Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity

European Journal of Medicinal Chemistry 46 (20 1 1 ) 1 103e1 116

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European Journal of Medicinal Chemistry

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Original article

Synthesis and application of a bromomethyl substituted scaffold to be used for

efﬁcient optimization of anti-virulence activity

,

Erik Chorell ^a, Christoffer Bengtsson ^a, Thomas Sainte-Luce Banchelin ^a, Pralay Das ^{a b}, Hanna Uvell ^c,

,

,c,e,

*

Arun K. Sinha ^{a b}, Jerome S. Pinkner ^d, Scott J. Hultgren ^d, Fredrik Almqvist ^a

^aDepartment of Chemistry, Umeå University, SE-90187 Umeå, Sweden

^bNPP Division I.H.B.T., C.S.I.R., Palampur, Himachal Pradesh 176061, India

^cLaboratories for Chemical Biology Umeå, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden

^dDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA

^eUmeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden

a r t i c l e i n f o

a b s t r a c t

Article history:

Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the

Received 26 October 2010

Received in revised form

10 January 2011

Accepted 13 January 2011

Available online 21 January 2011

chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the

peptidomimetic scaffold that the pilicides are based on can prevent both Ab aggregation and curli

formation. To facilitate optimizations towards the different targets, a new synthetic platform has been

developed that enables fast and simple introduction of various substituents in position C-7 on the

peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable

heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl

substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile

and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold

including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be intro-

duced to the sp³-hybridized bromomethyl substituted scaffold by SuzukieMiyaura cross couplings.

Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure

eactivity data and resulted in the identiﬁcation of a number of new pilicides with activity as good or

better than those developed previously.

Keywords:

Pilicide

Anti-virulence

2-Pyridone

peptidomimetic

1. Introduction

usher pathway the pilus subunits are incorporated in the growing

pilus ﬁber via an outer membrane assembly site called the usher

Anti-virulence strategies are one potential way to meet the

immense need for new antibacterial drugs with new modes of

action that arise in the wake of the global spread of bacterial

resistance [1,2]. Pilicides constitute a class of low molecular weight

compounds that target bacterial virulence in Gram negative

bacteria, thus rendering the bacteria unable to cause disease but

still fully viable [3,4]. In theory, this should result in a reduced

selective pressure on resistant bacteria and simultaneously be more

benign to the human microbiota.

[5e7]. Partial folding and transportation of the pilus subunits from

the bacterial inner membrane through the periplasm to the usher is

accomplished by the chaperone [8e10]. The pilicides have been

shown to bind to the same residues on the chaperone as the usher

and thereby block binding of chaperone-subunit complexes to the

usher [4,11]. Hence, by interfering with the chaperone/usher

pathway the pilicides block pilus assembly. Considering that this

assembly pathway is highly conserved [12], the pilicides could

potentially be applicable towards many bacterial strains.

The pilicides prevent assembly of extracellular proteinaceous

ﬁbres, pili or ﬁmbriae, important in many stages of bacterial

infections, by targeting the chaperone/usher pathway (demon-

strated for uropathogenic Escherichia coli) [4]. In the chaperone/

The peptidomimetic pilicide scaffold (3) is synthesized via an

acyl-ketene imine cyclocondensation from Meldrum’s acid deriv-

atives (1) and

substituents from the

D

²-thiazolines (2) (Fig. 1) [13e15]. In this reaction the

D

²-thiazolines and Meldrum’s acid deriva-

tives are introduced in position C-7 and C-8, respectively.

An early study of the pilicide scaffold 3 based on seven aryl and

alkyl C-7 substituents and in vitro assay data suggested that

a naphthyl substituent in position C-7 on the scaffold is beneﬁcial

for pilicide activity (e.g. pilicide 5 and 6, Fig. 2) [16]. As a result, the

* Corresponding author. Department of Chemistry, Umeå University, SE-90187

Umeå, Sweden. Tel.: þ46 90 7866925; fax: þ46 90 7867655.

E-mail address: fredrik.almqvist@chem.umu.se (F. Almqvist).

doi:10.1016/j.ejmech.2011.01.025

1104

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

a consequence, we wanted to develop a synthetic platform that

OEt

O

R¹

Cl

enable introduction of various C-7 substituents by fast and simple

transformations. The strategy is to synthesize a large amount of the

scaffold with a reactive C-7 “handle” for late introduction of the

various substituents.

R¹

R²OH

NH₂

O

HO

R²

O

+

S

O

+

H₂S

+

O

N

Here we describe the synthesis of the bromomethyl-substituted

pilicide scaffold 4a and 4b and the efﬁcient use of these versatile

scaffolds for introduction of various C-7 substituents. The two C-8

(R¹) substituents with different size were selected from previously

reported pilicides 5 and 6 (Fig. 2) [16e18]. From the two bromi-

nated compounds (4a and 4b) C-7 substituents were introduced by

reactions with amines or alcohols. Primary amines were also

prepared via substitution with azide followed by reduction, and

these were reacted further to generate amides and sulfonamides. In

addition, the versatility of this reactive scaffold was further

expanded to include carbonecarbon bonds that were introduced

via SuzukieMiyaura cross couplings on the sp³-hybridized carbon.

All generated compounds as carboxylic acids were biologically

evaluated in bioﬁlm and HA-titer assays.

Cl

H₃N

CO₂Me

1

2

O

CO₂Me

R¹

S¹

3

8

R²

9

R¹= alkyl or aryl

R²= alkyl or aryl

7

2

5

N

6

4

CO₂Me

3

O

Fig. 1. From Meldrum’s acid derivatives (1) and

D

²-thiazolines (2) the ring-fused

dihydrothiazolo 2-pyridone scaffold (3) is synthesized via an acyl-ketene imine

cyclocondensation [13,14].

2. Results and discussion

Size,

heteroatoms

2.1. Synthesis

Heteroatoms,

length

The common starting point for introduction of C-7 substituents

in this paper is the bromomethyl-substituted scaffold 4a and 4b

(Scheme 1). To obtain these compounds, the corresponding

brominated Meldrum’s acid derivative (7) was desired. By slightly

modifying the standard conditions, Meldrum’s acid derivative (7)

could be synthesized by coupling Meldrum’s acid with bromoacetic

R¹

O

S

X

N

CO₂H

CO₂Me

O

acid. Reacting 7 with the

D

²-thiazolines 2a and 2b generated the

4

target compounds 4a and 4b in high yields (Scheme 1). However,

the purity of 7 proved to be important and repeated recrystalliza-

tions were necessary to obtain high and reproducible yields. As

a consequence, an alternative approach to generate the key

compounds 4a and 4b was also developed using a different acyl-

ketene source (8). Synthesis of 8 could be accomplished by starting

CF₃

S

from the corresponding

a previously described procedure for similar compounds [19].

Subsequent ring closure of the -brominated -keto acid using

g-brominated b-keto acid, obtained by

N

CO₂H

O

6

g

b

5

conc. H₂SO₄, Ac₂O, and acetone gave the desired bromo-dioxinone

8. Using this acyl-ketene source in the cyclocondensation with the

D

respectively) (Scheme 1).

Fig. 2. Synthesis of a scaffold with a reactive C-7 group (4) for efﬁcient introduction of

various C-7 substituents. Known pilicides with CH₂-1-naphthyl substituent in C-7 (R²)

and a cyclopropyl (5) or 3-CF₃-phenyl (6) C-8 (R¹) substituent [16e18].

²-thiazolines gave reproducible yields of 4a and 4b (64% and 74%,

Having established robust methods for the synthesis of these

compounds, introduction of various C-7 substitutents was next

attempted. Introduction of amines was straightforward. Reactions

of 4a and 4b with piperidine, morpholine or 1,2,3,4-tetrahydro-

isoquinoline in DMF resulted in high yields of 9a, be11a,

b (Scheme 2). Synthesis of primary amines was accomplished in

a two-step process. First sodium azide was added to 4a or 4b giving

12a and 12b in 89% and 90% yields, respectively. This was followed

by reduction using zinc and ammonium chloride to give 13a and

13b in 83% and 81% yields, respectively (Scheme 2). From these

C-7-naphthyl substituent has been used in all of the following

studies of the pilicides. The lack of more comprehensive C-7 SAR

including heteroatoms can mainly be explained by the synthetic

method’s inherent restrictions both in terms of possible substitu-

ents in the synthesis of acyl Meldrum’s acid derivatives but also in

the subsequent acyl-ketene imine cyclocondensation. Furthermore,

the synthesis of a diverse set of C-7 substituted analogues via the

original synthesis, by synthesis of a new Meldrum’s acid derivative

for every compound, is both ineffective and time-consuming. As

R¹

O

R¹

O

HO

O

S

a

b

S

Br

O

+

N

Br

O

7

CO₂Me

8

2a: R¹= cyclopropyl-

4a: 64-87%

2a: R¹= cyclopropyl-

2b: R¹= 3-CF₃-ph-

4b: 74-92%

Scheme 1. (a) TFA, dichloroethane, MWI: 140 ^ꢀC, 2.5 min (4a and 4b: 87% and 92%, respectively); (b) TFA, dichloroethane, microwave irradiation: 140 ^ꢀC, 2 min (4a and 4b: 64% and

74%, respectively).

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1105

R¹

O

R²

O

S

N₃

N

H

N

CO₂Me

O

c

14a: R²= Ph-, 79%

14b: R²= Ph-, 79%

d

b

R¹

O

R¹

O

12a: 89%

12b: 90%

15a: R²= 1-naphthyl-, 78%

15b: R²= 1-naphthyl-, 81%

S

Br

H₂N

N

CO₂Me

4a: R¹= cyclopropyl-

13a: 83%

4b: R¹= 3-CF₃-Ph-

13b: 81%

e

a

R¹

O

R¹

O

S

R²

N

H

N

CO₂Me

O

9a: R²= Piperidine-, 81% , 9b: R²= Piperidine-, 83%

10a: R²= Morpholine-, 84%, 10b: R²= Morpholine-, 82%

11a: R²= 1,2,3,4-Tetrahydro-isoquinoline-, 84%

11b: R²= 1,2,3,4-Tetrahydro-isoquinoline-, 86%

16a: R²= Ph-, 83%

16b: R²= Ph-, 80%

17a: R²= 1-naphthyl-, 79%

17b: R²= 1-naphthyl-, 80%

Scheme 2. (a) Amine (piperidine, morpholine or 1,2,3,4-tetrahydroisoquinoline), DMF, rt, 30 min (9a: 81%, 9b: 83%, 10a: 84%, 10b: 82%, 11a: 84%, 11b: 86%); (b) NaN₃, DMF, rt, 15 min

(12a,b: 89% and 90%, respectively); (c) Zn, NH₄Cl, EtOH:H₂O (3:1), rt, 20 min (13a,b: 83% and 81%, respectively); (d) benzenesulfonyl chloride or 1-naphthalenesulfonyl chloride,

NEt₃, CH₂Cl₂, rt, o.n. (14a: 79%, 14b: 79%, 15a: 78%, 15b: 81%); (e) benzoyl chloride or 1-naphthoyl chloride, NEt₃, CH₂Cl₂, rt, o.n. (16a: 83%, 16b: 80%, 17a: 79%, 17b: 80%).

primary amines, compounds with C-7 amide and sulfonamide

substituents could be synthesized. Sulfonamides were prepared by

reacting amines 13a or 13b with phenylsulfonyl or 1-naph-

thylsulfonyl chloride to give 14a, b and 15a, b in 78e81% yields. The

amides were generated in a similar manner by reacting 13a or 13b

with benzoyl or 1-naphthoyl chloride to give 16a, b and 17a, b in

79e83% yields (Scheme 2).

After successful use of 4a and 4b to introduce a CeN linkage (e.g.

amines, amides and sulfonamides) the possibilities to use the same

substrates for introduction of a CeO linkage were investigated. The

presence of both a stereogenic centrum and a methyl ester in 4a

and 4b made the choice of proper reaction conditions crucial to

avoid epimerization and re-esteriﬁcation. Fortunately, the use of

Cs₂CO₃in combination with phenol or naphthol in DMF at 0 ^ꢀC gave

18a, be19a, b in high yields (82e96%, Scheme 3).

various aryl substituents was applied. However, directly applying

previously developed methods for SuzukieMiyaura couplings of

4a and 4b gave poor conversion (Table 1, entry 1) [11]. To improve

the reaction conditions for use on the bromomethyl substituted

scaffold three different Pd-catalysts were tested (Pd(PPh₃)₂Cl₂,

Pd-NHC ([1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-

chloropyridyl)palladium(II) dichlorid), and Pd(PPh₃)₄). The results

are summarized in Table 1.

The yields were signiﬁcantly improved at lower catalyst load-

ings by the use of Pd(PPh₃)₂Cl₂(Table 1, entry 2). Using these

conditions, three different boronic acids were coupled to the two

bromomethyl substituted scaffolds 4a and 4b (Table 2).

In all cases the method generated the desired products in

acceptable yields. The methoxynaphthyl and indole boronic acids

To further expand the use of the bromomethyl substituted

scaffold for C-7 derivatization, by late introduction of various

substituents, the possibility to introduce carbon-carbon bonds

was investigated. Because CH₂-aryl substituents in position C-7

previously was shown to result in interesting pilicide properties,

the use of SuzukieMiyaura cross couplings for introduction of

Table 1

Testing different Pd-catalysts for SuzukieMiyaura cross couplings.^a

CF₃

S

Br

N

R¹

CO₂Me

a^a

O

R²

4b

S

a

Br

O

N

(HO)₂B

MeO

N

CO₂Me

O

OMe

21b

CO₂Me

O

20

18a: R²= Ph-, 96%

4a: R¹= cyclopropyl-

4b: R¹= 3-CF₃-Ph-

Entry

Pd-catalyst

Pd(OAc)₂

Pd(PPh₃)₂Cl₂

Pd-NHC

Amount catalyst (mol%)

Yield^b(%)

18b: R²= Ph-, 82%

1

2

3

4

10

5

11

84

50

65

19a: R²= naphthyl-, 94%

19b: R²= naphthyl-, 84%

Pd(PPh₃)₄

5

a

Scheme 3. (a) Phenol or naphthol, DMF, Cs₂CO₃, 3A MS, 0 ^ꢀC, 3 h (18a: 96%, 18b: 82%,

19a: 94%, 19b: 84%).

KF, MeOH, microwave irradiation: 110 ^ꢀC, 10 min.

Isolated yields.

b

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E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

Table 2

gave best results (Entries 1e4, Table 2) while the p-ﬂuorobenzyloxy

substituted phenyl gave slightly lower yields (Entries 5e6, Table 2).

Synthesis of C-7 CH₂-aryl substituents by SuzukieMiyaura cross couplings.

