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.

This paper describes the development of a synthetic route for the multigram synthesis of (−)-(1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((−)-14, BMT-395173), a versatile scaffold for divergent drug discovery synthesis. This new process begins with readily available commercial starting materials and includes a highly scalable stereoselective Diels–Alder reaction between (Z)-4-(benzyloxy)-4-oxobut-2-enoic acid (21) and ferrocenium hexafluorophosphate (15), resulting in the formation of alcohol rac-20. Additionally, a stereoselective Wittig reaction of ketone rac-10 with (bromomethyl)triphenylphosphonium bromide introduces the bromomethylene group of (−)-14. The process was applied to the preparation of over 100 g of optically pure BMS-395173 via multiple batches for preclinical chemotype optimization.

An efficient large-scale synthesis of 2aHCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl3/NaIO4, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of 35a or 35b via a stable chelate with lithium cation 38 to give a stereoselective product, bicyclic scaffold 36a, with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester 37a afforded 2aHCl without the need for chiral separation utilized in the first-generation approach.

An enantioselective synthesis (>99% ee) of (-)-(1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((-)-1), a scaffold for divergent drug discovery synthesis, has been developed. The synthesis employed dimethyl(phenyl)silyl moiety as a "masked" hydroxy group and started with an exclusively endo selective Diels-Alder reaction of readily available cyclopenta-2,4-dien-1-yldimethyl(phenyl)silane (8) with maleic anhydride (3) to afford the tricyclic anhydride 17. Desymmetrization of this meso-anhydride 17 was enabled by a high yielding quinidine-mediated opening with benzyl alcohol to generate the benzyl hemiester 4 with >93% ee which was upgraded to greater than 99% ee by chiral resolution with (1R,2R)-(-)-1,2-diaminocyclohexane 19. Other key features of this synthetic route involved a Curtius rearrangement for the formation Teoc-protected amino bicyclo[2.2.1]heptane intermediate 23, a Fleming-Tamao oxidation for the conversion of dimethyl(phenyl)silyl to the hydroxy group and a Swern oxidation of the alcohol 30 to the strained-ring ketone 31. Finally, the bromo olefin of (-)-1 was installed by a stereoselective Wittig reaction of 31 using (bromomethyl)triphenylphosphonium bromide.

(S)- and (R)-N-Boc-3-(trifluoromethyl)piperazines are attractive building blocks for the rational design of drugs. Until now, their chiral syntheses were unknown. Exploration of three synthetic approaches via chiral 3,3,3-trifluoropropane-1,2-diamines yielded a scalable route that has been used for multigram synthesis. Two routes were not amendable for scale-up due to low yielding, tedious purification, limited availability of reagents, and safety issues. The successful and practical route relied on a modified process to mitigate the safety issues for the synthesis of (E)-3,3,3-trifluoro-1-nitroprop-1-ene, which was used as a stock solution for the highly diastereoselective aza-Michael addition of optically pure 4-phenyl-2-oxazolidinone. Boc protection of an amino group allowed subsequent transformations to chiral N-Boc-protected 3,3,3-trifluoropropane-1,2-diamine under mild conditions, without the need for chiral chromatography. The amidation of chiral N-Boc-protected 3,3,3-trifluoropropane-1,2-diamine with 2-chloroacetyl chloride, followed by intramolecular cyclization and subsequent reduction afforded enantiomerically pure N-Boc-3-(trifluoromethyl)piperazines.

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.

(S)-N-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (1) is a potent adaptor associated kinase 1 inhibitor, which may have the potential to treat neuropathic pain and other neurological disorders including schizophrenia, Parkinson's disease, bipolar disorder, and Alzheimer's disease. For preclinical studies, a substantial amount of high quality material was required. The original discovery route for the preparation of this compound suffered from scale-up issues that included a very low-yielding C-O coupling step and the use of expensive and toxic reagents. This paper describes a rapid scale-up synthesis accomplished in eight steps, which involves the coupling of phenol 17 with oxathiazolidine 18 as the key transformation.

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).

An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (BMS-929075), an allosteric, palm site inhibitor of the HCV NSSB replicase, is described. The highlights of the process involve (a) the copper-mediated, one-pot synthesis of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) from regiospecifically lithiated 1-bromo-2-fluoro-4-methoxybenzene (13) and ethyl 2-bromoacetate (18); and (b) the formation of the highly functionalized benzofuran core 26 through a chromatography-free, telescoped process that proceeds via acylation and a subsequent concomitant demethylation and Boc deprotection using BBr3, followed by an acid-catalyzed cyclization from Boc-protected 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide 23. This process was applied to the preparation of 110 g of high-quality BMS-929075 to enable preclinical toxicology studies.

N-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide (5) is a potent inhibitor of TGFβRI kinase that provides durable antitumor activity when combined with ...

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

The visible light-promoted intramolecular [2+2] cycloaddition of N-allylcinnamamines and N-allylcinnamamides in the presence of catalytic amounts of [Ir{dF(CF3)ppy}(2)(dtbpy)]PF6 is reported. Low energy visible light and a high triplet energy iridium-photosensitizer were efficient at promoting the cycloaddition reaction of N-allylcinnamamides and N-allylcinnamamines to the corresponding aryl-3-azabicyclo[3.2.0]heptanones and aryl-3-azabicyclo[3.2.0]heptanes, respectively, with high diastereoselectivity and under mild conditions. Azabicyclic fused rings have been employed as surrogates for piperidine motifs in drug discovery. Functional groups useful for deployment and/or elaboration in drug discovery campaigns were all shown to be tolerated, including halides, CF3, cyanide, ester, acetamide, acetate, CH3O, pyridyl, furan, carbamate, tosyl, benzyl, and benzoate.

The Cover Feature shows the [2+2] photocycloaddition of highly functionalized N-allylcinnamamides and N-allylcinnamamines, that could provide the corresponding aryl-3-azabicyclo[3.2.0]heptanones and aryl-3-azabicyclo[3.2.0]heptanes, respectively. Those compounds are useful as both scaffolds and fragments in drug design and discovery. We thank Dr. John Tokarski at BMS and Accdon, LLC/ LetPub for the cover design. More information can be found in the Full Paper by M. S. Oderinde et al.

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann’s ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ1-42 and Aβ1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ1-37 and Aβ1-38 were observed, with no change in the total amount of Aβ1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.

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.

BMS-911278 was identified as a potent triple reuptake inhibitor potentially useful for the treatment of depression. The original racemic synthesis suffered from tedious and low recovery resolution and HPLC separation, as well as low-yielding hazardous N-demethylation at the API step. To support further preclinical studies, a scalable enantioselective synthesis was developed. Herein, we report an efficient asymmetric synthesis of BMS-911278 featuring two key steps: an enantioselective Miyaura reaction and an intramolecular regioselective cyclization.