Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

Article

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Small Molecule Disruptors of the Glucokinase−Glucokinase

Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series,

Optimization Through Conformational Analysis

Nuria A. Tamayo,*^,†Mark H. Norman,^†Michael D. Bartberger,*^,‡Fang-Tsao Hong,^†Yunxin Bo,^†

Longbin Liu,^†Nobuko Nishimura,^†Kevin C. Yang,^†Seifu Tadesse,^†Christopher Fotsch,^†Jie Chen,^∥

Samer Chmait,^‡Rod Cupples,^§Clarence Hale,^§Steven R. Jordan,^‡David J. Lloyd,^§Glenn Sivits,^§

Gwyneth Van,^⊥and David J. St. Jean, Jr.^†

‡

^†Department of Therapeutic DiscoveryMedicinal Chemistry, Department of Therapeutic DiscoveryMolecular Structure and

§

∥

⊥

Characterization, Department of Metabolic Disorders, Department of Pharmacokinetics and Drug Metabolism, and Department

of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States

S

* Supporting Information

ABSTRACT: The glucokinase−glucokinase regulatory protein

(GK-GKRP) complex plays an important role in controlling

glucose homeostasis in the liver. We have recently disclosed a

series of arylpiperazines as in vitro and in vivo disruptors of the

GK-GKRP complex with eﬃcacy in rodent models of type 2

diabetes mellitus (T2DM). Herein, we describe a new class of

aryl sulfones as disruptors of the GK-GKRP complex, where the

central piperazine scaﬀold has been replaced by an aromatic group. Conformational analysis and exploration of the structure−

activity relationships of this new class of compounds led to the identiﬁcation of potent GK-GKRP disruptors. Further

optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in

vivo and, by doing so, increases cytoplasmic levels of unbound GK.

To identify an alternative series in this program, we postulated

that it would be possible to substitute the relatively ﬂat central N-

piperazine ring with other planar moieties such as aryl and

heteroaryl groups that did not disrupt the key hydrogen bonding

interactions between hGKRP and the substituents on the A- and

C-rings (general structure 3). To test this hypothesis, aryl sulfone

4 was prepared and tested for its ability to disrupt the hGK-

hGKRP complex in an AlphaScreen biochemical assay¹³(4, IC₅₀

= 1.01 μM vs 2, IC₅₀= 0.454 μM). Although a 3-fold loss of

potency was observed, this result was encouraging because it

represented a novel series of GK-GKRP disruptors lacking a

piperazine central ring. We obtained an X-ray cocrystal structure

of aryl sulfone 4 bound to hGKRP (Figure 2b) in which the same

key interactions between compound 4 and the protein were

maintained as described for arylpiperazine 1. Analysis of this

cocrystal structure showed that the dihedral angle between the

central B-ring and the Arg525-engaging C-ring was compressed

to a value of approximately −15°, which is smaller than that

typically observed for a biphenyl moiety in the free state

(∼40°).¹⁴This nonoptimal dihedral angle is a result of the steric

constraints imposed by the ﬂoor residues Val28, Pro29, and the

overhead residue Ala521.

INTRODUCTION

■

Glucokinase (GK) plays a central role in glucose homeostasis

and is the major glucose phosphorylating enzyme expressed in

hepatocytes and pancreatic β-cells.¹It acts as a glucose sensor

and regulates hepatic glucose metabolism in addition to glucose-

dependent insulin secretion.²Glucokinase activators (GKAs)

have been reported as a novel class of potential antidiabetic

agents.³They are associated with a dual mechanism for lowering

blood glucose by enhancing insulin secretion from pancreatic β-

cells and increasing glucose uptake in the liver, and several have

entered clinical development for the treatment of type 2

diabetes.^4,5Although dual-acting (liver and pancreas) GKAs

are eﬃcacious, many have been associated with a signiﬁcant risk

for hypoglycemia, attributed in part to increasing insulin

secretion at low glucose levels.⁶As an alternative, we have

recently disclosed the discovery and optimization of small

molecule GK-GKRP disruptors with excellent in vivo activ-

ity,⁷⁻¹¹as exempliﬁed by the aryl piperazines 1 and 2 (Figure 1).

We have also disclosed the cocrystal structure of N-aryl

piperazine 1 bound to hGKRP,⁹in which it was established that

the piperazine ring acts as a spacer, positioning the A- and C-rings

in optimal orientations to allow hydrogen-bonding interactions

between the small molecule and the protein. It was observed that

the amino group on the pyridyl A-ring forms hydrogen bonding

interactions with Gly181 and Met213, and the tertiary alcohol

substituent on the C-ring forms an additional bifurcated

hydrogen bonding interaction with Arg525 (Figure 2a).

We postulated that we should be able to improve the binding

aﬃnity of this new series by optimizing the dihedral angle

Received: November 24, 2014

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Figure 1. Aryl piperazine GK-GKRP disruptors (1 and 2), generic core structure used for SAR investigations (3), and aryl sulfone 4.

Figure 2. (a) X-ray cocrystal structure of N-aryl piperazine 1 bound to hGKRP. (b) X-ray cocrystal structure of aryl sulfone 4 bound to hGKRP.

Hydrogen bonds are shown by dashed yellow lines. The dihedral angles (ϕ) between the B- and C-rings are also shown.¹²

between the B- and C-rings, while maintaining the key hydrogen

bonding interactions elsewhere in the binding site. Toward this

goal, a novel series of biaryl sulfones (3) with diﬀerent 5- and 6-

membered aryl and heteroaryl groups were designed based on

their capacity to adopt a minimum-energy conformation with a

dihedral angle between the two rings (B−C) that is closer to

−15°. The new analogues were tested for their ability to disrupt

the hGK-hGKRP complex and were also evaluated in vitro for

their metabolic stability in rat liver microsomal (RLM)

preparations. This investigation provided an understanding of

the optimal biaryl (B−C) ring system and resulted in the

discovery of a novel series of hGK-hGKRP disruptors,

exempliﬁed by thiazole 93. This compound potently disrupted

the GK-GKRP complex in vitro in rat hepatocytes and also

showed a dose-dependent eﬀect on nuclear rat GK translocation

in vivo.

displacement of the chloride with ammonia provided 7. Bromide

7 was coupled with boronic ester 8¹⁶to give biaryl sulfone 4 in

excellent yield. Alternatively, 7 could be converted into boronic

ester 9 and then coupled to heterocyclic chlorides 10¹⁰and 11¹⁰

yielding sulfones 12 and 13, respectively. The synthesis of the

bipyridyl analogue, 17, required the use of organostannane 16¹⁶

as the coupling partner in the palladium-catalyzed reaction. The

requisite biaryl thioether 15 was prepared by a copper-catalyzed

reaction between iodopyridine 5 and 6-aminopyridine-3-thiol

(14). Stille coupling of aryl sulﬁde 15 and organostannane 16

followed by oxidation of the resulting thioether with oxone

provided bipyridyl sulfone 17 in moderate yield.

The syntheses of C-ring substituted pyridylsulfones are

outlined in Scheme 2. Suzuki-Miyaura coupling reaction of

boronic ester 9 with chloropyridines 18¹¹and 19¹¹gave pyridine

sulfones 20 and 21, respectively. Chloropyridine 20 was

converted to cyanopyridine 22 by microwave assisted

palladium-catalyzed cyanation using 2-dicyclohexylphosphino-

2′,4′,6′-triisopropylbiphenyl (XPhos) as the ligand. Alterna-

tively, copper-free Sonagashira coupling of 20 with a variety of

terminal alkynes in the presence of Cs₂CO₃or K₂CO₃aﬀorded

derivatives 23-27 in good yields.

CHEMISTRY

■

The preparation of the unsubstituted biaryl sulfones 4, 12, 13,

and 17 is outlined in Scheme 1. Copper catalyzed coupling of 2-

chloro-5-iodopyridine (5) and 4-bromothiophenol (6) led to the

formation of the corresponding biaryl thioether under relatively

mild conditions.¹⁵Oxidation of the thiol group to the sulfone

using 3-chloro peroxybenzoic acid (mCPBA), followed by

The B-ring substituted bipyridines 34−40 and 45−48 were

synthesized in ﬁve to six synthetic steps from (2,6-diﬂuoropyr-

idin-3-yl)boronic acid (28) (Scheme 3). Suzuki-Miyaura cross-

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a

Scheme 1. Synthesis of Unsubstituted (6,6)-Biaryl Sulfones

a

Reagents and conditions: (a) CuI, K₂CO₃, ethylene glycol, IPA, 80 °C; (b) mCPBA, CH₂Cl₂, rt; (c) NH₄OH, EtOH, 120 °C; (d) PdCl₂(dppf),

Cs₂CO₃, DME, water, 100 °C; (e) pinacol diborane, PdCl₂(dppf), KOAc, dioxane, 100 °C; (f) CuI, K₂CO₃, ethylene glycol, IPA, 90 °C; (g)

Pd(PPh₃)₄, LiCl, dioxane, 90 °C; then, oxone, dioxane, water, rt.

a

Scheme 2. Synthesis of C-Ring Substituted Pyridyl Sulfones

a

Reagents and conditions: (a) PdCl₂(dppf), Cs₂CO₃, DME, water, 100 °C; (b) PdCl₂(AmPhos)₂, K₂CO₃, dioxane, water, 140 °C; (c) Zn(CN)₂,

XPhos/Pd₂(dba)₃, DMF, 140 °C; (d) alkyne, XPhos precatalyst, Cs₂CO₃, MeCN, 80 to 140 °C; (e) alkyne, XPhos precatalyst, K₂CO₃, DMA, 110

°C; (f) alkyne, XPhos precatalyst, K₂CO₃, DMA, 110 °C; then TBAF, THF, rt.

a

Scheme 3. Synthesis of B-Ring Substituted Bipyridyl Sulfones

a

Reagents and conditions: (a) PdCl₂(AmPhos)₂, KOAc, dioxane, water, 80 °C; (b) K₂CO₃, DMF, 80 °C; (c) conc. H₂SO₄, water, then sodium

dichromate, 0 °C to rt; (d) amine, DMSO, 100 °C; (e) amine, KHMDS or LiHMDS, THF, −50−0 °C; (f) phenol, Cs₂CO₃, DMSO, 60 °C; (g)

aminopyridine, LiHMDS, THF, 0 °C.

coupling of 28 with bromopyridine 29¹⁰using AmPhos¹⁷gave

bipyridyl intermediate 30. The use of potassium acetate helped

minimize the hydrolysis of the 2-ﬂuoropyridine under the

reaction conditions compared with stronger bases such as

potassium or sodium carbonate. Base-mediated S_NAr reaction of

ﬂuoropyridine 30 with tert-butyl (5-mercaptopyridin-2-yl)-

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a

Scheme 4. Synthesis of Thiophene-Pyridine and Thiophene-Pyrimidine Analogues

a

Reagents and conditions: (a) PdCl₂(dppf), Cs₂CO₃, dioxane, 90 °C; (b) (4-methoxyphenyl)methanethiol, Josiphos/Pd(OAc)₂, NaO-t-Bu, DME,

90 °C; (c) TFA, 70 °C; (d) 5, CuI, N,N-dimethyl-1,2-ethanediamine, K₂CO₃, DMSO, 90 °C; (e) mCPBA, CH₂Cl₂, 0 °C; then NH₄OH, dioxane,

120 °C; (f) propyne, XPhos precatalyst, Cs₂CO₃, MeCN, 80 °C.

a

Scheme 5. Synthesis of Thiophene-Phenyl Analogue (65)

a

Reagents and conditions: (a) CuI, N,N,-dimethylethane-1,2-diamine, K₂CO₃, DMSO, 80 °C; (b) mCPBA, CH₂Cl₂, rt; then NH₄OH, dioxane, 100

°C; (c) 8, PdCl₂(dppf), Cs₂CO₃, dioxane, water, 100 °C.

carbamate (31) provided a 2:1 regioisomeric mixture of

bipyridines from which the desired and major ﬂuoropyridine

32 was isolated. Removal of the Boc group followed by oxidation

using sodium dichromate aﬀorded 33 in moderate yield.

Reaction of ﬂuoropyridine 33 with aliphatic amines, aniline,

and benzylamine aﬀorded pyridyl sulfones 34-40 in moderate to

good yields. The lower yields obtained were due, in part, to the

competing displacement of the sulfone when a strong base was

used. The most successful strategy to overcome this issue, was to

alter the order of the synthetic transformations. In the synthesis

of analogues 45-48, the substituent on the B-ring was introduced

before the oxidation of the sulﬁde to the sulfone, thus avoiding

the previously observed side reaction. Reaction of ﬂuoropyridine

32 with phenol or aminopyridines led to sulﬁdes 41−44 that

were then oxidized to the target sulfones 45−48, using sodium

dichromate.

deprotected in the presence of triﬂuoroacetic acid at 70 °C. The

rest of the syntheses were completed in a similar way as

previously described for the preparation of (6,6)-biaryls (Scheme

1) to provide the desired compounds 58 and 59. Palladium-

catalyzed coupling reaction of chloropyridine 59 with propyne

gave the alkyne analogue 60.

In the case of the aryl C-ring analogue 65 (Scheme 5), the

order of the synthetic steps was modiﬁed. The synthesis started

by a copper catalyzed S-arylation of diiodothiophene (61) with 6-

chloropyridine-3-thiol (62). This reaction led to a mixture of

mono- and dicoupled products, but 63, the monocoupled

product, could be isolated by silica gel column chromatography.

Oxidation of sulﬁde 63 with mCPBA followed by displacement

of the 2-chloro substituent with ammonia gave sulfone 64 that

was then coupled with boronic ester 8 to form the target

compound, 65.

The syntheses of analogues having a central thiophene group

and a heterocyclic C-ring (58-60) began with a Suzuki-Miyaura

palladium-catalyzed coupling reaction between commercially

available 5-chloro-2-thienylboronic acid (49) and heterocyclic

halides 50¹⁰and 51,¹¹resulting in the formation of

chlorothiophene analogues 52 and 53 (Scheme 4). It was

important to control the temperature during these reactions

because higher temperatures (>90 °C) led to the decomposition

of the boronic acid and resulted in very low conversions. The 2-

chlorothiophenes (52 and 53) were converted to 2-thiolthio-

phenes (54 and 55) by palladium-catalyzed reaction with (4-

methoxyphenyl)methanethiol as a hydrogen sulﬁde surrogate.

The reaction was optimized by the use of Josiphos¹⁸as the ligand.

The high degree of steric hindrance and strong electron donating

properties of this ligand, allowed for the preparation of the target

intermediates in good yields. The sulﬁde intermediates were then

The thiazole analogues 86−94 needed for this investigation

were prepared as outlined in Scheme 6. The syntheses started

with palladium-catalyzed Stille cross-coupling reaction between

2-(tributylstannanyl)-1,3-thiazole (66) and aryl bromides 67⁸-

69, giving aryl thiazoles 70, 71, and 74, respectively.

Methylketone 71 was a versatile synthetic intermediate used

for the preparation of other analogues. Thus, 71 was converted

into the triﬂuoromethyl alcohol 72 by treatment with TMS

triﬂuoromethane in the presence of TBAF at 0 °C. In an

analogous way, 71 was also treated with methyl magnesium

bromide to give the gem-dimethyl alcohol 73 in good yield.

Finally, diol 75 was prepared by a two-step procedure involving a

Corey-Chaykovsky epoxidation of 71 using trimethylsulfonium

iodide¹⁹followed by hydrolysis of the epoxide intermediate to

the diol in the presence of hydrochloric acid. Bromination of the

thiazoles 70, 72−75 with N-bromosuccinimide gave bromides

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a

Scheme 6. Synthesis of Thiazole-Phenyl Analogues

a

Reagents and conditions: (a) PdCl₂(PPh₃)₂, DMF, 90 °C; (b) CsF, TMSCF₃, DME, 0 °C; then TBAF, THF, 0 °C; (c) MeMgBr, THF, 0 °C; (d)

(CH₃)₃SOI, KO-t-Bu, DMSO, rt; then HCl (1N), 0 °C; (e) NBS, DMF, 70 °C; (f) methyl 3-sulfanylpropanoate, Xantphos/Pd₂(dba)₃, DIPEA,

dioxane, 120 °C; then KO-t-Bu, THF, −78 °C; (g) 5, CuI, K₂CO₃, ethylene glycol, IPA, 80−90 °C; (h) 62, Xantphos/Pd₂(dba)₃, dioxane, 120 °C;

(i) mCPBA, CH₂Cl₂, 0 °C; then NH₄OH, dioxane, 120 °C; (j) Na₂WO₄, H₂O₂, AcOH, 0 °C; then NH₄OH, EtOH, 100 °C; (k) chiral separation by

SFC (the absolute stereochemistries of compounds 88, 89, 93, and 94 were arbitrarily assigned).

a

Scheme 7. Synthesis of Thiazole-Phenyl Analogue (99)

a

Reagents and conditions: (a) PdCl₂(dppf), Cs₂CO₃, DME, water, 90 °C; (b) methyl 3-sulfanylpropanoate, Xantphos/Pd₂(dba)₃, DIPEA, dioxane,

120 °C; then KO-t-Bu, THF, −78 °C; (c) 5, CuI, K₂CO₃, ethylene glycol, IPA, 80 °C; (d) mCPBA, CH₂Cl₂, rt; then NH₄OH, EtOH, 120 °C.