R¹

S

R²

a

Br

2.2. Biological evaluation

N

CO₂Me

O

A previous study has shown that a free carboxylic acid or

lithium carboxylate is important for a retained pilicide activity

[16,17]. As a consequence, the methyl ester functionality in each of

the C7-substitued derivatives of the pilicide scaffold described

above was hydrolyzed before being evaluated for their ability to

prevent bioﬁlm formation (Table 3). The bioﬁlm formation assay is

based on the ability of E. coli to form type 1 pilus-dependent

bioﬁlms on PVC surfaces [20]. Blocking type 1 pili formation in this

assay also prevents the ability of the bacteria to form bioﬁlm and

the amount of bioﬁlm that is formed in the presence of pilicide is

thus related to the potency of the compound in blocking pili

formation. This assay is based on whole bacteria and, thus,

generates more relevant biological information than elementary in

vitro binding assays.

4a: R¹= cyclopropyl-

4b: R¹= 3-CF₃-Ph-

21a,b-23a,b

Entry

R¹

Compound

R²

Yield^a(%)

1

2

Cyclopropyl-

3-CF₃-Ph-

21a

21b

72

84

O

3

4

Cyclopropyl-

3-CF₃-Ph-

22a

22b

77

88

N

H

5

6

Cyclopropyl-

3-CF₃-Ph-

23a

23b

56

61

F

First, all compounds were screened for their ability to prevent

bioﬁlm formation at 200 mM. Compounds having a 60% or higher

O

inhibition of bioﬁlm formation at this concentration was consid-

ered interesting and were further diluted to generate EC₅₀-values.

The results are summarized in Table 3.

We found that proper substitution of position C-7 on the

pilicide scaffold was highly important for the biological response

a

Isolated yields.

Table 3

Biological evaluation of the compounds ability to prevent bioﬁlm formation.^a

R¹

a^a

S

R²

N

CO₂Me

CO₂R³

O

9a,b-11a,b

14a,b-19a,b

21a,b-23a,b

24a,b-35a,b

Entry

Substrate

Prod

R¹

R²

R³

200

m

M

EC₅₀(m

M)^b

1

2

9a

9b

24a

24b

Cyclopropyl-

3-CF₃-Ph-

Li

NA^c

30%

e

N

3

4

10a

10b

25a

25b

Cyclopropyl-

3-CF₃-Ph-

Li

NA^c

e

N

O

5

6

11a

11b

26a

26b

Cyclopropyl-

3-CF₃-Ph-

Li

NA^c

84%

e

N

O

130

7

8

14a

14b

27a

27b

Cyclopropyl-

3-CF₃-Ph-

H

NA^c

48%

e

O

S

N

H

9

10

15a

15b

28a

28b

Cyclopropyl-

3-CF₃-Ph-

H

NA^c

91%

e

O

38

S

N

H

11

12

16a

16b

29a

29b

Cyclopropyl-

3-CF₃-Ph-

H

NA^c

e

O

N

H

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1107

Table 3 (continued ).

Entry

Substrate

Prod

R¹

R²

R³

200

m

M

EC₅₀(m

M)^b

13

14

17a

17b

30a

30b

Cyclopropyl-

3-CF₃-Ph-

H

NA^c

65%

e

O

130

N

H

15

16

18a

18b

31a

31b

Cyclopropyl-

3-CF₃-Ph-

H

43%

80%

e

21

O

17

18

19a

19b

32a

32b

Cyclopropyl-

3-CF₃-Ph-

H

96%

72%

32

37

21

22

21a

21b

33a

33b

Cyclopropyl-

3-CF₃-Ph-

H

NA^c

93%

e

9

O

23

24

22a

22b

34a

34b

Cyclopropyl-

3-CF₃-Ph-

H

37%

97%

e

30

N

H

25

26

23a

23b

35a

35b

Cyclopropyl-

3-CF₃-Ph-

H

76%

75%

43

F

(3)^d

O

27

28

e

5

6

Cyclopropyl-

3-CF₃-Ph-

H

54%

92%

189

17

a

LiOH, THF, rt, 4e24 h, (for 27a-35b: acidic work up), yields normally over 90%, see Section 4 for details.

Estimated from triplicates on every concentration.

Not active.

b

c

d

Never reached higher than 80% inhibition even at 200 mM.

and that it was possible to improve activity over the parent

naphthyl substituent in 5 and 6 by varying this position. In

general, the cyclopropyl series of compounds did not show as

high activity as the 3-CF₃-phenyl series (Table 3, 24e35a vs.

24e35b). However, the 1-naphthoxy substituent in 32a is note-

worthy as it has a 6-fold increased potency compared to the

parent 1-naphthyl substituent in 5 (Table 3, entry 17 vs. 27).

Nevertheless, best of all compounds was 33b carrying the

Information) to verify that the observed bioﬁlm inhibition is

a result of reduced pili formation. In this assay, the degree of

piliation of the culture is related to the HA titer. Thus, after

growth in the presence of pilicide, the HA titers are determined to

evaluate the potencies of the compounds in blocking pilus

formation. Gratifyingly this correlated well with the observed

bioﬁlm inhibition and showed that these compounds did indeed

prevent pili formation. Finally, an initial study of the cytotoxic

properties of 28b, 31b, 32a,b, 33b, 34b, 35a, b, 5, and 6 against

HeLa cells was performed as a control experiment. This showed

that none of the tested compounds displayed toxicity close to the

estimated EC₅₀concentrations (Fig. S2 in Supporting Information).

6-methoxy-2-naphthyl substituent with an estimated EC₅₀of 9 mM

(Table 3, entry 22). Compound 35b also displayed interesting

properties, although it never completely inhibited the bioﬁlm

formation even at higher concentrations, it reached 50% bioﬁlm

inhibition at as low as 3 mM, again showing on the potential of

varying this position (Table 3, entry 26).

3. Conclusion

Exchange of the 1-naphthyl substituent in 6 to a 1-naphthyl

sulfonamide as in 28b retained much of the pilicide activity and

proved to be preferable compared to the 1-naphthyl amide in 30b

(Table 3, entries 10, 14 and 28). All smaller substituents resulted

in inactive compounds except for the phenoxy substituent in 31b

that quite unexpectedly showed activity in the same range as the

parent pilicide 6 (Table 3, entries 1e4, 7, 8, 11, 12, 15 and 16). It

should also be noted that none of the compounds showed any

A synthetic platform has been developed that gave access to

analogues carrying various C-7 substituents, including some that

previously were unattainable, by simple and fast transformations.

Central to the strategy is the synthesis of a C-7 bromomethyl

substituted scaffold onto which substituents were introduced by

different methods. First, amines and ethers were introduced in

a straightforward manner by substitution reactions. Secondly,

introduction of amides and sulfonamides were realized via the free

amine. Finally, the scaffold could further be used to introduce

carbon-carbon bonds via SuzukieMiyaura couplings. After ester

effect on bacterial growth at 200 mM (Fig. S1 in Supporting

Information). Furthermore, the best compounds were evaluated

in a hemagglutination (HA) titer assay (Table S1 in Supporting

1108

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

hydrolysis, all compounds were evaluated in a bioﬁlm assay and, to

verify pilicide activity, also further tested in a HA titer assay. From

this we learned that the nature of the substituents at the C-7

position is highly important for pilicide activity. It should be

possible to further improve and ﬁne-tune the activity by substit-

uent variation at this position. In general, sterically more

demanding substituents seem to be favorable, the heteroatom-

linked ethers and SuzukieMiyaura coupled aryl substituents being

most promising. Interestingly, the basic amine substituents and the

smaller amide- and sulfonamide-linked substituents mainly

resulted in inactive compounds.

saturated NaHCO₃(aq) and extracted with CH₂Cl₂. The solvent

was dried (Na₂SO₄), ﬁltered and concentrated to give a brown oil.

The crude product was used in the next step without puriﬁcation.

¹H NMR (400 MHz, CDCl₃)

d

1.72 (s, 6H), 3.88 (s, 2H), 5.53 (s, 1H).

24.9 (2C), 27.0, 95.9, 107.7, 160.6,

¹³C NMR (100 MHz, CDCl₃)

164.5.

d

4.5. (3R)-7-Bromomethyl-8-cyclopropyl-5-oxo-2,3-dihydro-5H-

thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (4a)

4.5.1. Using 7

The herein developed synthetic platform is not only beneﬁcial in

the optimization process of the pilicides but will in the future also

be highly useful in the design of peptidomimetics towards other

biological targets.

4.5.1.1. Synthesis of 7. Bromoacetic acid (5.00 g, 36.0 mmol, 1 eq),

DMAP (4.84 g, 39.6 mmol, 1.1 eq) and Meldrum’s acid (5.70 g,

39.6 mmol, 1.1 eq) were dissolved in 350 mL CH₂Cl₂at 0 ^ꢀC. DCC

(8.54 g, 41.4 mmol, 1.15 eq) dissolved in 50 mL CH₂Cl₂was

added dropwise to the solution over 10 minutes. The reaction

mixture was then left at room temperature over night. The

reaction was quenched with 6% (aq.) KHSO₄and the resulting

precipitate was ﬁltered off. The ﬁltrate was then washed twice

with 6% KHSO₄, dried with NaSO₄, ﬁltrated, and concentrated

giving 7 as an oil (6.77 g, 71% yield) that was used without

4. Experimental

4.1. General synthesis

All reactions were carried out under inert atmosphere, with dry

solvents and anhydrous conditions, unless otherwise stated. DMF

was distilled from P₂O₅and dried over 3 Å molecular sieves. EtOH,

MeOH was dried over 3 Å molecular sieves. Zinc dust was activated

by stirring in 10% HCl for 2 min and then ﬁltered and washed with

water and acetone. HCl (g) was passed through concentrated H₂SO₄

prior to use. TLC was performed on Silica Gel 60 F254 (Merck) using

UV light detection. Flash column chromatography employed

further puriﬁcation. ¹H NMR (400 MHz, CDCl₃)

d 1.74 (s, 6H),

4.65 (s, 2H).

4.5.1.2. Synthesis of 4a. 7 (1.33 g, 5.02 mmol) and 2a (0.76 g,

2.51 mmol, 1 eq) were dissolved in 8 mL 1,2-dichloroethane. TFA

(0.194 mL, 2.51 mmol) was added to the stirring solution and the

reaction vessel was sealed and heated for 140 seconds at 120 ^ꢀC

using microwave irradiation. The solution was diluted with CH₂Cl₂

and washed with water, NaHCO₃(aq. saturated), and brine followed

by drying with Na₂SO₄, ﬁltration, and concentration. Puriﬁcation by

column chromatography (heptane:ethylacetate 1:6) gave 4a as

a foam (0.75 g, 87%).

normal phase silica gel (Matrex, 60 Å, 35e70

and ¹³C NMR spectra were recorded on a Bruker DRX-400 or

a Bruker DRX-360 in CDCl₃[residual CHCl₃d_H7.26 ppm) or CDCl₃

d_C77.0 ppm) as internal standard], CD₃OD [residual CD₃OD (d_H

3.31 ppm) or CD₃OD (d_C49.0 ppm) as internal standard], DMSO-d₆

[residual DMSO (d_H2.50 ppm) or DMSO-d₆d_C40.0 ppm) as

m

m, Grace Amicon). ¹H

(

internal standard] at 298 K. Microwave reactions were carried out

using a monomode reactor (Smith Creator, Biotage AB) in Teﬂon

septa capped 0.5e2 mL or 2e5 mL Smith TM process vials with

stirring. Reaction times refer to irradiation time at target temper-

ature, as measured by IR sensor. IR spectra were recorded on an

FTIR spectrometer. Melting points are uncorrected.

4.5.2. Using 8

2a (0.54 g, 2.7 mmol) and 8 (1.5 g, 6.8 mmol) was dissolved in

1,2-dichloroethane (4 mL) and TFA (0.21 mL, 2.7 mmol) was added.

The reaction was heated in the microwave oven at 140 ^ꢀC for 2 min.

The reaction mixture was diluted with CH₂Cl₂and washed with

saturated NaHCO₃(aq), the organic phase was dried (Na₂SO₄),

ﬁltered and concentrated. The crude product was puriﬁed by

column chromatography on silica gel (heptane:EtOAc 50:50 /

30:70). The desired product was isolated as a foam (0.6 g, 64% yield).

4.2. Synthesis of 2a and 2b

2a and 2b were synthesized according to previously published

procedures. Data in agreement with published data [15,21].

[

a

]

¼ ꢁ106 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1746, 1648, 1577, 1481, and

D

1425. HRMS (ES^þ) calcd [M þ H^þ] for C₁₃H₁₄BrNO₃S 343.9956 obsd

343.9962.¹H NMR (400 MHz, CDCl₃)

d, 0.60e0.72 (m, 2H), 0.87e1.01

4.3. 4-Bromo-3-oxo-butyric acid

(m, 2H), 1.66e1.76 (m, 1H), 3.49 (dd, J ¼ 2.4, 11.8 Hz, 1H), 3.65 (dd,

J ¼ 8.6, 11.8 Hz, 1H), 3.77 (s, 3H), 4.31e4.52 (m, 2H), 5.56 (dd, J ¼ 2.4,

Tert-butyl acetoacetate (2.0 mL,12 mmol) was dissolved in CHCl₃

(6 mL) and cooled to 0 ^ꢀC. Br₂(0.62 mL,12 mmol) dissolved in CHCl₃

(3 mL) was added dropwise over 45 min, and the reaction was stir-

red for 17 h (0 ^ꢀC / rt). For the last 2 h, air was bubbled through the

solution. The crude reaction mixture was puriﬁed by column chro-

matography on silca gel (heptane:EtOAc:AcOH 80:19:1). 1.5 g of the

desired product was isolated as a colourless solid (69% yield). ¹H

8.6 Hz, 1H), 6.32 (s, 1H). ¹³C NMR (100 MHz, CDCl₃)

d 7.1, 7.4, 10.5,

29.1, 31.8, 53.4, 62.9, 112.7, 116.3, 148.7, 152.6, 161.0, 168.4.

4.6. (3R)-7-Bromomethyl-5-oxo-8-(3-triﬂuoromethyl-phenyl)-2,3-

dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester

(4b)

NMR (400 MHz, CDCl₃)

form) 3.87 (s, 2H), 5.35 (s, 1H), 11.61 (bs, 1H). ¹³C NMR (100 MHz,

CDCl₃) 28.3, 33.8, 45.5, 91.0, 172.1, 173.5, 176.2, 194.4.

d

(Keto form) 3.79 (s, 2H), 4.05 (s, 2H), (Enol

4.6.1. Using 7

Prepared according to the procedure described for compound 4a

starting from 7 (1.33 g, 5.02 mmol) and 2b (0.760 g, 2.51 mmol).

