The Gabriel amine synthesis is a textbook method for the preparation of primary amines from alkyl halides. In this work, we demonstrate a Gabriel amine synthesis with iodo-bicyclopentanes to make aminomethyl bicyclobutanes. DFT studies support the concerted rearrangement of a bicyclo[1.1.1]pentyl to a bicyclo[1.1.0]butyl carbocation, initiated by a carbon-halide dissociation. A carboxamide substituent stabilizes the carbocation intermediate with anchimeric assistance.

Herein, we describe the discovery of a novel immunostimulatory drug conjugate (IMC) that employs TLR7/8 agonists conjugated to a tumor-targeting LIV1 antibody. Targeting TLR7/8 agonists to LIV1-expressing tumors enables localized delivery, thereby minimizing systemic toxicity while promoting inflammation and T cell recruitment within the tumor microenvironment (TME) for enhanced antitumor efficacy. Dual activation of TLR7 and TLR8 within the TME facilitates the recruitment of diverse immune cells and induces a broad spectrum of pro-inflammatory cytokines, effectively reshaping the immunosuppressive TME by upregulating costimulatory molecules. The mechanism of action of the IMC involves tumor recognition via surface antigens and Fcγ-mediated phagocytosis, followed by activation of myeloid cells to efficiently present tumor antigens to T-cells, thereby eliciting antitumor immunity. The designed IMCs demonstrate the ability to activate myeloid cells in the presence of tumor cells, display robust antitumor activity, and are well tolerated in toxicology studies.

An efficient, scalable and stereoselective synthesis of optically pure (3R,4R)-1-benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines has been developed starting from commercially available N-benzyl-3-methyl-4-piperidone. The synthesis employed chiral resolution of N-benzyl-3-methyl-4-piperidone, cis-selective reduction of a keto group, and subsequent Mitsunobu inversion of the resulting hydroxy group to install an amine with the desired trans-stereochemistry as the key steps. The method described herein demonstrated a competent route to the title compounds in a cost-effective, and scalable manner.

The reaction of iodo-bicyclo[1.1.1]pentanes with potassium phthalimide yields phthalimide-substituted bicyclo[1.1.0]butanes (BCBs), which upon hydrazinolysis afford the corresponding aminomethyl-BCB products.

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50 = 2.8 μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).

Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.