Within the tumor microenvironment (TME), regulatory T (Treg) cells promote an immunosuppressive state with limited tumor antigen presentation and antitumor effector T (Teff) cell responses, which can drive resistance to cancer immunotherapies. IKZF2 (Helios) is a transcription factor essential for stabilizing the immunosuppressive Treg cell phenotype in tumors. Herein, we present the discovery of BMS-986449, a selective Cereblon E3 Ligase Modulatory Drug (CELMoD) degrader of IKZF2 and IKZF4 (Eos) that spares the closely related transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos). BMS-986449 is an orally available degrader that demonstrates single-agent growth inhibition of syngeneic MC38 tumors implanted in humanized Cereblon (CRBN) knock-in mice. Tumor growth inhibition was more robust when BMS-986449 was administered in combination with anti-PD-1. Nonhuman primates administered daily with BMS-986449 show sustained IKZF2 degradation in Treg cells providing confidence in human clinical doses. Collectively, these findings establish BMS-986449 as a promising clinical candidate for cancer immunotherapy.

While migratory functionalization reactions provide a powerful means to navigate broader chemical space, their application to aliphatic amines remains particularly elusive. Herein, we describe the nickel-catalyzed migratory arylation of aliphatic amines using Katritzky salts enabled by a “store-and-release” strategy. This strategy leverages dihydropyridines, which are traditionally viewed as chemical dead-ends under reductive cross-coupling conditions, as latent reservoirs to store and release translocated alkyl radicals, thereby decoupling the chain-walking event from the cross-coupling cycle. The developed protocol enables migratory functionalization of Katritzky salts derived from a wide range of primary amines, and a variety of aryl and heteroaryl bromides. The reaction exhibits broad functional group tolerance, accommodating alkenes, polar functionalities, and substrates derived from pharmaceutically relevant compounds. This methodology enables expanded small-molecule library synthesis through regiodivergent deaminative arylations. Preliminary mechanistic studies support the “store-and-release” design principle, rendering it as a platform that can be applied for other migratory functionalization reactions.

Sulfur(VI)-containing functional groups, such as sulfonamides, sulfinates and sulfonyl fluorides, are ubiquitous in pharmaceuticals, where they confer unique physicochemical properties that enhance metabolic stability, solubility and bioactivity across diverse therapeutic areas. Despite their prevalence, synthetic access to alkyl-sulfur(VI) derivatives remains fragmented, often requiring multi-step sequences from scarce precursors or harsh conditions that limit functional-group tolerance and scalability. Here we report a unified platform that enables divergent synthesis of alkyl-sulfur(VI) compounds from abundant, unactivated feedstocks including ketones, alcohols, amines and other structurally complex molecules. Central to this method is the use of alkyl hydrazines (or their sulfonylated derivatives) as practical radical precursors. Upon simple thermal activation, these hydrazines undergo efficient homolysis to generate alkyl radicals under mild and operationally simple conditions, without the need for photocatalysts, expensive metals or reagents and elaborate setups. Over 70 sulfur-containing molecules are synthesized, including direct functionalization of complex natural products without resorting to protecting group chemistry. A unified platform for divergent synthesis of alkyl-sulfur(VI) compounds is reported using alkyl hydrazines and hydrazides as practical radical precursors. Upon simple thermal activation, these readily accessible precursors undergo N2 extrusion to generate alkyl radicals under mild conditions, enabling chemoselective access to complex, functionality-rich sulfinates, sulfonyl fluorides and sulfinamides.

The hit‐to‐lead phase of drug discovery is frequently bottlenecked by the time‐consuming, iterative synthesis of analogs, especially when incorporating small C(sp 3 )‐rich fragments such as methyl, cyclopropyl, or oxetanyl groups—moieties known to improve drug solubility, bioactivity, and metabolic stability. Conventional approaches like Suzuki or Negishi couplings make use of unstable reagents, high costs, and harsh reaction conditions, while many modern radical‐based methods rely on exogenous redox agents or costly metal catalysts. To overcome these limitations, a toolbox of 15 sulfonyl hydrazide reagents is disclosed to facilitate redox‐neutral, nickel‐catalyzed radical cross‐coupling of 14 distinct small fragments onto (hetero)arenes under mild conditions. These crystalline, bench‐stable reagents are straightforward to synthesize from accessible precursors and require no additional oxidants, reductants, or precious metals, offering a modular and operationally simple platform. Demonstrated across a diverse set of over 60 (hetero)aryl halides, the method exhibits exceptional substrate scope and functional group tolerance, accommodating complex, medicinally relevant scaffolds. Comparative studies with existing techniques underscore its advantages, including a 51% yield for trideuteromethylation of a MET kinase inhibitor precursor (versus a precedented 14% via Kumada coupling) and a streamlined one‐step cyclobutylation of an NLRP3 inhibitor intermediate at 41% yield (versus a known < 5% over a four‐step sequence).

Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C-C bond-forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.

The pursuit of increasingly complex, three-dimensional molecules is pushing the boundaries of modern organic synthesis, particularly in drug discovery where rigid, saturated scaffolds such as cyclobutanes, azetidines and oxetanes are in high demand. Here we outline a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of nickel-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have been nearly impossible to access before without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry and related fields. Molecular scaffolds bearing 1,1-diaryl-substituted four-membered rings remain difficult to access using traditional synthesis. Now it has been shown that a modular, nickel-electrocatalytic sequence enables the programmable, scalable and chemoselective synthesis of these high-value motifs, offering broad utility across drug discovery and showcasing strategic applications to patented intermediates.

