1/en

https://patents.google.com/patent/US20230094124A1/en

• Step 1: Synthesis of tert-Butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl) fluoropyrrolidine-1-carboxylate (3): N-Boc-trans-4-Fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor under an atmosphere of nitrogen. The reaction mixture was cooled to 0±5° C. and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0±5° C. Methanesulfonyl chloride (29.97 kg) was slowly added to the reaction mixture followed by the addition of 2-amino-6-bromopyridine (2). The reaction temperature was warmed to room temperature and stirred for 12 h. The reaction was monitored by HPLC. After completion of the reaction water (2,000 kg) was added, the reaction was stirred and the DCM layer separated. The aqueous layer was once more extracted with DCM (1000 L). The combined DCM layer was washed in succession with dilute HCl, aqueous NaHCO₃ and brine. The DCM extract was evaporated to dryness and tert-butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (3) was isolated using DCM heptane mixture and dried. Yield, 71.76 Kg (84.86%))
• [0404]
  Step 2: Synthesis of (2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (4): To a solution 4M HCl/Dioxane (168 kg) was added intermediate 3 (40 kg) at 25±5° C. under an atmosphere of nitrogen and the reaction was stirred for 1 h. The reaction was monitored by HPLC and after completion, the reaction was diluted with DCM (800 L) and washed with aqueous NaHCO₃. The DCM layer was separated and concentrated. The product, 2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide, (4), was isolated using DCM/heptane and dried. Yield, 25.81 kg, 87%.
• [0405]
  Step 3: Synthesis of tert-Butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (6): 1-(5-Bromo-1H-indazol-yl)ethan-1-one (5, 30 kg) was added to a reactor containing DMF (210 L) under an atmosphere of nitrogen followed by potassium carbonate (4.05 kg). Tert-butyl bromoacetate (3.42 kg) was added to the reaction mixture with stirring and maintaining the temperature at 30±10° C. After addition was complete, the reaction mixture was heated at 50±5° C. for 1 h. After the reaction was complete the reaction mixture was cooled to 25±5° C. and diluted with water (630 L). The precipitated solid was filtered, washed with water (90 L) and dried. Yield, 43.13 kg, 97.13%.
• [0406]
  Step 4: Synthesis of tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (9): Bispinnacolato diboron (14.67 kg) was added to a solution of 4-bromo methylpyrimidine (7, 10 kg) in dioxane (206 kg) under an atmosphere of nitrogen followed by the addition of potassium acetate (17 kg). The reaction mixture was degassed using nitrogen. Pd(dppf)Cl₂ (0.94 kg) was added and the reaction mixture heated to 90±5° C. until the pyrimidine was consumed. The reaction mixture was cooled to 25±5° C. and intermediate 6 (16.33 kg) was added followed by potassium carbonate (20.7 kg) and water (16.33 kg) and the reaction was degassed using nitrogen. The reaction was again heated to 90±5° C. until completion. The reaction mixture was cooled to 25±5° C. and diluted with ethyl acetate (269 kg) and water (150 kg) maintaining the temp at 10±5° C. Activated charcoal (1 kg) was added to the mixture with stirring and then filtered through a bed of celite. The ethyl acetate layer was separated, washed with 5% aqueous sodium chloride followed by 5% L-Cysteine solution to remove palladium related impurities. The ethyl acetate layer was evaporated to dryness. The product (9) was isolated from MTBE/heptane. Yield, 11.8 kg, 56%.
• [0407]
  Step 5: Synthesis of 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (10): To a stirred solution of intermediate 9 (50 kg) in DCM (465 kg) at 15±5° C. was added TFA (374.5 kg) while maintaining the said temperature. The reaction was warmed to 35±5° C. and stirring continued until completion of the reaction. DCM and TFA were distilled off under reduced pressure. The residue was dissolved in DCM (kg) and stirred with aqueous sodium bicarbonate. The biphasic mixture was acidified with concentrated HCl and the pH was adjusted to 2-3. The precipitated solid was filtered, washed with water and dried. Yield, 42.4 kg, quantitative.
• [0408]
  Step 6: Synthesis of Compound 1: To a solution of intermediate 9 (42 kg) in DMF (277 kg) was added intermediate 4 (38.7 kg) and the reaction was cooled to 10±5° C. Coupling agent TBTU (56.7 kg) was added to the reaction mixture followed by the addition of DIPEA (86.5 kg) while maintaining the reaction temperature at 10±5° C. The reaction was warmed to 25±+5° C. and stirred until complete. The reaction mixture was diluted with ethyl acetate (1344 kg) and washed with water twice. (The reaction may be washed with aq. K₂CO₃ if fluorine related impurities are present.) Anhydrous sodium sulfate was added to silica gel and added to the ethyl acetate layer and filtered. The ethyl acetate layer was passed over a column of silica gel (40 kg) and the pure fractions were collected. The fractions were treated with activated charcoal and then filtered over celite. The palladium content was checked, and if above 10 ppm, the ethyl acetate layer was treated with palladium scavenging resin (SilabondThiol®). The ethyl acetate was evaporated to dryness under vacuum and the residue was crystallized from IPA (crystalline seed may be added) and heptane to afford Compound 1 Form II. Yield, 60 kg, 78%.

Society and culture

Legal status

In February 2024, the Committee for Medicinal Products for Human Use of the EMA adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Voydeya, intended as add-on therapy to ravulizumab or eculizumab for the treatment of residual hemolytic anemia in adults with paroxysmal nocturnal hemoglobinuria (PNH).^[2][5] The applicant for this medicinal product is Alexion Europe.^[2]

Names

Danicopan is the international nonproprietary name.^[6]

References

1. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration. 1 April 2024. Retrieved 2 April 2024.
2. ^ Jump up to:^a b c d “Voydeya EPAR”. European Medicines Agency. 22 February 2024. Archived from the original on 23 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
3. ^ “Voydeya (danicopan) granted first-ever regulatory approval in Japan for adults with PNH to be used in combination with C5 inhibitor therapy”. AstraZeneca (Press release). 19 January 2024. Archived from the original on 24 February 2024. Retrieved 24 February 2024.
4. ^ Research Cf (4 April 2024). “Novel Drug Approvals for 2024”. FDA.
5. ^ “First oral treatment against residual hemolytic anemia in patients with paroxysmal nocturnal hemoglobinuria”. European Medicines Agency (EMA) (Press release). 23 February 2024. Retrieved 24 February 2024.
6. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1). hdl:10665/330896.

Further reading

• Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, et al. (December 2023). “Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial”. The Lancet. Haematology. 10 (12): e955–e965. doi:10.1016/S2352-3026(23)00315-0. PMID 38030318.

External links

• “Danicopan (Code C148181)”. NCI Thesaurus.

//////////fda 2024, Voydeya, danicopan, approvals 2024, ACH-4471, ACH 4471, ACH 0144471, ACH-4471, ACH0144471, ALXN 2040, ALXN-2040, ALXN2040

C₂₀H₂₂N₈O₆S₂

534.57

209467-52-7

(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(N-hydroxyimino)acetamido]-8-oxo-3-{[(3E,3’R)-2-oxo-[1,3′-bipyrrolidin]-3-ylidene]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

• BAL-9141
• BAL-9141-000
• BAL-9141000
• BAL9141-000
• RO 63-9141
• RO-63-9141
• RO-639141

ceftobiprole medocaril sodium

• Ro-655788
• BAL-5788-001

fda approved 4/3/2024, To treat certain bloodstream infections, bacterial skin and associated tissue infections, and community-acquired bacterial pneumonia
Press Release  zevtera

Ceftobiprole, sold under the brand name Zevtera among others, is a fifth-generation^[5] cephalosporin antibacterial used for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia. It is marketed by Basilea Pharmaceutica under the brand names Zevtera and Mabelio.^{[6][7][8][9][10][11]} Like other cephalosporins, ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. Ceftobiprole has high affinity for penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus strains and retains its activity against strains that express divergent mecA gene homologues (mecC or mecALGA251). Ceftobiprole also binds to penicillin-binding protein 2b in Streptococcus pneumoniae (penicillin-intermediate), to penicillin-binding protein 2x in Streptococcus pneumoniae (penicillin-resistant), and to penicillin-binding protein 5 in Enterococcus faecalis.^[12]

Medical uses

In the US, ceftobiprole is indicated for the treatment of adults with Staphylococcus aureus bloodstream infections (bacteremia) including those with right-sided infective endocarditis;^[4] adults with acute bacterial skin and skin structure infections;^[4] and people with community-acquired bacterial pneumonia.^[4]