Giving 4b as a foam (1.03 g, 92%).

d

4.4. 6-Bromomethyl-2,2-dimethyl-[1,3]dioxin-4-one (8)

4.6.2. Using 8

4-Bromo-3-oxo-butyric acid (1.00 g, 5.53 mmol) was dissolved

in acetone (0.81 mL, 11 mmol) and Ac₂O (1.57 mL, 16.6 mmol) and

cooled to 0 ^ꢀC. Conc. H₂SO₄(0.10 mL, 1.8 mmol) was added and

the reaction was stirred for 3 h. The reaction was quenched with

Prepared according to the procedure described for compound

4a starting from 8 (0.910 g, 4.13 mmol), 2b (0.500 g, 1.65 mmol)

1,2-dichloroethane (4 mL) and TFA (0.13 mL, 1.7 mmol). The crude

product was puriﬁed by column chromatography on silica gel

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1109

(heptane:EtOAc 40:60) giving 4b as a foam (0.55 g, 74% yield).

4.7.4. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-piperidino-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (9b)

[

a

]

¼ ꢁ124 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1748, 1653, 1579, 1482,

D

1435, and 1327. HRMS (ES^þ) calcd [M þ H^þ] for C₁₇H₁₃BrF₃NO₃S

447.9830 obsd 447.9841. ¹H NMR (400 MHz, CDCl₃)

d

3.47e3.53

From 4b (0.012 g, 0.27 mmol) and piperidine (0.052 mL,

0.53 mmol) was prepared 9b (0.100 g, 83%) as an oil. [

]_D¼ ꢁ52 (c

(m, 1H), 3.66e3.75 (m, 1H), 3.84 (s, 3H), 3.89e4.04 (m, 2H), 5.66

a

(dd, J ¼ 2.4, 8.6 Hz, 1H), 6.47 (s, 1H), 7.51-7.71 (m, 4H). ¹³C NMR

0.5, CHCl₃). IR (n

cm^ꢁ1) 2936, 1753,1656, 1583, 1485, 1437, and 1329.

(100 MHz, CDCl₃)

d

28.7, 32.0, 53.6, 63.8, 113.5, 116.6, 123.9

HRMS (ES^þ) calcd [M þ H^þ] for C₂₂H₂₄F₃N₂O₃S 453.1460 obsd

(q, J ¼ 271 Hz, 1C), 125.7, 127.1 and 127.3 (1C), 129.7, 131.5

(splitted q, J ¼ 33 Hz, 1C), 133.6 and 133.9 (1C), 135.9, 148.7, 149.9,

161.0, 168.2.

453.1461. ¹H NMR (400 MHz, CDCl₃)

d 1.29e1.47 (m, 6H), 2.08e2.31

(m, 4H), 2.86e3.02 (m, 2H), 3.46 (dd, J₁¼2.25 Hz, J₂¼ 11.70 Hz, 1H),

3.67 (dd, J₁¼8.55 Hz, J₂¼11.69 Hz, 1H), 3.83 (s, 3H), 5.65 (dd,

J₁¼ 2.31 Hz, J₂¼ 8.51 Hz, 1H), 6.44 (s, 1H), 7.41e7.71 (m, 4H). ¹³C

4.7. General procedure for the preparation of 9a, be11a, b

NMR (100 MHz, CDCl₃) d 24.1, 25.8 (2C), 31.7, 53.3, 54.3 (2C), 60.6,

63.5, 114.8 (broad), 115.3 (broad), 123.9 (q, J ¼ 272.3 Hz), 124.8

(broad and split J ¼ 3.60 Hz), 127.2 (q, J ¼ 3.70 Hz), 128.9, 130.8

(q, J ¼ 31.17 Hz), 133.4, 137.2, 146.8, 151.9 (broad), 161.3, 168.4.

Amine (piperidine or morpholine or 1,2,3,4-tetrahydroiso-

quinoline, 2 mmol) was added dropwise to a stirred solution of 4a

or 4b (1 mmol) in dry DMF (8 mL) at rt under nitrogen atmosphere.

After being stirred for 30 min or till disappearance of starting

material, the reaction was quenched with aqueous saturated NH₄Cl,

and the solution was extracted with dichloromethane, dried over

Na₂SO₄, and concentrated. Puriﬁcation by silica gel chromatog-

raphy (heptane:EtOAc, 1:9) gave 9a, be11a, b.

4.7.5. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-morpholino-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (10b)

From 4b (0.23 g, 0.51 mmol) and morpholine (0.089 mL,

1.0 mmol) was prepared 10b (0.19 g, 82%), as an oil. [

a

]_D¼ ꢁ64 (c

0.5, CHCl₃). IR (n

cm^ꢁ1) 1753, 1656, 1583, 1485, 1436, and 1330.

4.7.1. (3R)-8-cyclopropyl-7-piperidino-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl ester

(9a)

HRMS (ES^þ) calcd [M þ H^þ] for C₂₁H₂₂F₃N₂O₄S 455.1252 obsd

455.1251. ¹H NMR (400 MHz, CDCl₃)

d 2.11e2.34 (m, 4H), 2.89e3.03

(m, 2H), 3.43 (dd, J₁¼ 2.26 Hz, J₂¼ 11.79 Hz,1H), 3.46e3.54 (m, 4H),

3.64 (dd, J₁¼8.51 Hz, J₂¼ 11.78 Hz, 1H), 3.77 (s, 3H), 5.60 (dd,

J₁¼ 2.17 Hz, J₂¼ 8.51 Hz, 1H), 6.36 (s, 1H), 7.38e7.67 (m, 4H). ¹³C

From 4a (0.065 g, 0.19 mmol) and piperidine (0.037 mL,

0.38 mmol) was prepared 9a (0.053 g, 81%) as an oil. [

a

]_D¼ ꢁ107 (c

0.5, CHCl₃). IR (

n

cm^ꢁ1) 1754, 1650, 1583, 1494, and 1206. HRMS

NMR (100 MHz, CDCl₃) d 31.7, 53.2 (2C), 53.4, 60.1, 63.5, 66.8 (2C),

(ES^þ) calcd [M þ H^þ] for C₁₈H₂₅N₂O₃S 349.1586 obsd 389.1611. ¹H

114.5 (broad), 115.6 (broad), 123.9 (q, J ¼ 272.3 Hz), 124.9 (broad),

127.2 (broad), 129.0, 130.9 (q, J ¼ 34.7 Hz), 133.4 (broad), 137.0,

147.3, 150.6 (broad), 161.1, 168.3.

NMR (400 MHz, CDCl₃)

d 0.54e0.63 (m, 2H), 0.80e0.92 (m, 2H),

1.37e1.48 (m, 2H), 1.51e1.68 (m, 5H), 2.34e2.47 (m, 4H), 3.28e3.52

(m, 3H), 3.63 (dd, J₁¼8.54 Hz, J₂¼ 11.67 Hz, 1H), 3.78 (s, 3H), 5.57

(dd, J₁¼2.30 Hz, J₂¼ 8.50 Hz, 1H), 6.46 (s, 1H). ¹³C NMR (100 MHz,

4.7.6. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-tetrahydroisoquinolino-

1-ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-

carboxylic acid methyl ester (11b)

CDCl₃) d 7.2, 7.5, 10.8, 24.3, 26.1 (2C), 31.6, 53.1, 54.9 (2C), 60.2, 62.7,

113.5, 114.3, 146.4, 155.0, 161.5, 168.8.

From 4b (0.078 g, 0.17 mmol) and 1,2,3,4-tetrahydroisoquino-

line (0.043 mL, 0.35 mmol) was prepared 11b (0.075 g, 86%) as

4.7.2. (3R)-8-cyclopropyl-7-morpholino-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl ester

(10a)

a foam, m.p. 70e72 ^ꢀC. [

a

]

¼ ꢁ77 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1751,

D

1655, 1582, 1484, 1436, and 1327. HRMS (ES^þ) calcd [M þ H^þ] for

From 4a (0.052 g, 0.15 mmol) and morpholine (0.026 mL,

0.30 mmol) was prepared 10a (0.044 g, 84%) as a foam, m.p.

C₂₆H₂₄F₃N₂O₃S 501.1460 obsd 501.1456. ¹H NMR (400 MHz, CDCl₃)

d

2.51e2.68 (m, 2H), 2.74e2.84 (m, 2H), 3.13e3.28 (m, 2H),

153e154 ^ꢀC. [

a]

¼ ꢁ27 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1752, 1652, 1581,

3.44e3.58 (m, 3H), 3.68 (dd, J₁¼8.59 Hz, J₂¼11.62 Hz, 1H), 3.85 (s,

3H), 5.67 (dd, J₁¼2.16 Hz, J₂¼ 8.51 Hz, 1H), 6.55 (s, 1H), 6.90e6.97

(m, 1H), 7.03e7.15 (m, 3H), 7.46e7.72 (m, 4H). ¹³C NMR (100 MHz,

D

1490, and 1208. HRMS (ES^þ) calcd [M þ H^þ] for C₁₇H₂₃N₂O₄S

351.1379 obsd 351.1376. ¹H NMR (400 MHz, CDCl₃)

d 0.55e0.64 (m,

2H), 0.81e0.94 (m, 2H), 1.59e1.69 (m, 1H), 2.43e2.54 (m, 4H),

3.39e3.55 (m, 3H), 3.58e3.74 (m, 5H), 3.78 (s, 3H), 5.57 (dd,

J₁¼2.34 Hz, J₂¼ 8.54 Hz, 1H), 6.44 (s, 1H). ¹³C NMR (100 MHz,

CDCl₃) d 29.0, 31.7, 50.8, 53.3, 55.5, 59.6, 63.5, 114.5 (broad), 115.2

(broad), 123.8 (q, J ¼ 272.5 Hz), 124.9 (broad), 125.5, 126.0, 126.3,

127.0 (broad), 128.5, 129.0, 130.9 (q, J ¼ 33.71 Hz), 133.6 (broad),

134.0, 134.3, 136.9, 147.1, 151.2, 161.2, 168.3.

CDCl₃) d 7.3, 7.4, 10.7, 31.6, 53.2, 53.8 (2C), 59.7, 62.7, 67.0 (2C), 113.4,

114.4, 147.0, 153.8, 161.4, 168.6.

4.8. General procedure for the preparation of 12a, b

4.7.3. (3R)-8-cyclopropyl-7-tetrahydroisoquinolino-1-ylmethyl-5-

oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (11a)

To a stirred solution of 4a or 4b (1 mmol) in dry DMF (5 mL) was

added sodium azide (1.6 mmol) and the mixture was stirred under

nitrogen atmosphere at rt for 15 min or till disappearance of

starting material. The reaction mixture was diluted with water and

extracted with dichloromethane, dried over Na₂SO₄, and concen-

trated. Puriﬁcation by silica gel chromatography (heptane:EtOAc,

1:9) gave 12a or 12b.

From 4a (0.100 g, 0.290 mmol) and 1,2,3,4-tetrahydroisoquino-

line (0.073 mL, 0.58 mmol) was prepared 11a (0.096 g, 84%), as an

oil. [

a

]

¼ ꢁ83 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1749, 1649, 1577, 1488,

D

1434, and 1209. HRMS (ES^þ) calcd [M þ H^þ] for C₂₂H₂₅N₂O₃S

397.1586 obsd 397.1585. ¹H NMR (400 MHz, CDCl₃)

d 0.58e0.68 (m,

2H), 0.81e0.96 (m, 2H), 1.66e1.75 (m, 1H), 2.72e2.84 (m, 2H),

2.88e2.94 (m, 2H), 3.49 (dd, J₁¼ 2.33 Hz, J₂¼11.71 Hz, 1H),

3.56e3.76 (m, 5H), 3.80 (s, 3H), 5.59 (dd, J₁¼2.31 Hz, J₂¼ 8.52 Hz,

1H), 6.49 (s, 1H), 6.97e7.02 (m, 1H), 7.07e7.16 (m, 3H). ¹³C NMR

4.8.1. (3R)-8-cyclopropyl-7-azido-1-ylmethyl-5-oxo-2,3-dihydro-

5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl ester (12a)

From 4a (1.20 g, 3.49 mmol) and sodium azide (0.379 g,

(100 MHz, CDCl₃)

62.7, 113.6, 114.5, 125.5, 126.1, 126.4, 128.6, 134.3, 134.7, 146.9, 154.3,

161.4, 168.7.

d

7.2, 7.4, 10.8, 29.3, 31.6, 51.1, 53.2, 56.2, 59.5,

5.58 mmol) was prepared 12a (0.95 g, 89%) an oil. [

0.5, CHCl₃). IR (

cm^ꢁ1) 2103, 1750, 1653, 1583, 1490, and 1433. ¹H

NMR (400 MHz, CDCl₃) 0.47e0.56 (m, 2H), 0.74e0.91 (m, 2H),

a

]

¼ ꢁ179 (c

D

n

d

1110

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1.43e1.53 (m, 1H), 3.40 (dd, J₁¼2.19 Hz, J₂¼ 11.78 Hz, 1H), 3.59 (dd,

J₁¼8.70 Hz, J₂¼ 11.74 Hz, 1H), 3.68 (s, 3H), 4.27e4.38 (m, 2H), 5.47

(dd, J₁¼2.13 Hz, J₂¼ 8.63 Hz, 1H), 6.20 (s, 1H). ¹³C NMR (100 MHz,

(2%), dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by

silica gel chromatography (heptane:EtOAc, 1:9 to 0:1) gave 14a,

be17a, b.

CDCl₃) d 6.87, 6.95, 9.9, 31.3, 51.4, 52.9, 62.4,111.3,113.3,148.0,150.6,

160.5, 168.1.

4.10.1. (3R)-8-cyclopropyl-7-benzenesulfonamido-1-ylmethyl-5-

oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (14a)

4.8.2. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-azido-1-ylmethyl-5-

oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (12b)

From 13a (0.050 g, 0.18 mmol), 1-benzenesulphonyl chloride

(0.034 mL, 0.27 mmol) and triethylamine (0.069 mL, 0.53 mmol)

was prepared 14a (0.059 g, 79%) as a foam, m.p. 108e110 ^ꢀC.

From 4b (0.50 g, 1.1 mmol) and sodium azide (0.120 g,

1.79 mmol) was prepared 12b (0.41 g, 90%) as a foam, m.p.