76−80 that were then converted into biaryl thiols by palladium-

catalyzed coupling reactions with methyl 3-sulfanylpropanoate, a

thiol surrogate. Deprotection of the thiol with potassium tert-

butoxide and copper-catalyzed cross-coupling between the thiols

and 2-chloro-5-iodopyridine (5) led to the biaryl sulﬁdes 81 and

82 in moderate yields. Alternatively, a one-step procedure was

developed to streamline the synthesis. This involved the direct

palladium-catalyzed cross-coupling reaction of 6-chloropyridine-

3-thiol (62) with bromothiazoles 78−80 giving the target biaryl

sulﬁdes (83−85) in moderate yields. Oxidation of the thiols

(81−85) to the sulfones was accomplished using mCPBA or

sodium tungstate-hydrogen peroxide that in some cases, gave

cleaner reactions. Treatment of the resulting chloropyridines

with ammonia led to the 2-aminopyridine analogues 86, 87, and

90−92. Chiral separation of the racemic sulfone 87 gave the two

enantiomerically pure analogues 88 and 89. Similarly, the

racemic diol 92 was also subjected to chiral puriﬁcation leading to

diols 93 and 94.

The synthesis of analogue 99 is described in Scheme 7,

palladium-catalyzed cross-coupling of 2,4-dibromothiazole (95)

with 1,1,1,3,3,3-hexaﬂuoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-diox-

aborolan-2-yl)phenyl)propan-2-ol (96)¹⁶gave compound 97 in

good yield. We were able to employ 2,4-dibromothiazole as the

starting material due to the higher reactivity of the 2- vs the 4-

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a

Scheme 8. Synthesis of Imidazole-Phenyl Analogues (105 and 110)

a

Reagents and conditions: (a) (4-methoxyphenyl)methanethiol, JosiPhos/Pd(OAc)₂, NaO-t-Bu, DME, 90 °C; (b) 96 or 8, PdCl₂(dppf), Cs₂CO₃,

dioxane, water, 100 °C; (c) TFA, 70 °C; then 103, CuI, N,N-dimethylethane-1,2-diamine, K₂CO₃, DMSO, 90 °C; (d) mCPBA, CH₂Cl₂, 0 °C.

bromo substituent in a palladium-catalyzed coupling reaction.

Palladium-catalyzed coupling with methyl 3-sulfanylpropanoate,

followed by deprotection of the thiol with potassium tert-

butoxide, and copper-catalyzed cross-coupling with 2-chloro-5-

iodopyridine (5) led to the biaryl sulﬁde 98. This compound was

then oxidized to the sulfone with mCPBA and treated with

ammonia to give the thiazole analogue 99.

Table 1. SAR of Unsubstituted 6,6-Biaryl Analogues

The last two analogues needed in this investigation, N-methyl

imidazoles 105 and 110, were prepared according to the routes

detailed in Scheme 8. First, 2,4-dibromo-1-methyl-1H-imidazole

(100) underwent palladium-catalyzed cross-coupling with (4-

methoxyphenyl)methanethiol, to give thiol 101. The aryl C-ring

was introduced by a Suzuki-Miyaura coupling leading to the

biaryl sulﬁde 102. Deprotection of the sulﬁde with triﬂuoroacetic

acid, followed by a copper catalyzed arylation with 2-amino-iodo-

pyridine (103) gave compound 104. Oxidation of 104 with

mCPBA provided the target N-methylimidazole 105. For the

preparation of the regiosiomeric N-methylimidazole 110, the

order of the synthetic steps was altered. First, 2,5-dibromo-1-

methyl-1H-imidazole (106) was coupled with boronic ester 8 to

give biaryl 107 that was subsequently coupled with (4-

methoxyphenyl)methanethiol. The rest of the sequence to

prepare 110 was similar to that previously described for 105.

RESULTS AND DISCUSSION

■

The compounds described herein were tested for their ability to

disrupt the hGK-hGKRP interaction in a biochemical

AlphaScreen assay¹³and the data is reported as IC₅₀values in

Tables 1−5. The in vitro rat microsomal stabilities of these

analogues are also shown in the same tables. In our previous work

on GK-GKRP disruptors, we disclosed a series of piperazine

analogues with potent in vitro and in vivo activities, exempliﬁed

by aryl piperazine 1. X-ray crystallographic studies revealed that

the piperazine ring acts as a spacer properly positioning the A-

and C-rings in the binding cavity. The sulfonamide functionality

provided the required length and “L-shaped” trajectory for the

amino group in the pyridine ring to form key hydrogen-bond

interactions with Gly181 and Met213 on the protein (Figure 2a).

The aryl C-ring attached to the piperazine core navigated a

a

b

Data reported as the mean and SD where n ≥ 3. In vitro rat

microsomal stability measurements were conducted in the presence of

NADPH at 37 °C for 30 min at a ﬁnal compound concentration of 1

μM. Racemic mixture.

c

hydrophobic channel delineated by Ala521(above), and Val28

and Glu32 (below), serving to present the terminal carbinol

functionality in a hydrogen bonding interaction with both

terminal and internal nitrogen atoms of the Arg525 side chain.

Based on our hypothesis that the N-aryl piperazine in 1 could

be replaced with an aromatic ring, biaryl sulfone 4 was prepared

and tested. While a 3-fold loss in potency was observed (4 vs 2,

Table 1), the cocrystal structure of sulfone 4 bound to hGKRP

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revealed that the ligand was able to achieve the same hydrogen-

bonding interactions with the protein as the parent piperazine 1

(Figure 2b). However, as previously discussed, the dihedral angle

between the B- and C-rings was found to be higher in energy than

the global minimum.

To investigate the conformations of this type of B−C-ring

system, a quantum mechanical conformational analysis was

performed²⁰on four model 6,6-biaryl sulfones (structures I to

IV), where the B-ring was phenyl or pyridine and the C-ring was

phenyl, pyridine, or pyrimidine (Figure 3). Substitution of one or

Attempts to correlate potency with cell permeability and

subsequently physicochemical properties (log P, PSA, pK_a)

were unsuccessful.²²

In spite of the lack of cellular potency, we were encouraged by

the improved biochemical potency of 13; therefore, we sought to

further explore substitution at the C-ring, as a potential access

point to a previously identiﬁed “shelf” region of the protein

comprised of Ala27-Val28-Pro29. We hypothesized that

improving the biochemical potency as well as the physicochem-

ical properties would be required to obtain signiﬁcant cellular

potency in this series.

The shelf region sits just below the biaryl plane, next to Tyr24

and above the region delimited by Ala27-Pro29. We sought to

introduce substituents that would allow additional interactions

with the protein while maintaining the two key hydrogen

bonding areas previously described that anchor the ligand to the

protein. The results of a series of C-ring substituted pyridines are

reported in Table 2. Small groups at the ortho position were

detrimental for activity (compounds 20−22). We speculated

that this loss of potency could be due to the disfavorable torsional

strain between the ortho substituent on the C-ring and the ortho

hydrogen on the central phenyl ring. To access the shelf region

and maintain the optimal torsional angle between the B- and C-

rings, a sterically minimal alkynyl functionality, which would

project further into the pocket, was employed. Consistent with

our hypothesis, the alkyne analogue 23 was 4-fold more potent

than the pyridine 12, and also demonstrated cellular potency in

the rat translocation assay (EC₅₀= 3.55 μM). Unfortunately, this

substituent also conferred poor rat in vitro metabolic stability

(CL_int= 177 μL/min/mg), making it a poor candidate for in vivo

evaluation. Given the fact that the alkyne group was tolerated,

additional analogues were prepared with polar substitutions at

the alkyne terminus (compounds 24-27). Introduction of

primary or secondary alcohols gave analogues (24 and 26) that

were equipotent to the methyl alkyne 23 in the biochemical

assay, but were signiﬁcantly more potent in the cellular assay as

well as more stable in rat liver microsomes (EC₅₀= 0.6 and 0.83

μM, CL_int= 36 and 29 μL/min/mg, respectively). A 3-fold

improvement in biochemical potency was obtained by

methylation of the terminal alcohol (25); however, this

substitution did not improve the cellular potency and was also

detrimental for in vitro stability in rat liver microsomes. The

tertiary alcohol 27 was also prepared and, although very stable in

vitro (CL_int< 14 μL/min/mg), a 5-fold loss in binding potency

was observed as compared with the secondary alcohol (26 vs 27,

IC₅₀42 vs 211 nM). Based on this SAR, we observed that the

introduction of a polar group was beneﬁcial to obtain

submicromolar potencies in the rat functional hepatocyte

assay, which led to a decrease in the large cell shift previously

observed.

Figure 3. SCRF-B3LYP/6-31G* dihedral proﬁle of (6,6)-biarylsulfone

structures (I−IV). The scanned dihedral angle is depicted in bold.

more of the ortho C−H bonds of the B- and/or C-rings with

nitrogen atoms was predicted to reduce the internal energy

penalty for coplanarization by replacing the eclipsing C−H

interactions with sterically less-demanding and electrostatically

favorable CH···N contacts. For the biphenyl core (structure I)

the binding conformation (Φ_B−C≈ 15°) lies approximately 1

kcal/mol above the ∼35° global minimum and does not

represent a stationary point. In contrast, aza analogs (structures

II−IV) were predicted to virtually eliminate the internal energy

penalty required for binding (Figure 3, relative energy <0.2 kcal/

mol at Φ_B−C≈ 15°).

Therefore, we began modifying our lead sulfone 4 by replacing

the B- and C-rings with the 6-membered heterocycles suggested

by the conformational analysis.²¹Pyridine derivative 12

demonstrated a 4-fold improvement in activity, achieving

potency similar to that of the starting piperazine analogue 2

(see Table 1). Introduction of an additional nitrogen in the B-

ring, giving rise to bipyridyl analogue 17, was well tolerated

providing an analogue with approximately the same potency as

pyridine 12. Incorporation of a pyrimidine group as the C-ring

(13) resulted in yet another 3-fold improvement in biochemical

activity compared to 12 (13, IC₅₀= 104 nM). In addition, all of

these analogues possessed excellent metabolic stability when

incubated with rat liver microsomes (<14 μL/min/mg). Having

improved the biochemical potency more than 10-fold (13 vs 4),

sulfone 13 was tested in a cellular assay where nuclear to

cytoplasmic GK translocation in rat primary hepatocytes was

quantiﬁed. Unfortunately, pyrimidine 13 did not demonstrate

measurable activity in this assay (EC₅₀> 12.5 μM). The large cell

shift observed for sulfone 13 in this assay was diﬃcult to

rationalize. Rat primary hepatocytes are complex structures and

many factors might inﬂuence the overall activity in this assay.

Given the planar nature of unsubstituted pyridine 12, we

hypothesized that we should also be able to reach the shelf region

of the protein from the central B-ring, a novel approach since this

could not be accomplished with our previous piperazine series.

To maintain the optimal dihedral angle between the B- and C-

rings, we postulated that we could lock the conformation of the

ligand by the introduction of an intramolecular hydrogen bond

between the substituent on the B-ring and the nitrogen of the C-

ring pyridine. The eﬀects on biochemical activity observed when

substituents were appended to the B-ring through an amine or

ether linkage are reported in Table 3. Aliphatic amines were well

tolerated with potencies roughly decreasing as the size of the

substituents increased [34, (R = NHMe) > 35, (R = NHEt) > 36,

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Table 2. SAR of Pyridyl C-ring Analogues

Table 3. SAR of Pyridyl B-ring Analogues

a

b

Racemic mixtures. Data reported as the mean and SD where n ≥ 3.

c

In vitro rat microsomal stability measurements were conducted in the

presence of NADPH at 37 °C for 30 min at a ﬁnal compound

d

concentration of 1 μM. NT = not tested.

activity. The result with ether 45 (IC₅₀= 6 μM) supports our

hypothesis that the amino group helps to anchor the B- and C-

ring at an optimal planar torsional angle. The X-ray cocrystal

structure of 39 (Figure 4) bound to hGKRP shows that the

compound binds as predicted and conﬁrmed the postulated

intramolecular hydrogen bond interaction between the amino

group on the B-ring and the pyridyl nitrogen of the C-ring.

Encouraged by the result obtained with analogue 39, we

replaced the phenyl group with the three regioisomeric pyridines

(46−48) with the goal of decreasing the log P and possibly

reducing the cell shift observed for 39 (>25-fold). Unfortunately,

the incorporation of the nitrogen atoms was detrimental to the

biochemical activity with IC₅₀values 2- to 15-fold higher than the

parent phenyl derivative, 39. However, introduction of a polar

pyridine substituent did reduce the cell shift in the case of

analogue 46 (only 10-fold).

Having optimized the biochemical and cellular potencies of

this set of analogues, we turned our attention to modiﬁcations of

the central B-ring. The goal was to improve biochemical potency

without a substantial increase in MW, lipophilicity, or polar

surface area that could impact cell shift and the PKDM proﬁle of

these compounds. We examined a small set of analogues that

contained replacement of the central 6-membered aromatic

group by 5-membered heterocycles (B-ring). To help in the

a

b

Data reported as the mean and SD where n ≥ 3. In vitro rat

microsomal stability measurements were conducted in the presence of

NADPH at 37 °C for 30 min at a ﬁnal compound concentration of 1

c

μM. NT = not tested.

(R = NHiPr) ≈ 37, (R = NHcPr)]. However, this trend did not

extend to the bulky cyclohexyl analogue 38, which exhibited

improved activity (IC₅₀= 99 nM) probably due to an increase in

van der Waals contacts with the protein. Further improvements

in potency were achieved when the planarity of the substituent at

this position was increased. An aniline at this position (39) gave

the best result, with a single-digit nanomolar IC₅₀in the

biochemical assay. Both the amino cyclohexyl derivative 38 and

the aniline analogue 39 had improved cellular activities with EC₅₀

values of 0.66 and 0.19 μM respectively; however, they were

quickly cleared in rat liver microsomal preparations. Extending

the projection of the substituent with a N-benzyl group (40) or

changing the nature of the linkage of the substituent to the B-ring

(oxygen vs nitrogen) to form ether 45 were detrimental for

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Figure 4. Top (a) and side (b) views of X-ray crystal structure of compound 39 bound to hGKRP. The hydrogen bonds to Gly181, Met213, and Arg525

are depicted in yellow.¹²

design of novel GK-GKRP disruptors, we analyzed the dihedral

angle proﬁles of biaryl sulfones having a thiophene, thiazole, and

N-methyl imidazole as the central B-ring. In the case of these 5,6-

heterocyclic ring systems, there were two dihedral angles that

inﬂuenced the overall conformation of these derivatives: the

angle between the 5-membered B-ring and the six-membered C-

ring (Figure 5) and the angle between the aryl sulfone A-ring and

the 5-membered B-ring (Figure 6).

Figure 6. SCRF-B3LYP/6-31G* dihedral proﬁle of (5,6)-biarylsulfone

structures (A- and B-rings). The scanned dihedral is depicted in bold.

conformation predisposes the amino on the pyridine A-ring for

optimal hydrogen bond interactions with Gly181 and Met213.

Figure 6 shows that the two thiophenes (structures V and X) and

one of the thiazoles (structure VI) had minima near the optimal

90° orientation, whereas thiazole VII and N-methyl imidazoles

VIII and IX had minima at nonoptimal orientations of ∼60−70°.

Figure 5. SCRF-B3LYP/6-31G* dihedral proﬁle of (5,6)-biarylsulfone

The repulsive interactions between either the N-methyl

structures (B- and C-rings). The scanned dihedral is depicted in bold.

substituent (in structure IX) or the in-plane nitrogen lone pair

(in structures VII and VIII) and the sulfonic oxygen may give rise

to a signiﬁcant energy penalty for adoption of the required ∼90°

binding conformation.

Figure 5 shows that the 5,6-heterocyclic B−C-ring systems

that can adopt low energy conformations near the optimal

coplanar geometry are thiophenes (structures V and X) and

thiazoles (structures VI and VII). On the other hand the N-

methyl imidazole scaﬀolds (structures VIII and IX) were

predicted to possess a disfavorable orientation of the B−C-ring

system, with a minimum at ∼30−40° and having a 1−2 kcal/mol

coplanarization penalty compared to other more favorable 5-

membered heterocyclic B-rings. Next we examined the dihedral

angle between the A- and B-rings (Figure 6). The optimal

dihedral angle in the binding conformation between the A- and

B-rings is found to be approximately 90° (Figure 2b). This

From the analysis of these two dihedral angles we would

predict that the thiophene-phenyl (V), thiazole-phenyl (VI), and

thiophene-pyrimidine (X) ring systems would provide the most

potent analogues and the thiazole-phenyl (VII) and N-methyl

imidazoles (VIII and IX) would be less favorable. To test this

hypothesis the derivatives shown in Table 4 were prepared and

evaluated. The results obtained in the biochemical assay were in

agreement with the quantum mechanical predictions (i.e., 58, 65,

and 86 were the most potent while 99, 105, and 110 were

signiﬁcantly less active). Speciﬁcally, substitution of the phenyl

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Table 4. SAR of Unsubstituted 5,6-Biaryl Sulfone Analogues

Table 5. SAR of Substituted 5,6-Biaryl Sulfones

a

b

Racemic mixtures. Data reported as the mean and SD where n ≥ 3.

c

In vitro rat microsomal stability measurements were conducted in the

presence of NADPH at 37 °C for 30 min at a ﬁnal compound

concentration of 1 μM.

B-ring on 13 by a thiophene, a standard bioisostere of a phenyl

group, gave sulfone 58, that was 5-fold less potent. This loss in

potency may be due to a decrease in van der Waals interactions

between the central ring and the protein, or to the slight change

in trajectory versus a six-membered B-ring (structure X, Figure

5). A more dramatic loss in potency was observed when the

pyrimidine C-ring was substituted with a phenyl ring (65).