Microbiology

Ceftobiprole has shown in vitro antimicrobial activity against a broad range of Gram-positive and Gram-negative pathogens. Among the Gram-positive pathogens, ceftobiprole has demonstrated good in vitro activity against methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, as well as against strains of methicillin-resistant Staphylococcus aureus with reduced susceptibility to linezolid, daptomycin or vancomycin.^[13] Ceftobiprole has also displayed potent activity against Streptococcus pneumoniae (including penicillin-sensitive, penicillin-resistant and ceftriaxone-resistant strains) and Enterococcus faecalis, but not against Enterococcus faecium. For Gram-negative pathogens, ceftobiprole has shown good in vitro activity against Haemophilus influenzae (including both ampicillin-susceptible and ampicillin-non-susceptible isolates), Pseudomonas aeruginosa and strains of Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis that do not produce extended-spectrum β-lactamases (ESBL). Like all other cephalosporins, ceftobiprole was inactive against strains that produce extended-spectrum β-lactamases.^[14]

The efficacy of ceftobiprole has been demonstrated in two large randomized, double-blind, phase 3 clinical trials in patients with hospital-acquired and community-acquired pneumonia. Ceftobiprole was non-inferior to ceftazidime plus linezolid in the treatment of hospital-acquired pneumonia (excluding ventilator-acquired pneumonia) and non-inferior to ceftriaxone with or without linezolid in the treatment of community-acquired pneumonia.^[15][16]

Pharmacology

Ceftobiprole is the active moiety of the prodrug ceftobiprole medocaril and is available for intravenous treatment only. It is mainly excreted via the kidney.^[17]

Society and culture

Legal status

Ceftobiprole has been approved for the treatment of adults with hospital acquired pneumonia (excluding ventilator-acquired pneumonia) and community-acquired pneumonia in twelve European countries, Canada, and Switzerland.^[18]

In February 2010, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a negative opinion, recommending the refusal of the marketing authorization for the medicinal product Zeftera, intended for treatment of complicated skin and soft-tissue infections in adults. The company that applied for authorization is Janssen-Cilag International N.V. The applicant requested a re-examination of the opinion. After considering the grounds for this request, the CHMP re-examined the opinion, and confirmed the refusal of the marketing authorization in June 2010.^[19]

syn

https://www.sciencedirect.com/topics/neuroscience/ceftobiprole

syn

WO2010136423

Processes for producing ceftobiprole medocaril are known per se. What the processes known from the prior art have in common is that, starting from 7-aminocephalosporanic acid, a large number of intermediates have to be produced, isolated and purified in order to obtain ceftobiprole medocaril of the general formula (1) in sufficient purity.

The compound of the general formula (1) is known per se and is described, for example, in WO 99/65920. It can be used for the treatment and prophylaxis of bacterial infectious diseases, especially infectious diseases caused by methicillin-resistant Staphylococcus Aureus strains.

WO 99/65920 describes, as the last step in the production process of ceftobiprole Medocaril, a reaction in which the Medocaril prodrug unit is introduced into a compound of the general formula (2).

The compound of the general formula (2) is also known per se and has been described, for example, in EP 0 849 269 A1. The compound of the general formula (2) is prepared according to EP 0 849 269 A1 starting from (2R,6R,7R)-te rt. B u toxyc abonylamin o-3-formyl-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester by Wittig reaction with (1 ‘-allyloxycarbonyl-2- oxo-[1,3’]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide. The resulting Δ2 reaction product is reisomerized to the desired Δ3 isomer by sulfoxidation and subsequent reduction and then deprotected from the benzhydryl ester with trifluoroacetic acid. The acylation in position 7 occurs by reaction with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)-trityloxyiminothioacetic acid S-benzothiazol-2-yl ester. The compound of the general formula (2) is then obtained by removing the protective groups.

In EP 1 067 131 A1 the formation of the ylide in toluene or a mixture of toluene and dichloromethane is tert by adding alkali. Butylate in tetrahydrofuran, which allows the base to be added as a solution. The reaction of the ylide with the corresponding aldehyde is described at a reaction temperature of -70 ⁰ C.

EP 0 841 339 A1 relates to cephalosporin derivatives and processes for their production. WO 95/29182 also discloses intermediates for the production of cephalosporins.

WO 01/90111 describes a further production of ceftobiprole Medocaril in several stages starting from desacetyl-7-aminocephalosporanic acid by acylation with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)- trityloxyiminothioacetic acid S-benzothiazol-2-yl ester in N,N-dimethylformamide, followed by in situ esterification with diphenyldiazomethane in dichloromethane to give the corresponding benzohydryl ester, which is precipitated and isolated by adding hexane. In the next step, this product is oxidized to the corresponding aldehyde using TEMPO/NaOCI in dichloromethane/water or with Braunstein in tetrahydrofuran/dichloromethane. The next reaction step involves the Wittig reaction to the 3-vinyl-substituted derivative, in which the reaction takes place in dichloromethane/toluene/tetrahydrofuran at -78°C. The crude product is stirred with ethanol and made from dichloromethane/tert. Butyl methyl ether recrystallized or purified chromatographically. According to the method disclosed in WO 01/901 11, the Wittig reaction is carried out at low temperatures of -80 to -70 ⁰ C in a complex solvent mixture of dichloromethane, toluene and tetrahydrofuran. This leads to significant disadvantages when carrying out the reaction on a production scale, since regeneration of the process solvents is difficult.

EXAMPLES

1. Example: (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[I.S’lbipyrrolidinyl-S-ylidenemethyll-β- oxo-S-thia-i -aza-bicyclo^^.Oloct^-ene-2-carboxylic acid

5 , 1 4 g of 7-amino-3-formyl-ceph-3-em-4-carboxy I at was dissolved in 2 7 , 8 m bis(trimethylsilyl)acetamide and 50 ml propylene oxide. ^16.8 g of (1 R/S,3’R)-(1′-tert-butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02/14332) slowly added in portions. Stirring was continued at 1 ° C until the starting material had reacted and then the crystalline precipitate was added

Nitrogen atmosphere filtered off and washed with 50 ml cyclohexane/bis(tirmethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the desired product was obtained in silylated form.

The material was dissolved in 100ml dichloromethane and at 0 ⁰ C with 50ml 3%

NaHCC> ₃ solution added. The phases were separated, the organic phase was washed with 30 ml of water and the combined water phases were adjusted to pH 3.5 with 3% H ₃ PO ₄ after activated carbon treatment. The crystalline precipitate was filtered, washed with water and dried under vacuum.

Auswaage: 6,09g

¹H-nmr(DMSO-d₆) δ 1.39(s,9H), 2.00(m, 2H), 2.8-3.2(m, 2H), 3.2-3.5(m,6H), 3.84(ABq, 2H, J= 18.2Hz), 4.57(m,1H), 4.82(d,1H, J=5.1Hz), 5.01 (d,1H, J=5.1Hz), 7.21 (m,1H)

¹³ C-nmr(DMSO-d ₆ ) d 24.63, 26.11 , 28.09, 28.89, 41.54, 44.94, 45.31 , 47.98, 48.34, 51.27, 52.00, 58.98, 63.76, 79.95, 121.95 , 126.19, 126.28, 129.90, 134.21, 154.97 , 164.36, 169.05, 169.13

MS- ESI negative mode: 927.2(2M-H, 100%, 463.1(M-H, 25%)

H2O content: _2.2 %

IR (golden gate, cm^“1): 2978, 1793, 1682, 1551, 1397, 1363, 1330

2. Beispiel: (6R,7R)-7-Trimethylsilylamino-3[E-(R)-1′-(5-tert.butyloxycarbonyl)-2- oxo-[1 , 3′]bipyrrolidinyl -3 -ylidenemethyll-δ-oxo-δ-thia-i-aza-bicyclo^^.0]oct- 2-ene-2-carbonsäure trimethylsilylester

10.28 g of 7-amino-3-formyl-ceph-3-em-4-carboxylate were dissolved in 55.6 ml of bis(trimethylsilyl)acetamide and 100 ml of propylene oxide. 33.6 g of (1R/S, 3’R)-(1′-tert. Butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02.) were then added at 0 ⁰ C /14332) slowly added in portions over 22 hours. The mixture was stirred at 1° C. until the starting material had reacted and then the reaction mixture was cooled to -20 ^° C. The crystalline precipitate was filtered off under a nitrogen atmosphere and washed in portions with 180 ml of cyclohexane/bis(trimethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the bissilylated

Product received.