[

a

]

¼ ꢁ170 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1751, 1655, 1568, 1498, and

D

142e143 ^ꢀC. [

a]

¼ 0 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 2116, 1755, 1655,

1321. HRMS (ES^þ) calcd [M þ H^þ] for C₁₉H₂₁N₂O₅S₂421.0892 obsd

D

1501, 1480, 1338, and 1312. ¹H NMR (400 MHz, CDCl₃)

d

3.49 (dd,

421.0895. ¹H NMR (400 MHz, CDCl₃)

d 0.48e0.61 (m, 2H),

J₁¼1.96 Hz, J₂¼ 11.79 Hz, 1H), 3.70 (dd, J₁¼8.89 Hz, J₂¼ 11.48 Hz,

1H), 3.82 (s, 3H), 3.89e4.00 (m, 2H), 5.66 (dd, J₁¼2.24 Hz,

J₂¼ 8.58 Hz, 1H), 6.43 (s, 1H), 7.43e7.50 (m, 1H), 7.51e7.62 (m, 2H),

0.74e0.92 (m, 2H), 1.43e1.52 (m, 1H), 3.44e3.52 (m, 1H), 3.62e3.72

(m, 1H), 3.75 (s, 3H), 4.04e4.25 (m, 2H), 5.71e5.78 (m, 1H), 6.31 (s,

1H), 6.64e6.70 (m, 1H), 7.45e7.58 (m, 3H), 7.84e7.92 (m, 2H). ¹³C

7.64e7.69 (m, 1H). ¹³C NMR (100 MHz, CDCl₃)

d

31.8, 51.8, 53.4, 63.5,

NMR (100 MHz, CDCl₃) d 7.2, 7.4, 10.2, 31.7, 43.8, 53.3, 62.9, 112.9,

112.6, 114.5, 123.6 (q, J ¼ 272.6 Hz), 125.5 (q, J ¼ 3.7 Hz), 126.7

(broad), 129.7, 131.5 (q, J ¼ 35.6 Hz), 133.3 (broad and split

J ¼ 33.4 Hz), 135.8, 147.9, 148.2, 160.7, 168.0.

113.0, 126.9 (2C), 129.0 (2C), 132.5, 140.1, 148.1, 153.3, 161.4, 168.4.

4.10.2. (3R)-8-cyclopropyl-7-naphthalenesulfonamido-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (15a)

4.9. General procedure for the preparation of 13a, b

From 13a (0.065 g, 0.23 mmol), 1-naphthalenesulfonyl chloride

(0.079 mL, 0.35 mmol) and triethylamine (0.090 mL, 0.70 mmol)

was prepared 15a (0.085 g, 78%) as a foam, m.p. 102e104 ^ꢀC.

To a stirred solution of 12a or 12b (1 mmol) in a mixture of

ethanol and water (3:1, 8 mL) was added activated zinc (6 mmol)

and ammonium chloride (6 mmol) and the mixture was stirred at rt

for 20 min or till complete disappearance of starting material. The

reaction mixture was ﬁltered (the residue was washed with

ethanol), and the solvent was removed under reduced pressure.

The obtained solid mass was dissolved in CH₂Cl₂, dried over

Na₂SO₄, ﬁltered, and concentrated to give 13a or 13b as a light

yellow solid. Used for the next step without further puriﬁcation.

[

a

]

¼ ꢁ152 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1749, 1648, 1570, 1493, and

D

1322. HRMS (ES^þ) calcd [M þ H^þ] for C₂₃H₂₃N₂O₅S₂471.1048 obsd

471.1052. ¹H NMR (400 MHz, CDCl₃)

d 0.39e0.48 (m, 2H), 0.61e0.72

(m, 2H), 1.28e1.37 (m, 1H), 3.44 (dd, J₁¼1.99 Hz, J₂¼ 11.75 Hz, 1H),

3.61 (dd, J₁¼8.63 Hz, J₂¼ 11.71 Hz, 1H), 3.74 (s, 3H), 4.01e4.22 (m,

2H), 5.65 (dd, J₁¼1.95 Hz, J₂¼ 8.54 Hz, 1H), 6.23 (s, 1H), 6.64e6.69

(m, 1H), 7.44e7.66 (m, 3H), 7.89e7.95 (m, 1H), 8.02e8.07 (m, 1H),

8.24e8.29 (m, 1H), 8.72e8.77 (m, 1H). ¹³C NMR (100 MHz, CDCl₃)

4.9.1. (3R)-8-cyclopropyl-7-amino-1-ylmethyl-5-oxo-2,3-dihydro-

5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl ester (13a)

From 12a (1.00 g, 3.26 mmol), zinc (1.27 g, 19.5 mmol) and

ammonium chloride (1.04 g, 19.5 mmol) was prepared 13a (0.76 g,

d 7.0, 7.3, 10.1, 31.7, 43.9, 53.2, 62.8, 112.5, 113.6, 124.0, 124.6, 126.9,

128.2, 128.3, 128.8, 129.4, 134.2 (2C), 135.0, 147.9, 152.8, 161.1, 168.4.

4.10.3. (3R)-8-cyclopropyl-7-benzamido-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl ester

(16a)

83%) as an oil, m.p. 157e159 ^ꢀC. [

a]

¼ ꢁ174 (c 0.5, MeOH). IR

D

(n

cm^ꢁ1) 1742, 1642, 1550, 1491, and 1438. ¹H NMR (400 MHz,

MeOD) 0.58e0.74 (m, 2H), 0.88e1.08 (m, 2H), 1.63e1.74 (m, 1H),

d

From 13a (0.073 g, 0.26 mmol), benzoyl chloride (0.055 mL,

0.39 mmol) and triethylamine (0.102 mL, 0.783 mmol) was

3.62 (dd, J₁¼2.09 Hz, J₂¼ 12.05 Hz, 1H), 3.78 (s, 3H), 3.86 (dd,

J₁¼8.99 Hz, J₂¼ 12.05 Hz, 1H), 4.20e4.38 (m, 2H), 5.66 (dd,

J₁¼ 2.06 Hz, J₂¼ 8.98 Hz, 1H), 6.28 (s, 1H).

prepared 16a (0.083 g, 83%) as a foam, m.p. 88e90 ^ꢀC. [

a]

¼ ꢁ158

D

(c 0.5, CHCl₃). IR (n

cm^ꢁ1) 3290, 1749, 1641, 1582, and 1488. HRMS

(ES^þ) calcd [M þ H^þ] for C₂₀H₂₁N₂O₄S 385.1222 obsd 385.1224. ¹H

4.9.2. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-amino-1-ylmethyl-5-

oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (13b)

NMR (400 MHz, CDCl₃) d 0.58e0.70 (m, 2H), 0.83e1.00 (m, 2H),

1.51e1.62 (m, 1H), 3.42e3.52 (m, 1H), 3.59e3.68 (m, 1H), 3.75 (s,

3H), 4.45e4.84 (m, 2H), 5.47e5.58 (m, 1H), 6.20 (s, 1H), 7.30e7.36

(bs, 1H), 7.35e7.54 (m, 3H), 7.81e7.90 (m, 2H). ¹³C NMR (100 MHz,

From 12b (0.500 g, 0.122 mmol), zinc (0.047 g, 0.73 mmol) and

ammonium chloride (0.039 g, 0.73 mmol) was prepared 13b

CDCl₃)

d 7.3, 7.5, 10.3, 31.7, 40.8, 53.2, 62.7, 111.9, 112.7, 127.1 (2C),

(0.034 g, 81%) as an oil, m.p. 185e187 ^ꢀC. [

a]

¼ ꢁ23 (c 0.5, CHCl₃).

128.5 (2C), 131.6, 133.8, 147.6, 154.7, 161.3, 167.5, 168.5.

D

IR (

n

cm^ꢁ1) 1746, 1646, 1560, 1484, 1437, and 1328. ¹H NMR

3.58e3.67 (m, 1H), 3.72e3.86 (m, 5H),

(400 MHz, MeOD)

d

4.10.4. (3R)-8-cyclopropyl-7-naphthalamido-1-ylmethyl-5-oxo-

2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl

ester (17a)

3.87e3.99 (m, 1H), 5.73e5.80 (m, 1H), 6.49 (s, 1H), 7.57e7.66 (m,

1H), 7.67e7.81 (m, 3H).

From 13a (0.052 g, 0.19 mmol), 1-naphthoyl chloride (0.042 mL,

0.28 mmol) and triethylamine (0.072 mL, 0.56 mmol) was prepared

4.10. General procedure for the preparation of 14a, be17a, b

17a (0.063 g, 79%) as a foam, m.p. 82e84 ^ꢀC. [

a

]

¼ ꢁ144 (c 0.5,

D

To a stirred solution of 13a or 13b (1 mmol) and triethylamine

(3 mmol) in CH₂Cl₂(8 mL) was added acylating agent (benzoyl

chloride or 1-naphthoyl chloride, 1.5 mmol) or sulfonylating agent

(benzenesulfonyl chloride or 1-naphthalenesulfonyl chloride,

1.5 mmol) dropwise and the mixture was stirred under nitrogen

atmosphere at rt over night. The reaction mixture was diluted with

water and extracted with CH₂Cl₂. The combined organic layers

were washed with saturated aqueous NaHCO₃and aqueous KHSO₄

CHCl₃). IR (n

cm^ꢁ1) 3270, 1749, 1641, and 1492. HRMS (ES^þ) calcd

[M þ H^þ] for C₂₄H₂₃N₂O₄S 435.1379 obsd 435.1383. ¹H NMR

(400 MHz, CDCl₃) d 0.62e0.71 (m, 2H), 0.84e1.03 (m, 2H),1.55e1.66

(m, 1H), 3.44 (dd, J₁¼ 2.08 Hz, J₂¼ 11.81 Hz, 1H), 3.58 (dd,

J₁¼8.60 Hz, J₂¼ 11.72 Hz, 1H), 3.74 (s, 3H), 4.58e4.83 (m, 2H),

5.39e5.45 (m, 1H), 6.28 (s, 1H), 6.90 (s, 1H), 7.36e7.43 (m, 1H),

7.46e7.55 (m, 2H), 7.63e7.69 (m, 1H), 7.81e7.91 (m, 2H), 8.28e8.33

(m, 1H). ¹³C NMR (100 MHz, CDCl₃)

d 7.4, 7.5, 10.4, 31.6, 40.7, 53.2,

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1111

62.7, 111.8, 112.5, 124.6, 125.2, 125.4, 126.4, 127.2, 128.2, 130.1, 130.7,

539.1255. ¹H NMR (400 MHz, CDCl₃)

d

3.40e3.49 (m, 1H), 3.61 (dd,

133.6, 133.7, 147.7, 154.3, 161.2, 168.4, 169.6.

J₁¼8.60 Hz, J₂¼11.70 Hz, 1H), 3.80 (s, 3H), 4.08e4.47 (m, 2H), 5.47

(dd, J₁¼8.27 Hz, J₂¼ 22.67 Hz, 1H), 6.38 (s, 1H), 6.64e6.75 (m, 1H),

7.37e7.45 (m, 1H), 7.47e7.70 (m, 7H), 7.81e7.86 (m, 1H), 7.87e7.92

4.10.5. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-benzenesulfonamido-1-

ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-

carboxylic acid methyl ester (14b)

(m, 1H), 8.17e8.24 (m, 1H). ¹³C NMR (100 MHz, CDCl₃)

d 31.7, 41.3,

53.4, 63.4, 112.5 (broad and split, J ¼ 7.1 Hz), 113.1, 123.7 (q,

J ¼ 272.8 Hz), 124.6, 125.1, 125.3, 125.5 (broad and split, J ¼ 73.6 Hz),

126.5, 126.8 (broad), 127.2, 128.2, 129.8, 130.0, 130.9, 131.5 (q,

J ¼ 32.7 Hz), 133.6 (broad, 3C), 136.1 (broad and split, J ¼ 11.2 Hz),

147.8, 151.4 (broad), 161.0, 168.1, 169.4.

From 13b (0.027 g, 0.073 mmol), 1-benzenesulfonyl chloride

(0.014 mL, 0.11 mmol) and triethylamine (0.029 mL, 0.21 mmol)

was prepared 14b (0.029 g, 79%) as a foam, m.p. 184e186 ^ꢀC.

[

a

]_D¼ ꢁ65 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 3109, 1755, 1657, 1572, 1503,

1486, 1441, and 1321. HRMS (ES^þ) calcd [M þ H^þ] for

C₂₃H₂₀F₃N₂O₅S₂525.0766 obsd 525.0769. ¹H NMR (400 MHz,

4.10.9. (3R)-8-cyclopropyl-7-phenoxymethyl-5-oxo-2,3-dihydro-

5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (18a)

The procedure described for 18a is representative.

CDCl₃)

d 3.45e3.52 (m, 1H), 3.65e3.78 (m, 3H), 3.80e3.84 (m, 3H),

5.75e5.83 (m, 1H), 6.09e6.24 (m, 1H), 6.43e6.48 (m, 1H), 7.37e7.57

(m, 6H), 7.62e7.67 (m, 1H), 7.72e7.78 (m, 2H). ¹³C NMR (100 MHz,

A solution of 4a (180 mg, 0.52 mmol) in dried DMF (10 mL) was

stirred with 3 Å MS at 0 ^ꢀC. After 5 min was added phenol (73 mg,

0.78 mmol) and cesium carbonate (254 mg, 0.78 mmol) and the

reaction was stirred for 3 h at 0 ^ꢀC. The reaction mixture was ﬁl-

trated and was diluted with EtOAc and washed with water three

times, and with brine. The organic phase was dried (Na₂SO₄),

ﬁltered, and concentrated. The crude product was puriﬁed with

column chromatography on silica gel (EtOAc:heptane, 5:1) to give

CDCl₃)

d 31.8, 44.3, 53.4, 63.7, 113.4 (broad), 113.6 (broad), 123.7 (q,

J ¼ 272.7 Hz), 125.5 (broad), 126.8 (broad, 3C), 129.1 (2C), 129.7,

131.4 (q, J ¼ 31.7 Hz), 132.6, 133.4 (broad and split, J ¼ 33.4 Hz),

135.6 (broad), 139.8, 148.1, 150.3, 161.3, 168.1.

4.10.6. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-naphthale

nesulfonamido-1-ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo

[3,2-a]pyridin-3-carboxylic acid methyl ester (15b)

18a (178 mg, 96%) as a white solid. [

a

]_D¼ ꢁ51 (c 0.5, CHCl₃). IR

From 13b (0.043 g, 0.11 mmol), 1-naphthalenesulfonyl chloride

(0.037 mL, 0.17 mmol) and triethylamine (0.043 mL, 0.33 mmol)

was prepared 15b (0.052 g, 81%) as a foam, m.p. 112e114 ^ꢀC.

(n

cm^ꢁ1) (neat) 1750, 1655, 1586, 1484, 1213 and 1117. HRMS (ES^þ)

calcd [M þ H^þ] for C19H19NO4S 358.1113, obsd 358.1117. ¹H NMR

(400 MHz, CDCl₃)

d 0.65e0.70 (m, 2H), 0.88e0.98 (m, 2H),

[

a

]_D¼ ꢁ53 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1751, 1653, 1576, 1486, 1437,

1.61e1.69 (m, 1H), 3.49e3.56 (m, 1H), 3.64e3.73 (m, 1H), 3.81 (s,

3H), 5.1 (s, 2H), 5.58e5.64 (m, 1H), 6.55 (s, 1H), 6.92e7.2 (m, 3H),

and 1323. HRMS (ES^þ) calcd [M þ H^þ] for C₂₇H₂₂F₃N₂O₅S₂575.0922

obsd 575.0918. ¹H NMR (400 MHz, CDCl₃)

d

3.44 (dd, J₁¼1.84 Hz,

7.27e7.35 (m, 2H). ¹³C NMR (100 MHz, CDCl₃)

d 7.1, 7.2, 10.2, 31.8,

J₂¼11.77 Hz, 1H), 3.62e3.73 (m, 3H), 3.80 (s, 3H), 5.68e5.78 (m,

1H), 5.82e5.99 (m, 1H), 6.41 (s, 1H), 7.27e7.32 (m, 1H), 7.33e7.50

(m, 3H), 7.53e7.68 (m, 3H), 7.91e7.96 (m, 1H), 8.01e8.06 (m, 1H),

8.10e8.15 (m, 1H), 8.59e8.65 (m, 1H). ¹³C NMR (100 MHz, CDCl₃)

53.3, 62.8, 66.4, 77.4, 111.4, 114.7, 121.4, 129.6, 147.5, 152.5, 158.2,

161.3, 168.6.

