High Molar Mass Polycarbonates as Closed-Loop Recyclable Thermoplastics.

Using carbon dioxide (CO2) to make recyclable thermoplastics could reduce greenhouse gas emissions associated with polymer manufacturing. CO2/cyclic epoxide ring-opening copolymerization (ROCOP) allows for >30 wt % of the polycarbonate to derive from CO2; so far, the field has largely focused on oligocarbonates. In contrast, efficient catalysts for high molar mass polycarbonates are underinvestigated, and the resulting thermoplastic structure-property relationships, processing, and recycling need to be elucidated. This work describes a new organometallic Mg(II)Co(II) catalyst that combines high productivity, low loading tolerance, and the highest polymerization control to yield polycarbonates with number average molecular weight (Mn) values from 4 to 130 kg mol-1, with narrow, monomodal distributions. It is used in the ROCOP of CO2 with bicyclic epoxides to produce a series of samples, each with Mn > 100 kg mol-1, of poly(cyclohexene carbonate) (PCHC), poly(vinyl-cyclohexene carbonate) (PvCHC), poly(ethyl-cyclohexene carbonate) (PeCHC, by hydrogenation of PvCHC), and poly(cyclopentene carbonate) (PCPC). All these materials are amorphous thermoplastics, with high glass transition temperatures (85 < Tg < 126 °C, by differential scanning calorimetry) and high thermal stability (Td > 260 °C). The cyclic ring substituents mediate the materials' chain entanglements, viscosity, and glass transition temperatures. Specifically, PCPC was found to have 10× lower entanglement molecular weight (Me)n and 100× lower zero-shear viscosity compared to those of PCHC, showing potential as a future thermoplastic. All these high molecular weight polymers are fully recyclable, either by reprocessing or by using the Mg(II)Co(II) catalyst for highly selective depolymerizations to epoxides and CO2. PCPC shows the fastest depolymerization rates, achieving an activity of 2500 h-1 and >99% selectivity for cyclopentene oxide and CO2.

Evaluating Heterodinuclear Mg(II)M(II) (M = Mn, Fe, Ni, Cu, and Zn) Catalysts for the Chemical Recycling of Poly(cyclohexene carbonate).

Polymer chemical recycling to monomers (CRM) is important to help achieve a circular plastic economy, but the "rules" governing catalyst design for such processes remain unclear. Here, carbon dioxide-derived polycarbonates undergo CRM to produce epoxides and carbon dioxide. A series of dinuclear catalysts, Mg(II)M(II) where M(II) = Mg, Mn, Fe, Co, Ni, Cu, and Zn, are compared for poly(cyclohexene carbonate) depolymerizations. The recycling is conducted in the solid state, at 140 °C monitored using thermal gravimetric analyses, or performed at larger-scale using laboratory glassware. The most active catalysts are, in order of decreasing rate, Mg(II)Co(II), Mg(II)Ni(II), and Mg(II)Zn(II), with the highest activity reaching 8100 h-1 and with >99% selectivity for cyclohexene oxide. Both the activity and selectivity values are the highest yet reported in this field, and the catalysts operate at low loadings and moderate temperatures (from 1:300 to 1:5000, 140 °C). For the best heterodinuclear catalysts, the depolymerization kinetics and activation barriers are determined. The rates in both reverse depolymerization and forward CHO/CO2 polymerization catalysis show broadly similar trends, but the processes feature different intermediates; forward polymerization depends upon a metal-carbonate intermediate, while reverse depolymerization depends upon a metal-alkoxide intermediate. These dinuclear catalysts are attractive for the chemical recycling of carbon dioxide-derived plastics and should be prioritized for recycling of other oxygenated polymers and copolymers, including polyesters and polyethers. This work provides insights into the factors controlling depolymerization catalysis and steers future recycling catalyst design toward exploitation of lightweight and abundant s-block metals, such as Mg(II).

Chemical Recycling of Commercial Poly(l-lactic acid) to l-Lactide Using a High-Performance Sn(II)/Alcohol Catalyst System.

Poly(l-lactic acid) (PLLA) is a leading commercial polymer produced from biomass, showing useful properties for plastics and fiber applications; after use, it is compostable. One area for improvement is postconsumer waste PLLA chemical recycling to monomer (CRM), i.e., the formation of l-lactide (l-LA) from waste plastic. This process is currently feasible at high reaction temperatures and shows low catalytic activity accompanied, in some cases, by side reactions, including epimerization. Here, a commercial Sn(II) catalyst, applied with nonvolatile commercial alcohol, enables highly efficient CRM of PLLA to yield l-LA in excellent yield and purity (92% yield, >99% l-LA from theoretical max.). The depolymerization is performed using neat polymer films at low temperatures (160 °C) under a nitrogen flow or vacuum. The chemical recycling operates with outstanding activity, achieving turnover frequencies which are up to 3000× higher than previously excellent catalysts and applied at loadings up to 6000× lower than previously leading catalysts. The catalyst system achieves a TOF = 3000 h-1 at 0.01 mol % or 1:10,000 catalyst:PLLA loading. The depolymerization of waste PLLA plastic packaging (coffee cup lids) produces pure l-LA in excellent yield and selectivity. The new catalyst system (Sn + alcohol) can itself be recycled four times in different PLLA "batch degradations" and maintains its high catalytic productivity, activity, and selectivity.

