Introduction

Macrocycles are Great Cycles. This was the title of a review we wrote in 2011 to reflect the increasing attention being then given by medicinal chemists toward this unique compound class. Six years later, the interest has only grown, which strongly indicates that the macrocycle field is not just another trend that becomes hot, generates frenetic activity, then rapidly vanishes or dissipates into irrelevance-quite the contrary. Macrocycles of very diverse chemical classes continue to generate a high level of interest from the drug discovery community, with an impressive number already in or entering the clinic. When we started working over 15?years ago at one of the pioneering companies in this area, NéoKimia (later Tranzyme Pharma), formed to realize the vision of Prof. Pierre Deslongchamps regarding libraries of conformationally defined and chemically diverse macrocyclic molecules, there was only one other company (Polyphor) primarily focused on using macrocycles for drug discovery purposes, and few academics had research focused on these structures. At the time, we met with considerable skepticism that such molecules could ever be effective synthetic drugs. Now, that situation has changed dramatically, with over 30 companies involved in pursuing macrocycles as a key aspect of their R&D, while the number of scientific papers on the topic has exploded. As a result, we felt it would be very timely to assemble a reference book on the medicinal chemistry of macrocycles. From the onset, we wanted this to be a practical guide targeting both experts and their teams, as well as neophytes.

Accordingly, this book is directed to both scientists engaged in drug discovery with macrocycles and those contemplating the use of macrocycles yet have no previous experience with this chemical class. We did not cover allied topics in macrocyclic chemistry, even if they could have some pharmaceutical relevance, including molecular recognition, supramolecular architectures, host-guest molecules, metal chelators, or chromatographic stationary phases.

Macrocycles actually are, in several ways, a polarizing molecular class. On the one hand, they attract researchers for their extraordinary potential to tackle difficult targets, their versatility as scaffolds for diversity generation, and the multiple opportunities they provide to optimize lead compounds. On the other hand, macrocycles can elicit untoward feelings because of notions-often outdated-on the challenges of synthesis, scale-up, diversification, or optimization of drug-like properties. Granted, macrocycles are often more synthetically challenging than traditional small molecules yet have definitely proven their worth to tackle difficult pharmacological target classes. In that sense, macrocycles can be considered as "high hanging molecules for high hanging targets."

In this volume, we have aimed to capture the important aspects of macrocycles as they pertain to medicinal chemistry. This ranges from critical challenges inherent to the class, to an analysis of the various subclasses of macrocycles and where they currently fit in drug discovery, through proven or exploratory methods to make and characterize them, and, finally, to further stimulate ideas of scientists interested in macrocycle drug discovery, several case studies from diverse compound classes and therapeutic indications. Throughout the preparation, we pressed individual authors to keep their contributions as hands-on and practical as possible-within the context of a reference book-to serve as a valuable information source or starting point depending on the reader's objectives. As a result, the book is separated into four main sections.

Part I focuses on challenges specific to macrocycles. The goal is to communicate what makes macrocycles special or distinctive in the context of drug discovery. In Chapter 1, Zaretsky and Yudin single out critical aspects related to the key transformation inherent in the synthesis of all macrocycles, that is, the cyclization process. The fact that this reaction is unimolecular brings significant challenges but also many opportunities. In Chapter 2, Craik, Kaas, and Wang give a detailed, hands-on description of the methods available to characterize and elucidate the structure of macrocycles, largely inspired from their extensive works on natural macrocyclic peptides, which have been structurally elucidated, synthesized, and diversified in all forms and sizes. Finally, in Chapter 3, Price, Mathiowetz, and Liras share their expertise, and that of their broad network of academic collaborators, on the current understanding of permeability and oral absorption of macrocycles and the ways to improve these important properties. This has been-and remains-an area of intense investigation in an effort to "crack the code," assuming there is one, of structure-permeability relationships in macrocycles. These works relate mostly to macrocyclic peptides and have been the genesis of efforts to understand what is now commonly known as the beyond-Rule-of-5 (bRo5) class.