4.10.10. (3R)-8-cyclopropyl-7-(naphthalen-1-yloxymethyl)-5-oxo-

2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl

ester (19a)

d

31.8, 44.3, 53.4, 63.6, 113.0, 114.0, 123.6 (q, J ¼ 272.6 Hz), 124.1,

124.4, 125.4 (broad), 126.6 (broad and split, J ¼ 30.8 Hz), 127.0,

128.0, 128.5, 129.1, 129.5, 129.6, 131.4 (q, J ¼ 32.5 Hz), 133.3 (broad

and split, J ¼ 39.5 Hz), 134.3, 134.4 (2C), 135.6, 148.0, 149.8, 161.0,

168.1.

Prepared according to the procedure described for compound

18a starting from 4a (167 mg, 0.48 mmol). Puriﬁcation by silica gel

chromatography (EtOAc:heptane, 5:1) gave 19a as a foam (183 mg,

94%). [

a

]_D¼ ꢁ50 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) (neat) 1749, 1652, 1549,

4.10.7. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-benzamido-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

methyl ester (16b)

1493, 1268 and 1177. HRMS (ES^þ) calcd [M þ H^þ] for C23H21NO4S

408.1270, obsd 408.1281. ¹H NMR (400 MHz, CDCl₃)

d 0.65e0.70 (m,

2H), 0.88e0.96 (m, 2H), 1.61e1.69 (m, 1H), 3.47e3.54 (m, 1H),

3.61e3.67 (m, 1H), 3.80 (s, 3H), 5.2 (s, 2H), 5.58e5.64 (m, 1H), 6.71

(s, 1H), 6.80e6.84 (m, 1H), 7.25e7.37 (m, 1H), 7.44e7.52 (m, 3H),

7.78e7.83 (m, 1H), 8.33e8.38 (m, 1H). ¹³C NMR (100 MHz, CDCl₃)

d 7.2, 7.2, 10.3, 31.8, 53.4, 62.9, 66.5, 77.4, 105.0, 111.5, 112.8,

121.0, 122.1, 125.6, 125.7, 126.7, 127.5, 134.6, 147.6, 152.5, 153.9, 161.4,

168.7.

From 13b (0.043 g, 0.11 mmol), benzoyl chloride (0.019 mL,

0.17 mmol) and triethylamine (0.042 mL, 0.33 mmol) was prepared

16b (0.043 g, 80%) as a foam, m.p. 104e106 ^ꢀC. [

a]

¼ ꢁ9 (c 0.5,

D

CHCl₃). IR (

n

cm^ꢁ1) 3308, 1751, 1647, 1484, and 1324. HRMS (ES^þ)

calcd [M þ H^þ] for C₂₄H₂₀F₃N₂O₄S 489.1096 obsd 489.1099. ¹H NMR

(400 MHz, CDCl₃)

d 3.42e3.50 (m, 1H), 3.61e3.71 (m, 1H), 3.77 (s,

3H), 3.94e4.44 (m, 2H), 5.59 (dd, J₁¼ 2.15 Hz, J₂¼ 8.56 Hz,1H), 6.34

(s, 1H), 7.31e7.66 (m, 7H), 7.73e7.81 (m, 2H). ¹³C NMR (100 MHz,

4.10.11. 5-Oxo-7-phenoxymethyl-8-(3-triﬂuoromethyl-phenyl)-2,3-

dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester

(18b)

CDCl₃)

d 31.6 (broad), 41.2, 53.3, 63.5, 112.3, 113.5, 123.7 (q,

J ¼ 272.7 Hz), 125.4 (broad and split, J ¼ 3.6 Hz), 126.7 (broad), 127.1

(2C), 128.4 (2C), 129.7 (broad), 131.3 (broad and split, J ¼ 33.1 Hz),

131.6, 133.4 (broad and split, J ¼ 10.2 Hz), 133.6 (broad), 136.0

(broad and split, J ¼ 6.6 Hz), 147.6, 152.0, 161.2, 167.4 (broad and

split, J ¼ 6.9 Hz), 168.1.

Prepared according to the procedure described for compound

18a starting from 4a (111 mg, 0.25 mmol). Puriﬁcation by silica gel

chromatography (EtOAc:heptane, 5:1) gave 18b as a foam (95 mg,

82%). [

a

]

¼ ꢁ25 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) (neat) 1749, 1655, 1586,

D

1484, 1213 and 1117. HRMS (ES^þ) calcd [M þ H^þ] for C23H18F3NO4S

4.10.8. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-naphthalamido-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid methyl

ester (17b)

462.0987 obsd 462.0992. ¹H NMR (400 MHz, CDCl₃)

d 3.49e3.57

(m, 1H), 3.66e3.78 (m, 1H), 3.86 (s, 3H), 4.63 (s, 2H), 5.67e5.75

(m, 1H), 6.67 (s, 1H), 6.74e6.81 (m, 2H), 6.92e7.00 (m, 1H),

7.20e7.31 (m, 2H), 7.49e7.71 (m, 4H). ¹³C NMR (100 MHz, CDCl₃)

From 13b (0.026 g, 0.067 mmol), 1-naphthoyl chloride

(0.015 mL, 0.10 mmol) and triethylamine (0.026 mL, 0.20 mmol)

was prepared 17b (0.028 g, 78%) as a foam, m.p. 124e127 ^ꢀC.

d

32.0, 53.6, 63.7, 66.8, 77.3, 112.5, 114.1, 114.8, 121.7, 123.9

(q, J ¼ 277.50 Hz), 125.6, 126.9 (d, J ¼ 19.50 Hz), 129.6, 129.7, 131.6

(q, J ¼ 41.94 Hz), 133.3 (d, J ¼ 40.6 Hz), 136.1, 147.8, 149.7, 157.9,

161.3, 168.4.

[

a

]_D¼ ꢁ3 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1751, 1648, 1484, and 1324.

HRMS (ES^þ) calcd [M þ H^þ] for C₂₈H₂₂F₃N₂O₄S 539.1252 obsd

1112

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

4.10.12. 5-Oxo-7-(naphtalen-1-yloxymethyl)–8-(3-triﬂuoromethyl-

phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

methyl ester (19b)

250 ꢂ 21.2 mm 5

mm, H₂O:MeCN 70:30 / 0:100 over 1 h, the

eluent contained 0.1% TFA) gave 23a as a colorless foam (115 mg,

56% yield). [

a

]_D¼ ꢁ130 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1750, 1652, 1580,

Prepared according to the procedure described for compound

18a starting from 4a (100 mg, 0.22 mmol). Puriﬁcation by silica gel

chromatography (EtOAc:heptane, 5:1) gave 19b as a foam (95 mg,

1486. HRMS (ES^þ) calcd [M þ H^þ] for C₂₆H₂₄FNO₄S 466.1488 obsd

466.1496. ¹H NMR (400 MHz, CDCl₃)

d 0.57e0.66 (m, 2H),

0.78e0.92 (m, 2H), 1.32e1.42 (m, 1H), 3.47 (dd, J ¼ 2.3, 11.8 Hz, 1H),

3.63 (dd, J ¼ 8.6, 11.8 Hz, 1H), 3.78 (s, 3H), 3.86e4.02 (m, 2H), 4.98

(s, 2H), 5.58 (dd, J ¼ 2.3, 8.6 Hz, 1H), 6.04 (s, 1H), 6.74e6.85 (m, 3H),

7.02e7.09 (m, 2H), 7.18e7.23 (m, 1H), 7.35e7.41 (m, 2H). ¹³C NMR

84%). [

a

]_D¼ ¼ ꢁ40 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) (neat) 1749,1657,1584,

1481, 1209 and 1116. HRMS (ES^þ) calcd [M þ H^þ] for

C27H20F3NO4S 512.1143 obsd 512.1151. ¹H NMR (400 MHz, CDCl₃)

d

3.50e3.56 (m, 1H), 3.67e3.77 (m, 1H), 3.87 (s, 3H), 4.80 (s, 2H),

(100 MHz, CDCl₃) d 7.7, 8.0, 11.3, 31.7, 39.3, 53.3, 62.8, 69.3, 112.9,

5.70e5.75 (m, 1H), 6.54e6.59 (m, 1H), 6.83 (s, 1H), 7.24e7.31 (m,

1H), 7.40e7.45 (m, 1H), 7.46e7.53 (m, 2H), 7.53e7.58 (m, 2H),

7.62e7.69 (m, 2H), 7.76e7.81 (m, 1H), 8.20e8.26 (m, 1H). ¹³C NMR

113.8,115.4,115.6,115.7,115.8,122.0, 129.4, 129.5, 129.7,132.8, 139.8,

147.4, 156.7, 158.9, 161.4, 162.5 (d, J ¼ 245 Hz, 1C), 168.7.

(100 MHz, CDCl₃)

d

32.0, 53.6, 63.8, 66.8, 105.0, 112.5, 113.9, 114.8,

4.10.16. (3R)-7-(6-Methoxy-naphthalen-2-ylmethyl)-5-oxo-8-(3-

triﬂuoromethyl-phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-

carboxylic acid methyl ester (21b)

Prepared according to the procedure described for compound

21a starting from 4a (22 mg, 0.05 mmol). Puriﬁcation by silica gel

chromatography (heptane:EtOAc 50:50 / 20:80) gave 21b as

121.3, 122.0, 123.9 (q, J ¼ 32.70 Hz), 125.6, 125.7, 126.8, 126.8 (d,

J ¼ 25.54 Hz), 127.6, 129.7, 129.8, 131.7 (q, J ¼ 275.83 Hz), 133.3 (d,

J ¼ 38.29 Hz), 134.6, 147.9, 149.7, 153.5, 161.3, 168.4.

4.10.13. (3R)-8-cyclopropyl-7-(6-methoxy-naphthalen-2-ylmethyl)-

5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

methyl ester (21a)

The procedure described for 21a is representative for all Suzu-

kieMiyaura cross couplings.

a colorless foam (22 mg, 84% yield). [

a

]

¼ ꢁ45 (c 0.5, CHCl₃). IR

D

(n

cm^ꢁ1) 1750, 1652, 1606, 1579, 1481, 1435. HRMS (ES^þ) calcd

[M þ H^þ] for C₂₈H₂₂F₃NO₄S 526.1300 obsd 526.1305. ¹H NMR

(400 MHz, CDCl₃)

d 3.44e3.50 (m, 1H), 3.63e3.71 (m, 3H), 3.84 (s,

4a (132 mg, 0.38 mmol), 6-methoxy-2-naphthaleneboronic acid

(115 mg, 0.57 mmol), Pd(PPh₃)₂Cl₂(13 mg, 0.019 mmol) and KF

(44 mg, 0.76 mmol) was dissolved in dry MeOH (3 mL, dried over

3Å MS) and the reaction was heated by microwave irradiation at

110 ^ꢀC for 10 min. The reaction mixture was diluted with saturated

NaHCO₃(aq) and extracted with EtOAc, the organic phase was dried

(Na₂SO₄), ﬁltered and concentrated. The crude product was puriﬁed

by column chromatography on silica gel (heptane:EtOAc

50:50 / 20:80) giving 21a as a colorless foam (115 mg, 72% yield).

3H), 3.90 (s, 3H), 5.66 (dd, J ¼ 2.4, 8.6 Hz,1H), 6.27 (s,1H), 6.93e6.99

(m,1H), 7.05e7.12 (m, 2H), 7.15 (s,1H), 7.20e7.49 (m, 3H), 7.50e7.63

(m, 3H). ¹³C NMR (100 MHz, CDCl₃)

d 31.9, 39.8, 53.4, 55.3, 63.6,

105.6, 114.9, 115.9, 119.0, 123.8 (q, J ¼ 272 Hz, 1C), 125.1, 127.1, 127.3,

127.5, 128.8, 129.0, 129.2 and 129.3 (1C), 131.2 (splitted q, J ¼ 35 Hz,

1C), 132.3, 133.3, 133.6, 133.9, 137.0, 147.4, 154.2, 157.6, 161.3, 168.4.

4.10.17. (3R)-7-Bromomethyl-5-oxo-8-(3-triﬂuoromethyl-phenyl)-

2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl

ester (22b)

Prepared according to the procedure described for compound

21a starting from 4a (130 mg, 0.29 mmol). Puriﬁcation by silica gel

chromatography (heptane:EtOAc 50:50 / 20:80) gave 22b as

[

a

]_D¼ ꢁ132 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1750, 1651, 1605, 1577, 1482.

HRMS (ES^þ) calcd [M þ H^þ] for C₂₄H₂₃NO₄S 422.1426 obsd

422.1422. ¹H NMR (400 MHz, CDCl₃)

d 0.59e0.70 (m, 2H),

0.80e0.97 (m, 2H), 1.36e1.45 (m, 1H), 3.46 (dd, J ¼ 2.2, 11.8 Hz, 1H),

3.61 (dd, J ¼ 8.5, 11.8 Hz, 1H), 3.78 (s, 3H), 3.89 (s, 3H), 4.00e4.17 (m,

2H), 5.58 (dd, J ¼ 2.2, 8.5 Hz, 1H), 6.08 (s, 1H), 7.08e7.14 (m, 2H),

7.24e7.28 (m, 1H), 7.54 (s, 1H), 7.65 (t, J ¼ 8.3 Hz, 2H). ¹³C NMR

a colorless foam (124 mg, 88% yield). [

a

]_D¼ ꢁ50 (c 0.5, CHCl₃). IR

(n

cm^ꢁ1) 3239, 1748, 1644, 1570, 1480, 1435, 1328. HRMS (ES^þ) calcd

[M þ H^þ] for C₂₅H₁₉F₃N₂O₃S 485.1147 obsd 485.1153. ¹H NMR

(100 MHz, CDCl₃)

d

7.7, 8.0, 11.3, 31.7, 39.3, 53.3, 55.3, 62.8, 105.7,

(400 MHz, CDCl₃) d 3.41e3.48 (m, 1H), 3.60e3.67 (m, 3H), 3.79 (s,

113.9, 115.7, 119.0, 127.1, 127.5, 128.0, 129.0, 129.1, 133.2, 133.4, 147.4,

157.1, 157.5, 161.4, 168.7.

