290815-01-9

Upstream product

• 153645-26-2 N-Boc-L-tert-leucinol 
• 372199-21-8 (S)-tert-butyl (1-amino-3,3-dimethyl-1-oxobutan-2-yl)carbamate 
• 1208257-66-2 tert-butyl [(2S)-1-azido-3,3-dimethylbutan-2-yl]carbamate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 20859-02-3 L-tert-Leucine 
• 290815-00-8 [(1S)-1-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-2,2-dimethylpropyl]carbamic acid 1,1-dimethylethyl ester 

Downstream Products

• 1242073-16-0 [(1S)-2,2-dimethyl-1-[[[(4-methylphenyl)sulfonyl]amino]methyl]propyl]carbamic acid 1,1-dimethylethyl ester 
• 864943-60-2 C₁₉H₃₀N₂O₆S 
• 864943-65-7 C₁₉H₃₁N₃O₆S 

Relevant academic research and scientific papers

Construction of Furan Derivatives with a Trifluoromethyl Stereogenic Center: Enantioselective Friedel-Crafts Alkylations via Formal Trienamine Catalysis

An asymmetric Friedel-Crafts alkylation reaction of 2-furfuryl ketones with β-trifluoromethyl enones has been developed via formal trienamine catalysis of a bifunctional primary amine-thiourea substance derived from L-tert-leucine, delivering the furan derivatives incorporating a stereogenic trifluoromethyl (CF3) group in good to high yields with excellent enantioselectivity.

Potent inhibitors of HCV-NS3 protease derived from boronic acids

Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200 pM. X-ray structure of compound 17 bound to NS3 protease is also discussed.

NOVEL NICOTINAMIDE DERIVATIVES OR SALTS THEREOF

An object of the present invention is to provide to a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity. Th e present invention provides a nicotinamide derivative represented by the follo wing formula (I) (wherein R 1 represents a halogen atom; R 2 represents a C 1-12 alkyl group, a C 2-12 alkenyl group, a C 2-12 alkynyl group, a C 3-8 cycloalkyl g roup, an aryl group, an ar-C 1-6 alkyl group or a heterocyclic group, each opti onally having at least one substituent; R 3 represents an aryl group or a hetero cyclic group each optionally having at least one substituent; and R 4 and R 5 e ach independently represent a hydrogen atom; and R 2 and R 4 may form a cyc lic amino group optionally having at least one substituent together with the ni trogen atom to which they bind) or a salt thereof, and a pharmaceutical comp osition for use in the treatment of a Syk-related disease which comprises the nicotinamide derivative or a salt thereof.

Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).

Synthesis of sterically hindered 3,5,5-trimethyl 2,6-dioxo tetrahydro pyrimidine as HCV protease inhibitors

An efficient route for the synthesis of sterically hindered substituted and unsubstituted 2,6-dioxo tetrahydropyrimidines from amine 1 is described. These analogs are active against HCV NS3 serine protease. The biological data for some of the representati

P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved po

Development of diphenylamine-linked bis(imidazoline) ligands and their application in asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes

The new diphenylamine-linked bis(imidazoline) ligands were prepared through Kelly-You's imidazoline formation procedure mediated by Hendrickson 's reagent in good yields. The novel ligands were tested in the asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes. In most cases, good yields (up to 97%) and excellent enantioselectivities (up to 98%) can be achieved. The optimized bis(imidazoline) ligand with trans-diphenyl substitution on the imidazoline ring gave better enantioselectivity than the corresponding bis(oxazoline) ligand.

Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies

Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-α or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only ～50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P3 sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P3 sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.

Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings

Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent Ki* of 5.3 nM and activity in replicon (EC90) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 μM h.

Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease

The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new tr