Compound 65 had an IC₅₀value of 1.93 μM, similar to the

original 6,6-biphenyl sulfone 4. The next set of derivatives

contained two heteroatoms within the 5-membered heterocyclic

core, two isomeric thiazoles (86 and 99) and two isomeric N-

methyl imidazoles (105 and 110). As mentioned above, the

imidazole analogues 105 and 110 are highly disfavored and these

analogues did not show any signiﬁcant activity in the GK-GKRP

biochemical assay. In contrast, there was a clear diﬀerence in

potency between the two isomeric thiazoles: the 2,5-

disubstituted thiazole 86 was more than 50-fold more potent

than the 2,4-disubstituted thiazole 99 (IC₅₀value of 534 nM vs

>33 μM).

a

b

All the compounds are racemic mixture unless stated. Data reported

c

as the mean and SD where n ≥ 3. In vitro rat microsomal stability

measurements were conducted in the presence of NADPH at 37 °C

for 30 min at a ﬁnal compound concentration of 1 μM. NT = Not

tested. The stereochemistry at carbinol carbon was assigned

arbitrarily.

d

e

We focused our continued eﬀorts on improving the

biochemical potency in the thiophene (58) and 2,5-thiazole

series (86). An initial set of compounds was prepared to

investigate the eﬀect of accessing the shelf region from the ortho

position of the C-ring on the thiophene series (Table 5).

Substitution of one of the pyrimidyl nitrogens on the C-ring of 58

by a C−Cl (59) or C-propyne (60) resulted in a greater than 5-

fold improvement in biochemical potency; however, the

metabolic stability of 60, the most potent thiophene analogue,

was very poor, and also a large cell shift was observed in the rat

hepatocyte assay. The X-ray cocrystal structure of 59 bound to

hGKRP is depicted in Figure 7.

Visual inspection of the complex structure revealed that 59

binds to hGKRP in a conformation other than its global

minimum. This conformation, possessing a syn orientation of the

chloro substituent with respect to the thiophene sulfur, allows

the chlorine atom to occupy the more spatially tolerant shelf

region. As a consequence, the thiophene sulfur and pyridine

nitrogen of the biaryl system are required to adopt a disfavored

anti conformation, rather than the preferred S−N syn-locked

orientation which would maximize the stabilizing interaction

between these heteroatoms.²³⁻²⁵

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This species (where S−Cl is syn) should instead bind hGKRP in

its minimum energy conformation, while still allowing access to

the shelf region by the ortho-chloro substituent.²⁶Therefore,

thiazole analogue 87 was prepared and found to be over 5-fold

more potent than its thiophene counterpart 59 (Table 5), in

addition this compound was found to be stable in rat liver

microsomes. Chiral separation of 87 by supercritical ﬂuid

chromatography (SFC) aﬀorded 88 and 89²⁷yielding

biochemical IC₅₀values of 37 and 18 nM, respectively, and

good activities were obtained in the rat cellular hepatocyte assay.

At this point, attention was turned to the tail piece, the tertiary

hydroxyl group on the C-ring, with the goal of optimizing the

physicochemical properties of the compound (clogP, PSA, and

MW), potentially leading to lower cell shift and consequently

higher cellular activity.¹⁰The hydroxyl group forms a key

hydrogen-bond interaction with the side chain guanidine of

Arg525 (Figure 2). This hydrophilic residue facilitated

incorporation of polarity into the molecule and the surrounding

hydrophobic region accommodated the bulky triﬂuoromethyl

group. The gem-dimethyl alcohol, 90 (Table 5), which had a

lower clogP and molecular weight compared to 89, had an IC₅₀in

the AlphaScreen similar to the chiral triﬂuoromethyl alcohol 89

and showed a small improvement in the translocation assay

(EC₅₀= 0.56 μM). To further decrease the lipophilicity of the

compound, sulfonamide 91 was prepared. Sulfonamides have

previously shown to be acceptable substitutions for the benzylic

alcohol as a tail group;¹⁰however, 91 showed signiﬁcantly lower

biochemical potency (IC₅₀= 257 nM). We hypothesized that in

the biaryl sulfone series the sulfonamide tail piece did not have

the optimal trajectory to completely satisfy the Arg525 hydrogen

bond as we have previously seen in the original piperazine series.

Incorporation of additional polarity at the tail in the form of a diol

(92) gave, not only one of the most potent analogues in this

series, but also the one with the higher binding eﬃciency (BE =

0.4).²⁸In order to further proﬁle this compound, the two

stereoisomers were separated by chiral SFC (93 and 94)²⁷and

tested in the biochemical and cellular assays. The more potent

enantiomer 93 not only showed single-digit nanomolar potency

in the AlphaScreen but was also the most potent analogue from

Figure 7. Top view of X-ray cocrystal structure of thiophene 59 bound

to hGKRP. Shape complementary of the ligand and hGKRP binding

pocket depicted by transparent and mesh surfaces, respectively.¹²

Figure 8 depicts the computed dihedral proﬁle for both the

thiophene-chloropyridine moiety present in 59 (structure XI)

this series in the rat hepatocyte GK translocation assay (EC₅₀

=

0.10 μM).

On the basis of its in vitro properties, sulfone 93 was selected

for pharmacokinetic (PK) studies in Sprague−Dawley rats

(Table 6). Pharmacokinetic parameters from the intravenous

(iv) route indicated a very low plasma clearance of 0.033 L/h/kg,

a V_ssof 0.18 L/kg, and a terminal half-life of 4.7 h. Following a

single oral dose of 10 mg/kg, maximal plasma concentration of

compound 93 (57.6 μM total and 0.43 μM free drug) was

reached 4 h post dosing and slowly declined over time. The oral

bioavailability of compound 93 was estimated to be over 80%.

These results allowed for in vivo coverage of the in vitro cellular

EC₅₀(0.10 μM) for over 12 h, allowing for evaluation in a PD

experiment where the compound was dosed orally at 10 and 100

mg/kg in Sprague−Dawley rats. In this experiment, liver GK

translocation from the cell nucleus was monitored by

Figure 8. PCM-B3LYP/6-31G* dihedral proﬁle for thiophene-

chloropyridine and thiazole-chlorophenyl moieties. The 0° orientation

is depicted above each of the respective curves.

and that of a proposed, regioisomeric thiazole-chlorophenyl ring

system (structure XII). The S−Cl syn, S−N anti conformation

(ϕ = 0°) for bound 59 (structure XI) is predicted to lie ∼1.6

kcal/mol higher in energy above its 180° minimum (Figure 8).

Conversely, the thiazole regioisomer (XII) would enrich the

population of binding conformer (0°) via elimination of the S−N

syn form, which is less suitable for binding (ϕ = 180°; Figure 8).

Table 6. Rat in Vivo PK Properties of Biaryl Sulfone 93

a

b

c

Cmpd No.

t_1/2(h)

V_ss(L/kg)

CL (L/h/kg)

C_max(μM)

AUC (μM·h)

F

(%)

82

f_u

0.0075

93

4.7

0.18

0.033

57.6

568

a

b

c

2 mg/kg intravenous dose (100% DMSO). 10 mg/kg oral dose (1% Tween 80, 2% HPMC, 97% water). Fraction unbound, determined via rapid

equilibrium dialysis.

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constraint. Total energies for a given system were then converted into

relative energies (kcal/mol) for graphical depiction.

Biology. hGK−hGKRP AlphaScreen, GK translocation in rat

hepatocytes, and in vivo PD studies in rats were performed as described

previously.⁸⁻¹¹

immunohistochemistry (IHC) at 6 and 24 h post oral dose

(Figure 9). An IHC score of four represented no pharmacody-

Chemistry. General Procedures. Unless otherwise noted, all

materials were obtained from commercial suppliers and used without

further puriﬁcation. Anhydrous solvents were obtained from Aldrich,

Acros, or EM Science and used directly. All reactions involving air- or

moisture-sensitive reagents were performed under a nitrogen or argon

atmosphere. Microwave-assisted reactions were conducted with either

an Initiator from Biotage, Uppsala, Sweden, or an Explorer from CEM,

Matthews, NC. Silica gel chromatography was performed using either

glass columns packed with silica gel (200−400 mesh, Aldrich Chemical)

or prepacked silica gel cartridges (Biotage or Redisep). NMR spectra

were determined with a Bruker 400 or 300 MHz spectrometer.

Chemical shifts were reported in parts per million (ppm, δ units). All

ﬁnal compounds were puriﬁed to >95% purity as determined by LC−

MS obtained on an Agilent 1100 spectrometer using the following

methods: (A) Agilent SB-C18 column (50 × 3.0 mm, 2.5 μm) at 40 °C

with a 1.5 mL/min ﬂow rate using a 5−95% gradient of 0.1% TFA in

CH₃CN in 0.1% TFA in water, over 3.5 min; (B) Phenomenex Gemini

NX C18 column (50 × 3.0 mm, 3 μm) at 40 °C with a 1.5 mL/min ﬂow

rate using a 5−95% gradient of 0.1% formic acid in CH₃CN in 0.1%

formic acid in water over 3.5 min. Low-resolution MS data were

obtained at the same time as the purity determination on the LC−MS

instrument using the ES ionization mode (positive).

5-((4-Bromophenyl)sulfonyl)pyridin-2-amine (7). A mixture of 2-

chloro-5-iodopyridine (5) (1.12 g, 4.64 mmol), 4-bromothiophenol (6)

(0.87 g, 4.64 mmol), CuI (44 mg, 0.23 mmol), K₂CO₃(1.28 g, 9.29

mmol), and ethylene glycol (0.52 mL, 9.29 mmol) in IPA (10 mL) was

heated under nitrogen at 80 °C for 16 h. The mixture was allowed to

cool to room temperature and partitioned between water and CH₂Cl₂.

The separated organic layer was dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure to provide the crude product. The

residue was puriﬁed by silica gel column chromatography (0−10%

EtOAc/hexanes) to aﬀord 5-((4-bromophenyl)thio)-2-chloropyridine

(1.17 g, 84%) as a white solid. MS (ESI pos. ion): m/z calcd for

C₁₁H₇BrClNS: 298; found 299 (M + H). ¹H NMR (400 MHz, DMSO-

d₆): δ 8.41 (d, J = 2.54 Hz, 1H), 7.81 (dd, J = 2.54, 8.41 Hz, 1H), 7.57−

7.61 (m, 2H), 7.54 (d, J = 8.41 Hz, 1H), 7.30−7.35 (m, 2H).

Figure 9. In vivo GK translocation (colored bars, left y axis) and

unbound plasma concentrations (red triangles, right y axis) in rats

following oral administration of 93 (10, 100 mg/kg, 6 and 12 h

postdose). The statistical signiﬁcance of the measurements were based

on comparison to the individual vehicle control groups (n = 6; * = p <

0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001). The dotted line

represents the GK translocation EC₅₀(0.10 μM) in rat primary

hepatocytes.

namic (PD) response, while a score of zero indicated complete

nuclear translocation of GK. As shown in Figure 9, the 100 mg/

kg dose of compound 93 showed complete translocation of GK

to the cytoplasm at the 6-h time point and a signiﬁcant PD eﬀect

remained for 24 h. The 10 mg/kg showed more than 60% GK

translocation at 6 h. At this dose and time point the mean free

drug concentration was 0.19 μM (Figure 9), which approximates

the rat hepatocyte cellular EC₅₀of 0.10 μM.

CONCLUSION

■

In summary, a new series of biaryl sulfones based on our

previously disclosed aryl piperazines GK-GKRP disruptors was

designed and prepared. Analysis of the X-ray crystal structure of

original biaryl sulfone 4 bound to hGKRP, coupled with

conformational analysis and SAR studies, led initially to the

discovery of unsubstituted biarylsulfones possessing good in

vitro activity but lacking cellular activity in rat hepatocytes.

Potency was further increased by accessing a previously

described hydrophobic shelf region from either the B- or C-

rings. Optimization of this series culminated in the discovery of

thiazole sulfone 93. This new sulfone, possessing a lipophilicity-

lowering, Arg525-engaging diol moiety, demonstrated single-

digit nanomolar potency as a GK-GKRP disruptor in a

biochemical assay and was also able to modulate the trans-

location of nuclear GK in rat hepatocytes. Pharmacokinetic data

indicated that 93 exhibited low clearance and high oral

bioavailability, and in vivo pharmacological studies showed that

93 was able to increase liver GK translocation to the cytoplasm

following a single oral dose. Taken together, the present work

represents an encouraging entry into a novel series of potent in

vitro and in vivo active GK-GKRP disruptors.

To a solution of 5-((4-bromophenyl)thio)-2-chloropyridine (0.27 g,

0.91 mmol) in CH₂Cl₂(5 mL) was added 3-chloroperoxybenzoic acid

(0.41 g, 1.82 mmol). The reaction mixture was stirred at room

temperature for 2 h and partitioned between saturated NaHCO₃and

CH₂Cl₂. The organic layer was separated, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. The crude material was

puriﬁed by silica gel chromatography (0−20% EtOAc/hexanes) to

aﬀord 5-((4-bromophenyl)sulfonyl)-2-chloropyridine (0.10 g, 33%) as

a white solid. MS (ESI pos. ion): m/z calcd for C₁₁H₇BrClNO₂S: 331;

found 332 (M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 9.02 (d, J = 2.54

Hz, 1H), 8.40 (dd, J = 2.64, 8.51 Hz, 1H), 7.93−8.02 (m, 2H), 7.84−

7.91 (m, 2H), 7.79 (d, J = 8.41 Hz, 1H).

To a 25 mL glass resealable vial was added 5-((4-bromophenyl)-

sulfonyl)-2-chloropyridine (98 mg, 0.29 mmol), aqueous NH₄OH (3

mL), and EtOH (3 mL). The vial was closed and heated at 120 °C for 18

h, the reaction was allowed to cool to room temperature, and the solvent

was partially removed under reduced pressure. The white precipitate

obtained was ﬁltered, washed with water, and dried under reduced

pressure. The title compound (75 mg, 81%) was obtained as a white

solid and used without further puriﬁcation. MS (ESI pos. ion): m/z calcd

EXPERIMENTAL SECTION

1

for C₁₁H₉BrN₂O₂S: 312; found 313 (M + H). H NMR (400 MHz,

■

Theoretical Methology and Conformational Analysis. All

quantum mechanical calculations were performed with the Gaussian 09

program system utilizing the B3LYP density functional, the 6-31G*

basis, and the standard IEFPCM self-consistent reaction ﬁeld (SCRF)

implicit aqueous solvation model.²⁰Dihedral scans were performed

using a series of constrained optimizations, whereby the speciﬁed

dihedral angle was kept frozen at a given value, with full optimization of

the remaining geometric parameters subject to the given dihedral

DMSO-d₆): δ 8.43 (d, J = 2.54 Hz, 1H), 7.78−7.86 (m, 4H), 7.76 (dd, J

= 2.54, 9.00 Hz, 1H), 7.15 (br s, 2H), 6.48 (d, J = 9.00 Hz, 1H).

2-(4′-((6-Aminopyridin-3-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)-1,1,1-

triﬂuoropropan-2-ol (4). A glass microwave reaction vessel was charged

with 7 (71 mg, 0.23 mmol), 1,1,1-triﬂuoro-2-(4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (8)¹⁶(86 mg, 0.27 mmol),

PdCl₂(dppf) (18 mg, 0.02 mmol), Cs₂CO₃(222 mg, 0.68 mmol), DME

(1 mL), and water (0.1 mL). The vessel was closed and purged with

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nitrogen for several minutes. The reaction mixture was stirred and

heated in a microwave reactor at 100 °C for 30 min. The organic layer

was separated, and the solvent was removed under reduced pressure.

The crude material was puriﬁed by silica gel chromatography (0−3% 2

M NH₃in MeOH/CH₂Cl₂) to provide the title compound (83 mg,

87%) as an oﬀ-white solid. MS (ESI pos. ion): m/z calcd for

C₂₀H₁₇F₃N₂O₃S: 422; found 423 (M + H). ¹H NMR (400 MHz,

DMSO-d₆): δ 8.47 (d, J = 2.54 Hz, 1H), 7.94−8.02 (m, 2H), 7.90 (d, J =

8.61 Hz, 2H), 7.81 (dd, J = 2.54, 9.00 Hz, 1H), 7.73 (q, J = 8.61 Hz, 4H),

7.10 (br s, 2H), 6.67 (s, 1H), 6.51 (d, J = 9.00 Hz, 1H), 1.72 (s, 3H).

5-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-

sulfonyl)pyridin-2-amine (9). A 25 mL glass resealable vial was charged

with 7 (0.53 g, 1.69 mmol), bis(pinacolato)diboron (0.43 g, 1.69 mmol),

PdCl₂(dppf) (69 mg, 0.08 mmol), KOAc (0.50 g, 5.1 mmol), and

dioxane (8 mL). The vial was closed, purged with nitrogen for several

minutes, and heated at 100 °C for 18 h. After cooling to room

temperature, the reaction mixture was ﬁltered through a pad of Celite

(diatomaceous earth), and the pad was washed with CH₂Cl₂. The ﬁltrate

was concentrated under reduced pressure to yield the title compound

(0.61 g, 100%) as a brown solid that was used without further

puriﬁcation. MS (ESI pos. ion): m/z calcd for C₁₇H₂₁BN₂O₄S: 360;

found 279 (M −C₆H₁₀).

2-(6-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)pyridin-3-yl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (12). A glass microwave reaction

vessel was charged with 9 (0.38 g, 1.06 mmol), 2-(6-chloro-3-pyridinyl)-

1,1,1,3,3,3-hexaﬂuoro-2-propanol (10)¹⁰(0.15 g, 0.53 mmol),

PdCl₂(dppf) (22 mg, 0.03 mmol), Cs₂CO₃(0.52 g, 1.59 mmol),

DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged

with nitrogen for several minutes and then stirred and heated in a

microwave at 100 °C for 30 min. The organic layer was separated and

the solvent was removed under reduced pressure. The crude material

was puriﬁed by silica gel chromatography (0−3% 2 M NH₃in MeOH/

CH₂Cl₂) to provide the title compound (99 mg, 39%) as an oﬀ-white

solid. MS (ESI pos. ion): m/z calcd for C₁₉H₁₃F₆N₃O₃S: 477; found 478

(M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s, 1H), 8.79 (s, 1H),

8.29 (d, J = 2.35 Hz, 1H), 8.13 (d, J = 8.80 Hz, 2H), 7.99−8.05 (m, 2H),

7.85 (d, J = 8.61 Hz, 2H), 7.62 (dd, J = 2.64, 8.90 Hz, 1H), 6.92 (s, 2H),

6.32 (d, J = 8.80 Hz, 1H).

reaction mixture was allowed to cool to room temperature and ﬁltered

through a short pad of Celite. The ﬁlter cake was washed with EtOAc (3

× 10 mL) and the combined organic phases were concentrated under

reduced pressure to give the crude residue. The crude material was

puriﬁed by silica gel chromatography (0−5% 2 M NH₃in MeOH/

CH₂Cl₂) to provide the corresponding thioether intermediate as a light-

yellow solid. This material was dissolved in dioxane (2 mL), and a

solution of oxone (0.27 g, 0.44 mmol) in water (1 mL) was slowly added.