3H), 5.65 (dd, J ¼ 2.3, 8.6 Hz, 1H), 6.27 (s, 1H), 6.37 (s, 1H), 6.63e6.72

(m,1H), 7.06 (s,1H), 7.12e7.20 (m, 2H), 7.27e7.49 (m, 3H), 7.58e7.64

(m, 1H), 8.71 (bs, 1H). ¹³C NMR (100 MHz, CDCl₃)

d 31.8, 40.0, 53.4,

4.10.14. (3R)-8-cyclopropyl-7-(1H-indol-5-ylmethyl)-5-oxo-2,3-

dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester

(22a)

Prepared according to the procedure described for compound

21a starting from 4a (132 mg, 0.38 mmol). Puriﬁcation by silica gel

chromatography (heptane:EtOAc 50:50 / 10:90) gave 22a as

63.7, 102.1, 111.3, 115.2, 115.7, 120.9, 122.9, 123.9 (q, J ¼ 272 Hz, 1C),

124.9, 125.1, 127.2 and 127.4 (1C), 128.2, 129.3, 131.1 (splitted q,

J ¼ 32 Hz, 1C), 133.7, 134.0, 134.9, 137.2, 147.1, 155.6, 161.6, 168.5.

4.10.18. (3R)-7-[3-(4-Fluoro-benzyloxy)-benzyl]-5-oxo-8-(3-

triﬂuoromethyl-phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-

carboxylic acid methyl ester (23b)

Prepared according to the procedure described for compound

21a starting from 4a (130 mg, 0.29 mmol). Puriﬁcation by HPLC (C₁₈

a colorless foam (112 mg, 77% yield). [

a

]

¼ ꢁ134 (c 0.5, CHCl₃). IR

D

(n

cm^ꢁ1) 3224, 1745, 1640, 1564, 1486, 1422. HRMS (ES^þ) calcd

[M þ H^þ] for C₂₁H₂₀N₂O₃S 381.1273 obsd 381.1274. ¹H NMR

(400 MHz, CDCl₃)

d

0.61e0.71 (m, 2H), 0.82e0.99 (m, 2H),1.42e1.51

250 ꢂ 21.2 mm 5

mm, H₂O:MeCN 70:30 / 0:100 over 1 h, the eluent

(m, 1H), 3.44 (dd, J ¼ 2.0, 11.7 Hz, 1H), 3.58 (dd, J ¼ 8.6, 11.7 Hz, 1H),

3.73 (s, 3H), 3.98e4.14 (m, 2H), 5.57 (dd, J ¼ 2.0, 8.6 Hz, 1H), 6.14 (s,

1H), 6.40e6.44 (m,1H), 6.91e6.96 (m,1H), 7.12e7.16 (m,1H), 7.23 (d,

J ¼ 8.4 Hz, 1H), 7.40e7.44 (m, 1H), 9.13 (bs, 1H). ¹³C NMR (100 MHz,

contained 0.1% TFA) gave 23b as a colorless foam (100 mg, 61% yield).

[a]

¼ ꢁ39 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1750, 1654, 1583, 1484. HRMS

D

(ES^þ) calcd [M þ H^þ] for C₃₀H₂₃F₄NO₄S 570.1362 obsd 570.1362. ¹H

NMR (400 MHz, CDCl₃) d 3.42e3.56 (m, 3H), 3.63e3.73 (m,1H), 3.84

CDCl₃)

d

7.7, 8.0, 11.3, 31.6, 39.5, 53.2, 62.8, 101.7, 111.5, 114.5, 115.3,

(s, 3H), 4.91 (s, 2H), 5.66 (d, J ¼ 8.0 Hz, 1H), 6.20e6.24 (m, 1H),

6.37e6.49 (m, 2H), 6.75 (dd, J ¼ 1.9, 8.2 Hz, 1H), 7.02e7.10 (m, 3H),

7.21e7.40 (m, 4H), 7.45 (t, J ¼ 7.5 Hz,1H), 7.55e7.62 (m,1H).¹³C NMR

120.8, 123.0, 125.0, 128.1, 128.7, 134.9, 147.2, 158.8, 161.6, 168.8.

4.10.15. (3R)-8-cyclopropyl-7-[3-(4-ﬂuoro-benzyloxy)-benzyl]-5-

oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

methyl ester (23a)

Prepared according to the procedure described for compound

21a starting from 4a (150 mg, 0.44 mmol). Puriﬁcation by HPLC (C₁₈

(100 MHz, CDCl₃) d 31.8, 39.9, 53.5, 63.7, 69.2,113.1,114.7,115.4,115.5,

115.6,116.1, 121.7 (splitted), 123.9 (q, J ¼ 271 Hz,1C), 125.1, 127.2 and

127.3 (1C), 129.3, 129.4, 129.5, 129.6, 131.1 (dq, J ¼ 11, 32 Hz, 1C),

132.8, 133.7 (d, J ¼ 26 Hz, 1C), 137.0 (splitted), 139.0, 147.5 (splitted),

153.7, 158.8, 161.3, 162.5 (d, J ¼ 245 Hz, 1C), 168.4.

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1113

General hydrolysis method 1: 0.10 M LiOH(aq) or 1.0 M LiOH(aq)

(1.0 equiv) was added to the substrate in THF (42 mL/mmol) at rt.

The reaction mixture was stirred for approximately 12 h before

being concentrated. The crude products were ﬁltered through a C₁₈

column [MeCN:H₂O].

General hydrolysis method 2: 0.10 M LiOH(aq) (1.05 equiv) was

added to the substrate in THF (42 mL/mmol) at rt. The reaction

mixture was stirred for approximately 12 h before being concen-

trated. The crude products were puriﬁed by column chromatog-

raphy on silica gel [CH₂Cl₂:MeOH 97:3 / CH₂Cl₂:MeOH 95:5 and

1% AcOH].

General hydrolysis method 3: 1.0 M LiOH(aq) (2 equiv) was added

to the substrate in THF (42 mL/mmol) at rt and the reaction mixture

was stirred for 1 h. The reaction mixture was diluted with water

and pH was set to approx 1 with 1 M HCl (aq), and extracted with

EtOAc. The organic phase was dried (Na₂SO₄), ﬁltered and

concentrated. The crude products were puriﬁed by column chro-

matography on silica gel (CH₂Cl₂:MeOH:AcOH).

(

n

cm^ꢁ1) 1734,1639,1556,1493, and 1324. HRMS (ES^þ) calcd [M þ H^þ]

for C₁₈H₁₈N₂O₅S₂407.0730 obsd 407.0720.¹H NMR (400 MHz, MeOD)

d

0.48e0.64 (m, 2 h), 0.76e0.96 (m, 2H), 1.48e1.62 (m, 1H), 3.58 (d,

J ¼ 11.82 Hz, 1H), 3.77 (dd, J₁¼8.76 Hz, J₂¼ 11.81 Hz, 1H), 4.09e4.28

(m, 2H), 5.54 (d, J ¼ 8.74 Hz, 1H), 6.28 (s, 1H), 7.52e7.70 (m, 3H),

7.83e7.94 (m, 2H). ¹³C NMR (100 MHz, MeOD)

d 8.0, 8.2, 11.1, 32.7,

44.8, 64.7,113.7,114.6,127.9 (2H),130.2 (2H),133.7,141.9,150.6,155.3,

163.4, 171.0.

4.10.23. (3R)-8-cyclopropyl-7-naphthalenesulfonamido-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

(28a)

By following general hydrolysis method 2, 15a (39 mg,

0.082 mmol) gave 28a (34 mg, 91% yield) as a solid. [

a]

¼ ꢁ144 (c

D

0.5, MeOH). IR (n

cm^ꢁ1) 1732, 1639, 1561, 1493, and 1321. HRMS

(ES^þ) calcd [M þ H^þ] for C₂₂H₂₀N₂O₅S₂457.0886 obsd 457.0883. ¹H

NMR (400 MHz, MeOD)

d 0.34e0.46 (m, 2H), 0.58e0.79 (m, 2H),

1.26e1.36 (m, 1H), 3.52 (dd, J₁¼1.56 Hz, J₂¼ 11.89 Hz, 1H), 3.68 (dd,

J₁¼8.72 Hz, J₂¼ 11.83 Hz, 1H), 4.04e4.28 (m, 2H), 5.42 (dd,

J₁¼1.45 Hz, J₂¼ 8.77 Hz, 1H), 6.12 (s, 1H), 7.53e7.72 (m, 3H),

7.98e8.04 (m, 1H), 8.10e8.22 (m, 2H), 8.67e8.73 (m, 1H). ¹³C NMR

(100 MHz, MeOD)

125.8, 128.1, 129.1, 129.4, 130.0, 130.4, 135.3, 135.7, 136.9, 150.5,

154.5, 163.1, 171.0.

4.10.19. (3R)-8-cyclopropyl-7-piperidino-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium carboxylate (24a)

By following general hydrolysis method 1 and using 0.10 M LiOH

(aq), 9a (43 mg, 0.12 mmol) gave 24a (40 mg, 95% yield) as a solid.

d 7.6, 8.1, 11.0, 32.8, 44.7, 64.6, 114.4, 114.7, 125.2,

[

a

]_D¼ ꢁ43 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1631, 1568, 1490, and 1395.

HRMS (ES^þ) calcd [M þ H^þ] for C₁₇H₂₁LiN₂O₃S 341.1506 obsd

341.1494. ¹H NMR (360 MHz, MeOD)

d

0.54e0.70 (m, 2H),

4.10.24. (3R)-8-cyclopropyl-7-benzamido-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid (29a)

By following general hydrolysis method 2,16a (41 mg, 0.11 mmol)

0.79e0.98 (m, 2H), 1.41e1.53 (m, 2H), 1.54e1.71 (m, 5H), 2.39e2.53

(m, 4H), 3.44e3.62 (m, 3H), 3.71 (dd, J₁¼8.60 Hz, J₂¼ 11.32 Hz, 1H),

5.40 (dd, J₁¼1.35 Hz, J₂¼ 8.53 Hz, 1H), 6.41 (s, 1H). ¹³C NMR

gave 29a (37 mg, 94% yield) as a solid. [

a

]_D¼ ꢁ92 (c 0.5, MeOH). IR

(90 MHz, MeOD)

d

8.0, 8.4, 11.7, 25.4, 27.1 (2C), 33.9, 56.0 (2C), 61.1,

(n

cm^ꢁ1) 1737, 1636, 1538, and 1489. HRMS (ES^þ) calcd [M þ H^þ] for

67.2, 114.0, 115.8, 150.8, 156.2, 163.9, 174.1.

C₁₉H₁₈N₂O₄S 371.1060 obsd 371.1056. ¹H NMR (360 MHz, MeOD)

d

0.64e0.76 (m, 2H), 0.90e1.08 (m, 2H), 1.64e1.76 (m, 1H), 3.62 (dd,

4.10.20. (3R)-8-cyclopropyl-7-morpholino-1-ylmethyl-5-oxo-2,3-

dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium carboxylate (25a)

By following general hydrolysis method 1 and using 0.10 M

LiOH(aq), 10a (25 mg, 0.072 mmol) gave 25a (23 mg, 92% yield) as

J₁¼1.36 Hz, J₂¼11.92 Hz, 1H), 3.82 (dd, J₁¼8.96 Hz, J₂¼ 11.90 Hz,

1H), 4.60e4.76 (m, 2H), 5.60(dd, J₁¼1.33 Hz, J₂¼ 8.76 Hz,1H), 6.22(s,

1H), 7.45e7.60 (m, 3H), 7.87e7.94 (m, 2H). ¹³C NMR (90 MHz, MeOD)

d

8.1, 8.3,11.2, 32.8, 41.8, 64.6,111.1,115.3,128.4 (2C),129.7 (2C),133.0,

a solid. [

a

]

¼ ꢁ33 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1731, 1632, 1566,

135.1, 150.9, 157.5, 163.4, 170.3, 170.7.

D

1490, and 1394. HRMS (ES^þ) calcd [M þ H^þ] for C₁₆H₁₉LiN₂O₄S

343.1298 obsd 343.1291. ¹H NMR (400 MHz, D₂O)

d

0.56e0.68 (m,

4.10.25. (3R)-8-cyclopropyl-7-naphthalamido-1-ylmethyl-5-oxo-

2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid (30a)

By following general hydrolysis method 2, 17a (31 mg,

2H), 0.87e1.09 (m, 2H), 1.62e1.72 (m, 2H), 2.68e2.82 (m, 4H),

3.55 (d, J ¼ 11.73 Hz, 1H), 3.74e3.87 (m, 7H), 5.41 (d, J ¼ 8.62 Hz,

1H), 6.36 (s, 1H). ¹³C NMR (100 MHz, D₂O)

d

7.1, 7.5, 10.4, 32.6,

0.072 mmol) gave 30a (27 mg, 90% yield) as a solid. [

a

]

¼ ꢁ86 (c

D

53.1 (2C), 58.2, 65.95 (2C), 61.02, 112.9, 116.4, 150.7, 152.9, 162.4,

174.2.

0.5, MeOH). IR (n

cm^ꢁ1) 1735, 1637, 1531, and 1493. HRMS (ES^þ)

calcd [M þ H^þ] for C₂₃H₂₀N₂O₄S 421.1217 obsd 421.1209. ¹H NMR

(360 MHz, MeOD)

d 0.66e0.78 (m, 2H), 0.92e1.10 (m, 2H),

4.10.21. (3R)-8-cyclopropyl-7-tetrahydroisoquinolino-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium

carboxylate (26a)

1.66e1.79 (m, 1H), 3.61 (d, J ¼ 11.83 Hz, 1H), 3.82 (dd,

J₁¼8.94 Hz, J₂¼11.74 Hz, 1H), 4.66e4.82 (m, 2H), 5.60 (d,

J ¼ 8.24 Hz, 1H), 6.35 (s, 1H), 7.49e7.64 (m, 3H), 7.71e7.80 (m,

1H), 7.88e8.06 (m, 2H), 8.20e8.31 (m, 1H). ¹³C NMR (90 MHz,

By following general hydrolysis method 1 and using 0.10 M LiOH

(aq), 11a (22 mg, 0.056 mmol) gave 26a (20 mg, 92% yield) as

MeOD)

d 8.2, 8.3, 11.3, 32.7, 41.7, 64.6, 111.7, 114.8, 125.9, 126.3,

a solid. [

a

]

¼ ꢁ42 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1629, 1565, 1490, and

126.5, 127.5, 128.1, 129.5, 131.5, 131.8, 135.1, 135.2, 150.7, 157.0,

163.7, 170.8, 172.6.

