Search

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.

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 Fce 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.

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fce receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties an...

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4′-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

[reaction: see text] The palladium-catalyzed carboamination of N-protected gamma-aminoalkenes with aryl bromides and triflates has been achieved under new, mild reaction conditions using the weak base Cs(2)CO(3) in dioxane solvent. These reactions tolerate a wide variety of functional groups, including enolizable ketones, nitro groups, methyl esters, and acetates, which are not compatible with previously described conditions.

The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of γ-(N-arylamino) alkenes, these transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl bromide substrates.

A new Pd-catalyzed reaction for the stereoselective synthesis of cyclopentane-fused benzocyclobutenes is described. These transformations likely proceed via carbamate-directed carbopalladation followed by intramolecular C-H activation of an alkylpalladium intermediate. The mechanistic relationship between these transformations and Pd-catalyzed reactions of gamma-(n-Boc-amino)alkenes with aryl bromides that afford pyrrolidines is discussed. Differences in reactivity between Pd-amino and Pd-amido complexes appear to play a key role in the outcome of these transformations.

A new tandem Wittig Rearrangement/aldol reaction of O-benzyl or O-allyl glycolate esters is described. This reaction generates two carbon−carbon bonds and two contiguous stereocenters in a single step from simple starting materials. The [1,2]-Wittig rearrangement proceeds under very mild reaction conditions that do not require the use of a strong base, and the 1,2-diol products are obtained in good yield with excellent diastereoselectivity (>20:1).

The use of the weak base Cs2CO3 in Pd-catalyzed carboamination reactions of N-protected γ-aminoalkenes with aryl bromides leads to greatly increased tolerance of functional groups and alkene substitution. Substrates derived from (E)- or (Z)-hex-4-enylamines are stereospecifically converted to 2,1′-disubstituted pyrrolidine products that result from suprafacial addition of the nitrogen atom and the aryl group across the alkene. Transformations of 4-substituted pent-4-enylamine derivatives proceed in high yield to afford 2,2-disubstituted products, and cis-2,5- or trans-2,3-disubstituted pyrrolidines are generated in good yield with excellent diastereoselectivity from N-protected pent-4-enylamines bearing substituents at C1 or C3. The reactions tolerate a broad array of functional groups, including esters, nitro groups, and enolizable ketones. The scope and limitations of these transformations are described in detail, along with models that account for the observed product stereochemistry. In addition, deut...

The use of the weak base Cs2CO3 in Pd-catalyzed carboamination reactions of N-protected gamma-aminoalkenes with aryl bromides leads to greatly increased tolerance of functional groups and alkene substitution. Substrates derived from (E)- or (Z)-hex-4-enylamines are stereospecifically converted to 2,1'-disubstituted pyrrolidine products that result from suprafacial addition of the nitrogen atom and the aryl group across the alkene. Transformations of 4-substituted pent-4-enylamine derivatives proceed in high yield to afford 2,2-disubstituted products, and cis-2,5- or trans-2,3-disubstituted pyrrolidines are generated in good yield with excellent diastereoselectivity from N-protected pent-4-enylamines bearing substituents at C1 or C3. The reactions tolerate a broad array of functional groups, including esters, nitro groups, and enolizable ketones. The scope and limitations of these transformations are described in detail, along with models that account for the observed product stereochemistry. In addition, deuterium labeling experiments, which indicate these reactions proceed via syn-aminopalladation of intermediate palladium(aryl)(amido)complexes regardless of degree of alkene substitution or reaction conditions, are also discussed.

[247940-06-3] C24H31P (MW 350.48) InChI = 1S/C24H31P/c1-4-12-20(13-5-1)23-18-10-11-19-24(23)25(21-14-6-2-7-15-21)22-16-8-3-9-17-22/h1,4-5,10-13,18-19,21-22H,2-3,6-9,14-17H2 InChIKey = LCSNDSFWVKMJCT-UHFFFAOYSA-N (reagent used as a ligand for a variety of palladium-catalyzed reactions) Alternate Name: 2-(dicyclohexylphosphino)biphenyl. Physical Data: mp 103 °C. Solubility: soluble in most organic solvents. Form Supplied in: white crystalline solid. Purification: recrystallized from hot methanol. Handling, Storage, and Precautions: stable to air and moisture.

[reaction: see text] A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N-C2 bond and the C1'-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogues bearing different aromatic groups.