Weight: 16.2g

¹H-nmr(CDCI₃) δ 0.04,0.10,0.12(3s, 9H), 0,34(s, 9H), 1,43 (s, 9H), 1.74 (br s, 1H),

1.9-2.2 (m, 2H), 2.8-3.0 (m,2H), 3.2-3.7 (m,8H), 4.7-4.95 (m, 3H), 7.43 (m, 1H)

3. Beispiel: Dicyclohexylammonium (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert. butyloxycarbonyl)-2-oxo-[1 ,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1 – aza-bicyclo[4.2.0]oct-2-ene-2-carboxylat

1.0g (6R,7R)-7-Trimethylsilylamino-3[E-(R)-1′-(5-tert.butyloxycarbonyl)-2-oxo-[I.Slbipyrrolidinyl-S-ylidenemethyO-δ-oxo-δ -thia-i-aza-bicyclo^^.Oloct^-ene^- carboxylic acid trimethylsilyl esters were dissolved in 10ml dichloromethane and a solution of 300mg dicyclohexylamine in 1ml EtOH and 10ml ethyl acetate was added. The precipitate was filtered off, washed with ethyl acetate and dried in vacuo.

Auswaage: 0,9g ¹H-nmr(D₂O/DMSO-d₆) δ 0.9-1 .3(m, 10H), 1 .30(s,9H), 1 .4-2.18m,12H), 2.7- 3.5(01,1 OH), 3.64(ABq, J= 17.2Hz, 2H), 4.5 (m,1 H) ^* , 4.58 (d,1 H, J=5.1 Hz); 4.88 (d,1 H, J=5.1 Hz), 7.07 (s,1 H)

^* partly overlaid by D20 signal

MS- ESI negative mode: 927.2(2M-H, 100%), 463.1 (M-H, 25%)

IR (golden gate, cm ^“1): 2932, 2856, 1754, 1692, 1671 , 1630, 1569, 1394, 1329

4. Specifically: (6R, 7R )-7-[(Z)-2-(5-Amino-[1 ,2,4]thiadiazol-3-yl)-2-hydroxyimino- acetylamino]-8-oxo- 3-[(E)-(R)-2-oxo-[1 , 3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-jen-2 carbons Trifluoroacetate

4.1 Variant A:

3.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 150 ml of dichloromethane at 0°. 600 μl of DMF/water 5/1 and 1.8 ml of bis(trimethylsilyl) acetamide and 2.29 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetic acid chloride were then added Hydrochoride (J. Antibiotics 37:557 – 571, 1984) was added in portions.

After 3 hours at 0°, the mixture was poured into 30 ml MeOH/120 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 66g and 25ml of trifluoroacetic acid was added. After 10 minutes, 1.5 ml triethylsilane and 10 ml water were added and the mixture was cooled to -15 ° C. The organic phase was separated off and again with 6 ml

Washed trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 150 ml with water and filtered through an adsorber resin column with XAD-1600. After washing out the column with water, elution was carried out with water/acetonitrile 85/15. The product-containing fractions were concentrated in vacuo and allowed to stand at 0° for post-crystallization. The crystalline

Product was filtered off, washed with water and dried under vacuum.

Auswaage: 2,66g

4.2 Variant B:

7.4g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid was dissolved at 0° in 781 ml of dichloromethane with the addition of 6.7 ml of triethylamine. 8.65 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid chloride hydrochloride were then added in portions. After the starting material had reacted, the mixture was poured into 500 ml of water and the methylene chloride phase was separated off. The organic phase was dried over Na ₂ SC> ₄ and concentrated in vacuo.

The residue was dissolved in 148 ml of dichloromethane and 4.5 ml of triethylsilane and 74 ml of trifluoroacetic acid were added at room temperature. After 30 minutes, 222 ml of dichloromethane and 222 ml of water were added and the mixture was cooled to -20 ⁰ C. The organic phase was separated off and washed again with a mixture of 37 ml of trifluoroacetic acid and 148 ml of water. The combined aqueous phases were diluted with water to 364 ml, filtered through an adsorber resin and eluted with acetonitrile/water 15/85.

The filtrate was concentrated to 35g on a Rotavapor, filtered and washed with water.

After drying in a vacuum, 4.5 g of the sample was obtained.

¹H-nmr(DMSO-d₆) δ 1.9-2.2(m,2H), 2.8-3.5(m, 8H), 3.85(Abq, 2H; J=18.3Hz), 4.63(m,1 H), 5.16(d, 2H, J=4.9Hz), 5.85(dd, 1 H, J1 = 4.9Hz, J2=8.4Hz), 7.23(s, 1 H),

8.06(s, 2H), 9.08 (br. s, 2H), 9.49(d, 2H, J=8.4Hz), 1 1.95 (s, 1 H)

5. Being typical: (6R.7R )-7-[(Z)-2-(5-Amino-[1 ,2,4]thiadiazol-3-yl)-2-hydroxyimino- acetylamino]- 8-oxo- . 3-[(E)-(R)-2-oxo-[1 ,3′]bipyrrolidinyl-3-ylidenemethyl]-5- thia-1 -aza-bicyclo[4.2.0]oct-2-jan-2 carbons

6.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 300 ml of dichloromethane at 0°. 1200 μl of DMF/water 5/1 and 8.1 ml of bis(tirmethylsilyl)acetamide were then added as well as 5.3g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid chloride Hydrochoride (J. Antibiotics 37:557 – 571, 1984) added in portions. The mixture was then poured into 60 ml MeOH/240 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 48g and 1.5 ml of triethylsilane was added. After adding 50ml

Trifluoroacetic acid was stirred at room temperature for 60 min, 20 ml of water was added and the mixture was cooled to -15°C. The organic phase was separated off and washed again with 20 ml trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 500 ml with water and treated with 2.0 g of activated carbon. After filtration, the solution was concentrated in vacuo.

The residue was diluted to 50 ml with water and adjusted to pH 6.9 with saturated NaHCO ₃ solution. The mixture was stirred at 0 ⁰ C for 2 hours, filtered and the precipitate washed with water.

Auswaage: 4,5g

¹H-nmr(DMSO-d₆/CF₃COOD) δ 1.9-2.3(m,2H), 2.8-3.5(m,8H), 3.85(ABq, 2H, 18.7Hz), 4.61 (m,1 H), 5.16(d, 1 H,J=4.8Hz), 5.86(dd, 1 H,J1 =4.8Hz, J2=8.4Hz),

7.24(s,1 H), 8.05(br s, 2H), 8.93(s, 2H), 9.50(d,1 H,J=8.4Hz), 11.96(s, 1 H)

MS- ESI negative mode: 533.2(M-H, 10%)

6. Beispiel: Ceftobiprol Medocaril Na-SaIz

0, 5 3 g ( 6 R , 7 R )-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8- oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1 – aza-bicyclo[4.2.0]oct-2-ene- 2 carboxylic acid were dissolved in 5 ml of dimethyl sulfoxide and 0.27 g of carbonic acid (5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-nitrophenyl ester were added and stirred at room temperature. A solution of sodium ethyl hexanoate in 30 ml of acetone was added for precipitation. The precipitate was filtered and washed with acetone.

Auswaage: 0,6g

¹H-nmr(DMSO-d₆) δ 1.9-2.05(m, 2H), 2.10(s,3H), 2.7-3.1 (m,2H), 3.1-3.6(m,6H), 3.64(q, 2H; J=17.1 Hz), 4.56(m,1 H), 4.87(s,2H), 4.98(d,1 H,J=4.9Hz), 5.65(dd,1 H,J1 =4.9Hz, J2=8.4Hz), 7.34(s,1 H), 8.02(s,2H), 9.36(d,1 H,J=8.4Hz)

MS- ESI negative mode: 689.0(M-H, 100%)