D

1393. HRMS (ES^þ) calcd [M þ H^þ] for C₂₁H₂₁LiN₂O₃S 389.1506 obsd

389.1494. ¹H NMR (400 MHz, MeOD)

d 0.58e0.72 (m, 2H),

0.81e0.99 (m, 2H), 1.64e1.73 (m, 1H), 2.73e2.86 (m, 2H), 2.87e2.94

(m, 2H), 3.58 (dd, J₁¼1.30 Hz, J₂¼11.31 Hz, 1H), 3.66e3.82 (m, 5H),

5.41 (dd, J₁¼1.19 Hz, J₂¼ 8.44 Hz, 1H), 6.47 (s, 1H), 6.96e7.03 (m,

4.10.26. (3R)-8-CYCLOPROPYL-7-phenoxymethyl-5-oxo-2,3-dihydro-

5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (31a)

By following general hydrolysis method 2, 18a (71 mg,

1H), 7.04e7.13 (m, 3H). ¹³C NMR (90 MHz, MeOD)

d

8.0, 8.4, 11.7,

0.20 mmol) gave 31a (66 mg, quant.) as a solid. [

a

]

¼ ꢁ28 (c 0.5,

D

30.2, 33.9, 52.3, 57.4, 60.1, 67.2, 113.9, 115.7, 126.7, 127.2, 127.5, 129.6,

135.3, 135.9, 151.0, 155.9, 163.9, 174.1.

DMSO). IR (n

cm^ꢁ1) (neat) 1634, 1558, 1491, 1397, 1236 and 1026.

HRMS (ES^þ) calcd [M þ H^þ] for C₁₈H₁₇NO₄S 344.0951 obsd

344.0953. ¹H NMR (400 MHz, d₆-DMSO)

d 0.51e0,70 (m, 2H),

4.10.22. (3R)-8-cyclopropyl-7-benzenesulfonamido-1-ylmethyl-5-

oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic acid

(27a)

0.78e0.91 (m, 2H), 1.61e1.73 (m, 1H), 3.51e3.58 (m, 1H), 3.66e3.76

(m, 1H), 509e5.21 (m, 2H), 5.27e5.35 (m, 1H), 6.14 (s, 1H),

6.93e7.07 (m, 3H), 7.29e7.37 (m, 2H).¹³C NMR (100 MHz, d₆-DMSO)

By following general hydrolysis method 2,14a (50 mg, 0.12 mmol)

d

7.1, 7.2, 24.4, 33.3, 65.8, 66.4, 79.7, 109,9, 111,9, 115,1, 121,5, 130,1,

gave 27a (45 mg, 93% yield) as a solid. [a]_D¼ ꢁ132 (c 0.5, MeOH). IR

149,6, 121,1, 158,5, 160,8, 171,2.

1114

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

4.10.27. (3R)-8-cyclopropyl-7-(naphthalen-1-yloxymethyl)-5-oxo-

2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (32a)

By following general hydrolysis method 2, 19a (102 mg,

[

a

]

¼ ꢁ4 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1626, 1568, 1487, 1437, 1405,

D

and 1330. HRMS (ES^þ) calcd [M þ H^þ] for C₂₁H₂₀F₃LiN₂O₃S

445.1380 obsd 445.1373. ¹H NMR (400 MHz, MeOD)

d 1.33e1.43 (m,

0.25 mmol) gave 32a (95 mg, quant.) as a solid. [

a

]_D¼ ꢁ35 (c 0.5,

2H), 1.44e1.56 (m, 4H), 2.22e2.44 (m, 4H), 3.04e3.24 (m, 2H), 3.58

(dd, J₁¼1.39 Hz, J₂¼ 11.39 Hz, 1H), 3.76 (dd, J₁¼8.92 Hz,

J₂¼ 11.02 Hz, 1H), 5.49 (dd, J₁¼1.39 Hz, J₂¼ 8.61 Hz, 1H), 6.46 (s,

DMSO). IR (n

cm^ꢁ1) (neat) 1624, 1567, 1496, 1397, 1268 and 1103.

HRMS (ES^þ) calcd [M þ H^þ] for C₂₂H₁₉NO₄S 394.1108 obsd 394.1102.

¹HNMR(400 MHz,d₆-DMSO)

d

0.52e0.74(m, 2H),0.78e0.93(m, 2H),

1H), 7.55e7.74 (m, 4H). ¹³C NMR (100 MHz, MeOD)

d 24.8, 26.5 (2C),

1.65e1.78 (m, 1H), 3.48e3.60 (m, 1H), 3.67e3.79 (m, 1H), 5.28e5.42

(m, 3H), 6.30 (s, 1H), 7.00e7.09 (m, 1H), 7.40e7.49 (m, 1H), 7.49e7.61

(m, 3H), 7.86e7.94 (m,1H), 8.20e8.30 (m,1H).¹³C NMR (100 MHz, d₆-

34.1, 55.2 (2C), 60.9, 68.1, 115.3 (broad), 116.6, 125.5 (q, J ¼ 271.9 Hz),

125.8 (broad and split J ¼ 3.43 Hz), 128.5 (d, J ¼ 31.6 Hz), 130,5, 131.8

(q, J ¼ 34.1 Hz), 135.3 (d, J ¼ 31.0 Hz), 139.0, 151.1, 151.9, 163.7, 173.9.

DMSO) d 6.7, 9.9, 31.3, 62.5, 66.1, 105.6, 110.1, 111.0, 120.5, 121.3, 124.8,

125.7, 126.1, 126.6, 127.6, 134.1, 148.5, 152.1, 153.1, 160.0, 169.6.

4.10.32. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-morpholino-1-

ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium

carboxylate (25b)

4.10.28. (3R)-8-cyclopropyl-7-(6-methoxy-naphthalen-2-ylmethyl)-

5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

(33a)

By following general hydrolysis method 3, 21a (110 mg,

0.26 mmol) gave 33a, after puriﬁcation by column chromatography

on silica gel (CH₂Cl₂:MeOH:AcOH 95:4:1), as a colourless foam

By following general hydrolysis method 1 and using 1.0 M LiOH

(aq), 10b (149 mg, 0.328 mmol) gave 25b (141 mg, 96% yield) as

a solid. [

a

]

¼ ꢁ21 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1622, 1570,1486, 1400,

D

and 1331. HRMS (ES^þ) calcd [M þ H^þ] for C₂₀H₁₈F₃LiN₂O₄S 447.1172

obsd 447.1158. ¹H NMR (400 MHz, MeOD)

d 2.15e2.36 (m, 4H),

(100 mg, 94% yield). [

a

]_D¼ ꢁ25 (c 0.25, CHCl₃:MeOH 9:1). IR (

n

cm^ꢁ1

)

3.01e3.18 (m, 2H), 3.47e3.60 (m, 5H), 3.75 (dd, J₁¼8.67 Hz,

1733, 1633, 1605, 1482. HRMS (ES^þ) calcd [M þ H^þ] for C₂₃H₂₁NO₄S

J₂¼ 11.38 Hz, 1H), 5.49 (dd, J₁¼1.39 Hz, J₂¼ 8.57 Hz, 1H), 6.40 (s,

408.1264 obsd 408.1270. ¹H NMR (400 MHz, d₆-DMSO)

d

0.50e0.68

1H), 7.57e7.74 (m, 4H). ¹³C NMR (100 MHz, MeOD)

d 34.1, 54.2 (2C),

(m, 2H), 0.80e0.97 (m, 2H), 1.38e1.47 (m, 1H), 3.49 (d, J ¼ 11.7 Hz),

3.75 (dd, J ¼ 9.5, 11.7 Hz, 1H), 3.86 (s, 3H), 4.02e4.15 (m, 2H),

5.35e5.42 (m,1H), 5.79 (s,1H), 7.14 (dd, J ¼ 2.1, 9.0 Hz,1H), 7.27e7.36

(m,1H), 7.66 (s,1H), 7.74e7.80 (m, 2H).¹³C NMR (100 MHz, d₆-DMSO)

61.0, 67.8 (2C), 68.0, 115.3 (broad), 116.6, 125.5 (q, J ¼ 271.9 Hz),

125.7 (broad and split J ¼ 3.7 Hz), 128.4 (d, J ¼ 40.2 Hz), 130,4, 131.7

(q, J ¼ 32.1 Hz), 135.1 (d, J ¼ 42.1 Hz), 139.1, 150.9, 152.1 (broad),

163.7, 173.9.

d

7.5, 7.7, 10.9, 31.3, 38.2, 55.2, 62.6, 105.8, 111.9, 114.1, 118.7, 126.9,

127.2, 128.1, 128.5, 129.0, 133.0, 133.7, 148.3, 156.5, 157.0, 160.1, 169.7.

4.10.33. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-tetrahydroisoquinolino-

1-ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium

carboxylate (26b)

4.10.29. (3R)-8-cyclopropyl-7-(1H-indol-5-ylmethyl)-5-oxo-2,3-

dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (34a)

By following general hydrolysis method 3, 22a (110 mg,

0.29 mmol)gave 34a, afterpuriﬁcation bycolumn chromatographyon

silica gel (CH₂Cl₂:MeOH:AcOH 90:9:1), as a colourless foam (100 mg,

By following general hydrolysis method 1 and using 1.0 M LiOH

(aq), 11b (60 mg, 0.12 mmol) gave 26b (56 mg, 94% yield) as a solid.

[

a

]

¼ ꢁ5 (c 0.5, MeOH). IR (

n

cm^ꢁ1) 1621, 1572, 1488, and 1331.

D

HRMS (ES^þ) calcd [M þ H^þ] for C₂₅H₂₀F₃LiN₂O₃S 493.1380 obsd

94% yield). [

a

]_D¼ ꢁ39 (c 0.25, DMSO). IR (

n

cm^ꢁ1) 3259, 1627, 1547,

493.1370. ¹H NMR (400 MHz, MeOD)

d 2.53e2.67 (m, 2H),

1486,1394. HRMS(ES^þ) calcd [M þ H^þ] for C₂₀H₁₈N₂O₃S 367.1111 obsd

2.72e2.80 (m, 2H), 3.23e3.38 (m, 2H), 3.49 (s, 2H), 3.56 (dd,

J₁¼1.40 Hz, J₂¼11.41 Hz, 1H), 3.70e3.80 (m, 1H), 5.50 (dd,

J₁¼1.37 Hz, J₂¼ 8.57 Hz, 1H), 6.52 (s, 1H), 6.88e6.94 (m, 1H),

6.99e7.10 (m, 3H), 7.54e7.72 (m, 4H). ¹³C NMR (100 MHz, MeOD)

367.1099. ¹H NMR (400 MHz, d₆-DMSO)

d 0.50e0.69 (m, 2H),

0.81e0.97 (m, 2H), 1.40e1.50 (m, 1H), 3.44e3.52 (m, 1H), 3.72e3.81

(m,1H), 3.95e4.09 (m, 2H), 5.36e5.42 (m,1H), 5.77 (s,1H), 6.35e6.39

(m,1H), 6.92e6.98 (m,1H), 7.28e7.40 (m, 3H),11.05 (bs,1H). ¹³C NMR

d

29.9, 34.2, 51.9, 56.6, 60.3, 68.0, 114.7 (broad), 116.5, 125.5 (q,

(100 MHz, d₆-DMSO)

114.0, 120.2, 122.5, 125.5, 127.9, 128.5, 134.7, 147.9, 157.8, 160.1, 169.7.

d

7.5, 7.7, 10.9, 31.2, 38.5, 62.4, 100.8, 111.4,112.2,

J ¼ 271.7 Hz), 125.8 (broad and split J ¼ 3.8 Hz), 126.6, 127.2, 127.4,

128.4 (d, J ¼ 38.3 Hz), 129.5, 130.5, 131.9 (q, J ¼ 33.4 Hz), 135.1, 135.3

(d, J ¼ 33.0 Hz), 135.4, 139.0, 151.0, 152.5, 163.8, 173.9.

4.10.30. (3R)-8-cyclopropyl-7-[3-(4-ﬂuoro-benzyloxy)-benzyl]-5-

oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

(35a)

By following general hydrolysis method 3, 23a (110 mg,

0.24 mmol) gave 35a, after puriﬁcation by column chromatography

on silica gel (CH₂Cl₂:MeOH:AcOH 95:4:1), as a colourless foam

4.10.34. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-benzenesulfonamido-

1-ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-

carboxylic acid (27b)

By following general hydrolysis method 3, 14b (25 mg,

0.047 mmol) gave 27b (22 mg, 93% yield) as a solid. [

a

]_D¼ ꢁ5 (c 0.5,

(100 mg, 92% yield). [

a

]_D¼ ꢁ12 (c 0.25, CHCl₃:MeOH 9:1). IR

MeOH). IR (n

cm^ꢁ1) 1735, 1643, 1564, 1486, 1446, and 1326. HRMS

(n

cm^ꢁ1) 1732, 1605, 1540, 1487. HRMS (ES^þ) calcd [M þ H^þ] for

(ES^þ) calcd [M þ H^þ] for C₂₂H₁₇F₃N₂O₅S₂511.0604 obsd 511.0601. ¹H

C₂₅H₂₂FNO₄S 452.1326 obsd 452.1329. ¹H NMR (400 MHz, d₆-

NMR (400 MHz, MeOD) d 3.55e3.73 (m, 3H), 3.78e3.89 (m, 1H),

DMSO)

d

0.46e0.63 (m, 2H), 0.76e0.91 (m, 2H), 1.30e1.40 (m, 1H),

5.59e5.70 (m, 1H), 6.42 (s, 1H), 7.41e7.65 (m, 6H), 7.66e7.78 (m,

3.46e3.52 (m, 1H), 3.75 (dd, J ¼ 9.2, 11.6 Hz, 1H), 3.87e3.99 (m, 2H),

5.06 (s, 2H), 5.36e5.41 (m, 1H), 5.79 (s, 1H), 6.79e6.91 (m, 3H),

7.16e7.27 (m, 3H), 7.45e7.52 (m, 2H). ¹³C NMR (100 MHz, d₆-DMSO)

3H). ¹³C NMR (100 MHz, MeOD)

d

33.1, 44.9, 65.8, 114.1, 115.1, 125.4

(q, J ¼ 271.5 Hz), 126.4 (broad), 127.8 (broad, 3C), 130.2 (2C), 131.0,

132.3 (q, J ¼ 32.6 Hz), 133.8, 135.1 (d, J ¼ 27.2 Hz), 137.7, 141.4, 150.7,

152.3, 163.4, 171.4 (broad).

d

7.4, 7.6, 10.8, 31.3, 38.2, 62.6, 68.4, 111.8, 112.7, 114.1, 115.1, 115.3,

115.6, 121.6, 129.5, 129.9, 130.0, 133.3, 140.2, 148.2, 156.1, 158.3,

160.1, 162.2 (d, J ¼ 243 Hz, 1C), 170.2.

4.10.35. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-naphthalenesulfonamido-

1-ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-carboxylic

acid (28b)

4.10.31. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-piperidino-1-ylmethyl-

5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-lithium carboxylate

(24b)

By following general hydrolysis method 1 and using 1.0 M LiOH

(aq), 9b (93 mg, 0.21 mmol) gave 24b (83 mg, 91% yield) as a solid.