The suspension was stirred at room temperature for 3 h. The reaction

mixture was diluted with water (5 mL) and extracted with EtOAc (3 ×

20 mL). The combined organic extracts were washed with brine (30

mL) and dried over Na₂SO₄. The solution was ﬁltered and concentrated

under reduced pressure to give the crude material as an oﬀ-white solid.

The crude material was puriﬁed by silica gel chromatography (0−5% 2

M NH₃in MeOH/CH₂Cl₂) to provide the title compound (9 mg, 10%)

as an oﬀ-white solid. MS (ESI pos. ion): m/z calcd for C₁₈H₁₅F₃N₄O₃S:

424; found 425 (M + H). ¹H NMR (400 MHz, CD₃OD): δ 9.15 (d, J =

1.76 Hz, 1H), 8.93 (s, 1H), 8.52−8.65 (m, 2H), 8.49 (d, J = 8.41 Hz,

1H), 8.41 (dd, J = 2.25, 8.51 Hz, 1H), 8.18 (dd, J = 1.76, 8.41 Hz, 1H),

7.90 (dd, J = 2.54, 9.00 Hz, 1H), 6.62 (d, J = 9.19 Hz, 1H), 1.83 (s, 3H).

2-(6-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)-5-chloropyridin-3-

yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (20). A glass microwave reaction

vessel was charged with 9 (0.40 g, 1.12 mmol), 2-(5,6-dichloropyridin-3-

yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (18)¹¹(0.10 g, 0.36 mmol),

PdCl₂(dppf) (38 mg, 0.05 mmol), Cs₂CO₃(0.91 g, 2.79 mmol),

DME (3 mL), and water (0.3 mL). The reaction mixture was purged

with nitrogen for several minutes and then stirred and heated in a

microwave at 100 °C for 30 min. The organic layer was separated and

concentrated under reduced pressure. The crude material was puriﬁed

by silica gel chromatography (0−2% 2 M NH₃in MeOH/CH₂Cl₂) to

provide the title compound (0.12 g, 68%) as a white solid. MS (ESI pos.

1

ion): m/z calcd for C₁₉H₁₂ClF₆N₃O₃S: 511; found 512 (M + H). H

NMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.90 (s, 1H), 8.49 (d, J =

2.54 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.41 Hz, 2H), 7.95 (d, J = 8.41

Hz, 2H), 7.82 (dd, J = 2.54, 9.00 Hz, 1H), 7.13 (s, 2H), 6.52 (d, J = 9.00

Hz, 1H).

2-(6-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)-5-methoxypyri-

din-3-yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (21). A glass microwave

reaction vessel was charged with 9 (0.14 g, 0.38 mmol), 2-(6-chloro-5-

methoxypyridin-3-yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (19)¹¹(78 mg,

0.25 mmol), PdCl₂(AmPhos)₂(9 mg, 0.01 mmol), K₂CO₃(0.10 g, 0.76

mmol), dioxane (1 mL), and water (0.1 mL). The vial was sealed and

purged with nitrogen for several minutes. The reaction mixture was

stirred and heated in a microwave at 140 °C for 40 min. The mixture was

ﬁltered through a short pad of Celite and the ﬁlter cake was washed with

EtOAc and CH₂Cl₂(3 × 10 mL each). The combined organic extracts

were concentrated under reduced pressure and the crude material was

puriﬁed by silica gel chromatography (0−7% 2 M NH₃in MeOH/

CH₂Cl₂) to provide the title compound (57 mg, 45%) as a white solid.

MS (ESI pos. ion): m/z calcd for C₂₀H₁₅F₆N₃O₄S: 507; found 508 (M +

H). ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s, 1H), 8.53 (s, 1H), 8.47

(d, J = 2.54 Hz, 1H), 8.05−8.16 (m, 2H), 7.93−8.04 (m, 2H), 7.80 (dd, J

= 2.54, 9.00 Hz, 1H), 7.73 (s, 1H), 7.10 (s, 2H), 6.51 (d, J = 9.00 Hz,

1H), 3.91 (s, 3H).

2-(2-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)pyrimidin-5-yl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (13). A glass microwave reaction

vessel was charged with 9 (0.26 g, 0.73 mmol), 2-(2-chloropyrimidin-5-

yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (11)¹⁰(0.10 g, 0.36 mmol),

PdCl₂(dppf) (15 mg, 0.02 mmol), Cs₂CO₃(0.36 g, 1.09 mmol),

DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged

with nitrogen for several minutes and then stirred and heated in a

microwave at 100 °C for 30 min. The organic layer was separated and

the solvent was removed under reduced pressure. The crude material

was puriﬁed by silica gel chromatography (0−3% 2 M NH₃in MeOH/

CH₂Cl₂) to provide the title compound (56 mg, 32%) as a tan solid. MS

(ESI pos. ion): m/z calcd for C₁₈H₁₂F₆N₄O₃S: 478; found 479 (M + H).

¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (br s, 1H), 9.04 (s, 2H), 8.42 (d,

J = 8.41 Hz, 2H), 8.31 (d, J = 2.74 Hz, 1H), 7.91 (d, J = 8.61 Hz, 2H),

7.63 (dd, J = 2.54, 9.00 Hz, 1H), 6.96 (s, 2H), 6.35 (s, 1H).

5-((6-Chloropyridin-3-yl)thio)pyridin-2-amine (15). To a stirred

suspension of 5 (0.98 g, 4.11 mmol) and 6-aminopyridine-3-thiol (14)

(0.52 g, 4.11 mmol) in IPA (7 mL) was added CuI (0.39 g, 2.05 mmol),

K₂CO₃(1.42 g, 10.26 mmol), and ethylene glycol (0.57 mL, 10.26

mmol). The reaction mixture was heated at 90 °C for 48 h. After cooling

to room temperature, the mixture was ﬁltered through a short pad of

Celite. The ﬁlter cake was washed with EtOAc and CH₂Cl₂(3 × 15 mL,

each) and the combined organics were concentrated under reduced

pressure. The crude material was puriﬁed by silica gel chromatography

(0−70% EtOAc/hexanes) to provide the title compound (0.45 g, 46%)

as an oﬀ-white solid. MS (ESI pos. ion): m/z calcd for C₁₀H₈ClN₃S: 237;

found 238 (M + H).

2-(5′-((6-Aminopyridin-3-yl)sulfonyl)-[2,2′-bipyridin]-5-yl)-1,1,1-

triﬂuoropropan-2-ol (17). A stirred mixture of 15 (52 mg, 0.22 mmol),

1,1,1-triﬂuoro-2-(6-(trimethylstannanyl)-3-pyridinyl)-2-propanol

(16)¹⁶(0.12 g, 0.33 mmol), Pd(PPh₃)₄(13 mg, 11 μmol), and LiCl (46

mg, 1.1 mmol) in dioxane (2 mL) was heated at 90 °C for 18 h. The

2-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)-5-(1,1,1,3,3,3-hexa-

ﬂuoro-2-hydroxypropan-2-yl)nicotinonitrile (22). A glass microwave

reaction vessel was charged with 20 (60 mg, 0.12 mmol), zinc cyanide

(21 mg, 0.18 mmol), XPhos (5 mg, 0.01 mmol), Pd₂(dba)₃(5 mg, 0.006

mmol), and DMF (0.5 mL). The vial was sealed and purged with

nitrogen for several minutes. The reaction mixture was stirred and

heated in a microwave reactor at 140 °C for 20 min. The mixture was

passed through a short plug of Celite. The ﬁlter cake was washed with

EtOAc (3 × 10 mL). The combined organic phases were concentrated

under reduced pressure and the crude material was puriﬁed by silica gel

chromatography (0−5% 1 M NH₃in MeOH/CH₂Cl₂), followed by

preparative silica gel TLC (3% 2 M NH₃in MeOH/CH₂Cl₂) to give the

title compound (10 mg, 17%) as a white solid. MS (ESI pos. ion): m/z

1

calcd for C₂₀H₁₂F₆N₄O₃S: 502; found 503 (M + H). H NMR (400

MHz, CDCl₃): δ 9.19 (br s, 1H), 8.67 (br s, 1H), 8.45 (br s, 1H), 8.03−

M

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Article

8.17 (m, 4H), 7.91 (d, J = 9.00 Hz, 1H), 6.53 (d, J = 9.00 Hz, 1H), 5.09

(br s, 2H), 4.25 (br s, 1H).

with water (5 mL) and extracted with EtOAc (2 × 10 mL). The

combined organic extracts were washed with brine (5 mL), dried over

Na₂SO₄, and concentrated under reduced pressure to give the crude

material. This material was puriﬁed by silica gel chromatography (2−5%

2 M NH₃in MeOH/CH₂Cl₂) to give the title compound (66 mg, 64%)

as an oﬀ-white solid. MS (ESI pos. ion): m/z calcd for C₂₃H₁₇F₆N₃O₄S:

545; found 546 (M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (br s,

1H), 8.93 (d, J = 1.76 Hz, 1H), 8.49 (d, J = 2.15 Hz, 1H), 8.16−8.24 (m,

2H), 8.14 (d, J = 1.96 Hz, 1H), 7.99−8.09 (m, 2H), 7.83 (dd, J = 2.54,

9.00 Hz, 1H), 7.16 (s, 2H), 6.53 (d, J = 8.80 Hz, 1H), 5.54 (d, J = 5.48

Hz, 1H), 4.57 (quin, J = 6.31 Hz, 1H), 1.30 (d, J = 6.65 Hz, 3H).

4-(2-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)-5-(1,1,1,3,3,3-hex-

aﬂuoro-2-hydroxypropan-2-yl)pyridin-3-yl)-2-methylbut-3-yn-2-ol

(27). A glass microwave reaction vessel was charged with 20 (105 mg,

0.20 mmol), XPhos palladium(II) phenethylamine chloride (7 mg, 10

μmol), Cs₂CO₃(0.20 g, 0.61 mmol), 2-methylbut-3-yn-2-ol (0.10 mL,

1.02 mmol), and MeCN (3 mL). The vial was sealed and purged with

nitrogen for several minutes. The reaction mixture was stirred and

heated in a microwave reactor at 140 °C for 40 min. The reaction

mixture was concentrated and puriﬁed by silica gel chromatography (4−

7% 2 M NH₃in MeOH/CH₂Cl₂) to give the title compound (4 mg, 4%)

as an oﬀ-white solid. MS (ESI pos. ion): m/z calcd for C₂₄H₁₉F₆N₃O₄S:

559; found 560 (M + H). ¹H NMR (400 MHz, CD₃OD): δ 8.91 (d, J =

1.76 Hz, 1H), 8.50 (d, J = 2.15 Hz, 1H), 8.22 (d, J = 1.96 Hz, 1H), 8.12−

8.17 (m, 2H), 8.04−8.08 (m, 2H), 7.86 (dd, J = 2.54, 9.00 Hz, 1H), 6.60

(d, J = 8.80 Hz, 1H), 1.43 (s, 6H).

2-(2′,6′-Diﬂuoro-[2,3′-bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol

(30). A 25 mL round-bottomed ﬂask was charged with 2-(6-

bromopyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (29)¹⁰(0.35 g, 1.30

mmol), 2,6-diﬂuoropyridine-3-boronic acid (28) (0.22 g, 1.39 mmol),

KOAc (0.14 g, 1.38 mmol), PdCl₂(AmPhos)₂(40 mg, 0.056 mmol),

dioxane (5 mL), and water (0.5 mL). The ﬂask was closed and purged

with nitrogen for several minutes. The reaction mixture was heated at 80

°C for 18 h and allowed to cool to room temperature. The reaction

mixture was diluted with water (5 mL) and extracted with EtOAc (2 ×

10 mL). The combined organic extracts were washed with brine (5 mL),

dried over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

The crude material was puriﬁed by silica gel chromatography (10−40%

EtOAc/hexanes) to give the title compound (0.25 g, 59%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₁₃H₉F₅N₂O: 304; found 305

(M + H). ¹H NMR (400 MHz, CDCl₃): δ 8.92 (s, 1H), 8.73 (q, J = 8.30

Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.00 (dd, J =

2.7, 8.2 Hz, 1H), 1.87 (s, 3H).

tert-Butyl (5-((2′-ﬂuoro-5-(1,1,1-triﬂuoro-2-hydroxypropan-2-yl)-

[2,3′-bipyridin]-6′-yl)thio)pyridin-2-yl)carbamate (32). A glass micro-

wave reaction vessel was charged with 30 (2.70 g, 8.88 mmol), tert-butyl

(5-mercaptopyridin-2-yl)carbamate (31)¹⁶(2.61 g, 11.54 mmol),

K₂CO₃(2.45 g, 17.75 mmol), and DMF (24 mL). The vial was sealed

and purged with nitrogen for several minutes. The reaction mixture was

stirred and heated in a microwave reactor at 80 °C for 15 min. The

reaction mixture was diluted with water (10 mL) and extracted with

EtOAc (2 × 15 mL). The organic extract was washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by silica gel chromatography (10−40%

EtOAc/hexanes) to give the title compound (2.65g, 58%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₂₃H₂₂F₄N₄O₃S: 510; found 533

(M + Na). ¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1 H), 8.89 (d, J

= 1.8 Hz, 1 H), 8.50−8.43 (m, 1 H), 8.39 (dd, J = 8.0, 9.9 Hz, 1 H), 8.10

(dd, J = 2.1, 8.4 Hz, 1 H), 8.05−7.92 (m, 2 H), 7.85 (d, J = 6.9 Hz, 1 H),

7.10 (dd, J = 1.8, 8.0 Hz, 1 H), 6.90 (s, 1 H), 1.76 (s, 3 H), 1.50 (s, 9 H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-ﬂuoro-[2,3′-bipyridin]-5-

yl)-1,1,1-triﬂuoropropan-2-ol (33). To a suspension of 32 (1.80 g, 4.39

mmol) in water (10 mL) at 0 °C was slowly added H₂SO₄(11.7 mL, 219

mmol). After stirring for 5 min, sodium dichromate dihydrate (3.27 g,

10.97 mmol) was added and the cooling bath was removed. The reaction

mixture was stirred at room temperature for 1.5 h, cooled to 0 °C, and

quenched with ice (∼7 g). The resulting mixture was basiﬁed to pH ∼ 6

using 5 N NaOH and then extracted with EtOAc (3 × 60 mL). The

combined organic extracts were dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure to give the title compound (0.80 g,

2-(6-(4-((6-Aminopyridin-3-yl)sulfonyl)phenyl)-5-(prop-1-yn-1-

yl)pyridin-3-yl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (23). A sealable

reaction vial was charged with 20 (98 mg, 0.19 mmol), XPhos

palladium(II) phenethylamine chloride (7 mg, 10 μmol), Cs₂CO₃(0.19

g, 0.57 mmol), 1-(trimethylsilyl)-1-propyne (0.14 mL, 0.96 mmol), and

MeCN (2 mL). The vial was sealed and purged with nitrogen for several

minutes. The reaction mixture was heated at 80 °C for 18 h and allowed

to cool to room temperature. The solvent was removed under reduced

pressure and the crude material was puriﬁed by silica gel

chromatography (0−3% 2 M NH₃in MeOH/CH₂Cl₂) to give the

title compound (68 mg, 70%) as an oﬀ-white solid. MS (ESI pos. ion):

m/z calcd for C₂₂H₁₅F₆N₃O₃S: 515; found 516 (M + H). ¹H NMR (400

MHz, DMSO-d₆): δ 9.30 (br s, 1H), 8.87 (br s, 1H), 8.48 (d, J = 2.35 Hz,

1H), 8.17 (d, J = 8.41 Hz, 2H), 8.12 (s, 1H), 8.02 (d, J = 8.41 Hz, 2H),

7.82 (dd, J = 2.45, 8.90 Hz, 1H), 7.13 (s, 2H), 6.52 (d, J = 9.00 Hz, 1H),

2.05 (s, 3H).

3-(2-(4-((6-Amino-3-pyridinyl)sulfonyl)phenyl)-5-(2,2,2-triﬂuoro-

1-hydroxy-1-(triﬂuoromethyl)ethyl)-3-pyridinyl)-2-propyn-1-ol (24).

A glass reaction vial was charged with 20 (73 mg, 0.14 mmol), XPhos

palladium(II) phenethylamine chloride (5 mg, 7 μmol), K₂CO₃(30 mg,

0.21 mmol), tert-butyl(dimethyl)(2-propyn-1-yloxy)silane (0.043 mL,

0.21 mmol), and DMA (2 mL). The vial was closed and purged with

nitrogen for several minutes. The reaction mixture was heated at 110 °C

for 2 h and allowed to cool to room temperature. The reaction mixture

was diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL).

