Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole 1 and found that it was relatively straightforward. Following your paper, we have reclassied the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures. 1. S. L. Price, B, Patel, P. Pridhanani-Jethani and A. Torrisi, Crystal structure prediction and polymorphism -some mutual insights, Transactions of the American Crystallography Association, 2004, 39, 1-12.Sven Schroeder replied: We are working towards this aim. We have so far established that NEXAFS is extremely sensitive to variations in speciation in † Electronic Supplementary Information available: copies of the slides presented at the meeting by Wenhao Sun on the subject of metastable aragonite CaCO 3 nucleation in seawater. This journal is

An efficient route to AZD4635 has been developed utilizing the Suzuki−Miyaura reaction of a boronate ester prepared by C−H borylation on a multikilogram scale. Preparation of the cross-coupling partner using bromine/pyridine/ methanol has highlighted the incompatibility of this reagent/solvent combination with tantalum, which is commonly used in the construction and repair of standard manufacturing vessels.

Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scaleup challenges, and the solutions implemented are described.

Kenneth Harris opened a general discussion of the paper by Herma Cuppen: It is well established from solid-state NMR and other techniques that the NH 3 + group in crystalline amino acids undergoes rapid rotation about the C-NH 3 + bond. Is the phase transition between the b and a phases of DL-norleucine associated with any signicant discontinuity in the rate of this motion, and/or the temperature dependence of the rate of this motion? Furthermore, is there any evidence for disorder (dynamic or static) of the alkyl chain of the norleucine molecules in the a and b phases, and if so, does the nature of this disorder change signicantly at the phase transition?Herma Cuppen answered: Rotation barriers about the C-NH 3 + bond depend on the motive of the hydrogen bonding network in the crystalline phases. For DLnorleucine this motive stays intact during the transition, and I therefore do not expect a large difference for the two phases. The changes occur where the aliphatic chains interact. In a previous study, 1 we determined the rotation barrier of the methyl group by means of molecular dynamics simulations for both phases. We found them to be identical, and to be in agreement with experimental values for DL-norvaline 2 and DL-norleucine. 3 We did not nd any correlation between internal movement of the molecules and the onset of the transition. 1. J. A. van den Ende and H. M. Cuppen, Cryst. Growth Des., 2014, 14, 3343.This journal is