By following general hydrolysis method 3, 15b (35 mg,

0.060 mmol) gave 28b (31 mg, 93% yield) as a solid. [

a

]_D¼ ꢁ4 (c 0.5,

MeOH). IR (n

cm^ꢁ1) 1733, 1642, 1568, 1485, 1436, and 1325. HRMS

(ES^þ) calcd [M þ H^þ] for C₂₆H₁₉F₃N₂O₅S₂561.0760 obsd 561.0769.

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

1115

¹H NMR (400 MHz, MeOD)

d

3.53 (d, J ¼ 11.91 Hz, 1H), 3.58e3.71

67.1, 105.8, 111.8, 113.6, 121.0, 124.4 (q, J ¼ 275.78 Hz), 125.1, 125.4,

125.9, 126.4, 126.8, 127.0, 130.0 (q, J ¼ 35.23 Hz), 130.40, 134.4, 137.2,

133.3, 149.3, 149.6, 153.3, 160.5, 169.9.

(m, 2H), 3.72e3.84 (m, 1H), 5.57 (d, J ¼ 8.46 Hz, 1H), 6.37 (s, 1H),

7.25e7.74 (m, 7H), 7.94e8.15 (m, 3H), 8.58e8.66 (m, 1H). ¹³C NMR

(100 MHz, MeOD) d 33.1, 44.7, 65.7 (broad), 114.3, 115.0, 125.1, 125.3

(q, J ¼ 272.2 Hz), 125.7, 126.3 (broad), 128.0 (broad, 2C), 129.2, 129.3,

130.1, 130.2, 130.9, 132.2 (q, J ¼ 31.9 Hz), 135.0 (d, J ¼ 29.7 Hz), 135.4,

135.7, 136.2 (broad), 137.5, 150.5, 152.2, 163.3, 171.3 (broad).

4.10.40. (3R)-7-(6-Methoxy-naphthalen-2-ylmethyl)-5-oxo-8-(3-

triﬂuoromethyl-phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-

carboxylic acid (33b)

By following general hydrolysis method 3, 21b (38 mg,

0.07 mmol) gave 33b, after puriﬁcation by column chromatography

on silica gel (CH₂Cl₂:MeOH:AcOH 85:14:1), as a colourless foam

4.10.36. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-benzamido-1-

ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-

carboxylic acid (29b)

(35 mg, 98% yield). [

a

]_D¼ ꢁ2 (c 0.5, CHCl₃). IR (

n

cm^ꢁ1) 1733, 1634,

By following general hydrolysis method 3, 16b (36 mg,

1606, 1550, 1482. HRMS (ES^þ) calcd [M þ H^þ] for C₂₇H₂₀F₃NO₄S

0.073 mmol) gave 29b (33 mg, 96% yield) as a solid. [

a

]_D¼ ꢁ0 (c 0.5,

512.1138 obsd 512.1141. ¹H NMR (400 MHz, d₆-DMSO)

d 3.44e3.51

MeOH). IR (

n

cm^ꢁ1) 1632, 1536, 1485, and 1328. HRMS (ES^þ) calcd

(m, 1H), 3.68e3.84 (m, 3H), 3.84 (s, 3H), 5.42e5.48 (m, 1H), 6.05

(s, 1H), 6.98e7.02 (m, 1H), 7.09 (dd, J ¼ 2.4, 8.9 Hz, 1H), 7.17 (s, 1H),

7.21e7.25 (m, 1H), 7.31e7.41 (m, 1H), 7.47e7.56 (m, 1H), 7.56e7.66

[M þ H^þ] for C₂₃H₁₇F₃N₂O₄S 475.0934 obsd 475.0940. ¹H NMR

(400 MHz, MeOD)

d

3.58 (dd, J₁¼1.38 Hz, J₂¼11.42 Hz, 1H),

3.71e3.85 (m, 1H), 4.06e4.34 (m, 2H), 5.50 (dd, J₁¼1.37 Hz,

J₂¼ 8.60 Hz, 1H), 6.30 (s, 1H), 7.40e7.58 (m, 3H), 7.60e7.84 (m, 6H).

(m, 3H), 7.67e7.75 (m, 1H). ¹³C NMR (100 MHz, d₆-DMSO)

d 31.8,

38.6, 55.1, 63.8, 105.7, 112.8, 114.5, 118.6, 123.9, (q, J ¼ 271 Hz, 1C),

124.7 (broad), 126.9, 126.8 (broad), 126.9, 127.5, 128.3, 128.7,

129.3 (q, J ¼ 32 Hz,1C),129.8, 132.9 (splitted, 2C),134.4, 137.4, 148.5,

153.1, 157.0, 160.1, 169.5.

¹³C NMR (100 MHz, MeOD)

d 34.1, 42.4, 67.8, 112.6 (broad and split

J ¼ 14.6 Hz), 115.1, 125.4 (q, J ¼ 271.9 Hz), 126.2 (broad and split

J ¼ 3.7 Hz), 128.2 (d, J ¼ 35.4 Hz), 128.3 (2C), 129.5 (2C), 131.0, 132.3

(q, J ¼ 32.3 Hz), 132.9, 135.0, 135.2 (d, J ¼ 47.0 Hz), 138.4 (broad),

151.2, 152.8, 163.8, 170.0, 173.5, 173.6 (d, J ¼ 12.4 Hz).

4.10.41. (3R)-7-(1H-Indol-5-ylmethyl)-5-oxo-8-(3-triﬂuoromethyl-

phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

(34b)

4.10.37. (3R)-8-(3-Triﬂuoromethyl)phenyl-7-naphthalamido-1-

ylmethyl-5-oxo-2,3-dihydro-5-H-thiazolo [3,2-a]pyridin-3-

carboxylic acid (30b)

By following general hydrolysis method 3, 22b (120 mg, 0.25 mmol)

gave 34b, after puriﬁcation by column chromatography on silica gel

(CH₂Cl₂:MeOH:AcOH 85:14:1), as a colourless foam (110 mg, 93%

By following general hydrolysis method 3, 17b (21 mg,

0.040 mmol) gave 30b (19 mg, 92% yield) as a solid. [

a

]

¼ ꢁ0 (c 0.5,

yield). [

a

]

¼ 7 (c 0.25, CHCl₃). IR (

n

cm^ꢁ1) 3242, 1732, 1634, 1558,

D

MeOH). IR (

n

cm^ꢁ1) 1725, 1638, 1486, and 1327. HRMS (ES^þ) calcd

1482, 1332. HRMS (ES^þ) calcd [M þ H^þ] for C₂₄H₁₇F₃N₂O₃S 471.0985

[M þ H^þ] for C₂₇H₁₉F₃N₂O₄S 525.1090 obsd 525.1074. ¹H NMR

obsd 471.0987. ¹H NMR (400 MHz, d₆-DMSO)

d 3.43e3.53 (m, 1H),

(400 MHz, MeOD)

d

3.60 (d, J ¼ 11.69 Hz, 1H), 3.78e3.91 (m, 1H),

3.57e3.68 (m, 2H), 3.77e3.90 (m1H), 5.43e5.53 (m,1H), 5.98 (s,1H),

6.24e6.29 (m,1H), 6.56e6.63 (m,1H), 6.99 (s,1H), 7.21 (d, J ¼ 8.1 Hz,

1H), 7.25e7.30 (m,1H), 7.32e7.43 (m,1H), 7.48e7.60 (m,1H), 7.65 (t,

J ¼ 7.8 Hz, 1H), 7.71e7.79 (m, 1H), 10.99 (bs, 1H), 13.45 (bs, 1H). ¹³C

4.16e4.39 (m, 2H), 5.63 (d, J ¼ 8.54 Hz, 1H), 6.45 (s, 1H), 7.46e7.84

(m, 8H), 7.87e7.94 (m, 1H), 7.97 (d, 8.19 Hz, 1H), 8.10e8.17 (m, 1H).

¹³C NMR (100 MHz, MeOD)

d 33.38, 42.3, 66.3 (broad), 112.7 (d,

J ¼ 12.8 Hz), 115.3, 125.4 (q, J ¼ 271.5 Hz), 125.8, 126.3, 236.5 (2C),

127.5, 128.1 (2C), 129.4, 131.1, 131.4, 131.8, 132.4 (q, J ¼ 32.7 Hz),

134.8, 135.1, 135.2 (d, J ¼ 32.3 Hz), 138.1 (d, J ¼ 8.5 Hz), 151.0, 153.3,

163.6, 171.9 (broad), 172.3.

NMR (100 MHz, d₆-DMSO) d 31.7, 38.8, 63.5,100.7,111.2,113.0,114.2,

120.0, 122.1, 124.0 (q, J ¼ 272 Hz, 1C), 124.7, 125.5, 126.9, 127.7, 127.9,

129.4 (q, J ¼ 31 Hz, 1C), 129.8, 134.4, 134.6, 137.5, 148.1, 154.5, 160.2,

169.5.

4.10.38. 5-Oxo-7-phenoxymethyl-8-(3-triﬂuoromethyl-phenyl)-

2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (31b)

By following general hydrolysis method 2, 18b (63 mg,

4.10.42. (3R)-7-[3-(4-Fluoro-benzyloxy)-benzyl]-5-oxo-8-(3-

triﬂuoromethyl-phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-

carboxylic acid (35b)

0.12 mmol) gave 31b (53 mg, quant.) as a solid. [

a

]

¼ ꢁ24 (c 0.5,

By following general hydrolysis method 3, 23b (95 mg,

0.17 mmol) gave 35b, after puriﬁcation by column chromatography

on silica gel (CH₂Cl₂:MeOH:AcOH 95:4:1), as a colourless foam

D

DMSO). IR (n

cm^ꢁ1) (neat) 1642, 1568, 1486, 1326 1164 and 1118.

HRMS (ES^þ) calcd [M þ H^þ] for C₂₂H₁₆F₃NO₄S 448.0825 obsd

448.0824. ¹H NMR (400 MHz, CDCl₃)

d

3.49e3.57 (m, 1H),

(85 mg, 90% yield). [

a

]

¼ 6 (c 0.25, CHCl₃). IR (

n

cm^ꢁ1) 1731, 1626,

D

3.82e3.92(m, 1H), 4.73 (s, 2H), 5.50e5.58 (m, 1H), 6.37 (s, 1H),

6.74e6.82 (m, 2H), 6.87e6.94 (m, 1H), 7.18e7.27 (m, 2H), 7.57e7.84

1544, 1484, 1440, 1334. HRMS (ES^þ) calcd [M þ H^þ] for

C₂₉H₂₁F₄NO₄S 556.1200 obsd 556.1194. ¹H NMR (400 MHz, d₆-

(m, 4H). ¹³C NMR (100 MHz, CDCl₃)

d

32.0, 63.9, 66.8, 111.8, 113.5,

DMSO) d 3.46e3.63 (m, 3H), 3.77e3.87 (m, 1H), 4.95 (s, 2H),

115.0, 121.6, 124.5 (q, J ¼ 275.06 Hz), 125.5 (d, J ¼ 3.95 Hz), 126.9 (d,

J ¼ 3.40 Hz), 129.9, 130.0 (q, J ¼ 29.68 Hz), 130.4, 134.5, 137.0, 149.4,

157.9, 160.5, 169.9.

5.48e5.55 (m, 1H), 6.06 (s, 1H), 6.39e6.45 (m, 1H), 6.48 (s, 1H),

6.75e6.81 (m, 1H), 7.04e7.12 (m, 1H), 7.16e7.24 (m, 2H), 7.26e7.36

(m, 1H), 7.40e7.54 (m, 3H), 7.58e7.66 (m, 1H), 7.67e7.75 (m, 1H).

¹³C NMR (100 MHz, d₆-DMSO)

d 31.7, 38.6, 63.6, 68.3, 112.7, 112.9,

4.10.39. 5-Oxo-7-(naphtalen-1-yloxymethyl)-8-(3-triﬂuoromethyl-

phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid

(32b)

114.6, 115.1 (splitted, 2C), 115.3, 121.2, 123.9 (q, J ¼ 271 Hz, 1C), 124.7

(broad), 126.8 (broad and splitted), 129.3, 129.4 (q, J ¼ 32 Hz, 1C),

129.8 (splitted, 3C), 133.2 (splitted), 134.3, 137.3, 139.5, 148.4, 153.0,

158.2, 160.1, 161.7 (d, J ¼ 243 Hz, 1C), 169.5.

By following general hydrolysis method 2, 19b (95 mg,

0.19 mmol) gave 32b (94 mg, quant.) as a solid. [

a

]_D¼ ꢁ28 (c 0.5,

DMSO). IR (

n

cm^ꢁ1) (neat) 1634, 1485, 1326, 1238, 1120 and 1072.

Acknowledgements

HRMS (ES^þ) calcd [M þ H^þ] for C₂₆H₁₈F₃NO₄S 498.0981 obsd

498.0975. ¹H NMR (400 MHz, CDCl₃)

d

3.50e3.61 (m, 1H),

FA was supported by the Swedish Natural Research Council, the

Knut and Alice Wallenberg Foundation, JC Kempe Foundation

(SJCKMS) and SH was supported by AI048689, AI049950, AI029549,

and DK086378 grants.

3.81e3.95 (m, 1H), 5.00 (s, 2H), 5.52e5.63 (m, 1H), 6.53 (s, 1H),

6.75e6.84 (m, 1H), 7.28e7.37 (m, 1H), 7.40e7.55 (m, 3H), 7.57e7.88

(m, 5H), 7.89e7.98 (m, 1H.). ¹³C NMR (100 MHz, CDCl₃)

d 32.1, 64.0,

1116

E. Chorell et al. / European Journal of Medicinal Chemistry 46 (2011) 1103e1116

[7] G. Waksman, S.J. Hultgren, Nat. Rev. Microbiol. 7 (2009) 765e774.

Appendix A. Supplementary data

[8] J.G. Bann, J.S. Pinkner, C. Frieden, S.J. Hultgren, Proc. Natl. Acad. Sci. U S A 101

(2004) 17389e17393.

Supplementary data (Bacterial Growth for all biologically evalu-

ated compounds, HA-titer assay results for 33b, 34b, 32a, 32b, 5, and

6, cytotoxic properties of 28b, 31b, 32a,b, 33b, 34b, 35a,b, 5, and 6,

NMR spectra for all new compounds) associated with this article can

be found, in the online version, at doi:10.1016/j.ejmech.20 1 1 .01.025.

[9] F.G. Sauer, J.S. Pinkner, G. Waksman, S.J. Hultgren, Cell 111 (2002) 543e551.

[10] M. Vetsch, C. Puorger, T. Spirig, U. Grauschopf, E.U. Weber-Ban,

R. Glockshuber, Nature 431 (2004) 329e332.

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Article Doi

Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity

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