Part II is devoted to covering the main chemical classes of macrocycles and their potential in drug discovery, as these constitute the knowledge base for medicinal chemists and the starting points of their future efforts. In Chapter 4, this begins with naturally inspired macrocycles by Wessjohann, Bartelt, and Brandt. Chapter 5, from Bockus and Lokey, is devoted to macrocyclic peptides, which constitute one of the two main classes of macrocycles from natural and unnatural origins. Since diversity generation is an integral tool in drug discovery, with high-throughput screening of compound libraries providing the initiation point for most projects, we subsequently move to two chapters specifically aimed at exploring and expanding the chemical diversity of macrocycles. In Chapter 6, Qian, Dougherty, and Pei describe existing chemical approaches to macrocycle libraries. Vitali and Fasan in Chapter 7 then extensively review hybrid chemistry/biology strategies used for diversity generation. Indeed, these approaches, despite limitations inherent to the biological machinery employed, have exploded the numbers of compounds accessible and become a rapidly evolving mainstream method for massive diversity generation. Finally, in Chapter 8, Leitch and Tavassoli expand on the role of macrocycles specifically as modulators of protein-protein interactions (PPI), a target class for which small molecules have generally performed poorly and for which macrocycles have emerged as privileged scaffolds owing to their unique combination of large molecular surface area, conformational restriction, and spatial display of pharmacophores.

Part III, the synthetic toolbox, makes available to the reader the many and diverse synthetic methods useful to construct macrocycles. In Chapter 9, Biron, Vézina-Dawod, and Bédard describe the various methods for making macrocyclic peptides. Gaddam, Mallurwar, Konda, Khatravath, Aeluri, Mitra, and Arya exemplify in Chapter 10 the use of ring-closing metathesis (RCM), a method that nowadays needs no introduction since it became the subject of the Nobel Prize in Chemistry in 2005, to build specific pharmacologically relevant structural types of macrocycles investigated in their myriad synthetic efforts toward diversity generation. Owing to the numerous excellent reviews and books devoted to RCM, we decided not to provide yet another review on the topic here but rather to exemplify the actual use of RCM in diversity generation. In Chapter 11, Pehere and Abell describe Huisgen cycloadditions in the context of macrocyclization. Subsequently, Ronson, Unsworth, and Fairlamb describe the various and versatile Pd-catalyzed approaches employed for the synthesis of macrocycles in Chapter 12, whereas in Chapter 13, Santandrea, Bédard, de Léséleuc, Raymond, and Collins summarize the numerous other strategies used to make macrocycles. As a testimony to chemists' creativity, this chapter presents a broad range of methods, leading to a wealth of macrocyclic structures. In Chapter 14, Wessjohann, Neves Filho, Puentes, and Morejón relate several multicomponent reactions (MCR) applied to the macrocyclization reaction. Finally, since efficient large-scale synthesis is one of the limiting steps to advance compounds into clinical development and macrocycles were perceived, at least 15?years ago as we recounted earlier, as molecules too difficult to prepare to be exploited as pharmaceutical agents, Kong presents in Chapter 15 several methods successfully applied to macrocycle synthesis at manufacturing scale. Although a number of these are proprietary and the subject of carefully guarded know-how, this chapter exemplifies how creative synthetic methods can deliver multi-kilogram quantities of macrocycles.

Finally, Part IV is dedicated to case studies of macrocycles in clinical development or approved as drugs. In Chapter 16, as an introduction to this section, Stotani and Giordanetto summarize the various classes of macrocycles and the individual compounds of each in clinical development. In Chapter 17, Terrett relates the discovery of XIAP antagonists stemming from DNA-encoded technologies. In Chapter 18, Yamazaki, Lam, and Johnson then share their experience in the discovery of lorlatinib, an inhibitor of the ALK kinase able to tackle resistant forms of the kinase, including those found in brain...