The organic extract was washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. The crude material was

puriﬁed by silica gel chromatography (0−4% 2 M NH₃in MeOH/

CH₂Cl₂) to give 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-(3-

((tert-butyl(dimethyl)silyl)oxy)-1-propyn-1-yl)-3-pyridinyl)-

1,1,1,3,3,3-hexaﬂuoro-2-propanol as tan solid. This solid was dissolved

in THF (3 mL) and tetra-N-butylammoniun ﬂuoride (0.19 mL, 0.19

mmol, 1 M in THF) was added. The reaction mixture was stirred at

room temperature for 2 h and then diluted with satd NH₄Cl (5 mL) and

extracted with EtOAc (5 mL). The organic extract was washed with

water (3 mL) and dried over Na₂SO₄. The solution was ﬁltered and

concentrated under reduced pressure to give the crude material. The

residue was puriﬁed by silica gel chromatography (5−7% 2 M NH₃in

MeOH/CH₂Cl₂) to give the title compound (43 mg, 58%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₂₂H₁₅F₆N₃O₄S: 531; found 532

(M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (br s, 1H), 8.94 (d, J =

1.37 Hz, 1H), 8.50 (d, J = 2.54 Hz, 1H), 8.14−8.28 (m, 3H), 8.03 (d, J =

8.61 Hz, 2H), 7.84 (dd, J = 2.64, 8.90 Hz, 1H), 7.17 (s, 2H), 6.53 (d, J =

9.00 Hz, 1H), 5.42 (t, J = 6.06 Hz, 1H), 4.31 (d, J = 6.06 Hz, 2H).

2-(6-(4-((6-Amino-3-pyridinyl)sulfonyl)phenyl)-5-(3-methoxy-1-

propyn-1-yl)-3-pyridinyl)-1,1,1,3,3,3-hexaﬂuoro-2-propanol (25). A

25 mL glass resealable vial was charged with 20 (0.10 g, 0.20 mmol),

XPhos palladium(II) phenethylamine chloride (7 mg, 10 μmol),

Cs₂CO₃(0.20 g, 0.61 mmol), 3-methoxy-1-propyne (0.09 mL, 1.03

mmol), and MeCN (3 mL). The vial was closed and purged with

nitrogen for several minutes. The reaction mixture was heated at 80 °C

for 18 h and allowed to cool to room temperature. The solvent was

removed under reduced pressure and the crude material was puriﬁed by

silica gel chromatography (4−7% 2 M NH₃in MeOH/CH₂Cl₂) to give

the title compound (83 mg, 76%) as an oﬀ-white solid. MS (ESI pos.

ion): m/z calcd for C₂₃H₁₇F₆N₃O₄S: 545; found 546 (M + H). ¹H NMR

(400 MHz, DMSO-d₆): δ 9.38 (br s, 1H), 8.94 (s, 1H), 8.48 (s, 1H),

8.19 (br s, 1H), 8.13 (d, J = 7.43 Hz, 2H), 8.03 (d, J = 7.63 Hz, 2H), 7.82

(d, J = 8.41 Hz, 1H), 7.15 (br s, 2H), 6.52 (d, J = 8.61 Hz, 1H), 4.30 (br s,

2H), 3.13 (s, 3H).

(2R)-4-(2-(4-((6-Amino-3-pyridinyl)sulfonyl)phenyl)-5-(2,2,2-tri-

ﬂuoro-1-hydroxy-1-(triﬂuoromethyl)ethyl)-3-pyridinyl)-3-butyn-2-ol

(26). A 25 mL glass resealable vial was charged with 20 (98 mg, 0.19

mmol), XPhos palladium(II) phenethylamine chloride (7 mg, 10 μmol),

K₂CO₃(40 mg, 0.29 mmol), (2R)-3-butyn-2-ol (0.02 mL, 0.29 mmol),

and DMA (2 mL). The vial was closed and purged with nitrogen for

several minutes. The reaction mixture was heated at 110 °C for 2 h and

allowed to cool to room temperature. The reaction mixture was diluted

N

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41%) as a white solid. MS (ESI pos. ion): m/z calcd for C₁₈H₁₄F₄N₄O₃S:

442; found 443 (M + H). ¹H NMR (300 MHz, DMSO-d₆): δ 8.95 (d, J =

1.9 Hz, 1H), 8.77 (dd, J = 7.8, 9.3 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H),

8.26−8.09 (m, 2H), 7.96 (dd, J = 1.7, 8.4 Hz, 1H), 7.81 (dd, J = 2.6, 8.9

Hz, 1H), 7.24 (s, 2H), 6.96 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 1.77 (s,

3H).

General S_N2′ Methods for the Preparation of Aminopyridines

(34−40 and 42−44). Method A. To a solution of 33 (1 equiv) in

DMSO was added the amine (2−11 equiv). The reaction mixture was

stirred and heated in a microwave at 100 °C for 15 min. The reaction

mixture was allowed to cool to room temperature then directly subjected

to chromatographic puriﬁcation or partitioned between water and an

organic solvent (EtOAc or CH₂Cl₂). The combined organic phases were

dried, ﬁltered, concentrated under reduced pressure, and then puriﬁed

by silica gel column chromatography.

Method B. To a solution of 32 or 33 (1 equiv) in THF at −50 °C was

added KHMDS or LiHMDS (5−10 equiv) followed by the amine (2

equiv). The solution was stirred at 0 °C for 15 min and quenched by the

addition of HCl (2 N). The reaction mixture was partitioned between

water and EtOAc. The organic layer was separated, dried over Na₂SO₄,

ﬁltered, concentrated under reduced pressure, and puriﬁed by silica gel

column chromatography.

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(methylamino)-[2,3′-bi-

pyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol dihydrochloride (34). This

compound was prepared from 33 (17 mg, 0.038 mmol) and MeNH₂

(0.3 mL, 9.66 mmol, 40% solution) according to the general synthesis

(method A). The product was isolated as a dihydrochloride salt and a

yellow solid by treatment with HCl (20 μL, 4 N in dioxane) and

ﬁltration (18 mg, 52%). MS (ESI pos. ion): m/z calcd for

C₁₉H₁₈F₃N₅O₃S: 453; found 454 (M + H). ¹H NMR (400 MHz,

DMSO-d₆): δ 8.89 (s, 1H), 8.54 (d, J = 2.20 Hz, 1H), 8.31 (d, J = 8.00

Hz, 1H), 8.20−8.12 (m, 1H), 8.12−8.03 (m, 1H), 7.31 (d, J = 7.80 Hz,

1H), 8.84 (d, J = 9.20 Hz, 1H), 2.90 (s, 3H), 1.78 (s, 3H).

ion): m/z calcd for C₂₄H₂₆F₃N₅O₃S: 521; found 522 (M + H). ¹H NMR

(300 MHz, CDCl₃): δ 9.34 (d, J = 6.0 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H),

8.69 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 2.3, 8.8 Hz, 1H), 8.01 (dd, J = 2.4,

8.6 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.35 (d, J

= 7.7 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 5.23 (s, 2H), 3.89 (dd, J = 3.9, 9.4

Hz, 1H), 2.70 (br s, 1H), 1.91 (d, J = 12.1 Hz, 2H), 1.87 (s, 3H), 1.80−

1.58 (m, 3 H), 1.50−1.36 (m, 2H), 1.31−1.18 (m, 3H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(phenylamino)-[2,3′-bi-

pyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (39). This compound was

prepared from 33 (0.12 g, 0.28 mmol) and aniline (0.05 mL, 0.55 mmol)

according to the general synthesis (method B). The title compound (43

mg, 29%) was obtained as a yellow solid. MS (ESI pos. ion): m/z calcd

1

for C₂₄H₂₀F₃N₅O₃S: 515; found 516 (M + H). H NMR (300 MHz,

CDCl₃/CD₃OD): δ 8.94 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H),

8.24 (d, J = 8.0 Hz, 1H), 8.14 (dd, J = 2.2, 8.5 Hz, 1H), 7.97−7.88 (m,

2H), 7.60−7.53 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.3 Hz,

1H), 6.57 (d, J = 8.8 Hz, 1H), 1.82 (s, 3H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(benzylamino)-[2,3′-bi-

pyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (40). This compound was

prepared from 33 (30 mg, 0.07 mmol) and benzylamine (80 mg, 0.75

mmol) according to the general synthesis (method A). The title

compound (23 mg, 64%) was obtained as a yellow solid. MS (ESI pos.

ion): m/z calcd for C₂₅H₂₂F₃N₅O₃S: 529; found 530 (M + H). ¹H NMR

(400 MHz, CD₃OD): δ 8.86 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.27 (d, J

= 7.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.71

(dd, J = 2.2, 8.9 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.31−7.19 (m, 5H),

6.46 (d, J = 9.0 Hz, 1H), 4.70 (s, 2H), 1.81 (s, 3H).

tert-Butyl (5-((2′-phenoxy-5-(1,1,1-triﬂuoro-2-hydroxypropan-2-

yl)-[2,3′-bipyridin]-6′-yl)thio)pyridin-2-yl)carbamate (41). To a 25

mL round-bottomed ﬂask was added 32 (80 mg, 0.16 mmol), phenol

(44 mg, 0.47 mmol), Cs₂CO₃(0.26 g, 0.78 mmol), and DMSO (1 mL).

The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture

was diluted with water (30 mL) and extracted with EtOAc (50 mL). The

organic extract was dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The crude mixture was puriﬁed by silica gel column

chromatography (10−40% acetone/hexanes) to give the title

compound (65 mg, 71%) as a white solid. MS (ESI pos. ion): m/z

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(ethylamino)-[2,3′-bipyri-

din]-5-yl)-1,1,1-triﬂuoropropan-2-ol (35). This compound was pre-

pared from 33 (21 mg, 0.05 mmol) and EtNH₂(0.1 mL, 0.2 mmol, 2 M

in THF) according to the general synthesis (method A). The title

compound (13 mg, 56%) was obtained as a yellow solid. MS (ESI pos.

ion): m/z calcd for C₂₀H₂₀F₃N₅O₃S: 467; found 468 (M + H). ¹H NMR

(400 MHz, CD₃OD): δ 8.75 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H),

8.11−7.98 (m, 2H), 7.89−7.76 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 6.51

(d, J = 8.9 Hz, 1H), 3.35 (q, J = 7.2 Hz, 2H), 1.69 (s, 3H), 1.07 (t, J = 7.2

Hz, 3H).

1

calcd for C₂₉H₂₇F₃N₄O₄S: 584; found 585 (M + H). H NMR (300

MHz, CDCl₃): δ 8.89 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.20

(d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 2.3, 8.4 Hz,

1H), 7.77 (d, J = 8.6 Hz, 1H), 7.64−7.51 (m, 2H), 7.30 (s, 1H), 7.24 (s,

1H), 7.17−7.08 (m, 1H), 6.95 (d, J = 8.0 Hz, 3H), 2.53 (s, 1H), 1.85 (s,

3H), 1.59 (s, 9H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(isopropylamino)-[2,3′-

bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (36). This compound was

prepared from 33 (70 mg, 0.16 mmol) and i-PrNH₂(0.07 mL, 0.79

mmol) according to the general synthesis (method A). The title

compound (56 mg, 73%) was obtained as a yellow solid. MS (ESI pos.

ion): m/z calcd for C₂₁H₂₂F₃N₅O₃S: 481; found 482 (M + H). ¹H NMR

(300 MHz, CDCl₃): δ 9.19 (d, J = 6.1 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H),

8.72 (d, J = 2.3 Hz, 1H), 8.06 (dd, J = 2.5, 8.8 Hz, 1H), 8.01 (dd, J = 2.3,

8.6 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.36 (d, J

= 7.7 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 5.12 (s, 2H), 4.27−4.09 (m, 1H),

2.82 (br s, 1H), 1.87 (s, 3H), 1.21 (d, J = 6.6 Hz, 6H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(cyclopropylamino)-

[2,3′-bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (37). This compound

was prepared from 33 (70 mg, 0.16 mmol) and cyclopropylamine (0.06

mL, 0.79 mmol) according to the general synthesis (method A). The

title compound (58 mg, 76%) was obtained as a yellow solid. MS (ESI

pos. ion): m/z calcd for C₂₁H₂₀F₃N₅O₃S: 479; found 480 (M + H). ¹H

NMR (300 MHz, CDCl₃): δ 9.32 (br s, 1H), 8.79 (dd, J = 2.0, 8.3 Hz,

2H), 8.14 (dd, J = 2.3, 8.8 Hz, 1H), 8.02 (dd, J = 2.2, 8.6 Hz, 1H), 7.96

(d, J = 7.9 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H),

6.54 (dd, J = 0.6, 8.8 Hz, 1H), 5.11 (s, 2H), 2.89−2.72 (m, 2H), 1.86 (s,

3H), 0.85−0.70 (m, 2H), 0.53−0.37 (m, 2H).

tert-Butyl (5-((2′-(pyridin-4-ylamino)-5-(1,1,1-triﬂuoro-2-hydroxy-

propan-2-yl)-[2,3′-bipyridin]-6′-yl)thio)pyridin-2-yl)carbamate (42).

This compound was prepared from 32 (0.10 g, 0.28 mmol) and 4-

aminopyridine (0.09 g, 1.0 mmol) according to the general synthesis

(method B). The title compound (80 mg, 70%) was obtained as a white

solid. MS (ESI pos. ion): m/z calcd for C₂₈H₂₇F₃N₆O₃S: 584; found 585

(M + H). ¹H NMR (300 MHz, DMSO-d₆): δ 12.78 (s, 1H), 10.25 (s,

1H), 9.01 (s, 1H), 8.48 (dd, J = 0.7, 2.2 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H),

8.19−8.07 (m, 4H), 8.07−7.93 (m, 2H), 7.30−7.20 (m, 2H), 6.99−6.90

(m, 2H), 1.78 (s, 3H), 1.52 (s, 9H).

tert-Butyl (5-((2′-(pyridin-3-ylamino)-5-(1,1,1-triﬂuoro-2-hydroxy-

propan-2-yl)-[2,3′-bipyridin]-6′-yl)thio)pyridin-2-yl)carbamate (43).

This compound was prepared from 32 (70 mg, 0.14 mmol) and 3-

aminopyridine (65 mg, 0.69 mmol) according to the general synthesis

(method B). The title compound (60 mg, 75%) was obtained as a light-

yellow solid. MS (ESI pos. ion): m/z calcd for C₂₈H₂₇F₃N₆O₃S: 584;

found 585 (M + H). ¹H NMR (300 MHz, DMSO-d₆): δ 12.61 (s, 1H),

10.18 (s, 1H), 9.01 (s, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 0.8, 2.1

Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 1.2 Hz, 2H), 8.07−8.01

(m, 1H), 8.00−7.91 (m, 2H), 7.84−7.74 (m, 1H), 6.99 (dd, J = 4.8, 8.4

Hz, 1H), 6.93 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 1.78 (s, 3H), 1.52 (s,

9H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(cyclohexylamino)-[2,3′-

bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (38). This compound was

prepared from 33 (70 mg, 0.16 mmol) and cyclohexylamine (0.09 mL,

0.79 mmol) according to the general synthesis (method A). The title

compound (62 mg, 75%) was obtained as a yellow solid. MS (ESI pos.

tert-Butyl (5-((2′-(pyridin-2-ylamino)-5-(1,1,1-triﬂuoro-2-hydroxy-

propan-2-yl)-[2,3′-bipyridin]-6′-yl)thio)pyridin-2-yl)carbamate (44).

This compound was prepared from 32 (70 mg, 0.14 mmol) and 2-

aminopyridine (65 mg, 0.69 mmol) according to the general synthesis

(method B). The title compound (62 mg, 77%) was obtained as a tan

O

DOI: 10.1021/jm5018175

J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Article

solid. MS (ESI pos. ion): m/z calcd for C₂₈H₂₇F₃N₆O₃S: 584; found 585

(M + H). ¹H NMR (300 MHz, DMSO-d₆): δ 12.46 (s, 1H), 10.22 (s,

1H), 8.90 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 8.3

Hz, 1H), 8.20 (dd, J = 1.0, 4.8 Hz, 1H), 8.18−8.13 (m, 1H), 8.13−8.07

(m, 1H), 8.07−8.01 (m, 1H), 8.00−7.94 (m, 1H), 7.49 (d, J = 8.5 Hz,

1H), 7.33 (dt, J = 2.0, 7.9 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H),

6.85 (dt, J = 0.8, 6.0 Hz, 1H), 1.80 (s, 3H), 1.53 (s, 9H).

General Method for the Oxidation of Sulﬁdes to Sulfones. To

a suspension of 41, 42, 43, or 44 (1 equiv) in water was added H₂SO₄

(40 equiv) and the solution was stirred at room temperature for 15 min.

Then, Na₂Cr₂O₇(2 equiv) was added, and the solution was stirred at

room temperature for 2−3 h. The reaction mixture was quenched by the

addition of NaOH (5 N) (pH ∼6) and partitioned between water and

EtOAc. The organic extract was dried, ﬁltered, concentrated under

reduced pressure, and then puriﬁed by silica gel column chromatog-

raphy.

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-phenoxy-[2,3′-bipyridin]-

5-yl)-1,1,1-triﬂuoropropan-2-ol (45). This compound was prepared

from 41 (75 mg, 0.13 mmol), according to the general oxidation method

to aﬀord the title compound (40 mg, 60%) as a white solid. MS (ESI pos.

ion): m/z calcd for C₂₄H₁₉F₃N₄O₄S: 516; found 517 (M + H). ¹H NMR

(300 MHz, DMSO-d₆): δ 8.96 (d, J = 1.8 Hz, 1H), 8.61 (d, J = 7.7 Hz,

1H), 8.28−8.06 (m, 3H), 7.91 (d, J = 7.7 Hz, 1H), 7.50−7.38 (m, 3H),

7.36−7.21 (m, 2H), 7.20−7.09 (m, 2H), 6.93 (br s, 1H), 6.42 (d, J = 8.9

Hz, 1H), 3.17 (s, 1H), 1.78 (s, 3H).