References

1. ^ Hebeisen P, Heinze-Krauss I, Angehrn P, Hohl P, Page MG, Then RL (March 2001). “In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci”. Antimicrobial Agents and Chemotherapy. 45 (3): 825–836. doi:10.1128/AAC.45.3.825-836.2001. PMC 90381. PMID 11181368.
2. ^ Jones RN, Deshpande LM, Mutnick AH, Biedenbach DJ (December 2002). “In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci”. The Journal of Antimicrobial Chemotherapy. 50 (6): 915–932. doi:10.1093/jac/dkf249. PMID 12461013.
3. ^ “Prescription medicines: registration of new chemical entities in Australia, 2015”. Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
4. ^ Jump up to:^a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218275s000lbl.pdf
5. ^ Scheeren TW (1 January 2015). “Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia”. Future Microbiology. 10 (12): 1913–1928. doi:10.2217/fmb.15.115. PMID 26573022.
6. ^ “Basilea announces distribution agreement with Cardiome to commercialize antibiotic Zevtera/Mabelio (ceftobiprole) in Europe and Israel”. Basilea (Press release). 12 September 2017. Retrieved 7 April 2024.
7. ^ “Basilea to launch Zevtera/Mabelio (ceftobiprole medocaril) in Europe through a commercial services provider” (Press release). Basilea Pharmaceutica. Archived from the original on 31 March 2019. Retrieved 20 September 2016.
8. ^ “Basilea announces launch of antibiotic Zevtera (ceftobiprole medocaril) in Germany”. Basilea (Press release). 5 December 2014. Retrieved 7 April 2024.
9. ^ “Swissmedic approves Basilea’s antibiotic Zevtera (ceftobiprole medocaril) for the treatment of pneumonia”. Basilea (Press release). 22 December 2014. Retrieved 7 April 2024.
10. ^ “Basilea signs exclusive distribution agreement for Zevtera (ceftobiprole medocaril) in the Middle East and North Africa with Hikma Pharmaceuticals LLC”. Basilea (Press release). 15 October 2015. Retrieved 7 April 2024.
11. ^ “Basilea announces that Health Canada approved Zevtera for the treatment of bacterial lung infections”. Basilea (Press release). 12 October 2015. Retrieved 7 April 2024.
12. ^ Syed YY (September 2014). “Ceftobiprole medocaril: a review of its use in patients with hospital- or community-acquired pneumonia”. Drugs. 74 (13): 1523–1542. doi:10.1007/s40265-014-0273-x. PMID 25117196. S2CID 2925496.
13. ^ Zhanel GG, Lam A, Schweizer F, Thomson K, Walkty A, Rubinstein E, et al. (2008). “Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin”. American Journal of Clinical Dermatology. 9 (4): 245–254. doi:10.2165/00128071-200809040-00004. PMID 18572975. S2CID 24357533.
14. ^ Farrell DJ, Flamm RK, Sader HS, Jones RN (July 2014). “Ceftobiprole activity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010”. Antimicrobial Agents and Chemotherapy. 58 (7): 3882–3888. doi:10.1128/AAC.02465-14. PMC 4068590. PMID 24777091.
15. ^ Farrell DJ, Flamm RK, Sader HS, Jones RN (April 2014). “Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin, linezolid or vancomycin, and strains with defined SCCmec types”. International Journal of Antimicrobial Agents. 43 (4): 323–327. doi:10.1016/j.ijantimicag.2013.11.005. PMID 24411474.
16. ^ Nicholson SC, Welte T, File TM, Strauss RS, Michiels B, Kaul P, et al. (March 2012). “A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation”. International Journal of Antimicrobial Agents. 39 (3): 240–246. doi:10.1016/j.ijantimicag.2011.11.005. PMID 22230331.
17. ^ Awad SS, Rodriguez AH, Chuang YC, Marjanek Z, Pareigis AJ, Reis G, et al. (July 2014). “A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia”. Clinical Infectious Diseases. 59 (1): 51–61. doi:10.1093/cid/ciu219. PMC 4305133. PMID 24723282.
18. ^ “Zevtera 500 mg powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC)”. (emc). 5 April 2023. Retrieved 1 June 2023.
19. ^ “Zeftera (previously Zevtera) EPAR”. European Medicines Agency (EMA). 18 February 2010. Retrieved 6 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

• Clinical trial number NCT03138733 for “Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia” at ClinicalTrials.gov
• Clinical trial number NCT03137173 for “Ceftobiprole in the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infections” at ClinicalTrials.gov
• Clinical trial number NCT00326287 for “Ceftobiprole in the Treatment of Patients With Community-Acquired Pneumonia” at ClinicalTrials.gov
• Clinical trial number NCT03439124 for “Ceftobiprole in the Treatment of Pediatric Patients With Pneumonia” at ClinicalTrials.gov

////////Ceftobiprole, BAL-9141, BAL-9141-000, BAL-9141000, BAL9141-000, RO 63-9141, RO-63-9141, RO-639141, fda 2024, zevtera, approvals 2024, Ceftobiprole medocaril sodium salt

[H][C@@]1(NC(=O)C(=N/O)\C2=NSC(N)=N2)C(=O)N2C(C(O)=O)=C(CS[C@]12[H])\C=C1/CCN(C1=O)[C@]1([H])CCNC1

Tovorafenib

506.29

C₁₇H₁₂Cl₂F₃N₇O₂S

1096708-71-2

6-amino-5-chloro-N-[(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}-1,3-thiazol-2-yl)ethyl]pyrimidine-4-carboxamide

4/23/2024 FDA APROVED, To treat relapsed or refractory pediatric low-grade glioma, Ojemda

• AMG 2112819
• BIIB 024
• BIIB-024
• BIIB024
• DAY 101
• DAY-101
• DAY101
• MLN 2480
• MLN-2480
• MLN2480
• TAK 580
• TAK-580
• TAK580

Tovorafenib, sold under the brand name Ojemda, is a medication used for the treatment of glioma.^[1] It is a kinase inhibitor.^[1]

The most common adverse reactions include rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.^[2] The most common grade 3 or 4 laboratory abnormalities include decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.^[2]

It was approved for medical use in the United States in April 2024,^[1][2][3][4] and is the first approval of a systemic therapy for the treatment of people with pediatric low-grade glioma with BRAF rearrangements, including fusions.^[2]

Medical uses

Tovorafenib is indicated for the treatment of people six months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.^[1][2]

History

Efficacy was evaluated in 76 participants enrolled in FIREFLY-1 (NCT04775485), a multicenter, open-label, single-arm trial in participants with relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy.^[2] Participants were required to have documented evidence of radiographic progression and at least one measurable lesion.^[2] Participants with tumors harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded.^[2] Participants received tovorafenib based on body surface area (range: 290 to 476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.^[2] The US Food and Drug Administration (FDA) granted the application for tovorafenib priority review, breakthrough therapy, and orphan drug designations.^[2]

Society and culture

Names

Tovorafenib is the international nonproprietary name.^[5]

SYN

PATENT

 WO 2009/006389

Huang et al., Angew. Chem. int. Ed. (2016), 55, 5309-5317

 Jiang Xiao-bin et al., Org. Lett. (2003), 5, 1503

10Da

SYN

Patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US131345763&_cid=P22-LW02NH-45076-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US201396258&_cid=P22-LW02NH-45076-1

PATENT

References

1. ^ Jump up to:^{a b c d e} “Archived copy” (PDF). Archived (PDF) from the original on 24 April 2024. Retrieved 24 April 2024.
2. ^ Jump up to:^{a b c d e f g h i j} “FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma”. U.S. Food and Drug Administration (FDA). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 25 April 2024.  This article incorporates text from this source, which is in the public domain.
3. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
4. ^ “Day One’s Ojemda (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor”. Day One Biopharmaceuticals (Press release). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 24 April 2024.
5. ^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

External links

• “Tovorafenib”. NCI Drug Dictionary.
• “Tovorafenib (Code C106254)”. NCI Thesaurus.
• Clinical trial number NCT04775485 for “A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)” at ClinicalTrials.gov

////////Tovorafenib, Ojemda, FDA 2024. APPROVALS 2024, AMG 2112819, BIIB 024, BIIB-024, BIIB024, DAY 101, DAY-101, DAY101, MLN 2480, MLN-2480, MLN2480, TAK 580, TAK-580, TAK580

Berdazimer

1846565-00-1

CAS NA SALT, 1846565-00-1

FDA APPROVE 1 /5/2024, To treat molluscum contagiosum
Drug Trials Snapshot

• NVN-1000 free acid
• NVN1000 free acid
• Silsesquioxanes, 3-(2-hydroxy-1-methyl-2-nitrosohydrazinyl)propyl 3-(methylamino)propyl, polymers with silicic acid (h4sio4) tetra-et ester, hydroxy-terminated

Berdazimer sodium, sold under the brand name Zelsuvmi, is a medication used for the treatment for molluscum contagiosum.^[1] Berdazimer sodium is a nitric oxide releasing agent.^[1] It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3-(trimethoxysilyl)propyl)-1-triazene-2-oxide and tetraethyl silicate.^[2]

Berdazimer sodium was approved for medical use in the United States in January 2024.^[3][4][5]

Medical uses

Berdazimer sodium is indicated for the topical treatment of molluscum contagiosum.^[1]

