Optimization of chemical reactions requires a thorough analysis of reaction products and intermediates over a given time course. Chemical reactions are often analyzed by liquid chromatography-mass spectrometry (LC-MS), but generating LC-MS samples and data analysis is time-consuming and produces a significant amount of waste. We sought to remove the sample preparation and data analysis steps by implementing an iChemExplorer/Agilent LC-MS instrument as our reactor and analysis tool, coupled with an automated report generator of reaction progress over time. Herein, we show that our easy-to-use walk-up automated reaction profiling (WARP) system can sample chemical reactions multiple times to produce a data-rich report of reaction progress over time.

Historically, thalidomide-induced congenital malformations have served as an important example of the enhanced susceptibility of developing embryos to chemical perturbation. The compound produced a wide variety of congenital malformations in humans, which were initially detected by an association with a relatively rare limb defect labeled phocomelia. Although true phocomelia in the most severe form is a transverse defect with intercalary absence of limb regions, it is proposed that thalidomide produces a longitudinal limb phenotype in humans under usual circumstances that can become transverse in severe cases with a preferential sensitivity of forelimb over hindlimb, preaxial over postaxial, and left more impacted than the corresponding non-autopod limb bones on the right. The thalidomide-induced limb phenotype in humans is described and followed by a hierarchical comparison with various laboratory animal species. Mechanistic studies have been hampered by the fact that only non-human primates and rabbits have malformations that are anatomically similar to humans. Included in this review are unpublished data on limb malformations produced by thalidomide in rhesus monkeys from experiments performed more than 50 years ago. The critical period in gestation for the induction of phocomelia may initiate prior to the development of the embryonic limb bud, which contrasts with other chemical and physical agents that are known to produce this phenotype. The importance of toxicokinetic parameters is reviewed including dose, enantiomers, absorption, distribution, and both non-enzymatic and enzymatic biotransformations. The limb embryopathy mechanism that provides a partial explanation of the limb phenotype is that cereblon binds to thalidomide creating a protein complex that ubiquitinates protein substrates (CRL4CRBN) that are not targets for the complex in the absence of the thalidomide. One of these neosubstrates is SALL4 which when mutated causes a syndrome that phenocopies aspects of thalidomide embryopathy. Other candidate neosubstrates for the complex that have been found in non-human species may contribute to an understanding of the limb defect including PLZF, p63, and various zinc finger transcription factors. It is proposed that it is important to consider the species-specificity of the compound when considering potential mechanistic pathways and that some of the more traditional mechanisms for explaining the embryopathy, such as anti-angiogenesis and redox perturbation, may contribute to a full understanding of this teratogen.

A cost-efficient approach for the synthesis of a key intermediate of the EZH2 inhibitor PF-06821497 was identified after performing process chemistry development. A wide route scouting effort was initially deployed to finally identify a successful oxidative decyanation approach. Widely available raw materials were utilized to access a desired oxetanyl-ketone as a precursor for a KRED process to generate the enantioenriched alcohol in 99% ee. Subsequent methylation followed by a carboxylation led to our targeted building block in seven steps with an overall yield of 28%. This process was demonstrated on a large scale to produce up to 50 kg of our key intermediate in the synthesis of PF-06821497.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (21, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Electrophilic halogenation is a widely-used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom in drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely either on the invention of new reagents or activating commercially available reagents with various additives such as Lewis/Brønsted acids, Lewis bases and hydrogen bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Herein we report the invention a new class of powerful halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up). Their high halogenating prowess is also demonstrated in other reactivity contexts. A DFT computational study supports the defining role of the anomeric amide motif.

The key aim of this paper is to suggest a more quantitative approach to designing a dose–response experiment, and more specifically, a concentration–response experiment. The work proposes a departure from the traditional experimental design to determine a dose–response relationship in a developmental toxicology study. It is proposed that a model-based approach to determine a dose–response relationship can provide the most accurate statistical inference for the underlying parameters of interest, which may be estimating one or more model parameters or pre-specified functions of the model parameters, such as lethal dose, at maximal efficiency. When the design criterion or criteria can be determined at the onset, there are demonstrated efficiency gains using a more carefully selected model-based optimal design as opposed to an ad-hoc empirical design. As an illustration, a model-based approach was theoretically used to construct efficient designs for inference in a developmental toxicity study of sea urchin embryos exposed to trimethoprim. This study compares and contrasts the results obtained using model-based optimal designs versus an ad-hoc empirical design.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The synthesis of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles has been achieved from a simple common intermediate. Several ortho and/or meta-substituted benzene analogues as well as simple molecular matched pairs have also been prepared using this platform. In-depth biological and computational studies are currently in progress to validate the ortho and/or meta-character of these new bioisosteres. Results of these investigations will be reported in due course.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

Rh-catalyzed C–H functionalization of O-pivaloyl benzhydroxamic acids with propene gas provides access to 4-methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are achieved using [CptRhCl2]2 as a precatalyst under optimized conditions. Thorough examination of aryl/heteroaryl O-pivaloyl hydroxamic acid substrates, ligand effects on C–H site selectivity, alkene scope, and demonstration of scale are discussed within.

Hindered ethers represent an underexplored area of chemical space due to the difficulty and inoperability associated with conventional reactions, despite the high-value of such structural motifs in a variety of societal applications. Demonstrated herein is an exceptionally simple solution to this problem that leverages the power of electrochemical oxidation to liberate high-energy carbocations from simple carboxylic acids. The controlled formation of these reactive intermediates takes place with low electrochemical potentials under non-acidic conditions to capture an alcohol donor thereby producing a range (>80) of ethers that would be extremely difficult to otherwise access. Simple nucleophiles can also intercept such cations, leading to hindered alcohols and even alkyl fluorides. This method has been field tested to solve the synthetic bottlenecks encountered on twelve real-world chemical scaffolds with documented societal impact, resulting in a dramatic reduction in step-count and labor required, accompanied with a higher yield (average step-count, time, and yield = 6.3, ca. 100 h, 19% vs. 1.5, 9.8 h, 43%). Finally, the use of molecular probes coupled to kinetic studies support the proposed mechanism and role of additives in the conditions employed.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp(2))-C(sp(3)) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.