1,1,1-Triﬂuoro-2-(2-(5-mercaptothiophen-2-yl)pyrimidin-5-yl)-

propan-2-ol (54). To a 50 mL round-bottomed ﬂask was added 52

(0.18 g, 0.58 mmol), 2-(diphenylphosphino)ferrocenyl]-

ethyldicyclohexylphosphine (32 mg, 0.06 mmol), Pd(OAc)₂(13 mg,

0.06 mmol), sodium tert-butoxide (0.18 g, 1.73 mmol), (4-

methoxyphenyl)methanethiol (0.096 mL, 0.69 mmol), and DME (3

mL). The reaction mixture was stirred at 90 °C for 18 h and allowed to

cool to room temperature. The reaction mixture was diluted with

saturated NH₄Cl (5 mL) and extracted with EtOAc (2 × 30 mL). The

combined organic extracts were washed with brine, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude material

was puriﬁed by silica gel chromatography (30% EtOAc/hexanes) to

provide 1,1,1-triﬂuoro-2-(2-(5-((4-methoxybenzyl)thio)thiophen-2-

yl)pyrimidin-5-yl)propan-2-ol (0.17 g, 69%) as a yellow solid. MS

(ESI pos. ion): m/z calcd for C₁₉H₁₇F₃N₂O₂S₂: 426; found 427 (M +

H). The protected thiol was dissolved in TFA (3 mL) and stirred at 70

°C for 18 h. The solvent was removed under reduced pressure to provide

the title compound (122 mg, 100%) as a yellow ﬁlm. MS (ESI pos. ion):

m/z calcd for C₁₁H₉F₃N₂OS₂306, found 307 (M + H).

2-(2-(5-((6-Chloropyridin-3-yl)thio)thiophen-2-yl)pyrimidin-5-yl)-

1,1,1-triﬂuoropropan-2-ol (56). To a 25 mL round-bottomed ﬂask was

added 54 (0.13 g, 0.42 mmol), 2-chloro-5-iodopyridine (5) (0.10 g, 0.42

mmol), CuI (16 mg, 0.08 mmol), K₂CO₃(0.18 g, 1.27 mmol), N,N-

dimethyl-1,2-ethanediamine (0.02 mL, 0.17 mmol), and DMSO (3

mL). The reaction mixture was stirred at 90 °C for 3 h and allowed to

cool to room temperature. The reaction mixture was diluted with water

(20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic

extracts were washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude material was puriﬁed

by silica gel chromatography (20% EtOAc/CH₂Cl₂) to provide the title

compound (0.17 g, 69%) as a yellow solid. MS (ESI pos. ion): m/z calcd

for C₁₆H₁₁ClF₃N₃OS₂: 417; found 418 (M + H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(pyridin-4-ylamino)-

[2,3′-bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (46). This compound

was prepared from 42 (62 mg, 0.11 mmol) according to the general

oxidation method to aﬀord the title compound (17 mg, 31%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₂₃H₁₉F₃N₆O₃S: 516; found 517

1

(M + H). H NMR (300 MHz, DMSO-d₆): δ 13.52 (s, 1H), 9.14 (s,

1H), 8.81 (d, J = 8.2 Hz, 1H), 8.65 (d, J = 7.2 Hz, 2H), 8.58 (d, J = 2.3

Hz, 1H), 8.34−8.26 (m, 2H), 8.22 (d, J = 7.2 Hz, 2H), 8.00−7.89 (m,

2H), 7.45 (br s, 1H), 7.09 (br s, 1H), 6.65 (d, J = 9.1 Hz, 1H), 1.81 (s,

3H).

2-(2-(5-((6-Aminopyridin-3-yl)sulfonyl)thiophen-2-yl)pyrimidin-5-

yl)-1,1,1-triﬂuoropropan-2-ol (58). To a solution of 56 (72 mg, 0.17

mmol) in CH₂Cl₂(2 mL) at 0 °C was added 3-chloroperoxybenzoic acid

(60 mg, 0.34 mmol). The reaction mixture was stirred at 0 °C for 2 h and

partitioned between saturated NaHCO₃and CH₂Cl₂. The organic layer

was separated, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The crude material was puriﬁed by silica gel

chromatography (40% EtOAc/hexanes) to aﬀord 2-(2-(5-((6-chlor-

opyridin-3-yl)sulfonyl)thiophen-2-yl)pyrimidin-5-yl)-1,1,1-triﬂuoro-

propan-2-ol (72 mg, 95%) as a white solid. MS (ESI pos. ion): m/z calcd

for C₁₆H₁₁ClF₃N₃O₃S₂: 449; found 450 (M + H). This material was

dissolved in dioxane (2 mL) and NH₄OH (0.5 mL, 20% in water) was

added. The reaction mixture was heated at 120 °C for 18 h. The reaction

mixture was allowed to cool to room temperature, and the solvent was

removed under reduced pressure. The crude material was puriﬁed by

silica gel chromatography (80% EtOAc/hexanes) to aﬀord the title

compound (54 mg, 78%). MS (ESI pos. ion): m/z calcd for

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(pyridin-3-ylamino)-

[2,3′-bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (47). This compound

was prepared from 43 (56 mg, 0.12 mmol) according to the general

oxidation method to aﬀord the title compound (17 mg, 31%) as a yellow

solid. MS (ESI pos. ion): m/z calcd for C₂₃H₁₉F₃N₆O₃S: 516; found 517

1

(M + H). H NMR (300 MHz, DMSO-d₆): δ 12.55 (s, 1H), 9.10 (s,

1H), 8.97 (d, J = 2.3 Hz, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 2.3

Hz, 1H), 8.36−8.13 (m, 4H), 7.81 (dd, J = 2.6, 8.9 Hz, 1H), 7.63 (d, J =

8.0 Hz, 1H), 7.46 (dd, J = 4.9, 8.4 Hz, 1H), 7.19 (br s, 2H), 7.02 (s, 1H),

6.55 (d, J = 8.9 Hz, 1H), 1.80 (s, 3H).

2-(6′-((6-Aminopyridin-3-yl)sulfonyl)-2′-(pyridin-2-ylamino)-

[2,3′-bipyridin]-5-yl)-1,1,1-triﬂuoropropan-2-ol (48). This compound

was prepared from 44 (58 mg, 0.12 mmol) according to the general

oxidation method to aﬀord the title compound (25 mg, 40%) as a yellow

solid. MS (ESI pos. ion): m/z calcd for C₂₃H₁₉F₃N₆O₃S: 516; found 517

1

C₁₆H₁₃F₃N₄O₃S₂: 430; found 431 (M + H). H NMR (300 MHz,

1

(M + H). H NMR (300 MHz, DMSO-d₆): δ 12.42 (s, 1H), 9.00 (s,

CD₃OD): δ 8.98 (s, 2H), 8.51 (d, J = 2.19 Hz, 1H), 7.99 (d, J = 3.95 Hz,

1H), 7.89 (dd, J = 2.48, 8.92 Hz, 1H), 7.73 (d, J = 3.95 Hz, 1H), 6.63 (d, J

= 9.06 Hz, 1H), 1.82 (s, 3H).

1H), 8.62 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.34−8.17 (m,

3H), 8.06 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 2.5, 8.9 Hz, 1H), 7.81−7.72

(m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.23 (br s, 2H), 7.10−6.96 (m, 2H),

6.58 (d, J = 8.9 Hz, 1H), 1.81 (s, 3H).

2-(5-Chloro-6-(5-chlorothiophen-2-yl)pyridin-3-yl)-1,1,1-triﬂuoro-

propan-2-ol (53). Following the procedure outlined above for

compound 52, the reaction of 2-(6-bromo-5-chloro-3-pyridinyl)-1,1,1-

triﬂuoro-2-propanol (51)¹¹and 5-chloro-2-thienylboronic acid (49)

produced the title compound (22%) as a brown solid. MS (ESI pos.

ion): m/z calcd for C₁₂H₈Cl₂F₃NOS: 341, found 342 (M + H).

2-(5-Chloro-6-(5-mercaptothiophen-2-yl)pyridin-3-yl)-1,1,1-tri-

ﬂuoropropan-2-ol (55). Following the procedure outlined for

compound 54, 2-(5-chloro-6-(5-chlorothiophen-2-yl)pyridin-3-yl)-

1,1,1-triﬂuoropropan-2-ol (53) delivered the title compound (74%) as

a brown oil. MS (ESI pos. ion): m/z calcd for C₁₂H₉ClF₃NOS₂: 339;

found 340 (M + H).

2-(5-Chloro-6-(5-((6-chloropyridin-3-yl)thio)thiophen-2-yl)-

pyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (57). Following the procedure

outlined above for compound 56, the reaction of 2-(5-chloro-6-(5-

mercaptothiophen-2-yl)pyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (55)

and 2-chloro-5-iodopyridine (5) produced the title compound (51%)

2-(2-(5-Chlorothiophen-2-yl)pyrimidin-5-yl)-1,1,1-triﬂuoropro-

pan-2-ol (52). To a 100 mL round-bottomed ﬂask was added 5-chloro-

2-thienylboronic acid (49) (0.49 g, 3.02 mmol), 2-(2-chloro-5-

pyrimidinyl)-1,1,1-triﬂuoro-2-propanol (50)¹⁰(0.46 g, 2.01 mmol),

PdCl₂(dppf) (0.16 g, 0.20 mmol), Cs₂CO₃(1.31 g, 4.03 mmol), and

dioxane (10 mL). The reaction mixture was stirred at 90 °C for 18 h and

allowed to cool to room temperature. The reaction mixture was diluted

with water (20 mL) and extracted with EtOAc (2 × 30 mL). The

combined organic extracts were washed with brine, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude material

was puriﬁed by silica gel chromatography (10% EtOAc/CH₂Cl₂) to

provide the title compound (0.20 g, 33%) as a yellow solid. MS (ESI pos.

1

ion): m/z calcd for C₁₁H₈ClF₃N₂OS: 308; found 309 (M + H). H

NMR (400 MHz, CDCl₃): δ 8.85 (s, 2H), 7.82 (d, J = 4.09 Hz, 1H), 7.26

(s, 1H), 6.98 (d, J = 3.95 Hz, 1H), 1.84 (d, J = 0.73 Hz, 3H).

P

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as a white solid. MS (ESI pos. ion): m/z calcd for C₁₇H₁₁Cl₂F₃N₂OS₂:

450; found 451 (M + H).

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The crude

material was puriﬁed by silica gel chromatography (80% EtOAc/

hexanes) to provide the title compound (7 mg, 50%) as a white solid.

MS (ESI pos. ion): m/z calcd for C₁₈H₁₅F₃N₂O₃S₂: 428; found 429 (M

+ H). ¹H NMR (300 MHz, CD₃OD): δ 8.49 (d, J = 1.90 Hz, 1H), 7.87

(dd, J = 2.56, 8.99 Hz, 1H), 7.63−7.73 (m, 5H), 7.46 (d, J = 3.95 Hz,

1H), 6.61 (dd, J = 0.58, 9.06 Hz, 1H), 1.22 (s, 3H).

1,1,1,3,3,3-Hexaﬂuoro-2-(4-(thiazol-2-yl)phenyl)propan-2-ol (70).

A 25 mL resealable glass vial was charged with 2-(4-bromophenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (67)⁸(1.41 g, 4.37 mmol), 2-

(tributylstannanyl)-1,3-thiazole (66) (1.92 mL, 6.12 mmol),

PdCl₂(PPh₃)₂(0.15 g, 0.22 mmol), and DMF (5 mL). The vial was

sealed, purged with nitrogen for several minutes, and heated at 90 °C for

2 h. After cooling to room temperature, the mixture was diluted with

water (10 mL) and extracted with EtOAc (15 mL). The organic layer

was separated, washed with water (10 mL), dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure to yield the crude product.

The crude material was puriﬁed by silica gel chromatography (0−15%

EtOAc/hexanes) to provide the title compound (0.43 g, 30%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₁₂H₇F₆NOS: 327; found 328

(M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 1H), 8.07−8.15

(m, 2H), 7.98 (d, J = 3.13 Hz, 1H), 7.87 (d, J = 3.13 Hz, 1H), 7.82 (d, J =

8.41 Hz, 2H).

2-(6-(5-((6-Aminopyridin-3-yl)sulfonyl)thiophen-2-yl)-5-chloro-

pyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (59). Following the procedure

outlined above for compound 58, 2-(5-chloro-6-(5-((6-chloropyridin-3-

yl)thio)thiophen-2-yl)pyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (57) de-

livered the title compound (87%) as a white solid. MS (ESI pos. ion): m/

z calcd for C₁₇H₁₃ClF₃N₃O₃S₂: 463; found 464 (M + H). ¹H NMR (300

MHz, CD₃OD): δ 8.72 (br s, 1H), 8.51 (d, J = 2.05 Hz, 1H), 8.15 (d, J =

1.75 Hz, 1H), 8.11 (dd, J = 1.17, 4.09 Hz, 1H), 7.88 (dd, J = 2.56, 8.99

Hz, 1H), 7.71 (d, J = 4.09 Hz, 1H), 6.63 (dd, J = 0.58, 9.06 Hz, 1H), 1.80

(s, 3H).

2-(6-(5-((6-Aminopyridin-3-yl)sulfonyl)thiophen-2-yl)-5-(prop-1-

yn-1-yl)pyridin-3-yl)-1,1,1-triﬂuoropropan-2-ol (60). To a 50 mL

round-bottomed ﬂask was added 59 (41 mg, 0.09 mmol), XPhos

palladium(II) phenethylamine chloride (6 mg, 9 μmol), Cs₂CO₃(86

mg, 0.26 mmol), 1-(trimethylsilyl)propyne (0.07 mL, 0.44 mmol), and

MeCN (2 mL). The reaction mixture was heated at 80 °C under a

nitrogen atmosphere for 4 h. The reaction mixture was diluted with

water (10 mL) and extracted with EtOAc (2 × 30 mL). The combined

organic extracts were washed with brine (10 mL), dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude material

was puriﬁed by silica gel chromatography (80% EtOAc/hexanes) to

provide the title compound (18 mg, 43%) as a white solid. MS (ESI pos.

2-(4-(5-Bromothiazol-2-yl)phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-

2-ol (76). A 25 mL round-bottomed ﬂask was charged with 70 (0.31 g,

0.96 mmol), N-bromosuccinimide (0.26 g, 1.43 mmol), and DMF (4

mL). The reaction mixture was stirred at 70 °C for 3 h and was allowed

to cool to room temperature. The reaction mixture was diluted with

saturated NaHCO₃(5 mL) and extracted with EtOAc. The organic

extract was sequentially washed with water (5 mL), and brine (5 mL),

dried over Na₂SO₄, ﬁltered, and concentrated under reduced pressure to

yield the title compound (379 mg, 97%) as a white solid. MS (ESI pos.

ion): m/z calcd for C₁₂H₆F₆BrNOS: 405; found 406 (M + H).

2-(4-(5-((6-Chloropyridin-3-yl)thio)thiazol-2-yl)phenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (81). A glass microwave reaction

vessel was charged 76 (0.22 g, 0.54 mmol), methyl 3-sulfanylpropanoate

(0.06 mL, 0.60 mmol), Pd₂(dba)₃(25 mg, 0.03 mmol), Xantphos (31

mg, 0.05 mmol), N,N-diisopropylethylamine (0.19 mL, 1.08 mmol), and

dioxane (1.5 mL). The reaction mixture was purged with nitrogen for

several minutes, and then stirred and heated in a microwave reactor at

120 °C for 30 min. The reaction mixture was diluted with water (3 mL)

and extracted with CH₂Cl₂(5 mL). The organic extract was washed

sequentially with water (5 mL), and brine (5 mL), dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure to yield the crude

product. The crude material was puriﬁed by silica gel chromatography

(0−20% EtOAc/hexanes) to provide 3-((2-(4-(2,2,2-triﬂuoro-1-

hydroxy-1-(triﬂuoromethyl)ethyl)phenyl)-1,3-thiazol-5-yl)sulfanyl)-

propanoate (0.22 g, 92%) as a yellow oil. MS (ESI pos. ion): m/z calcd

1

ion): m/z calcd for C₂₀H₁₆F₃N₃O₃S₂: 467; found 468 (M + H). H

NMR (300 MHz, CD₃OD): δ 8.68 (d, J = 2.19 Hz, 1H), 8.51 (d, J = 2.05

Hz, 1H), 8.28 (d, J = 4.09 Hz, 1H), 8.06 (d, J = 2.05 Hz, 1H), 7.88 (dd, J

= 2.56, 8.99 Hz, 1H), 7.69 (d, J = 4.09 Hz, 1H), 6.62 (dd, J = 0.51, 8.99

Hz, 1H), 2.22 (s, 1H), 1.78 (s, 1H).

2-Chloro-5-((5-iodothiophen-2-yl)thio)pyridine (63). To a 50 mL

round-bottomed ﬂask was added 2,5-diiodothiophene (61) (0.23 g, 0.68

mmol), 6-chloropyridine-3-thiol (62) (0.10 g, 0.68 mmol), CuI (26 mg,

0.14 mmol), K₂CO₃(0.19 g, 1.37 mmol), N,N-dimethyl-1,2-ethanedi-

amine (0.03 mL, 0.27 mmol), and DMSO (3 mL). The reaction mixture

was stirred at 80 °C for 3 h and allowed to cool to room temperature.

The reaction mixture was diluted with water (20 mL) and extracted with

EtOAc (2 × 30 mL). The combined organic extracts were washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude material was puriﬁed by silica gel chromatography

(10% EtOAc/hexanes) to provide the title compound (24 mg, 10%) as a

yellow solid. MS (ESI pos. ion): m/z calcd for C₉H₅ClINS₂: 353; found

354 (M + H).