Pharmacology

Mechanism of action

Berdazimer sodium is a nitric oxide releasing agent.^[1] The mechanism of action for the treatment of molluscum contagiosum is unknown.^[1]

Pharmacodynamics

The pharmacodynamics of berdazimer sodium are unknown.^[1]

Society and culture

Legal status

Berdazimer sodium was approved for medical use in the United States in January 2024.^[4]

Names

Berdazimer sodium is the international nonproprietary name.^[6]

Berdazimer

Berdazimer is a polymeric substance consisting of a polysiloxane backbone (Si-O-Si bonds) with covalently bound N-diazeniumdiolate nitric oxide (NO) donors. It releases NO through exposure to proton donors like water, which will degrade the N-diazeniumdiolate entity.² Berdazimer was previously investigated as a potential treatment for molluscum contagiosum, a viral cutaneous infection mainly affecting children, sexually active adults, and immunocompromised patients. It is one of the 5 most prevalent skin diseases in the world and the third-most common viral skin infection in children.³ Previously, the first line treatment for molluscum contagiosum was surgical excision, although it poses challenges such as repeated doctor visits, post-surgical scarring and skin discoloration, and fear and anxiety in the pediatric population.³

On Jan 05, 2024, the FDA approved berdazimer under the brand name ZELSUVMI for the treatment of adult and pediatric molluscum contagiosum, and it is the first drug to be approved for this condition. This decision is based on positive results demonstrated in 2 Phase 3 trials, B-SIMPLE 4 and B-SIMPLE 2, where reduced lesion counts were observed with once-a-day uses of berdazimer.⁵

References

1. ^ Jump up to:^{a b c d e f g h i} “Zelsuvmi (berdazimer) topical gel” (PDF). Archived (PDF) from the original on 19 January 2024. Retrieved 9 January 2024.
2. ^ “GSRS”. gsrs.ncats.nih.gov. Archived from the original on 8 January 2024. Retrieved 8 January 2024.
3. ^ “Drug Approval Package: Zelsuvmi”. U.S. Food and Drug Administration (FDA). 2 February 2024. Archived from the original on 11 March 2024. Retrieved 11 March 2024.
4. ^ Jump up to:^a b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
5. ^ “U.S. Food and Drug Administration Approves Zelsuvmi as a First-in-Class Medication for the Treatment of Molluscum Contagiosum”. Ligand Pharmaceuticals. 5 January 2024. Archived from the original on 8 January 2024. Retrieved 8 January 2024 – via Business Wire.
6. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.

Further reading

• Pera Calvi I, R Marques I, Cruz SA, Mesquita YL, Padrao EM, Souza RM, et al. (2023). “Safety and efficacy of topical nitric oxide-releasing berdazimer gel for molluscum contagiosum clearance: A systematic review and meta-analysis of randomized controlled trials”. Pediatric Dermatology. 40 (6): 1060–1063. doi:10.1111/pde.15419. PMID 37721050. S2CID 262045499.
• Han H, Smythe C, Yousefian F, Berman B (February 2023). “Molluscum Contagiosum Virus Evasion of Immune Surveillance: A Review”. Journal of Drugs in Dermatology. 22 (2): 182–189. doi:10.36849/JDD.7230. PMID 36745361. S2CID 256613906.
• Lacarrubba F, Micali G, Trecarichi AC, Quattrocchi E, Monfrecola G, Verzì AE (December 2022). “New Developing Treatments for Molluscum Contagiosum”. Dermatology and Therapy. 12 (12): 2669–2678. doi:10.1007/s13555-022-00826-7. PMC 9674806. PMID 36239905.
• Ward BM, Riccio DA, Cartwright M, Maeda-Chubachi T (November 2023). “The Antiviral Effect of Berdazimer Sodium on Molluscum Contagiosum Virus Using a Novel In Vitro Methodology”. Viruses. 15 (12): 2360. doi:10.3390/v15122360. PMC 10747301. PMID 38140601.

External links

• “Berdazimer Sodium (Code C174810)”. NCI Thesaurus.
• Clinical trial number NCT04535531 for “A Phase 3 Molluscum Contagiosum Efficacy and Safety Study (B-SIMPLE4)” at ClinicalTrials.gov
• Clinical trial number NCT03927703 for “A Phase 3 Efficacy & Safety of SB206 & Vehicle Gel for the Treatment of MC (B-SIMPLE2)” at ClinicalTrials.gov
• Clinical trial number NCT03927716 for “A Phase 3 Randomized Parallel Group Study Comparing the Efficacy & Safety of SB206 & Vehicle Gel in the Treatment of MC (B-SIMPLE1)” at ClinicalTrials.gov

/////Berdazimer, Zelsuvmi, FDA 2024, APPROVALS 2024, NVN-1000 free acid, NVN1000 free acid

Cefepime

88040-23-7

Cefepime

CAS Registry Number: 88040-23-7

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt

Additional Names: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium hydroxide inner salt 72-(Z)-2-(O-methyloxime); 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate

Manufacturers’ Codes: BMY-28142

Molecular Formula: C19H24N6O5S2

Molecular Weight: 480.56

Percent Composition: C 47.49%, H 5.03%, N 17.49%, O 16.65%, S 13.34%

Literature References: Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al.,DE3307550; eidem,US4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al.,J. Antibiot.39, 1092 (1986). In vitro comparative antimicrobial spectrum: N. J. Khan et al.,Antimicrob. Agents Chemother.26, 585 (1984); and b-lactamase stability: H. C. Neu et al.,J. Antimicrob. Chemother.17, 441 (1986). HPLC determn in plasma and urine: R. H. Barbhaiya et al.,Antimicrob. Agents Chemother.31, 55 (1987). Clinical evaluations in infection: N. Clynes et al.,Diagn. Microbiol. Infect. Dis.12, 257 (1989); S. Oster et al.,Antimicrob. Agents Chemother.34, 954 (1990). Review of clinical pharmacokinetics: M. P. Okamoto et al.,Clin. Pharmacokinet.25, 88-102 (1993).

Properties: Colorless powder, mp 150° (dec). uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100).

Melting point: mp 150° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100)

Derivative Type: Sulfate

Molecular Formula: C19H24N6O5S2.H2SO4

Molecular Weight: 578.64

Percent Composition: C 39.44%, H 4.53%, N 14.52%, O 24.89%, S 16.62%

Properties: mp 210° (dec). uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900).

Melting point: mp 210° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900)

Derivative Type: Hydrochloride monohydrate

CAS Registry Number: 123171-59-5

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride monohydrochloride monohydrate

Additional Names: cefepime hydrochloride

Trademarks: Axepim (BMS); Cepimex (Mead Johnson); Maxipime (BMS)

Molecular Formula: C19H25ClN6O5S2.HCl.H2O

Molecular Weight: 571.50

Percent Composition: C 39.93%, H 4.94%, Cl 12.41%, N 14.71%, O 16.80%, S 11.22%

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

FDA APPROVED 2/22/2024, To treat complicated urinary tract infections, Exblifep

• BMY 28142
• BMY-28142

Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics.^[1] In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.^[2]

Cefepime was patented in 1982 by Bristol-Myers Squibb and approved for medical use in 1994.^[3] It is available as a generic drug and sold under a variety of trade names worldwide.^{[citation needed][4]}

It was removed from the World Health Organization’s List of Essential Medicines in 2019.^[5]

Medical use

Cefepime is usually reserved to treat moderate to severe nosocomial pneumonia, infections caused by multiple drug-resistant microorganisms (e.g. Pseudomonas aeruginosa) and empirical treatment of febrile neutropenia.^[6]

Cefepime has good activity against important pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and multiple drug-resistant Streptococcus pneumoniae. A particular strength is its activity against Enterobacteriaceae. Whereas other cephalosporins are degraded by many plasmid– and chromosome-mediated beta-lactamases, cefepime is stable and is a front-line agent when infection with Enterobacteriaceae is known or suspected.^{[medical citation needed]}

Spectrum of bacterial susceptibility

Cefepime is a broad-spectrum cephalosporin antibiotic and has been used to treat bacteria responsible for causing pneumonia and infections of the skin and urinary tract. Some of these bacteria include Pseudomonas, Escherichia, and Streptococcus species. The following represents MIC susceptibility data for a few medically significant microorganisms:^[7]

• Escherichia coli: ≤0.007 – 128 μg/ml
• Pseudomonas aeruginosa: 0.06 – >256 μg/ml
• Streptococcus pneumoniae: ≤0.007 – >8 μg/ml

Chemistry

The combination of the syn-configuration of the methoxy imino moiety and the aminothiazole moiety confers extra stability to β-lactamase enzymes produced by many bacteria. The N–methyl pyrrolidine moiety increases penetration into Gram-negative bacteria. These factors increase the activity of cefepime against otherwise resistant organisms including Pseudomonas aeruginosa and Staphylococcus aureus.

Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al., DE 3307550; eidem, US 4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al., J. Antibiot. 39, 1092 (1986).

Trade names

Following expiration of the Bristol-Myers Squibb patent,^[] cefepime became available as a generic and is now^] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.

References

1. ^ Yahav D, Paul M, Fraser A, Sarid N, Leibovici L (May 2007). “Efficacy and safety of cefepime: a systematic review and meta-analysis”. The Lancet. Infectious Diseases. 7 (5): 338–348. doi:10.1016/S1473-3099(07)70109-3. PMID 17448937.
2. ^ “FDA Alert: Cefepime (marketed as Maxipime)”. Information for Healthcare Professionals. Food and Drug Administration. Archived from the original on 2 November 2017. Retrieved 2 August 2009.
3. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 496. ISBN 9783527607495. Archived from the original on 19 June 2021. Retrieved 19 September 2020.
4. ^ “Cefepime (maxipime), large spectrum 4th generation cephalosporin, resistant to beta-lactamases]”.
5. ^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
6. ^ Chapman TM, Perry CM (2003). “Cefepime: a review of its use in the management of hospitalized patients with pneumonia”. American Journal of Respiratory Medicine. 2 (1): 75–107. doi:10.1007/bf03256641. PMID 14720024.
7. ^ “Cefepime Susceptibility and Concentration Range (μg/ml) Minimum Inhibitory Concentration (MIC) Data” (PDF). The Antimicrobial Index. toku-e.com. Archived from the original (PDF) on 1 November 2018.

External links

• “Cefepime”. Drug Information Portal. U.S. National Library of Medicine.

//////////cefepime, Exblifep, FDA 2024, APPROVALS 2024, BMY 28142, BMY-28142

ACT-132577, Aprocitentan, 

• N-Despropyl-macitentan

1103522-45-7

546.19, C₁₆H₁₄Br₂N₆O₄S

• WHO 10552

3/19/2024 FDA APPROVED, To treat hypertension, Tryvio

N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]aminosulfonamide

Aprocitentan, sold under the brand name Tryvio, is a medication used to treat hypertension (high blood pressure).^[1] It is developed by Idorsia.^[2] It is taken by mouth.^[1]

Aprocitentan is a dual endothelin-1 antagonist that targets both endothelin A and endothelin B receptors.^[3][4]

Aprocitentan was approved for medical use in the United States in March 2024.^[1][2][5] It is the first endothelin receptor antagonist to be approved by the US Food and Drug Administration (FDA) to treat systemic hypertension.^[2]

Medical uses

Aprocitentan is indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other medications.^[1]

Adverse effects

Aprocitentan may cause hepatotoxicity (liver damage), edema (fluid retention), anemia (reduced hemoglobin), and decreased sperm count.^[1]

Contraindications

Data from animal reproductive toxicity studies with other endothelin-receptor agonists indicate that use is contraindicated in pregnant women.^[1]

Mechanism of action

Aprocitentan is an endothelin receptor agonist that inhibits the protein endothelin-1 from binding to endothelin A and endothelin B receptors.^[1][4] Endothelin-1 mediates various adverse effects via its receptors, such as inflammation, cell proliferation, fibrosis, and vasoconstriction.^[1]

Society and culture

Economics

Aprocitentan is developed by Idorsia, which sold it to Janssen and purchased the rights back in 2023, for US$343 million.^[6]

Legal status

Aprocitentan was approved for medical use in the United States in March 2024.^[1]

In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jeraygo, intended for the treatment of resistant hypertension in adults.^[7] The applicant for this medicinal product is Idorsia Pharmaceuticals Deutschland GmbH.^[7]

SYN

US Patent

Trade Name

Application Number

Applicant

8324232

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11174247

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11787782

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11680058

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

10919881

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

PATENT

WO 02/053557

PATENT

Martin Bolli, Christoph Boss, Alexander Treiber. ” 4-pyrimidinesulfamide derivative “, US Patent US8324232B2.

EXAMPLE

Preparation A: Benzylsulfamide Potassium Salt

A.i. Benzylsulfamide

A.ii. Benzylsulfamide Potassium Salt

Preparation B: 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

B.i. 4-bromophenylacetic acid methyl ester

B.ii. 2-(4-bromophenyl)-malonic acid dimethyl ester

B.iii. 5-(4-bromophenyl)-pyrimidine-4,6-diol

B.iv. 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

Example 1

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

1.i. Benzyl-sulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide

1.ii. Benzyl-sulfamic acid [5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-amide

1.iii Benzyl-sulfamic acid [5-(4-bromophenyl)-6-{2-(5-bromo-pyrimidin-2-yloxy)-ethoxy}-pyrimidin-4-yl]-amide

1.iv. {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

References

1. ^ Jump up to:^{a b c d e f g h i j} “Tryvio- aprocitentan tablet, film coated”. DailyMed. 29 March 2024. Archived from the original on 25 April 2024. Retrieved 25 April 2024.
2. ^ Jump up to:^a b c “US FDA approves Idorsia’s once-daily Tryvio (aprocitentan) – the first and only endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled in combination with other antihypertensives” (Press release). Idorsia. 20 March 2024. Archived from the original on 28 April 2024. Retrieved 28 April 2024 – via PR Newswire.
3. ^ Ojha, Utkarsh; Ruddaraju, Sanjay; Sabapathy, Navukkarasu; Ravindran, Varun; Worapongsatitaya, Pitchaya; Haq, Jeesanul; et al. (2022). “Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension”. American Journal of Cardiovascular Drugs. 22 (3): 271–285. doi:10.1007/s40256-021-00510-9. PMC 8651502. PMID 34878631.
4. ^ Jump up to:^a b Xu, Jingjing; Jiang, Xiaohua; Xu, Suowen (November 2023). “Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential”. Drug Discovery Today. 28 (11): 103788. doi:10.1016/j.drudis.2023.103788. PMID 37742911.
5. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
6. ^ Deswal, Phalguni (6 September 2023). “Idorsia reacquires aprocitentan rights from Janssen for $343m”. Pharmaceutical Technology. Archived from the original on 8 November 2023. Retrieved 8 November 2023.
7. ^ Jump up to:^a b “Jeraygo EPAR”. European Medicines Agency. 25 April 2024. Archived from the original on 30 April 2024. Retrieved 27 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Further reading

• Mahfooz K, Najeed S, Tun HN, Khamosh M, Grewal D, Hussain A, et al. (July 2023). “New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension: A Systematic Review and Meta-Analysis”. Current Problems in Cardiology. 48 (7): 101686. doi:10.1016/j.cpcardiol.2023.101686. PMID 36893968.

/////ACT-132577, Aprocitentan, Tryvio, FDA 2024, APPROVALS 2024, N-Despropyl-macitentan, WHO 10552

Palopegteriparatide

Yorvipath , FDA 2024, 8/9/2024, To treat hypoparathyroidism

• G2N64C3385
• 2222514-07-8
• Palopegteriparatide
• UNII-G2N64C3385
• ACP-014
• Mpeg 40000-teriparatide
• Palopegteriparatide [INN]
• Transcon parathyroid hormone (1-34)
• Transcon pth (1-34)
• Palopegteriparatide [USAN]
• TransCon PTH
• WHO 11060

Palopegteriparatide, sold under the brand name Yorvipath, is a hormone replacement therapy used for the treatment of hypoparathyroidism.^[1][2] It is a transiently pegylated parathyroid hormone.^[4] It is a parathyroid hormone analog.^[1]

Palopegteriparatide was approved for medical use in the European Union in November 2023,^[2] and in the United States in August 2024.^[1][5]

Medical uses

Palopegteriparatide is indicated for the treatment of adults with hypoparathyroidism.^[1][2]

Adverse effects

The US Food and Drug Administration (FDA) prescription label for palopegteriparatide includes warnings for a potential risk of risk of unintended changes in serum calcium levels related to number of daily injections and total delivered dose, serious hypocalcemia and hypercalcemia (blood calcium levels that are too high), osteosarcoma (a rare bone cancer) based on findings in rats, orthostatic hypotension (dizziness when standing), and a risk of a drug interaction with digoxin (a medicine for certain heart conditions).^[5]

