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Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.

[Image: see text] The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline–P2 surrogate onto the P2–P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia–Kocienski olefination and macrolactamization to assemble the P2–P4 macrocyclic core containing the novel spirocyclic proline–P2 moiety is presented as well.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

A practical, gram-scale synthesis of l-pyrazinylalanine (Paa) is described, utilizing Schollkopf's d-valine-derived bis-lactim ether chiral auxiliary.

An alanine scan performed in the 1970s suggested that Phe(6) and Phe(11) are required for the binding of somatostatin (SRIF-14). Molecular modeling studies and replacement of Phe(6) and Phe(11) with a cystine bridge affording ligands with the retention of high biological activity, however, led to the alternate conclusion that Phe(6) and Phe(11) stabilize the bioactive conformation of SRIF-14. Subsequent studies revealed that Phe(11) shields Phe(6) in a "herringbone" arrangement. More recently, a report from this laboratory demonstrated that Spartan 3-21G MO calculations can be invaluable in explaining SARs in medicinal chemistry. For example, the ability of benzene and indole rings to bind the Trp(8) binding pocket for SRIF-14 and the inability of pyrazine to do so was explained through differences in electrostatic potentials. To investigate the role of Phe(6) and Phe(11) more fully, we report here the synthesis of two analogues of D-Trp(8)-SRIF in which Phe(6) and Phe(11) were replaced by the pryazinylalanine congeners, respectively. The NMR spectra in D(2)O and the K(i)s fully support the proposition that Phe(11) stabilizes the bioactive conformation through pi-bonding or aromatic edge-to-face interaction and that pyrazinylalanine(6) can be shielded by Phe(11). The data also show unexpectedly that Phe(6), via the pi-bond, interacts with the receptor, consistent with the original interpretation of the alanine scan. Heretofore it had only been known that Lys(9) interacts with an aspartate anion of the receptor. These conclusions are supported by recent studies of Lewis et al. on the effects on K(i)s of Ala(6)-SRIF-14-amide at the five receptor subtargets. We also found that pyrazinylalanine(7)-D-Trp(8)-SRIF-14 does not bind, suggesting a repulsive interaction with the receptor. Taken together, our results not only validate predictions based on Spartan 3-21G MO analysis but also provide valuable information about the nature of the receptor interaction at the molecular level. Finally, the chirality of Trp(8) was unexpectedly found to have a striking effect on NMR spectra in methanol, especially at lower temperatures.

Protocols for the efficient preparation of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-methanesulfenyloctane and 1,1,1,2,2,3,3,4,4-nonafluoro-6-methanesulfenylhexane (fluorous dimethyl sulfide) and for their oxidation to the corresponding sulfoxides (fluorous dimethyl sulfoxide) are reported. The lower molecular weight sulfoxide, in conjunction with oxalyl chloride and Hunig's base, brings about the oxidation of diversely functionalized primary and secondary alcohols to aldehydes and ketones in excellent yield. The fluorous sulfoxide is efficiently recovered for reuse by a simple continuous fluorous extraction and hydrogen peroxide oxidation protocol. The whole process is odor-free. A deuterium-labeling experiment is used to demonstrate that the oxidations take place via the classical Swern mechanism, i.e. by intramolecular hydride abstraction from a sulfur ylid. Corey–Kim oxidations may be performed with the higher molecular weight fluorous sulfide, although recycling is not as efficient.

Protocols for the efficient preparation of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-methanesulfenyloctane and 1,1,1,2,2,3,3,4,4-nonafluoro-6-methanesulfenylhexane (fluorous dimethyl sulfide) and for their oxidation to the corresponding sulfoxides (fluorous dimethyl sulfoxide) are reported. The lower molecular weight sulfoxide, in conjunction with oxalyl chloride and Hunig's base, brings about the oxidation of diversely functionalized primary and secondary alcohols to aldehydes and ketones in excellent yield. The fluorous sulfoxide is efficiently recovered for reuse by a simple continuous fluorous extraction and hydrogen peroxide oxidation protocol. The whole process is odor-free. A deuterium-labeling experiment is used to demonstrate that the oxidations take place via the classical Swern mechanism, i.e. by intramolecular hydride abstraction from a sulfur ylid. Corey–Kim oxidations may be performed with the higher molecular weight fluorous sulfide, although recycling is not as efficient.

It is demonstrated that alkene radical cations generated by the radical ionic fragmentation of β-(phosphatoxy)alkyl radicals undergo efficient nucleophilic capture by amines in either the 6-exo or 6-endo modes, leading to six-membered nitrogen heterocycles. Suitable placement of an alkene enables the juxtaposition of a radical cyclization resulting in the formation of both the indolizidine and 1-azabicyclo[3.2.1]octane skeleta.

In conjunction with sodium borohydride as stoichiometric reagent a catalytic quantity of bis(4-perfluorohexylphenyl) diselenide converts vicinal dimesylates to the corresponding alkenes in good yield on warming in ethanol. The diselenide is recovered in high yield by continuous fluorous extraction.

