Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity

European Journal of Medicinal Chemistry 208 (2020) 1 12767

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European Journal of Medicinal Chemistry

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Research paper

Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]

pyrimidines and study of their antiplatelet and antibacterial activity

,

1

b

Eric Gofﬁn ^{a 1}, Nicolas Jacques ^b, Lucia Musumeci , Alain Nchimi , Cecile Oury ,

ꢀ

Patrizio Lancellotti ^b, Bernard Pirotte ^a

^aLaboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, CHU Sart Tilman, Liege, Belgium

,

*

b

ꢁ

Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liege, Department of Cardiology, University of Liege Hospital, CHU Sart Tilman,

Liege, Belgium

a r t i c l e i n f o

a b s t r a c t

Article history:

Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert

bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines struc-

turally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial

agents. The aim was to assess the possibility of dissociating the two biological properties and to ﬁnd

novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial

activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally

simpliﬁed analogues. Some of them were found to express antiplatelet activity and to lose the anti-

bacterial activity, supporting the view that the two activities were not necessarily linked.

Received 27 May 2020

Received in revised form

13 August 2020

Accepted 15 August 2020

Available online 23 August 2020

Keywords:

Ticagrelor

Antiplatelet agents

Antibiotics

1,2,3-triazolo[4,5-d]pyrimidines

8-Azapurines

̀

1. Introduction

with cardiovascular disease at risk for gram-positive bacterial in-

fections such as infective endocarditis [6]. Another well-known

additional beneﬁt of ticagrelor compared to other clinically used

P2Y12 inhibitors is also its ability to exert anti-inﬂammatory ac-

tivity, notably by decreasing inﬂammatory cytokines such as

interleukin 6 and tumor necrosis factor alpha as well as platelet-

leukocyte aggregates or by acting directly on endothelial cells,

independently of the P2Y12 receptor [7e1 1].

Ticagrelor (1; Fig. 1) is an orally active antiplatelet drug

belonging to 1,2,3-triazolo[4,5-d]pyrimidines (8-azapurines),

which acts by reversibly inhibiting the platelet P2Y12 receptor for

ADP in a noncompetitive manner [1,2]. This drug used in human

medicine was developed to improve the efﬁcacy and circumvent

the limitations of the ﬁrst-generation P2Y12 inhibitors [3,4].

Although ticagrelor doesn’t need to be metabolized to be active

in vivo, this drug is known to be extensively metabolized via cy-

tochrome P450 3A4 and 3A5 to form a main metabolite known as

AR-C124910, representing approximately one third of ticagrelor in

the circulation [5]. Ticagrelor and its main metabolite inhibit P2Y12

receptors with equivalent potency [5]. Recently, we observed that

ticagrelor and its active metabolite AR-124910 also exert in vitro

bactericidal activity against Gram-positive strains, including

antibiotic-resistant strains, such as Staphylococcus aureus, Staphy-

lococcus epidermidis and Enterococcus faecalis [6]. As a result, tica-

grelor might prove superior to other P2Y12 inhibitors in patients

N⁷-substituted 7-amino-5-alkylsulfanyl-1,2,3-triazolo[4,5-d]py-

rimidines, among which the antiplatelet agent ticagrelor, are rela-

tively poorly described in the literature. Besides examples of P2Y12

receptor antagonists structurally related to ticagrelor [1,12], recent

publications also reported compounds of this chemical class

expressing antiproliferative activity [i.e. compound 2 [13]; com-

pound 3 [14]; compound 4 [15]; compound 5 [16]; i.e. compound 6,

identiﬁed as a lysine speciﬁc demethylase 1 (LSD1) inhibitor [1 7];

Fig. 1]. No indication of antibacterial activity was reported for

compounds of this class until the recent discovery of the antibiotic

effect of ticagrelor on several Gram-positive bacterial strains.

The present work aims at establishing structure-activity re-

lationships in order to identify the structural elements responsible,

on the one hand, for the antiplatelet activity, and, on the other

hand, for the antibacterial activity of ticagrelor analogues i.e. some

* Corresponding author.

E-mail address: b.pirotte@uliege.be (B. Pirotte).

These authors (E.G., N.J.) contributed equally.

1

https://doi.org/10.1016/j.ejmech.2020.1 12767

2

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

O₂N

OH

CH₃

F

H

N

H

N

H

N

S

OH

N

S

OH

S

HO

O

HO

2

3

1

OCH₃

H

N

H

N

H

N

S

H

S

N

H

N

H

S

N

S

N

H

OH

4

5

6

Fig. 1. Examples of N⁷-substituted 7-amino-5-alkylsulfanyl-1,2,3-triazolo[4,5-d]pyrimidines described in the literature (1: ticagrelor).

of its metabolites as well as simpliﬁed structures (general formula,

see 7; Fig. 2).

reduction in the presence of iron powder in a mixture of acetic acid

and methanol. The appropriate primary amine [R³-NH₂: methyl-

amine, ethylamine, cyclopentylamine, (3aR,4S,6R,6aS)-6-amino-

2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol

and

2-

2. Results and discussion

(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo-

penta[d][1,3]dioxol-4-yl)oxy)ethanol] was introduced at the 3-

position of intermediates 12a-b after nucleophilic substitution in

methanol of one chlorine atom linked to the ortho position of the

amine function. Ring closure reaction occurred after diazotization

in the presence of sodium nitrite and acetic acid to provide the

triazolo[4,5-d]pyrimidine intermediates 14a-c. Due to the

increased sensitivity of the 7-position of triazolo[4,5-d]pyrimidines

to nucleophilic substitution as a probable result of the vicinity of

the triazole ring, the chlorine atom at this position was easily

substituted with the appropriate alkyl/aralkylamine [R²-NH₂;