5-((5-Iodothiophen-2-yl)sulfonyl)pyridin-2-amine (64). To a sol-

ution of 63 (24 mg, 0.07 mmol) in CH₂Cl₂(1 mL) at 0 °C was added 3-

chloroperoxybenzoic acid (23 mg, 0.14 mmol). The reaction mixture

was stirred at room temperature for 18 h and partitioned between

saturated NaHCO₃and CH₂Cl₂. The organic layer was separated, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by silica gel chromatography (40% EtOAc/

hexanes) to aﬀord 2-chloro-5-((5-iodothiophen-2-yl)sulfonyl)pyridine

(21 mg, 80%) as a white solid. MS (ESI pos. ion): m/z calcd for

C₉H₅ClINO₂S₂: 385; found 386 (M + H). This material was dissolved in

dioxane (1 mL) and NH₄OH (0.2 mL, 20% in water). The reaction

mixture was heated at 100 °C for 18 h. The reaction mixture was allowed

to cool to room temperature and the solvent was removed under

reduced pressure. The crude material was puriﬁed by silica gel

chromatography (70% EtOAc/hexanes) to aﬀord the title compound

(12 mg, 63%). MS (ESI pos. ion): m/z calcd for C₉H₇IN₂O₂S₂: 366;

found 367 (M + H). ¹H NMR (300 MHz, CD₃OD): δ 6.94 (d, J = 2.19

Hz, 1H), 6.31 (dd, J = 2.56, 8.99 Hz, 1H), 5.85 (s, 2H), 5.09 (d, J = 8.92

Hz, 1H).

1

for C₁₆H₁₃F₆NO₃S₂: 445; found 446 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.93 (s, 1H), 8.04−8.13 (m, 2H), 7.98 (s, 1H), 7.84 (d, J =

8.22 Hz, 2H), 3.62 (s, 3H), 3.13 (t, J = 6.94 Hz, 2H), 2.70 (t, J = 6.85 Hz,

2H).

To a 25 mL round-bottomed ﬂask was added 3-((2-(4-(2,2,2-

triﬂuoro-1-hydroxy-1-(triﬂuoromethyl)ethyl)phenyl)-1,3-thiazol-5-yl)-

sulfanyl)propanoate (0.21 g, 0.47 mmol) and THF (3 mL). The

reaction mixture was cooled to −78 °C, and under a nitrogen

atmosphere, potassium tert-butoxide (0.57 mL, 0.57 mmol, 1 M in

THF) was added. The reaction mixture was stirred at −78 °C for 1.5 h

and at room temperature for 1.5 h. Removal of the solvent under

reduced pressure provided potassium 2-(4-(1,1,1,3,3,3-hexaﬂuoro-2-

hydroxypropan-2-yl)phenyl)thiazole-5-thiolate (0.17 g, 91%) as a

yellow solid. MS (ESI pos. ion): m/z calcd for C₁₂H₁₇F₆NOS₂: 359;

found 360.

To a 25 mL resealable glass vial was added potassium 2-(4-

(1,1,1,3,3,3-hexaﬂuoro-2-hydroxypropan-2-yl)phenyl)thiazole-5-thio-

late (0.17 g, 0.42 mmol), 2-chloro-5-iodopyridine (0.11 g, 0.47 mmol),

CuI (5 mg, 0.02 mmol), K₂CO₃(0.10 g, 0.71 mmol), ethylene glycol

(0.05 mL, 0.94 mmol), and IPA (1.5 mL). The vial was sealed, purged

with nitrogen for several minutes, and heated at 80 °C for 16 h. After

cooling to room temperature, the reaction mixture was diluted with

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiophen-2-yl)phenyl)-

1,1,1-triﬂuoropropan-2-ol (65). To a 25 mL round-bottomed ﬂask was

added 64 (12 mg, 0.03 mmol), 1,1,1-triﬂuoro-2-(4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (8) (10 mg, 0.03 mmol),

PdCl₂(dppf) (3 mg, 0.003 mmol), Cs₂CO₃(21 mg, 0.07 mmol), dioxane

(1 mL), and water (0.1 mL). The reaction mixture was stirred at 100 °C

for 2 h and allowed to cool to room temperature. The reaction mixture

was diluted with water (5 mL) and extracted with EtOAc (2 × 5 mL).

The combined organic extracts were washed with brine, dried over

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1

water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined

organic extracts were washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude material was puriﬁed

by silica gel chromatography (0−25% EtOAc/hexanes) to provide the

title compound (39 mg, 20%) as a white solid. MS (ESI pos. ion): m/z

calcd for C₁₇H₉ClF₆N₂OS₂: 470; found 471 (M + H).

C₁₇H₁₃ClF₃N₃O₃S₂: 463; found 464 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.60 (s, 1H), 8.53 (d, J = 2.54 Hz, 1H), 8.31 (d, J = 8.41

Hz, 1H), 7.84−7.92 (m, 2H), 7.74 (d, J = 8.61 Hz, 1H), 7.28 (br s, 2H),

6.98 (s, 1H), 6.55 (d, J = 9.00 Hz, 1H), 1.74 (s, 3H).

The individual enantiomers (88 and 89) were isolated using chiral

SFC Chiralpak ADH column (21 × 250 mm, 5 μ) eluting with MeOH in

supercritical CO₂(total ﬂow was 70 mL/min). The two enantiomers

were isolated with enantiomeric excesses >98%.

(R)-2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chloro-

phenyl)-1,1,1-triﬂuoropropan-2-ol (88). MS (ESI pos. ion): m/z calcd

for C₁₇H₁₃ClF₃N₃O₃S₂: 463; found 464 (M + H). ¹H NMR (400 MHz,

DMSO-d₆): δ 8.62 (s, 1H), 8.54 (d, J = 2.74 Hz, 1H), 8.32 (d, J = 8.41

Hz, 1H), 7.86−7.93 (m, 2H), 7.73−7.79 (m, J = 8.80 Hz, 1H), 7.31 (s,

2H), 7.00 (s, 1H), 6.56 (d, J = 9.00 Hz, 1H), 1.75 (s, 3H).

(S)-2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chloro-

phenyl)-1,1,1-triﬂuoropropan-2-ol (89). MS (ESI pos. ion): m/z calcd

for C₁₇H₁₃ClF₃N₃O₃S₂: 463; found 464 (M + H). ¹H NMR (400 MHz,

DMSO-d₆): δ 8.62 (s, 1H), 8.54 (d, J = 2.54 Hz, 1H), 8.32 (d, J = 8.41

Hz, 1H), 7.86−7.93 (m, 2H), 7.75 (d, J = 8.61 Hz, 1H), 7.31 (s, 2H),

7.00 (s, 1H), 6.56 (d, J = 9.00 Hz, 1H), 1.75 (s, 3H).

2-(3-Chloro-4-(thiazol-2-yl)phenyl)propan-2-ol (73). To a stirred

solution of 71 (0.36 g, 1.52 mmol) in THF (4 mL) at 0 °C was added

MeMgBr (0.76 mL, 2.28 mmol, 3 M in ether). The reaction mixture was

stirred at 0 °C for 1 h, quenched by the addition of HCl (10 mL, 1 N)

and extracted with EtOAc (15 mL). The organic extract was sequentially

washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure to yield the title

compound (0.28 g, 73%) as a yellow oil.

2-(4-(5-Bromothiazol-2-yl)-3-chlorophenyl)propan-2-ol (78). Fol-

lowing the procedure outlined above for compound 76, the reaction of

2-(3-chloro-4-(thiazol-2-yl)phenyl)propan-2-ol (73) and N-bromosuc-

cinimide produced the title compound (98%) as yellow oil. MS (ESI

pos. ion): m/z calcd for C₁₂H₁₁BrClNOS: 331; found 332 (M + H).

2-(3-Chloro-4-(5-((6-chloropyridin-3-yl)thio)thiazol-2-yl)phenyl)-

propan-2-ol (83). Following the procedure outlined for compound 82,

the reaction of 2-(4-(5-bromothiazol-2-yl)-3-chlorophenyl)propan-2-ol

(78) and potassium 6-chloropyridine-3-thiolate, produced the title

compound (50%) as a yellow solid. MS (ESI pos. ion): m/z calcd for

C₁₇H₁₄Cl₂N₂OS₂: 396; found 397 (M + H).

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-

chlorophenyl)propan-2-ol (90). To a solution of 83 (0.21 g, 0.54

mmol) in AcOH (2 mL) at 0 °C was added sodium tungstate (8 mg, 0.03

mmol), followed by hydrogen peroxide (0.16 mL, 1.62 mmol, 30% in

water). The reaction mixture was stirred at 0 °C for 3 h and water (5 mL)

was added. The yellow precipitate obtained was ﬁltered, washed with

water, and dried. This material was dissolved in EtOH (2 mL) and added

NH₄OH (1.5 mL, 20% in water). The reaction mixture was heated at

100 °C for 18 h and cooled to room temperature, and the solvent was

removed under reduced pressure. The crude material was puriﬁed by

silica gel chromatography (0−7% 2 M NH₃in MeOH/CH₂Cl₂) to

provide the title compound (66 mg, 30%) as a light-yellow solid. MS

(ESI pos. ion): m/z calcd for C₁₇H₁₆ClN₃O₃S₂: 409; found 410 (M +

H). ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 8.51 (d, J = 2.54

Hz, 1H), 8.21 (d, J = 8.41 Hz, 1H), 7.87 (dd, J = 2.64, 8.90 Hz, 1H), 7.73

(d, J = 1.76 Hz, 1H), 7.60 (dd, J = 1.76, 8.22 Hz, 1H), 7.28 (s, 2H), 6.53

(d, J = 9.00 Hz, 1H), 5.35 (s, 1H), 1.44 (s, 6H).

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)phenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (86). Following the procedure

outlined above for compound 58, 2-(4-(5-((6-chloropyridin-3-yl)thio)-

thiazol-2-yl)phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (81) delivered

the title compound (87%) as a white solid. MS (ESI pos. ion): m/z calcd

1

for C₁₇H₁₁F₆N₃O₃S₂: 483; found 484 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.99 (s, 1H), 8.49−8.55 (m, 2H), 8.16 (d, J = 8.61 Hz,

2H), 7.82−7.91 (m, 3H), 7.28 (s, 2H), 6.56 (d, J = 9.00 Hz, 1H).

1-(3-Chloro-4-(thiazol-2-yl)phenyl)ethanone (71). Following the

procedure outlined for compound 70, the reaction of 2-(tributyl-

stannanyl)-1,3-thiazole (66) and 1-(4-bromo-3-chlorophenyl)ethanone

(68) produced the title compound (69%) as a white solid. MS (ESI pos.

ion): m/z calcd for C₁₁H₈ClNOS: 237; found 238 (M + H). ¹H NMR

(400 MHz, DMSO-d₆): δ 8.40 (d, J = 8.22 Hz, 1H), 8.17 (d, J = 1.76 Hz,

1H), 8.14 (d, J = 3.13 Hz, 1H), 8.09 (d, J = 3.33 Hz, 1H), 8.05 (dd, J =

1.76, 8.41 Hz, 1H), 2.67 (s, 3H).

2-(3-Chloro-4-(thiazol-2-yl)phenyl)-1,1,1-triﬂuoropropan-2-ol

(72). To a 100 mL round-bottomed ﬂask was added 71 (2.08 g, 8.76

mmol), CsF (67 mg, 0.44 mmol), and DME (10 mL). The reaction

mixture was cooled to 0 °C, and under a nitrogen atmosphere

(triﬂuoromethyl)trimethylsilane (1.55 mL, 10.52 mmol) was added.

The reaction mixture was stirred at 0 °C for 1 h and at room temperature

for 30 min. The reaction mixture was diluted with satd NH₄Cl (15 mL)

and extracted with EtOAc (20 mL). The organic extract was washed

with water (10 mL) and dried over Na₂SO₄. The solution was ﬁltered

and concentrated under reduced pressure to give 2-(2-chloro-4-(1,1,1-

triﬂuoro-2-((trimethylsilyl)oxy)propan-2-yl)phenyl)thiazole as a yellow

oil that was used without further puriﬁcation.

To a 100 mL round-bottomed ﬂask was added 2-(2-chloro-4-(1,1,1-

triﬂuoro-2-((trimethylsilyl)oxy)propan-2-yl)phenyl)thiazole (3.31 g,

8.72 mmol) and THF (15 mL). The reaction mixture was cooled to 0

°C, and tetra-N-butyl ammonium ﬂuoride (5.82 mL, 8.72 mmol, 1 M in

THF) was added. The reaction mixture was stirred at 0 °C for 20 min

and allowed to warm to room temperature. The reaction mixture was

diluted with saturated NH₄Cl (10 mL) and extracted with EtOAc (20

mL). The organic extract was washed with water (10 mL), dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure to give the

title compound (2.68 g, 100%) as yellow oil. MS (ESI pos. ion): m/z

calcd for C₁₂H₉ClF₃NOS: 307; found 308 (M + H).

2-(4-(5-Bromothiazol-2-yl)-3-chlorophenyl)-1,1,1-triﬂuoropro-

pan-2-ol (77). Following the procedure outlined for compound 76, the

reaction of 2-(3-chloro-4-(thiazol-2-yl)phenyl)-1,1,1-triﬂuoropropan-2-

ol (72) and N-bromosuccinimide produced the title compound (96%)

as yellow oil. MS (ESI pos. ion): m/z calcd for C₁₂H₈BrClF₃NOS: 385;

found 386 (M + H).

2-(3-Chloro-4-(5-((6-chloropyridin-3-yl)thio)thiazol-2-yl)phenyl)-

1,1,1-triﬂuoropropan-2-ol (82). A glass microwave reaction vessel was

charged with 77 (1.63 g, 4.22 mmol), potassium 6-chloropyridine-3-

thiolate (0.75 g, 4.22 mmol), Pd₂(dba)₃(0.39 g, 0.42 mmol), Xantphos

(0.49 g, 0.84 mmol), and dioxane (12 mL). The reaction mixture was

purged with nitrogen for several minutes and then stirred and heated in a

microwave reactor at 120 °C for 40 min. The reaction mixture was

diluted with water (10 mL) and extracted with EtOAc (15 mL). The

organic extract was washed sequentially with water (10 mL) and brine

(10 mL), dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure to yield the crude product. The crude material was puriﬁed by

silica gel chromatography (0−25% EtOAc/hexanes) to give the title

compound (0.83 g, 44%) as a white solid. MS (ESI pos. ion): m/z calcd

for C₁₇H₁₁Cl₂F₃N₂OS₂: 450; found 451 (M + H).

3-Chloro-4-(thiazol-2-yl)benzenesulfonamide (74). Following the

procedure outlined for compound 70, the reaction of 2-(tributyl-

stannanyl)-1,3-thiazole (66) and 4-bromo-3-chlorobenzenesulfona-

mide (69) produced the title compound (34%) as an oﬀ-white solid.

MS (ESI pos. ion): m/z calcd for C₉H₇ClN₂O₂S₂: 274; found 275 (M +

H).

4-(5-Bromothiazol-2-yl)-3-chlorobenzenesulfonamide (79). Fol-

lowing the procedure outlined for compound 76, the reaction of 3-

chloro-4-(thiazol-2-yl)benzenesulfonamide (74) and N-bromosuccini-

mide produced the title compound (60%) as a white solid. MS (ESI pos.

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chloro-

phenyl)-1,1,1-triﬂuoropropan-2-ol (87). Following the procedure

outlined for compound 86, 2-(3-chloro-4-(5-((6-chloropyridin-3-yl)-

thio)thiazol-2-yl)phenyl)-1,1,1-triﬂuoropropan-2-ol (82) delivered the

title compound (76%) as a white solid. MS (ESI pos. ion): m/z calcd for

1

ion): m/z calcd for C₉H₆BrClN₂O₂S₂: 352; found 353 (M + H). H

NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J = 8.41 Hz, 1H), 8.22 (s, 1H),

8.03 (d, J = 1.76 Hz, 1H), 7.91 (dd, J = 1.76, 8.41 Hz, 1H), 7.64 (s, 2H).

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DOI: 10.1021/jm5018175

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Article

3-Chloro-4-(5-((6-chloropyridin-3-yl)thio)thiazol-2-yl)-

benzenesulfonamide (84). Following the procedure outlined above for

compound 82, the reaction of 4-(5-bromothiazol-2-yl)-3-chlorobenze-

nesulfonamide (79) and potassium 6-chloropyridine-3-thiolate pro-

duced the title compound (60%) as a white solid. MS (ESI pos. ion): m/

z calcd for C₁₄H₉Cl₂N₃O₂S₃: 417; found 418 (M + H).

4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chlorobenze-

nesulfonamide (91). Following the procedure outlined for compound

90, 3-chloro-4-(5-((6-chloropyridin-3-yl)thio)thiazol-2-yl)-

benzenesulfonamide (84) delivered the title compound (58%) as an

oﬀ-white solid. MS (ESI pos. ion): m/z calcd for C₁₄H₁₁ClN₄O₄S₃: 430;

found 431 (M + H). ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H),

8.55 (d, J = 2.35 Hz, 1H), 8.42−8.51 (m, 1H), 8.06 (d, J = 1.37 Hz, 1H),

7.88−7.97 (m, 3H), 7.69 (br s, 2H), 7.38 (d, J = 5.28 Hz, 1H), 6.59 (d, J

= 9.00 Hz, 1H).

8.31 Hz, 1H), 6.63 (d, J = 9.00 Hz, 1H), 3.64 (q, J = 11.5 Hz, 2H), 1.53

(s, 3H).

2-(4-(4-Bromothiazol-2-yl)phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-

2-ol (97). A 25 mL glass resealable vial was charged with 2,4-

dibromothiazole (95) (0.78 g, 3.21 mmol), 1,1,1,3,3,3-hexaﬂuoro-2-(4-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

(96)¹⁶(1.19 g, 3.21 mmol), PdCl₂(dppf) (0.13 g, 0.16 mmol), Cs₂CO₃

(3.14 g, 9.63 mmol), DME (6 mL), and water (0.5 mL). The vial was

closed and purged with nitrogen for several minutes and then stirred and

heated at 90 °C for 4 h. The reaction mixture was allowed to cool to

room temperature, the organic layer was separated, and the solvent was

removed under reduced pressure. The crude material was puriﬁed by

silica gel chromatography (0−10% EtOAc/hexanes) to provide the title

compound (0.83 g, 63%) as a colorless oil. MS (ESI pos. ion): m/z calcd

for C₁₂H₆BrF₆NOS: 405; found 406 (M + H).