Functionalized cyclobutanes are three-dimensional scaffolds widely found in natural products and bioactive molecules. Herein, we report a visible-light-induced intermolecular [2+2] cycloaddition reaction of a diverse array of alkenes with N-substituted maleimides to access functionalized azabicyclo[3.2.0]heptanes. The reaction showed broad substrate scope with good chemo-, regio- and diastereoselectivity under mild conditions. The robustness of this photo-mediated [2+2] cycloaddition was demonstrated by carrying out a reaction on a 100 g scale (58 % yield). The prepared functionalized azabicyclo[3.2.0]heptanes are synthetic scaffolds for drug discovery.

C–C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial -bromoglutaramide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multistep sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1 beta, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFN alpha and TNF alpha cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl frag-ments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species are sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

Decarboxylative cross-coupling methodologies are now widely employed in pharmaceutical drug discovery research, forming the basis of strategic retrosynthetic analysis and radical-based bond disconnections. Herein, we unveil the diastereoselectivity aspects of metallaphotoredox decarboxylative arylation of substituted cyclic carboxylic acids. Through judicious screening of conditions, ligands, and additives, photoredox-promoted Ni-catalyzed decarboxylative arylation was rendered highly diastereoselective, enabling modular access to complex cyclic architectures. The reaction tolerates various functional groups, including free alcohols and basic amines. Computational DFT structural and energetic studies of L2ArXNi(III)R complexes of 1,2-, 1,3-, and 1,4-methyl cyclohexanes revealed a conformational preference for all equatorial over equatorial/axial conformations. The L2ArXNi(III)R, which undergoes reductive elimination, is the diastereo-determining intermediate based on calculated free energies and product isomeric distribution. To showcase the robustness and scalability of this methodology for drug discovery and process development, a 200 mmol (51.5 g) reaction was successfully carried out in flow. Finally, to demonstrate the simplifying power of this coupling approach, we employed it to truncate the synthesis of Iptacopan (LNP023), a recently FDA-approved drug for treating Paroxysmal nocturnal hemoglobinuria (PNH) disorder in adults, from the previously reported 12-steps (racemic route) to 4-steps (enantioselective route).

A simple protocol for the Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C-N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant decrease in step count from known syntheses in the patent literature.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Br & oslash;nsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of 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). Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

The merger of photoredox and nickel catalysis for the decarboxylative arylation of carboxylic acids has evolved into an effective strategy to forge C-C bonds from readily available feedstock. Despite its rapid industrial adoption, the mechanism of this dual-catalyzed cross-coupling reaction has remained unclear and under-studied. Here, we propose an alternative mechanism for the photoredox-Ni dual-catalyzed decarboxylative arylation of alpha-amino acids based on control experiments with (NiArBr)-Ar-II complexes, cyclic voltammetry (CV), and computational studies. Our mechanistic studies revealed that a Ni-0-Ni-II-Ni-I-Ni-II-Ni-0 cycle is feasible in the dual- catalyzed C-sp(2)-C-sp(3) cross-coupling. Distinct from previous mechanism proposals, we show with a series of CV studies and density functional theory (DFT) calculations that a single electron transfer reduction of (NiArBr)-Ar-II to (NiAr)-Ar-I by Ir-II is thermodynamically favorable. Reductive elimination via a Ni-II-species rather than via a Ni-III-species is also supported by DFT calculations. Those mechanistic insights allowed for the reaction scope to be extended to encompass alpha-amino acids bearing pharmacophoric elements, which were previously unexplored coupling partners. alpha-Amino acids bearing broad functional groups, including heterocycles, successfully underwent decarboxylative arylation with a diverse set of aryl bromides. This strategy represents an advance in photoredox and Ni-catalysis and broadens its industrial applicability as well as mechanistic understanding.

Triplet-triplet energy transfer (EnT) is a powerful activation pathway in photocatalysis that unlocks new organic transformations and improves the sustainability of organic synthesis. Many current examples, however, still rely on platinum-group metal complexes as photosensitizers, with associated high costs and environmental impacts. Photosensitizers that exhibit thermally activated delayed fluorescence (TADF) are attractive fully organic alternatives in EnT photocatalysis. However, TADF photocatalysts incorporating heavy atoms remain rare, despite their utility in inducing efficient spin-orbit-coupling, intersystem-crossing, and consequently a high triplet population. Here, we describe the synthesis of imidazo-phenothiazine (IPTZ), a sulfur-containing heterocycle with a locked planar structure and a shallow LUMO level. This acceptor is used to prepare seven TADF-active photocatalysts with triplet energies up to 63.9 kcal mol-1. We show that sulfur incorporation improves spin-orbit coupling and increases triplet lifetimes up to 3.64 ms, while also allowing for tuning of photophysical properties via oxidation at the sulfur atom. These IPTZ materials are applied as photocatalysts in five seminal EnT reactions: [2 + 2] cycloaddition, the disulfide-ene reaction, and Ni-mediated C-O and C-N cross-coupling to afford etherification, esterification, and amination products, outcompeting the industry-standard TADF photocatalyst 2CzPN in four of the five studied scenarios. Detailed photophysical and theoretical studies are used to understand structure-activity relationships and to demonstrate the key role of the heavy atom effect in the design of TADF materials with superior photocatalytic performance.

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 first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

Dual nickel photoredox catalysis conditions have been developed for the decarboxylative cross-coupling of aryl halides and carboxylic acids containing fully substituted alpha carbons, a valuable but challenging substrate class for C(sp2)–C(sp3) bond-forming reactions. High-throughput experimentation identified Ni(TMHD)2 as the optimal precatalyst for this reaction in contrast to the nickel-bipyridyl complexes typically employed in decarboxylative couplings, which predominantly furnished undesired C–O products. Computational work provides insight into the potential mechanistic underpinnings for the C–C vs. C–O selectivity for the nickel-diketonate complex.