History

The effectiveness of palopegteriparatide was evaluated in a 26-week, randomized, double-blind, placebo-controlled trial that enrolled 82 adults with hypoparathyroidism.^[5] Prior to randomization, all participants underwent an approximate four-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration ≥1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL.^[5] During the double-blind period, participants were randomized to either palopegteriparatide (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D).^[5] Study drug and conventional therapy were subsequently adjusted according to the albumin-corrected serum calcium levels.^[5] At the end of the trial, 69% of the participants in the palopegteriparatide group compared to 5% of the participants in the placebo group were able to maintain their calcium level in the normal range, without needing active vitamin D and high doses of calcium (calcium dose ≤ 600 mg/day).^[5]

The FDA granted the application for palopegteriparatide orphan drug and priority review designations.^[5]

Society and culture

Legal status

In September 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yorvipath, intended for the treatment of chronic hypoparathyroidism in adults.^[4][6] The applicant for this medicinal product is Ascendis Pharma Bone Diseases A/S.^[4] Palopegteriparatide was approved for medical use in the European Union in November 2023.^[2]

Palopegteriparatide was granted an orphan drug designation by the US Food and Drug Administration (FDA) in 2018,^[7] and by the EMA in 2020.^[8]

Brand names

Palopegteriparatide is the international nonproprietary name.^[9][10]

Palopegteriparatide is sold under the brand name Yorvipath.^[2]

References

1. ^ Jump up to:^{a b c d e} “Yorvipath injection, solution”. DailyMed. 14 August 2024. Retrieved 5 September 2024.
2. ^ Jump up to:^{a b c d e f} “Yorvipath EPAR”. European Medicines Agency. 19 October 2020. Archived from the original on 10 December 2023. Retrieved 11 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
3. ^ “Yorvipath Product information”. Union Register of medicinal products. 20 November 2023. Archived from the original on 26 November 2023. Retrieved 11 December 2023.
4. ^ Jump up to:^a b c “Yorvipath: Pending EC decision”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
5. ^ Jump up to:^{a b c d e f g h} “FDA approves new drug for hypoparathyroidism, a rare disorder”. U.S. Food and Drug Administration (FDA) (Press release). 9 August 2024. Archived from the original on 13 August 2024. Retrieved 13 August 2024.  This article incorporates text from this source, which is in the public domain.
6. ^ “Ascendis Pharma Receives Positive CHMP Opinion for TransCon PTH (palopegteriparatide) for Adults with Chronic Hypoparathyroidism”. Ascendis Pharma (Press release). 14 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
7. ^ “TransCon Parathyroid Hormone (mPEG conjugated parathyroid hormone 1-34) Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Archived from the original on 24 September 2023. Retrieved 24 September 2023.
8. ^ “EU/3/20/2350”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
9. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
10. ^ World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89”. WHO Drug Information. 37 (1). hdl:10665/366661.

External links

• Palopegteriparatide Global Substance Registration System
• Palopegteriparatide NCI Thesaurus
• Clinical trial number NCT04701203 for “A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism (PaTHway)” at ClinicalTrials.gov

//////Palopegteriparatide, APPRoVALS 2024, FDA 2024, Yorvipath, hypoparathyroidism, UNII-G2N64C3385, ACP-014, TransCon PTH, WHO 11060

Zelicapavir, Enanta Pharmaceuticals

Alternative Names: EDP-938; EP 023938

cas 2070852-76-3

RSV-IN-7
549.5 g/mol, C₂₇H₂₂F₃N₇O₃

UNII U4OI721DMD

(3S)-3-[[5-[3-morpholin-4-yl-5-(trifluoromethyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one

SYN

New England Journal of Medicine (2022), 386(7), 655-666 

WO2022157327

WO2018152413

WO2019067864 

WO2017015449 

PATENT

WO2018152413

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018152413&_cid=P20-M0V26A-30323-1

Step 5 : (_<S^f)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1.3.4-oxadiazol-2-

To a mixture of (5)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl)hydrazine-l-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was charged with 4A-MS (1.4 kg) and stirred at 20±5 °C for 2hrs. Then, it was cooled to 0°C, charged with triethylamine (0.62 Kg, 2.5 eq.) and stirred for 10 min. /^-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) solution was dropwise added to the reaction mixture with maintaining below 5°C and stirred at at 0±5 °C for 5 hrs. The reaction mixture was filtered and washed with DCM (2 X 4.2 L). The filtrate was treated with water (4.2 L) at 0°C and stirred between 0 and 10°C for 5 min. After separation, the organic phase was washed with 5% aqueous NaHCC solution (7 L), water (7 L) and brine (7 L) successively and separated. The DCM layer was concentrated in vacuo at below 30°C to leave ~7L of organic layer. MTBE (7 L) was added to organic layer and concentrated in vacuo to leave ~ 7 L of organic layer (This step was repeated once). The organic layer was charged with water (7 L) and stirred at 20±5 °C for 4 hrs. The solid was filtered and washed with MTBE (3 X 2.1 L) and purified water (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12 hrs, charged with n-heptane (14 L) and stirred at 20±5 °C for 5 hrs. The solid was filtered, washed with n-heptane (2 X 2.8 L) and dried under vacuum at ambient temperature to provide the title compound (0.776 kg, 99.6% purity by HPLC, 97.8%

chiral purity by chiral HPLC) as a pale yellowish solid. LC-MS(ESI, m/z): 550.17 [M+H]⁺;

¾ NMR: ( DMSO-c ₆400 MHz): δ 10.98 (br-s, 1H), 9.40 (d, J=8.0 Hz, 1H), 8.69 (br-d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.68 (dt, J=8.0 and 4.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.49-7.45 (m, 2H), 7.38-7.35 (m, 2H), 7.29 (br-t, J=8.0 Hz, 1H)

5.22 (d, J=8.0 Hz, 1H), 3.75-3.72 (m, 4H), 3.09-3.07 (m, 4H); ¹³C (DMSO-c¾, 100 MHz): δ 167.3, 167.0, 162.8, 156.4, 147.2, 139.2, 138.7, 138.4, 138.3, 138.0, 132.30, 130.7, 130.5, 129.5, 128.4, 126.2, 124.5, 123.4, 121.5, 71.8, 65.9, 51.0.

SCHEME

PATENT

US11390631, Example 253

https://patentscope.wipo.int/search/en/detail.jsf?docId=US368999603&_cid=P20-M0V2BF-36596-1

Example 253

• US11390631, Example 442
• US11390631, Example 443

//////////////Zelicapavir, EDP-938, EP 023938, EDP 938, RSV-IN-7, ENANTA

Arbemnifosbuvir, AT-752, 1998705-63-7, PD160572

E9V7VHK36U INN 12706

C₂₄H₃₃FN₇O₇P 581.5 g/mol

SYN

propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

L-ALANINE, N-((P(R),2’R)-2-AMINO-2′-DEOXY-2′-FLUORO-N,2′-DIMETHYL-P-PHENYL-5′ -ADENYLYL)-, 1-METHYLETHYL ESTER
N-((P(R),2’R)-2-AMINO-2′-DEOXY-2′-FLUORO-N,2′-DIMETHYL-P-PHENYL-5′ -ADENYLYL)-L-ALANINE 1-METHYLETHYL ESTER

WO2022040473   Atea Pharmaceuticals, Inc.

CN113784721

US20160257706 

WO2022076903  US10874687

PATENT

US20160257706

https://patentscope.wipo.int/search/en/detail.jsf?docId=US177601863&_cid=P11-M0VTE4-38538-1

Example 1. Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-L-alaninate

Step 1. Preparation of ((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate (2)

Step 2. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (3)

Step 3. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (4)

Step 4. Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-L-alaninate (5)

PATENT

US10874687, Compound 1B

/////Arbemnifosbuvir, AT-752, 1998705-63-7, PD160572, E9V7VHK36U INN 12706

Vorasidenib
6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine

CAS 1644545-52-7, C₁₄H₁₃ClF₆N₆, 414.74

FDA APPROVED, 8/6/2024, Voranigo, To treat Grade 2 astrocytoma or oligodendroglioma

UNII 789Q85GA8P

• AG 881
• AG-881
• AG881

Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.^[1][2] Vorasidenib acts to inhibit the enzymes isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2).^[1][2]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2]

Vorasidenib was approved for medical use in the United States in August 2024.^[2][3] It is the first approval by the US Food and Drug Administration (FDA) of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.^[2]

Medical uses

Vorasidenib is indicated for the treatment of people aged twelve years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.^[2]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.^[2]

History

Efficacy was evaluated in 331 participants with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial.^[2] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.^[2] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.^[2] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.^[2] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.^[2]