[180840-34-0]] C11H20BN (MW 177.09) InChI = 1S/C11H17N.BH3/c1-4-12(10(2)3)11-8-6-5-7-9-11;/h5-10H,4H2,1-3H3;1H3 InChIKey = XYUIGBMTIMBDDQ-UHFFFAOYSA-N (reagent used for hydroboration) Physical Data: liquid above 0 °C.1, 2 Solubility: soluble in Et2O, THF, and DCM. Analysis of Reagent Purity: the reagent is analyzed for active hydrogen by a standard procedure involving hydrolysis with 2.0 M hydrochloric acid-glycerol-water (2:1:1) and determination of the hydrogen evolved. 11B NMR: δ −14.4 (CCl4, JB–H = 98.6 Hz).1, 2 Preparative Methods: the title reagent is prepared by passing freshly generated diborane into neat N-ethyl-N-isopropylaniline at 0 °C (eq 1). The amine is prepared by heating a mixture of N-ethylaniline and 2-bromopropane to 120 °C. Diborane was generated by treating boron trifluoride-diglyme dropwise with a 2.0 M solution of sodium borohydride in triglyme.1, 2 (1) Handling, Storage, and Precautions: stable reagent, stored under argon, may be toxic.

An alanine scan performed in the 1970s suggested that Phe(6) and Phe(11) are required for the binding of somatostatin (SRIF-14). Molecular modeling studies and replacement of Phe(6) and Phe(11) with a cystine bridge affording ligands with the retention of high biological activity, however, led to the alternate conclusion that Phe(6) and Phe(11) stabilize the bioactive conformation of SRIF-14. Subsequent studies revealed that Phe(11) shields Phe(6) in a "herringbone" arrangement. More recently, a report from this laboratory demonstrated that Spartan 3-21G MO calculations can be invaluable in explaining SARs in medicinal chemistry. For example, the ability of benzene and indole rings to bind the Trp(8) binding pocket for SRIF-14 and the inability of pyrazine to do so was explained through differences in electrostatic potentials. To investigate the role of Phe(6) and Phe(11) more fully, we report here the synthesis of two analogues of D-Trp(8)-SRIF in which Phe(6) and Phe(11) were replaced by the pryazinylalanine congeners, respectively. The NMR spectra in D(2)O and the K(i)s fully support the proposition that Phe(11) stabilizes the bioactive conformation through pi-bonding or aromatic edge-to-face interaction and that pyrazinylalanine(6) can be shielded by Phe(11). The data also show unexpectedly that Phe(6), via the pi-bond, interacts with the receptor, consistent with the original interpretation of the alanine scan. Heretofore it had only been known that Lys(9) interacts with an aspartate anion of the receptor. These conclusions are supported by recent studies of Lewis et al. on the effects on K(i)s of Ala(6)-SRIF-14-amide at the five receptor subtargets. We also found that pyrazinylalanine(7)-D-Trp(8)-SRIF-14 does not bind, suggesting a repulsive interaction with the receptor. Taken together, our results not only validate predictions based on Spartan 3-21G MO analysis but also provide valuable information about the nature of the receptor interaction at the molecular level. Finally, the chirality of Trp(8) was unexpectedly found to have a striking effect on NMR spectra in methanol, especially at lower temperatures.

[51779-32-9] C10H19NO4 (MW 217.26) InChI = 1S/C10H19NO4/c1-9(2,3)14-7(12)11-8(13)15-10(4,5)6/h1-6H3,(H,11,12,13) InChIKey = XCAQIUOFDMREBA-UHFFFAOYSA-N (a versatile Gabriel reagent for preparation of amines) Physical Data: mp 119–121 °C.1, 2 Solubility: soluble in CH3CN, CHCl3, CCl4, and DMF. Analysis of Reagent Purity: 1H NMR, IR, elemental analysis.1, 2 Preparative Methods: the title reagent is prepared from the corresponding di-Boc-formamide by addition of 2-diethylaminoethylamine (DEAEA) to cleave the formyl group. The di-Boc-formamide is in turn prepared from exhaustive tert-butoxycarbonylation of formamide in the presence of catalytic DMAP (eq 1).1 The preparation of title reagent can also be accomplished by treatment of ethyl tert-butyl oxalate with hydrazine to give the ester hydrazide, followed by diazotization to give the corresponding azide, and conversion directly through Curtius rearrangement in the presence of tert-butyl alcohol (eq 2).2 (1) (2) Purification: recrystallized from petroleum ether or hexanes.1, 2 Handling, Storage, and Precautions: stable reagent; stored under argon; may be toxic.

It is demonstrated that phosphorylated forms of beta-nitro alcohols provide an excellent means of entry into beta-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux. These radicals then undergo heterolytic cleavage of the phosphate group to yield alkene radical cation/phosphate anion contact ion pairs which are trapped intramolecularly in a tandem polar/radical crossover sequence involving radical ionic chain reactions by allylic and propargylic amines. The substitution pattern of the alkene radical cation dictates the cyclization mode, and this may be engineered to form fused ring systems by an initial exo-mode nucleophilic cyclization or bridged bicyclic systems when the nucleophilic attack takes place in the endo-mode.

