Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor.

Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

Synthesis of Pyridopyrazine-1,6-dione γ-Secretase Modulators via Selective 4-Methylimidazole N1-Buchwald Arylation.

An efficient synthesis of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) is described. Our route features the construction of a crystalline lactone intermediate via a selective palladium-catalyzed 4-methylimidazole N1-arylation using the Buchwald Xantphos Pd G4 precatalyst, which does not require a preactivation step. The weak inorganic base KHCO3 was employed to minimize saponification of a particularly sensitive lactone substrate. Additional key transformations include DABAL-Me3-mediated lactone aminolysis and a mild TBD/ethyl trifluoroacetate mediated lactam ring closure to afford a representative GSM in high yield.

Ru/Ni Dual Catalytic Desulfinative Photoredox Csp2-Csp3 Cross-Coupling of Alkyl Sulfinate Salts and Aryl Halides.

A mild Ru/Ni dual catalytic desulfinative photoredox Csp2-Csp3 cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)3Cl2, Ni(COD)2, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the Csp2-Csp3 cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort.

Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones.

We present an operationally simple lactone-to-lactam transformation utilizing diverse amine nucleophiles. The key steps of amidation, alcohol activation, and cyclization are all mediated by one reagent (TBD) in a single vessel at room temperature. We illustrate the convenience of this protocol by synthesizing a wide range of N-alkyl, N-aryl, and N-hetereoaryl pyridopyrazine-1,6-diones, an important class of medicinally significant lactams. Furthermore, the reported methodology can be applied to the synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones without the use of specialized equipment.

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy.

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-ß42 (Aß42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.

A general strategy for organocatalytic activation of C-H bonds via photoredox catalysis: direct arylation of benzylic ethers.

Direct C-H functionalization and arylation of benzyl ethers has been accomplished via photoredox organocatalysis. The productive merger of a thiol catalyst and a commercially available iridium photoredox catalyst in the presence of household light directly affords benzylic arylation products in good to excellent yield. The utility of this methodology is further demonstrated in direct arylation of 2,5-dihydrofuran to form a single regioisomer.

Photoredox activation for the direct ß-arylation of ketones and aldehydes.

The direct ß-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron ß-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl ß-position. This mode of activation is suitable for a broad range of carbonyl ß-functionalization reactions and is amenable to enantioselective catalysis.

Aza-Morita-Baylis-Hillman reactions and cyclizations of conjugated dienes activated by sulfone, ester, and keto groups.

The aza-Morita-Baylis-Hillman reactions of aldimines 2 with several activated conjugated dienes were found to proceed smoothly in DMF in the presence of 3-hydroxyquinuclidine (HQD). Imines 2 reacted with 1-(p-toluenesulfonyl)-1,3-butadiene (3), methyl 2,4-pentadienoate (6), hexa-3,5-dien-2-one (7), and 1-phenylpenta-2,4-dien-1-one (8) to afford adducts 4, 13, 14, and 15, respectively. While products 4, 13, and 15 were formed as E,Z mixtures, adducts 14 were obtained as essentially pure E-isomers. Cyclization of the E-isomers of the products derived from the dienyl sulfone 3 and the dienoate ester 6 occurred via intramolecular conjugate addition under base-catalyzed conditions to afford functionalized piperidines 5 and 16, respectively. The aza-Morita-Baylis-Hillman reaction and subsequent cyclization of the imine 2a with 3 were also carried out as a one-pot reaction, while the reaction mixture was simultaneously irradiated at 300 nm to effect the photoisomerization of the unreactive Z-adduct of the corresponding 4 to the more reactive E-isomer.

Morita-Baylis-Hillman reaction and cyclization of 1-(p-toluenesulfonyl)-1,3-butadiene with aldimines.

[reaction: see text] Aldimines 2 underwent Morita-Baylis-Hillman reaction with 1-(p-toluenesulfonyl)-1,3-butadiene (3) in the presence of 3-hydroxyquinuclidine (HQD) to afford adducts 4. The E-isomers of the products cyclized to the corresponding functionalized piperidines 8 under base-catalyzed conditions. Simultaneous equilibration of (E)-4 and (Z)-4 was effected by photoisomerization to improve the efficiency of the cyclization.