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3 )-C(sp2 ) Cross-Coupling Enabled by Synergistic Boron Activation.

We report the development of a C(sp3 )-C(sp2 ) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology.

Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology. At the outset, no potent and selective MCT4 inhibitors had been reported, but a screen identified a triazolopyrimidine hit, with no close structural analogues. Minor modifications to the triazolopyrimidine were made, alongside design of a constrained linker and broad SAR exploration of the biaryl tail to improve potency, physical properties, PK, and hERG. The resulting clinical candidate 15 (AZD0095) has excellent potency (1.3 nM), MCT1 selectivity (>1000×), secondary pharmacology, clean mechanism of action, suitable properties for oral administration in the clinic, and good preclinical efficacy in combination with cediranib.

Solid-State Chemical Recycling of Polycarbonates to Epoxides and Carbon Dioxide Using a Heterodinuclear Mg(II)Co(II) Catalyst.

Polymer chemical recycling to monomers (CRM) could help improve polymer sustainability, but its implementation requires much better understanding of depolymerization catalysis, ensuring high rates and selectivity. Here, a heterodinuclear [Mg(II)Co(II)] catalyst is applied for CRM of aliphatic polycarbonates, including poly(cyclohexene carbonate) (PCHC), to epoxides and carbon dioxide using solid-state conditions, in contrast with many other CRM strategies that rely on high dilution. The depolymerizations are performed in the solid state giving very high activity and selectivity (PCHC, TOF = 25700 h-1, CHO selectivity >99 %, 0.02 mol %, 140 °C). Reactions may also be performed in air without impacting on the rate or selectivity of epoxide formation. The depolymerization can be performed on a 2 g scale to isolate the epoxides in up to 95 % yield with >99 % selectivity. In addition, the catalyst can be re-used four times without compromising its productivity or selectivity.

An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols.

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos (sSPhos), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.

Chemical Recycling of Poly(Cyclohexene Carbonate) Using a Di-MgII Catalyst.

Chemical recycling of polymers to true monomers is pivotal for a circular plastics economy. Here, the first catalyzed chemical recycling of the widely investigated carbon dioxide derived polymer, poly(cyclohexene carbonate), to cyclohexene oxide and carbon dioxide is reported. The reaction requires dinuclear catalysis, with the di-MgII catalyst showing both high monomer selectivity (>98 %) and activity (TOF=150 h-1 , 0.33 mol %, 120 °C). The depolymerization occurs via a chain-end catalyzed depolymerization mechanism and DFT calculations indicate the high selectivity arises from Mg-alkoxide catalyzed epoxide extrusion being kinetically favorable compared to cyclic carbonate formation.

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement.

Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.

Cu(OTf)2 -Mediated Cross-Coupling of Nitriles and N-Heterocycles with Arylboronic Acids to Generate Nitrilium and Pyridinium Products*.

Metal-catalyzed C-N cross-coupling generally forms C-N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C-N cross-coupling that uses a dative N-ligand in the bond-forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a CuII complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative CuIII complex enables the oxidative C-N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2 ) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from d- and l-Xylose.

Manipulating the stereochemistry of polymers is a powerful method to alter their physical properties. Despite the chirality of monosaccharides, reports on the impact of stereochemistry in natural polysaccharides and synthetic carbohydrate polymers remain absent. Herein, we report the cocrystallisation of regio- and stereoregular polyethers derived from d- and l-xylose, leading to enhanced thermal properties compared to the enantiopure polymers. To the best of our knowledge, this is the first example of a stereocomplex between carbohydrate polymers of opposite chirality. In contrast, atactic polymers obtained from a racemic mixture of monomers are amorphous. We also show that the polymer hydroxyl groups are amenable to post-polymerisation functionalization. These strategies afford a family of carbohydrate polyethers, the physical and chemical properties of which can both be controlled, and which opens new possibilities for polysaccharide mimics in biomedical applications or as advanced materials.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

Divergent Catalytic Strategies for the Cis/Trans Stereoselective Ring-Opening Polymerization of a Dual Cyclic Carbonate/Olefin Monomer.

A dual seven-membered cyclic carbonate/olefin monomer was synthesized from CO2 and cis-1,4-butenediol and polymerized. The properties of the polymer were controlled using divergent catalytic strategies toward the stereochemistry of the olefin. Ring-opening polymerization of the cyclic carbonate using an organocatalytic approach retained the cis-stereoconfiguration of the olefin and yielded a hard semicrystalline polymer (Tm 115 °C). Ring-opening metathesis polymerization using Grubbs' catalyst proceeded with high trans-stereoregularity (95%) and produced a soft amorphous polymer (Tg -22 °C). Cis to trans isomerization of the polymer was possible using Cu(I) salts under UV light. In all polymers, the C═C double bond remained available for postpolymerization modification and thermoset resins were formed by cross-linking. From this single monomer, cis-trans-cis triblock copolymers, with potential applications as thermoplastic elastomers, were synthesized by combining both strategies using cis-1,4-butenediol as a chain transfer agent.

Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors.

We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21, a highly potent ATM inhibitor (ATM cell IC50 0.0028 µM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo, 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound 21 was selected for preclinical evaluation alongside AZD0156.

The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one).

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.

Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.

Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology.

The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.

Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.