CC-92480,Dalcetrapib,Tovorafenib and AZD4604

Product Manager：Nick Wilde

The targets of action of drugs involve receptors, enzymes, ion channels, transporters, immune system, genes and many others. This paper describes four drugs involving enzyme targets of action and their synthetic routes.

1.Mezigdomide

Mezigdomide (CC-92480) is a Cereblon (CRBN) E3 ubiquitin ligase modulating active molecule (CELMoD), which belongs to a new class of protein degraders. As the first novel cerebral Cereblon E3 ligase modulator (CLMoD) to enter clinical development, Mezigdomide acts by means of a molecular glue. It binds tightly to Cereblon, exhibits anti-myeloma activity, and is used to treat relapsed and refractory multiple myeloma.

Synthetic route to Mezigdomide (CAS: 2259648-80-9)

Synthesis of Intermediate 10: Intermediate 10 was obtained by Fischer esterification of 3-hydroxy-2-methylbenzoic acid and radical bromination of toluene groups.

Asymmetric synthesis of target product 4: The hydroxyl group was obtained by reacting the lactam with tert-butyl (4S)-4,5-diamino-5-oxopentanoate in intermediate 10, which was subsequently deprotected with silanes to give hydroxyl group 74. aryl piperazine intermediate 73 was prepared by monoalkylation of 1,4-bis(chloromethyl)benzene with 3-fluoro-4-(piperazin-1-yl)benzonitrile (72). then. intermediate 74 was alkylated with benzyl chloride 73 to ultimately produce glutarimide. The enantiomeric excess of 4 (CC-92480) was obtained with an enantiomeric excess of greater than 98% by dehydration to form a glutarimide ring at 85°C under acidic conditions.

2. Dalcetrapib

Dalcetrapib is a rhCETP inhibitor with an inhibitory constant (IC50) of 0.2 μM.It contributes to an increase in plasma HDL cholesterol by modulating the activity of cholesteryl ester transporter proteins, thereby increasing plasma high-density lipoprotein (HDL) cholesterol levels. Its mechanism of action aims to reduce the risk of atherosclerosis (cardiovascular disease) by improving lipid levels.

Synthetic route to Dalcetrapib (CAS: 211513-37-0)

In a structural study of CETP inhibition, the investigators finalized an optimal compound, S-(2-((1-(2-ethylbutyl)cyclohexyl)carbonylamino)phenyl)2-methylpropanethiolate (27) (JTT-705). This compound significantly inhibited CETP in human plasma and significantly increased high-density lipoprotein (HDL) cholesterol levels in male Japanese white rabbits (JW rabbits). The mechanism for this inhibitory effect is thought to be the formation of a disulfide bond between the thiol form of compound 27 and the 13th cysteine residue (Cys13) in CETP.

Bis(2-(acylamino)phenyl) disulfides (precursors of 1-9 and 17-24) are synthesized by N-acylation of bis(2-aminophenyl) disulfides with the corresponding acyl chlorides. Reduction of the disulfide bond to 2-acylaminothiophenols (16-24) can be carried out using triphenylphosphine. In contrast, the target product Dalcetrapib (27) was prepared by coupling reaction of benzenethiol with the corresponding acyl chloride.

3. Tovorafenib

Tovorafenib is a highly specific pan-RAF kinase inhibitor whose mechanism of action is to inhibit the growth of tumors carrying BRAF fusions or BRAF V600 mutations. This drug has significant brain penetration and has been previously recognized by the FDA as a breakthrough therapy, as well as receiving Rare Pediatric Disease status, primarily for the treatment of pediatric low-grade gliomas carrying activating RAF variants.

Synthetic route to Tovorafenib (CAS: 1096708-71-2)

Intermediate compound 6: Synthesis of (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide:

Synthesis of target product 9 (Tovorafenib):

4. AZD4604

Londamocitinib (AZD4604; JAK1-IN-7) is a potent and selective JAK1 inhibitor that exhibits significant anti-inflammatory effects.The Janus kinase (JAK) family of proteins is a group of non-receptor-associated tyrosine kinases that play an essential role in cytokine receptor-mediated signaling. Currently, nine oral JAK inhibitors have been approved for the treatment of rheumatic, dermatologic, hematologic, and gastrointestinal diseases.

Synthetic route to AZD4604 (CAS: 2241039-81-4)

Synthesis of 2-fluoro-3-(methylsulfonyl)aniline 2:

Intermediate compound 6: Synthesis of 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine:

Synthesis of target product 9 (AZD4604):

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