Society and culture

Legal status

Vorasidenib was approved for medical use in the United States in August 2024.^[2]

The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.^[2]

SYN

WO/2024/161041NOVEL COMPOUNDS THAT CAN BE USED AS THERAPEUTIC AGENTS

20240254118PRMT5 INHIBITORS AND USES THEREOF

118359585共晶体、其药物组合物以及涉及其的治疗方法

WO/2024/148437USE OF PCLX-001 OR PCLX-002 AS A RADIOSENSITIZER

20240238424HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE

1020240097895CD73 화합물

WO/2024/137852PRMT5 INHIBITORS AND USES THEREOF

2024057088THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

20240116928CD73 COMPOUNDS

117586228Preparation method of triazine medicine

20240041892THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

117529323Therapeutically active compounds and methods of use thereof

WO/2024/006929CD73 COMPOUNDS

PATENT

US10028961, Compound 101

https://patents.google.com/patent/US10028961B2/en

Step 3: Preparation of 6-(6-chloropyridin-2-yl)-N²,N⁴-bis((R)-1,1,1-trifluoro propan-2-yl)-1,3,5-triazine-2,4-diamine

A mixture of 2,4-dichloro-6-(6-chloro-pyridin-2-yl)-1,3,5-triazine (0.27 g, 1.04 mol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (0.39 g, 2.6 mol), and potassium carbonate (0.43 g, 3.1 mol) in dry 1,4-dioxane (2.5 mL) was stirred under the atmosphere of N₂ at 50° C. for 36 hr then at 100° C. for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired product.

¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 5.61 (m, 1.5H), 5.25 (m, 0.5H), 5.09 (m, 0.5H), 4.88 (m, 1.5H), 1.54-1.26 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²—((R)-1,1,1-trifluoropropan-2-yl)-N⁴—((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.41-8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J=6.2 Hz, 1H), 5.68-5.20 (m, 2H), 5.18-4.81 (m, 2H), 1.48-1.39 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

References

^ Jump up to:^a b c “Voranigo- vorasidenib citrate tablet, film coated”. DailyMed. 9 August 2024. Retrieved 15 August 2024.

1. ^ Jump up to:^{a b c d e f g h i j k l m n o} “FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation”. U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024.  This article incorporates text from this source, which is in the public domain.
2. ^ “Servier’s Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma” (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.

Further reading

• Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, et al. (March 2023). “Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial”. Nature Medicine. 29 (3): 615–622. doi:10.1038/s41591-022-02141-2. PMC 10313524. PMID 36823302.
• Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA, Maher EA, Janku F, et al. (August 2021). “Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial”. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 27 (16): 4491–4499. doi:10.1158/1078-0432.CCR-21-0611. PMC 8364866. PMID 34078652.
• Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, et al. (August 2023). “Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma”. The New England Journal of Medicine. 389 (7): 589–601. doi:10.1056/NEJMoa2304194. PMID 37272516.
• Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). “Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers”. ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.

External links

Clinical trial number NCT04164901 for “Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)” at ClinicalTrials.gov

• Clinical trial number NCT02481154 for “Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation” at ClinicalTrials.gov
• Clinical trial number NCT03343197 for “Study of AG-120 and AG-881 in Subjects With Low Grade Glioma” at ClinicalTrials.gov

////////Vorasidenib, Voranigo, FDA 2024, APPROVALS 2024, AG 881, AG-881, AG881

Zelatriazin,

C₁₈H₁₅F₃N₄O₃, 392.3 g/mol

1929519-13-0

NBI-1065846 or TAK-041

Phase 2

(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

Zelatriazin (NBI-1065846 or TAK-041) is a small-molecule agonist of GPR139. It was developed for schizophrenia and anhedonia in depression but trials were unsuccessful and its development was discontinued in 2023.^{[1][2][3][4][5][6][7]}

SCHEME

SYN

WO2016081736

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016081736&_cid=P21-M0X9BK-38013-1

Example 2: (S)-2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)-N-(l-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0166] To a vial containing 2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μΕ). After stirring at RT for 5 min, (S)- 1 -(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was

allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71 % yield). ^XH NMR

(500 MHz, DMSO-i¾) δ ppm 1.40 (d, J=6.8 Hz, 3 H), 4.98 (quin, J=7.1 Hz, 1 H), 5.09 (s, 2

H), 7.33 (d, J=7.8 Hz, 2 H), 7.44 – 7.49 (m, 2 H), 7.93 – 7.98 (m, 1 H), 8.09 – 8.15 (m, 1 H),

8.21 – 8.29 (m, 2 H), 8.85 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 393.9.

REF

Takeda Pharmaceutical Company Limited, WO2016081736

WO2022058791

Journal of Medicinal Chemistry (2021), 64(15), 11527-11542 

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Publication Name: Journal of Medicinal Chemistry, Publication Date: 2023-10-13, PMID: 37830160

DOI: 10.1021/acs.jmedchem.3c01034

PATENT

US9556130, test 2

https://patents.google.com/patent/US9556130B2/en

Example 2(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 393.9.

PATENT

compound 56 [PMID: 34260228]

References

1. ^ Kamel, Amin; Bowlin, Steve; Hosea, Natalie; Arkilo, Dimitrios; Laurenza, Antonio (February 2021). “In Vitro Metabolism of Slowly Cleared G Protein–Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism”. Drug Metabolism and Disposition. 49 (2): 121–132. doi:10.1124/dmd.120.000246. PMID 33273044. S2CID 227282766.
2. ^ Schiffer, Hans; Atienza, Josephine; Reichard, Holly; Mulligan, Victoria; Cilia, Jackie; Monenschein, Holger; Collia, Deanna; Ray, Jim; Kilpatrick, Gavin; Brice, Nicola; Carlton, Mark; Hitchcock, Steve; Corbett, Ged; Hodgson, Robert (18 May 2020). “S180. The Selective Gpr139 Agonist Tak-041 Reverses Anhedonia and Social Interaction Deficits in Rodent Models Related to Negative Symptoms in Schizophrenia”. Schizophrenia Bulletin. 46 (Supplement_1): S106–S107. doi:10.1093/schbul/sbaa031.246. PMC 7234360.
3. ^ Yin, Wei; Han, David; Khudyakov, Polyna; Behrje, Rhett; Posener, Joel; Laurenza, Antonio; Arkilo, Dimitrios (August 2022). “A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia”. British Journal of Clinical Pharmacology. 88 (8): 3872–3882. doi:10.1111/bcp.15305. PMC 9544063. PMID 35277995. S2CID 247407736.
4. ^ Rabiner, Eugenii A.; Uz, Tolga; Mansur, Ayla; Brown, Terry; Chen, Grace; Wu, Jingtao; Atienza, Joy; Schwarz, Adam J.; Yin, Wei; Lewis, Yvonne; Searle, Graham E.; Dennison, Jeremy M. T. J.; Passchier, Jan; Gunn, Roger N.; Tauscher, Johannes (June 2022). “Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET”. Neuropsychopharmacology. 47 (7): 1405–1412. doi:10.1038/s41386-021-01204-1. PMC 9117280. PMID 34675381.
5. ^ Reichard, Holly A.; Schiffer, Hans H.; Monenschein, Holger; Atienza, Josephine M.; Corbett, Gerard; Skaggs, Alton W.; Collia, Deanna R.; Ray, William J.; Serrats, Jordi; Bliesath, Joshua; Kaushal, Nidhi; Lam, Betty P.; Amador-Arjona, Alejandro; Rahbaek, Lisa; McConn, Donavon J.; Mulligan, Victoria J.; Brice, Nicola; Gaskin, Philip L. R.; Cilia, Jackie; Hitchcock, Stephen (12 August 2021). “Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia”. Journal of Medicinal Chemistry. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID 34260228. S2CID 235908256.
6. ^ Münster, Alexandra; Sommer, Susanne; Kúkeľová, Diana; Sigrist, Hannes; Koros, Eliza; Deiana, Serena; Klinder, Klaus; Baader-Pagler, Tamara; Mayer-Wrangowski, Svenja; Ferger, Boris; Bretschneider, Tom; Pryce, Christopher R.; Hauber, Wolfgang; von Heimendahl, Moritz (August 2022). “Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions”. Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID 35561791. S2CID 248574904.
7. ^ Taylor, Nick Paul (10 November 2023). “Neurocrine hit with one-two punch as Takeda and Xenon pacts deliver midphase flops”. Fierce Biotech. Retrieved 4 December 2023.

//////Zelatriazin, 1929519-13-0, NBI-1065846, TAK-041, Phase 2