A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular arylation reactions with previously inaccessible arenes, opening the door for the development of other new direct arylation processes.

An assay recapitulating the 3′ processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/ aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

[reactions: see text] Palladium hydroxide on carbon (Pearlman's catalyst) effectively catalyzes direct arylation reactions of aryl iodides and bromides, providing excellent arylation-to-hydrodehalogenation ratios (>30:1) with broad scope for both intra- and intermolecular arylation processes. Studies aimed at determining the nature of the active catalyst indicate that an active homogeneous palladium species is produced under the reaction conditions.

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Toward the library generation of natural product-like polycyclic derivatives by stereocontrolled diversity-oriented synthesis Arya, P.; Quevillon, S.; Joseph, R.; Wei, C.-Q.; Gan, Z.; Parisien, M.; Sesmilo, E.; Reddy, P. T.; Chen, Z. Abstract: Due to the growing interest in small molecules that could help in understanding protein-protein interactions based on signal transduction, the demand for the generation of small-molecule libraries that are inspired by bioactive natural products has grown significantly. Many of these pathways are highly complex and present tremendous challenges with the use of classical tools. A rapid access to natural product-like small molecules having structural complexity and diversity is crucial for systematically dissecting the functions of complex protein networking and understanding cell signaling pathways. The complex nature, the three-dimensional architecture, and the number of protein binding functional groups presented in three-dimensional arrays are some of the attractive features to incorporate in smallmolecule chemical probes to be used as modulators of protein function.

2006 C-C bond formation O 0282Catalytic Direct Arylation with Aryl Chlorides, Bromides, and Iodides: Intramolecular Studies Leading to New Intermolecular Reactions. -The intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides occurs in excellent yield and is highly selective. The utility of the methodology is illustrated by a rapid synthesis of the carbazole natural product mukonine (VI) (to be continued). -(CAMPEAU, L.-C.; PARISIEN, M.; JEAN, A.; FAGNOU*, K.; J. Am. Chem. Soc. 128 (2006) 2, 581-590; Dep. Chem., Univ. Ottawa, Ottawa, Ont. K1N 6N5, Can.; Eng.) -Bartels 18-042

Direct Arylation Reactions Catalyzed by Pd(OH) 2 /C: Evidence for a Soluble Palladium Catalyst. -Pd(OH)2/C is found to be a highly efficient catalyst for direct arylation of aryl iodides and bromides. It provides excellent arylation-to-hydrodehalogenation ratios (>30:1). Experimental studies indicate that a homogeneous Pd species is formed which is the active catalyst. -(PARISIEN, M.; VALETTE, D.; FAGNOU*, K.; J. Org. Chem. 70 (2005) 19, 7578-7584; Dep. Chem., Univ. Ottawa, Ottawa, Ont. K1N 6N5, Can.; Eng.) -Jannicke 05-049

ABSTRACT:A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 μM inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the viral life cycle. Mechanism of action studies also revealed that this series inhibited infection of MRC-5 and ARPE19 cells by free virus and via direct cell-to-cell spread from infected to uninfected cells. Preliminary structure−activity relationships demonstrated that the potency of compound 1 could be improved to a low nanomolar level, but metabolic stability was a key optimization parameter for this series. A strategy focused on minimizing metabolic hydrolysis of the N1-amide led to an alternative scaffold in this series with improved metabolic stability and good pharmacokinetic parameters in rat. KEYWORDS: HCMV, cell-to-cell spread, replication inhibitors, antiviral agents A lthough infection with human cytomegalovirus (HCMV) does not lead to disease in healthy individuals, it can cause end-organ disease in the fetus, in the allograft recipient, in bone marrow transplant patients, and in AIDS patients. 1 Since HCMV infects approximately 60% of people in the developed world and over 99% in developing countries, the risk of morbidity and mortality due to HCMV disease is a significant problem for public health on a global scale. 1 Furthermore, a recent study has linked HCMV infection to increased mortality in the general population in the US. The current gold standard therapy for HCMV infection is either gancyclovir or its prodrug valgancyclovir. 2 However, when resistance or poor tolerability arise with these medications, second line options frequently suffer from lack of efficacy due to poor bioavailability, modest potency, and poor tolerability due to their toxicity at efficacious exposures. 2 Thus, a significant gap in treatment options exists, which has led to substantial efforts to develop new drugs to treat this opportunistic infection. There has been a sustained effort to discover an effective HCMV vaccine for the prevention of HCMV infection and although there have been positive outcomes in a number of clinical proof of concept studies, no marketed vaccine yet exists. 3 Currently, the leading edge in the discovery of new small molecule therapeutic agents includes the ongoing development of maribavir, letermovir, and brincidofovir, inhibitors of UL97, terminase, and HCMV polymerase, respectively. 1 These compounds have all demonstrated positive clinical proof of concept in phase II studies and may represent the next generation of therapy options for patients that have or are at risk of developing HCMV disease.Due to the significant unmet medical need for patients at risk for HCMV-related end organ disease, a drug discovery effort aimed at discovery of potent and selective inhibitors of HCMV replication was initiated at Boehringer Ingelheim. In the se...