1384258-97-2

Upstream product

• 1204417-44-6 C₃₁H₃₄ClNO₄ 
• 90719-32-7 (S)-4-Benzyl-2-oxazolidinone 
• 139962-95-1 2-formyl-4-methoxyphenylboronic acid 
• 1204417-91-3 tert-butyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate 
• 958002-18-1 1H-indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester 
• 928844-30-8 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid 10-(1,1-dimethylethyl) ester 6-methyl ester 

Downstream Products

• 1204417-54-8 (1aS,12bR)-1a-[(2-{2-[(aminosulfonyl)(methyl)amino]ethoxy}ethyl)(methyl)carbamoyl]-8-cyclohexyl-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylic acid 
• 1204417-51-5 (4bR,5aS)-9-(tert-butoxycarbonyl)-12-cyclohexyl-3-methoxy-4b,5,5a,6-tetrahydrobenzo[3,4]cyclopropa[5,6]azepino[1,2-a]indole-5a-carboxylic acid 
• 1204600-90-7 (1aS,12bR)-8-cyclohexyl-11-methoxy-16,22-dimethyl-1,12b-dihydro-5,1a-(methanoiminothioiminoethanooxyethanoiminomethano)cyclopropa[d]indolo [2,1-a][2]benzazepine-13,23(2H)-dione 15,15-dioxide 
• 1204417-53-7 tert-butyl (1aS,12bR)-1a-[(2-{2-[(aminosulfonyl)(methyl)amino]-ethoxy}ethyl)(methyl)carbamoyl]-8-cyclohexyl-11-methoxy-1,1a,2,12b-tetrahydro-cyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylate 
• 1204417-52-6 tert-butyl (1aS,12bR)-8-cyclohexyl-11-methoxy-1a-(methyl{2-[2-(methylamino)ethoxy]ethyl}carbamoyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylate 

Relevant academic research and scientific papers

Discovery and early development of TMC647055, a non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase

Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435.

Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055

Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. F

MACROCYCLIC INDOLE DERIVATIVES USEFUL AS HEPATITIS C VIRUS INHIBITORS

Inhibitors of HCV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R1, R2, R4, R5, R6 and R7 have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.