Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

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 .

Mechanistic Insights into a CDK9 Inhibitor Via Orthogonal Proteomics Methods.

Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).

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 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 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 and . 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 .

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity.

α-Heteroarylation of Thioethers via Photoredox and Weak Brønsted Base Catalysis.

We report the C-H activation of thioethers to α-thio alkyl radicals and their addition to -methoxyheteroarenium salts for the redox-neutral synthesis of α-heteroaromatic thioethers. Studies are consistent with a two-step activation mechanism, where oxidation of thioethers to sulfide radical cations by a photoredox catalyst is followed by α-C-H deprotonation by a weak Brønsted base catalyst to afford α-thio alkyl radicals. Further, -methoxyheteroarenium salts play additional roles as a source of methoxyl radical that contributes to α-thio alkyl radical generation and a sacrificial oxidant that regenerates the photoredox catalytic cycle.

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 ), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound , a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9.

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.

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 -[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6,8)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3-pyrazolo[4,3-]isoquinolin-6-yl]pyridin-3-amine (). 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.

Palladium-catalyzed intramolecular carboborylation of 1,3-diene and synthesis of ABCD ring of communesins.

A palladium-catalyzed intramolecular carboborylation of 1,3-diene has been developed for the synthesis of iminoindolines with a quaternary carbon centre. This method was applied to a substrate bearing several functional groups to afford a complex iminoindoline, which was subsequently converted into an ABCD ring model compound of communesins via an intramolecular Friedel-Crafts-type reaction.

Photochemistry of mycolactone A/B, the causative toxin of Buruli ulcer.

Photochemistry of mycolactone A/B and related unsaturated fatty acid esters is reported. On exposure to visible light, mycolactone A/B gave a mixture of four photomycolactones. Pentaenoates and tetraenoates, representing the unsaturated fatty acid portion of mycolactone A/B, were found to show the reactivity profile parallel with that of mycolactone A/B.

Synthesis and structure of two new mycolactones isolated from M. ulcerans subsp. shinshuense.

Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products.

Flexible strategy for syntheses of spirooxindoles using palladium-catalyzed carbosilylation and Sakurai-type cyclization.

The intramolecular carbosilylation of N-[2-(1,3-butenyl)aryl]carbamoyl chloride has been investigated. The reaction with hexamethyldisilane proceeds smoothly in the presence of a catalytic amount of [Pd(η(3)-allyl)Cl](2) to give oxindoles with an allylsilane functional group in good yield. The subsequent subjection of the products to a Sakurai-type reaction provides more advanced tricyclic spirooxindoles by controlling the stereochemistry of three contiguous stereogenic centers.

Stereochemistry of intermolecular oxypalladation: Pd(II)-catalyzed 1,3-chirality transfer reaction of chiral allylic alcohol with methanol.

The intermolecular oxypalladation of chiral nonracemic allylic alcohols (S)-1, (R)-1, and (R)-3 in methanol gave chiral nonracemic methyl allyl ethers (S)-2 and/or (R)-2 with excellent selectivity. The reaction induced the 1,3-chirality transfer to give syn-S(N)2' product exclusively through syn oxypalladation. On the other hand, the anti-S(N)2' product was produced in 20-33% in THF, toluene, and CH2Cl2 and predominantly in CH3CN.

An efficient synthesis of 2- and 2,6-substituted piperidines using Pd(II)-catalyzed 1,3-chirality transfer reaction.

An efficient and general method for 2- and 2,6-substituted piperidine syntheses using Pd(II)-catalyzed 1,3-chirality transfer reaction has been developed. The various N-protected zeta-amino allylic alcohols cyclize in the presence of PdCl2(CH3CN)2 to give substituted piperidines with high stereoselectivities. The syntheses of (S)-(+)- and (R)-(-)-coniine were achieved in 3 steps from the optically pure allylic alcohols (S)-14c and (R)-14c, respectively.