Structure-activity Relationship Study Of Novel Indazole–based Inhibitors Of The Hepatitis C Virus And The Development Of Novel Methods For The Synthesis Of Heterocyclic Skeleton

The work of this thesis includes two parts: One is the Structure-Activity Relationship study of novel indazole–based inhibitors of the Hepatitis C Virus; the other is the development of new synthesis methods of heterocyclic skeleton.1. The Structure-Activity Relationship study of novel indazole–based inhibitors of the Hepatitis C VirusStarting from the novel indazole–based HCV inhibitor 2, an extensive Structure-Activity Relationship(SAR) development of 2 was carried out and eight compounds with an IC50 less than 20 n M were obtained.Three potent inhibitors were selected to assess pharmacokinetic properties in male SD rats through oral administration, thus enabling us to have a certain understanding about the pharmacokinetic properties.2. The development of new synthesis methods of heterocyclic skeletonBased on the strategy of C–H activation and cascade reaction, several novel and efficient methods were developed, including the preparation of isoindolinones, pyrrolones and indolones, the direct thiolation and diversified amination of aromatic C–H bond, and the C(sp3) –H alkylation or alkenylation reactions.1) A novel and efficient method was developed to prepare substituted 3–methyleneisoindolin–1–ones and 5–ylidene pyrrol–2(5H)–ones via a Rh(III)–catalyzed addition of an aryl or alkenyl C–H bond to isocyanates with subsequent cyclization. Importantly, the directing group was utilized to convert into the functional group of products, so an additional removal step was not required. The possible reaction pathway was proposed based on mechanism experiments and the isolated reaction intermediate. The synthetic utility of this method is further demonstrated by the synthesis of two compounds with anesthetic activity and sedative activity respectively.2) The Ir(III)–catalyzed C–7 selective C–H amination of indolines was developed by using sulfonyl, acyl, and aryl azides as the amino source. Notable features of this method include mild conditions and good functional group tolerance. The synthetic utility of this method is further demonstrated by coupling C–7 of indoline and C–12 of methyl dehydroabietate to give novel compound 18.3) The first example of Rh(III)–catalyzed direct C–H thiolation was developed by using readily available disulfides as thiolation reagents. Significantly, mono– or dithiolation can be selectively achieved.4) A Rh(III)–Catalyzed direct C(sp3)–H alkylation or alkenylation of 8–methylquinolines was developed with diazo compounds. The selective formation of alkylation or vinylation products is controlled by the electric property of diazo compounds. This reaction shows good functional group tolerance and broad substrate scope, and proceeds smoothly on 2 gram scale. A possible mechanism was proposed based on mechanism experiments and DFT calculation. The synthetic utility of this method is further demonstrated by the readily conversion of the products into derivatives of Julolidine, which is a famous organic luminophor.5) A Cu Cl catalyzed arylation or alkenylation of electron–deficient alkenes with iodonium(III) Salts was developed to prepare 3, 3–disubstituted indolones. This reaction shows good functional group tolerance and broad substrate scope. The synthetic utility of this method is further demonstrated by the synthesis of compound 35 l with potential activity against Rice Blast Disease, and the highly efficient and concise formal synthesis of(±)–physostigmine and(±)–physovenine.