12 research outputs found
Palladium(II)-Catalyzed Ī³-Selective Hydroarylation of Alkenyl Carbonyl Compounds with Arylboronic Acids
A catalytic Ī³-selective <i>syn</i>-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(II) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene
Copper-Catalyzed ChanāLam Cyclopropylation of Phenols and Azaheterocycles
Small molecules containing
cyclopropaneāheteroatom linkages
are commonly needed in medicinal chemistry campaigns yet are problematic
to prepare using existing methods. To address this issue, a scalable
ChanāLam cyclopropylation reaction using potassium cyclopropyl
trifluoroborate has been developed. With phenol nucleophiles, the
reaction effects <i>O</i>-cyclopropylation, whereas with
2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction
brings about <i>N</i>-cyclopropylation. The transformation
is catalyzed by CuĀ(OAc)<sub>2</sub> and 1,10-phenanthroline and employs
1 atm of O<sub>2</sub> as the terminal oxidant. This method is operationally
convenient to perform and provides a simple, strategic disconnection
toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine
derivatives bearing an array of functional groups
A Disconnection for Rapid Access to Heterocyclic Benzylic Amines with Fully Substituted Ī±āCarbons
2-
or 4-Pyridyl benzylic amines represent a privileged motif in
drug discovery. However, the formation of heterocyclic benzylic amines
with fully substituted Ī±-carbons can require the execution of
lengthy synthetic routes, which limit their application. Addition
of various nucleophilic agents to Ellmanās imines has been
well established; however, there is no precedented literature reported
for pyridyl-type nucleophiles, which are very important for medicinal
chemistry. In this letter, we disclose the development of a one-step
synthesis of heterocyclic benzylic amines with fully substituted Ī±-carbons
from heteroaryl halides and sulfinyl imines. Starting from 2,4-dibromopyridine,
regioselective synthesis of 2- or 4-pyridyl benzylic amines could
be achieved by choosing toluene or MTBE as a solvent
Studies on the Regioselective Nucleophilic Aromatic Substitution (S<sub>N</sub>Ar) Reaction of 2āSubstituted 3,5-Dichloropyrazines
Differences in regioselectivity were observed during the S<sub>N</sub>Ar reaction of amines with unsymmetrical 3,5-dichloropyrazines. This study revealed that when the 2-position of the pyrazine was occupied with an electron-withdrawing group (EWG), nucleophilic attack occurred preferentially at the 5-position. When the 2-position was substituted with an electron-donating group (EDG), nucleophilic attack occurred preferentially at the 3-position. These results are reported along with a computational rationale for the experimental observations based on the Fukui index at the reacting centers
Synthesis of Small 3āFluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry
Here,
we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines
through a 1,3-dipolar cycloaddition with a simple azomethine ylide
and a variety of vinyl fluorides and vinyl difluorides. We demonstrate
that vinyl fluorides within Ī±,Ī²-unsaturated, styrenyl
and even enol ether systems can participate in the cycloaddition reaction.
The vinyl fluorides are relatively easy to synthesize through a variety
of methods, making the 3-fluoropyrrolidines very accessible
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340
Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2<i>H</i>)āones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors
A new
enhancer of zeste homolog
2 (EZH2) inhibitor series comprising a substituted phenyl ring
joined to a dimethylpyridone moiety via an amide linkage has been
designed. A preferential amide torsion that improved the binding properties
of the compounds was identified for this series via computational
analysis. Cyclization of the amide linker resulted in a six-membered
lactam analogue, compound <b>18</b>. This transformation significantly
improved the ligand efficiency/potency of the cyclized compound relative
to its acyclic analogue. Additional optimization of the lactam-containing
EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement,
which provided compound <b>31.</b> Compound <b>31</b> displayed
improved LipE and on-target potency in both biochemical and cellular
readouts relative to compound <b>18</b>. Inhibitor <b>31</b> also displayed robust in vivo antitumor growth activity and dose-dependent
de-repression of EZH2 target genes