2-(3-Chloro-4-(thiazol-2-yl)phenyl)propane-1,2-diol (75). To a

stirred mixture of trimethylsulfoxonium iodide (0.85 g, 3.85 mmol) in

DMSO (3 mL) was added potassium tert-butoxide (0.43 g, 3.85 mmol),

and the suspension was stirred at room temperature for 1 h. This mixture

was added via cannula to a suspension of 71 (0.61 g, 2.57 mmol) in

DMSO (3 mL). The reaction mixture was stirred at room temperature

for 3 h and quenched by the addition of ice-water. The precipitate

obtained was isolated by ﬁltration and dried under reduced pressure.

The crude material was dissolved in THF (3 mL) and at 0 °C, HCl (3

mL, 1 N) was added. The reaction mixture was stirred at 0 °C for 1 h and

diluted with EtOAc. The organic extract was washed sequentially with

water (10 mL) and brine (10 mL), dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure to yield the title compound (0.49

g, 71%) as a light-yellow solid. MS (ESI pos. ion): m/z calcd for

C₁₂H₁₂ClNO₂S: 269; found 270 (M + H).

2-(4-(5-Bromothiazol-2-yl)-3-chlorophenyl)propane-1,2-diol (80).

Following the procedure outlined above for compound 76, the reaction

of 2-(3-chloro-4-(thiazol-2-yl)phenyl)propane-1,2-diol (75) and N-

bromosuccinimide produced the title compound (100%) as a light-

yellow solid. MS (ESI pos. ion): m/z calcd for C₁₂H₁₁BrClNO₂S: 347;

found 348 (M + H).

2-(3-Chloro-4-(5-((6-chloropyridin-3-yl)thio)thiazol-2-yl)phenyl)-

propane-1,2-diol (85). Following the procedure outlined for

compound 82, the reaction of 2-(4-(5-bromothiazol-2-yl)-3-

chlorophenyl)propane-1,2-diol (80) and potassium 6-chloropyridine-

3-thiolate, produced the title compound (62%) as a light-yellow solid.

MS (ESI pos. ion): m/z calcd for C₁₇H₁₄Cl₂N₂O₂S₂: 412; found 413 (M

+ H).

2-(4-(4-((6-Chloropyridin-3-yl)thio)thiazol-2-yl)phenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (98). Following the procedure

outlined for compound 76, 2-(4-(4-bromothiazol-2-yl)phenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (97) delivered the title compound

(20%) as white solid. MS (ESI pos. ion): m/z calcd for

1

C₁₇H₉ClF₆N₂OS₂: 470; found 471 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.95 (s, 1H), 8.47 (d, J = 1.96 Hz, 1H), 8.10 (d, J = 8.61

Hz, 2H), 8.01 (s, 1H), 7.90 (dd, J = 2.74, 8.41 Hz, 1H), 7.84 (d, J = 8.41

Hz, 2H), 7.55 (dd, J = 0.60, 8.41 Hz, 1H).

2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)phenyl)-

1,1,1,3,3,3-hexaﬂuoropropan-2-ol (99). Following the procedure

outlined above for compound 86, 2-(4-(4-((6-chloropyridin-3-yl)thio)-

thiazol-2-yl)phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (98) delivered

the title compound (69%) as a white solid. MS (ESI pos. ion): m/z calcd

1

for C₁₇H₁₁F₆N₃O₃S₂: 483; found 484 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.97 (br s, 1H), 8.64 (br s, 1H), 8.49 (br s, 1H), 8.08 (d, J

= 7.04 Hz, 2H), 7.72−7.95 (m, 3H), 7.19 (br s, 2H), 6.54 (d, J = 8.22 Hz,

1H).

2-Bromo-4-((4-methoxybenzyl)thio)-1-methyl-1H-imidazole

(101). To a 50 mL round-bottomed ﬂask was added 2,4-dibromo-1-

methyl-1H-imidazole (100) (0.47 g, 1.98 mmol), 2-

(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (55 mg,

0.10 mmol), Pd(OAc)₂(22 mg, 0.10 mmol), sodium tert-butoxide

(0.38 g, 3.95 mmol), (4-methoxyphenyl)methanethiol (0.27 mL, 1.98

mmol), and DME (5 mL). The reaction mixture was stirred at 90 °C for

3 h and allowed to cool to room temperature. The reaction mixture was

diluted with saturated NH₄Cl (10 mL) and extracted with EtOAc (2 ×

20 mL). The combined organic extracts were washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by silica gel chromatography (30% EtOAc/

hexanes) to provide the title compound (0.42 g, 67%) as a brown oil. MS

(ESI pos. ion): m/z calcd for C₁₂H₁₃BrN₂OS: 312; found 313 (M + H).

1,1,1,3,3,3-Hexaﬂuoro-2-(4-(4-((4-methoxybenzyl)thio)-1-methyl-

1H-imidazol-2-yl)phenyl)propan-2-ol (102). To a 25 mL round-

bottomed ﬂask was added 101 (0.36 g, 1.14 mmol), 1,1,1,3,3,3-

hexaﬂuoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-

propan-2-ol (8) (0.42 g, 1.14 mmol), PdCl₂(dppf) (93 mg, 0.11 mmol),

Cs₂CO₃(0.74 g, 2.29 mmol), dioxane (6 mL), and water (0.6 mL). The

reaction mixture was purged with nitrogen for several minutes and then

stirred and heated at 100 °C for 5 h. The reaction mixture was diluted

with saturated NH₄Cl (10 mL) and extracted with EtOAc (2 × 20 mL).

The combined organic extracts were washed with brine, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The crude

material was puriﬁed by silica gel chromatography (30% EtOAc/

hexanes) to provide the title compound (0.26 g, 48%) as a colorless oil.

MS (ESI pos. ion): m/z calcd for C₂₁H₁₈F₆N₂O₂S: 476; found 477 (M +

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-

chlorophenyl)propane-1,2-diol (92). Following the procedure out-

lined above for compound 90, 2-(3-chloro-4-(5-((6-chloropyridin-3-

yl)thio)thiazol-2-yl)phenyl)propane-1,2-diol (85) delivered the title

compound (28%) as a light-yellow solid. MS (ESI pos. ion): m/z calcd

1

for C₁₇H₁₆ClN₃O₄S₂: 425; found 426 (M + H). H NMR (400 MHz,

DMSO-d₆): δ 8.58 (s, 1H), 8.53 (d, J = 2.74 Hz, 1H), 8.22 (d, J = 8.22

Hz, 1H), 7.89 (dd, J = 2.54, 9.00 Hz, 1H), 7.73 (d, J = 1.57 Hz, 1H), 7.60

(dd, J = 1.57, 8.41 Hz, 1H), 7.30 (s, 2H), 6.56 (d, J = 9.00 Hz, 1H), 5.28

(s, 1H), 4.86 (t, J = 5.87 Hz, 1H), 3.39−3.54 (m, 2H), 3.18 (d, J = 5.28

Hz, 1H), 1.42 (s, 3H).

The individual enantiomers (93 and 94) were isolated using chiral

SFC Chiralpak ADH column (21 × 250 mm, 5 μ) eluting with MeOH in

supercritical CO₂(total ﬂow was 70 mL/min). This produced the two

enantiomers with enantiomeric excesses >98%.

(R)-2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-

chlorophenyl)propane-1,2-diol (93). MS (ESI pos. ion): m/z calcd for

1

C₁₇H₁₆ClN₃O₄S₂: 425; found 426 (M + H). H NMR (400 MHz,

1

CD₃OD): δ 8.55 (d, J = 1.96 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J = 8.41 Hz,

1H), 7.91 (dd, J = 2.64, 9.10 Hz, 1H), 7.76 (d, J = 1.56 Hz, 1H), 7.57 (dd,

J = 1.76, 8.41 Hz, 1H), 6.63 (d, J = 9.00 Hz, 1H), 3.64 (q, J = 11.50 Hz,

2H), 1.53 (s, 1H).

H). H NMR (300 MHz, CDCl₃): δ 7.79−7.88 (m, 2H), 7.70 (d, J =

8.33 Hz, 2H), 7.20 (s, 1H), 7.05−7.12 (m, 2H), 6.79 (s, 2H), 4.19 (s,

2H), 3.78 (s, 3H), 3.31 (s, 3H).

2-(4-(4-((6-Aminopyridin-3-yl)thio)-1-methyl-1H-imidazol-2-yl)-

phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (104). To a 25 mL round-

bottomed ﬂask was added 102 (0.23 g, 0.47 mmol) and TFA (2 mL).

The reaction mixture was stirred at 70 °C for 18 h. The solvent was

removed under reduced pressure. The crude product was dissolved in

DMSO (2 mL) and added 2-amino-5-iodopyridine (103) (0.10 g, 0.47

(S)-2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-

chlorophenyl)propane-1,2-diol (94). MS (ESI pos. ion): m/z calcd for

1

C₁₇H₁₆ClN₃O₄S₂: 425; found 426 (M + H). H NMR (400 MHz,

CD₃OD): δ 8.55 (br s, 1H), 8.39 (s, 1H), 8.27 (d, J = 8.41 Hz, 1H), 7.91

(dd, J = 2.45, 9.10 Hz, 1H), 7.76 (d, J = 1.76 Hz, 1H), 7.57 (dd, J = 1.66,

S

DOI: 10.1021/jm5018175

J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Article

mmol), CuI (18 mg, 0.09 mmol), K₂CO₃(0.26 g, 1.90 mmol), and N,N-

dimethyl-1,2-ethanediamine (0.021 mL, 0.19 mmol). The reaction

mixture was stirred at 90 °C for 18 h and allowed to cool to room

temperature. The reaction mixture was diluted with water (20 mL) and

extracted with EtOAc (2 × 30 mL). The combined organic extracts were

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The crude material was puriﬁed by silica gel

chromatography (EtOAc) to provide the title compound (65 mg,

31%) as a white solid. MS (ESI pos. ion): m/z calcd for C₁₈H₁₄F₆N₄OS:

448; found 449 (M + H).

2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)-1-methyl-1H-imidazol-2-

yl)phenyl)-1,1,1,3,3,3-hexaﬂuoropropan-2-ol (105). To a solution of

104 (41 mg, 0.09 mmol), in CH₂Cl₂(2 mL) at 0 °C was added mCPBA

(32 mg, 0.18 mmol). The reaction mixture was stirred at 0 °C for 1 h and

partitioned between saturated NaHCO₃and CH₂Cl₂. The organic

extract was dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude material was puriﬁed by silica gel chromatography

(15% MeOH/CH₂Cl₂) to aﬀord the title compound (21 mg, 48%) as a

white solid. MS (ESI pos. ion): m/z calcd for C₁₈H₁₄F₆N₄O₃S: 480;

found 481 (M + H). ¹H NMR (300 MHz, CD₃OD): δ 6.96 (d, J = 1.90

Hz, 1H), 6.27−6.38 (m, 3H), 6.24 (s, 2H), 6.09 (dd, J = 1.97, 8.99 Hz,

1H), 5.52−5.62 (m, 1H), 2.41 (s, 3H).

4OP3, and 4OP1, respectively. The Supporting Information is

available free of charge on the ACS Publications website at DOI:

10.1021/jm5018175.

AUTHOR INFORMATION

Corresponding Authors

*Phone: 805-447-8814. E-mail: ntamayo@amgen.com.

*Phone: 805-447-3446. E-mail: mbartber@amgen.com.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank Kyung Gahm, Wesley Barnhart, and Samuel Thomas

for conducting the SFC separations; Robert Kurzeja for

providing the puriﬁed proteins; Robert Wahl and Kathy Chen

for assay development; and Carolyn Moyer for her assistance in

the pharmacodynamic assay. Additionally, we thank Scott

Simonet, Murielle Veniant, Dean Hickman, Philip Tagari, and

Randall Hungate for their support of this research.

2-(4-(5-Bromo-1-methyl-1H-imidazol-2-yl)phenyl)-1,1,1-triﬂuoro-

propan-2-ol (107). To a 25 mL round-bottomed ﬂask was added 2,5-

dibromo-1-methyl-1H-imidazole (106) (0.24 g, 1.00 mmol), 1,1,1-

triﬂuoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-

propan-2-ol (96) (0.32 g, 1.00 mmol), PdCl₂(dppf) (82 mg, 0.10

mmol), Cs₂CO₃(0.65 g, 2.00 mmol), dioxane (4 mL), and water (0.4

mL). The reaction mixture was purged with nitrogen for several minutes

and then stirred and heated at 100 °C for 5 h. The reaction mixture was

diluted with saturated NH₄Cl (10 mL) and extracted with EtOAc (2 ×

20 mL). The combined organic extracts were washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by silica gel chromatography (30% EtOAc/

CH₂Cl₂) to provide the title compound (0.20 g, 58%) as a white solid.

MS (ESI pos. ion): m/z calcd for C₁₃H₁₂BrF₃N₂O: 348; found 349 (M +

H).

1,1,1-Triﬂuoro-2-(4-(5-((4-methoxybenzyl)thio)-1-methyl-1H-imi-

dazol-2-yl)phenyl)propan-2-ol (108). Following the procedure out-

lined for compound 100, the reaction of 2-(4-(5-bromo-1-methyl-1H-

imidazol-2-yl)phenyl)-1,1,1-triﬂuoropropan-2-ol (107) and (4-

methoxyphenyl)methanethiol produced the title compound (80%) as

a brown solid. MS (ESI pos. ion): m/z calcd for C₂₁H₂₁F₃N₂O₂S: 422;

found 423 (M + H). ¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, J = 8.18

Hz, 2H), 7.28−7.38 (m, 2H), 7.18 (s, 1H), 7.05−7.13 (m, 2H), 6.73−

6.86 (m, 2H), 4.19 (s, 2H), 3.78 (s, 3H), 3.27 (s, 3H), 1.82 (d, J = 0.73

Hz, 3H).

2-(4-(5-((6-Aminopyridin-3-yl)thio)-1-methyl-1H-imidazol-2-yl)-

phenyl)-1,1,1-triﬂuoropropan-2-ol (109). Following the procedure

outlined for compound 104, 1,1,1-triﬂuoro-2-(4-(5-((4-

methoxybenzyl)thio)-1-methyl-1H-imidazol-2-yl)phenyl)propan-2-ol

(108) delivered the title compound (25%) as a white solid. MS (ESI pos.

ion): m/z calcd for C₁₈H₁₇F₃N₄OS: 394; found 395 (M + H).

2-(4-(5-((6-Aminopyridin-3-yl)sulfonyl)-1-methyl-1H-imidazol-2-

yl)phenyl)-1,1,1-triﬂuoropropan-2-ol (110). Following the procedure

outlined for compound 105, the reaction of 2-(4-(5-((6-aminopyridin-

3-yl)thio)-1-methyl-1H-imidazol-2-yl)phenyl)-1,1,1-triﬂuoropropan-2-

ol (109) and mCPBA produced the title compound (40%) as a white

solid. MS (ESI pos. ion): m/z calcd for C₁₈H₁₇F₃N₄O₃S: 426; found 427

(M + H). ¹H NMR (300 MHz, CD₃OD): δ 8.44 (d, J = 1.90 Hz, 1H),

7.77 (d, J = 8.33 Hz, 2H), 7.58 (dd, J = 1.97, 8.99 Hz, 1H), 7.52 (d, J =

8.48 Hz, 2H), 7.28 (s, 1H), 7.10 (d, J = 9.06 Hz, 1H), 3.86 (s, 3H), 1.77

(s, 3H).

ABBREVIATIONS USED

■

AlphaScreen, ampliﬁed luminescent proximity assay; AmPhos, 4-

(dimethylamino)phenyl]bis(tert-butyl)phosphine; calcd, calcu-

lated; CL, clearance; DME, 1,2-dimethoxyethane; DMF, N,N-

dimethylformamide; DMSO, dimethyl sulfoxide; dppf, 1,1′-

bis(diphenylphosphino)ferrocene; EC₅₀, eﬀective concentra-

tion; GK, glucokinase; GKA, glucokinase activator; GKRP,

glucokinase regulatory protein; IPA, isopropylalcohol; Josiphos,

2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine;

mCPBA, 3-chloroperoxybenzoic acid; pos, positive; RLM, rat

liver microsomes; IC₅₀, inhibitory concentration at half maximal

eﬀect; iv, intravenous; rt, room temperature; TBAF, tetra-N-

butylammonium ﬂuoride; TFA, triﬂuoroacetic acid; THF,

tetrahydrofuran; Xantphos, 4,5-bis(diphenylphosphino)-9,9-di-

methylxanthene; XPhos, 2-dicyclohexylphosphino-2′,4′,6′-trii-

sopropylbiphenyl; XPhos precatalyst, chloro(2-dicyclohexyl-

phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-

aminoethyl)phenyl)]palladium

REFERENCES

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ASSOCIATED CONTENT

■

S

* Supporting Information

Syntheses of intermediates 8, 16, 31, and 96. The cocrystal

structures of hGKRP + compounds 4, 39, and 59 have been

deposited in the Protein DataBank with PDB codes: 4OP2,

T

DOI: 10.1021/jm5018175

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Journal of Medicinal Chemistry

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U

DOI: 10.1021/jm5018175

J. Med. Chem. XXXX, XXX, XXX−XXX

Article Doi

Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

DOI: 10.1021/jm5018175

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Article abstract of DOI:10.1021/jm5018175

Full text of DOI:10.1021/jm5018175

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