[252668-49-8] C11H11ClO4S (MW 274.72) InChI = 1S/C11H11ClO4S/c1-17(14,15)10(8-16-11(12)13)7-9-5-3-2-4-6-9/h2-7H,8H2,1H3 InChIKey = OAPIEQWHMLVMLO-UHFFFAOYSA-N (reagent used for the introduction of a protecting group for amines) Alternate Name: Mspoc-Cl. Physical Data: mp 118–120 °C, colorless crystals.1 Solubility: soluble in CH2Cl2 and CHCl3; insoluble in hexanes. Purification: recrystallized from CH2Cl2/hexanes. Analysis of Reagent Purity: 1H NMR, IR, elemental analysis.1 Preparative Methods: the title reagent is prepared by the reaction of 2-(methylsulfonyl)-3-phenyl-2-propenyl alcohol and phosgene (eq 1).1 The alcohol is obtained from the corresponding allylic bromide2 by formate-catalyzed hydrolysis.3 The synthesis of the bromide involves the Cu(OAc)2-catalyzed addition of methanesulfonyl chloride to β-methylstyrene followed by elimination of hydrogen chloride and subsequent free radical bromination of the methyl group (eq 1).2 (1) Handling, Storage, and Precautions: relatively stable reagent, but moisture sensitive and best when freshly recrystallized before use. Used in a well-ventilated fume hood.

[234449-42-4] C24H8F26Se2 (MW 948.20) InChI = 1S/C24H8F26Se2/c25-13(26,15(29,30)17(33,34)19(37,38)21(41,42)23(45,46)47)9-1-5-11(6-2-9)51-52-12-7-3-10(4-8-12)14(27,28)16(31,32)18(35,36)20(39,40)22(43,44)24(48,49)50/h1-8H InChIKey = YCRFNIGNXWPRSG-UHFFFAOYSA-N (reagent used as a recyclable fluorous1, 2 alternative to diphenyl diselenide) Physical Data: mp 95–97 °C, yellow crystalline solid.3 Solubility: soluble in CH2Cl2, CHCl3, THF, and FC-72. Analysis of Reagent Purity: 1H, 13C, 19F, and 77Se NMR; elemental analysis.3 Preparative Methods: the title reagent is prepared from 4-perfluorohexylphenyl selenocyanate by borohydride reduction followed by exposure to air (eq 1).3 The fluorous selenocyanate is obtained from the corresponding diazonium salt by treatment with potassium selenocyanate. The synthesis of the diazonium salt involves copper-mediated coupling of 4-iodoaniline with perfluorohexyl iodide, and subsequent reaction with isoamyl nitrite (eq 1).3 (1) Purification: recrystallized from EtOH. Handling, Storage, and Precautions: stable reagent, stored under argon, may be toxic.

[89797-68-2] C3H6N4S (MW 130.17) InChI = 1S/C3H6N4S/c1-2-8-3-4-6-7-5-3/h2H2,1H3,(H,4,5,6,7) InChIKey = GONFBOIJNUKKST-UHFFFAOYSA-N (reagent used a powerful activator in DNA and RNA syntheses) Physical Data: mp 86–88 °C.1, 2 Solubility: soluble in CH3CN, DMF. Purification: recrystallized from toluene. Analysis of Reagent Purity: IR, UV, elemental analysis.2 Preparative Methods: the title reagent 1 is prepared from the corresponding alkyl thiocyanate and sodium azide through a [2 + 3] cycloaddition under phase transfer catalytic conditions (eq 1).1 The ratio of the solvent (water to toluene) as well as the reaction temperature are important factors in obtaining preparative yields of the alkylthiotetrazoles. 5-Ethylthio-1H-tetrazole has also been prepared using DMF as solvent albeit in much lower yield.2 (1) Handling, Storage, and Precautions: stable reagent; stored under argon, may be toxic.

Borane gas and 2-(perfluorooctyl)ethyl methyl sulfide form a solid comprised of an approximately 1:1 mixture (fluorous BMS) of sulfide and the corresponding sulfide-borane. Fluorous BMS permits hydroboration of alkenes in a dichloromethane/perfluorinated hydrocarbon mixture with subsequent recycling of the fluorous sulfide by fluorous extraction. The use of fluorous BMS in the asymmetric reduction of ketones catalyzed by a chiral oxaborolidine catalyst, and in the reduction of other functional groups, is also reported. [reaction: see text]

[reaction: see text] It is demonstrated that alkene radical cations generated by the radical ionic fragmentation of beta-(phosphatoxy)alkyl radicals undergo efficient nucleophilic capture by amines in either the 6-exo or 6-endo modes, leading to six-membered nitrogen heterocycles. Suitable placement of an alkene enables the juxtaposition of a radical cyclization resulting in the formation of both the indolizidine and 1-azabicyclo[3.2.1]octane skeleta.

In conjunction with sodium borohydride as stoichiometric reagent a catalytic quantity of bis(4-perfluorohexylphenyl) diselenide converts vicinal dimesylates to the corresponding alkenes in good yield on warming in ethanol. The diselenide is recovered in high yield by continuous fluorous extraction.