2.1. Chemistry

The synthesis of the target compounds (7; Fig. 2) is described in

Scheme 1. Several steps were adaptations of previously described

processes [12]. Starting from thiobarbituric acid (8), alkylation in

aqueous alkaline medium using an appropriate alkyl halide led to

the 2-alkylsulfanyl-substituted derivatives of general formula 9,

which in turn were converted into the corresponding 5-nitro-

substituted derivatives 10 after reaction with nitric acid in glacial

acetic acid. The latter compounds reacted with phosphorus oxy-

chloride in the presence of 2,6-lutidine to provide the corre-

sponding 4,6-dichloro-substituted compounds 11b. These

intermediates 11b, as well as the commercially available 2,4,6-

trichloro-substituted analogue 11a, were easily converted into the

corresponding 5-amino-substituted compounds 12a and 12b after

cyclopropylamine,

3,4-diﬂuorophenethylamine,

(1R,2S)-2-

phenylcyclopropylamine or (1R,2S)-2-(3,4-diﬂuorophenyl)cyclo-

propylamine] in acetonitrile in the presence of triethylamine,

leading to intermediates 15a-c. Strong nucleophiles such as thiols

were able to displace the last chlorine atom linked at the 5-position

of the triazolo[4,5-d]pyrimidine ring system giving access to com-

pounds of general formula 7. The ﬁnal compounds bearing a pol-

yhydroxypentane group (compounds 7h-t) at the 3-position were

obtained after removal of the acetonide protecting group under

strong acidic conditions.

An interesting observation was made with the target com-

pounds bearing an aralkylamino group at the 7-position of the

1,2,3-triazolo[4,5-d]pyrimidine core structure. The ¹H NMR spectral

data of these drugs recorded in DMSO‑d₆always revealed the

presence of two groups of signals. This was particularly evident for

the N-H proton linked at the 7-position of the triazolopyrimidine

ring and for the C-H proton linked at the ﬁrst carbon atom of the

cyclopropyl

ring

of

(3,4-diﬂuorophenyl)cyclopropylamino-

substituted compounds (Table 2). Such an observation is in accor-

dance with the existence of an equilibrium between two

Fig. 2. General formula of the newly synthesized compounds.

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

3

Scheme 1. Synthesis of Ticagrelor Analogues Belonging to 1,2,3-Triazolo[4,5-d]pyrimidines.

Reagents and conditions: (i) R¹X, KOH, water, 80 ^ꢀC, sealed tube, 2 h; (ii) nitric acid, acetic acid, 0 ^ꢀC to r.t., 1 h; (iii) POCl₃, 2,6-lutidine, 0 ^ꢀCe80 ^ꢀC, 2 h; (iv) iron powder, acetic acid,

methanol, r.t., 2 h; (v) R³NH₂, methanol, 110 ^ꢀC, sealed tube, 1 h; (vi) NaNO₂, acetic acid, 0 ^ꢀC to r.t., 2 h; (vii) R²NH₂, TEA, acetonitrile, 80 ^ꢀC, 1e4 h; (viii) R¹SH, K₂CO₃, acetonitrile,

60e110 ^ꢀC, 3 h; (ix) HCl, methanol, r.t., 30 min.

conformational isomers resulting from the rotation around the C⁸-

N^1’bond (Fig. 3) (also reported for azaadenine derivatives [18]), the

former isomers being the two preferred conformations assuming

an optimal delocalization of electrons in the planar “amidine”

system (numbering N⁷-C⁸-N^1’in Fig. 3). In accordance with the

planarity of the system, and for steric reasons, conformer B is ex-

pected to be the major form (estimation from NMR data in

DMSO‑d₆at r.t.: 80% of conformer B versus 20% of conformer A). The

preference of the B conformation for ticagrelor (and for related

analogues) is conﬁrmed by crystallographic data obtained with the

antiplatelet agent (alone or in co-crystalisation) revealing the

presence of conformer B in the crystal lattices [19e21]. The

planarity of the “amidine” system was also conﬁrmed from the

crystallographic data obtained with ticagrelor alone providing a

torsion angle C⁹-C⁸-N^1’-C^1’of 178.6^ꢀ, thus not far fom the planarity

(180.0^ꢀ) [20].

The attribution of the chemical shifts reported in Table 2 is

deduced from the inﬂuence of the proximity of the N¹nitrogen

atom, which is expected to induce a greater deshielding of the C-H

proton in the case of conformer A, and a greater deshielding of the

N-H proton in the case of conformer B.

4

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

Table 2

¹H NMR Chemical Shifts (in ppm) Attributed to the C-H Proton (H^aor H^a’) Linked to

the First Cyclopropyl Carbon Atom and to the N-H Proton (H^bor H^b’) at the 7-Position

of the 1,2,3-Triazolo[4,5-d]pyrimidine Ring.

Conformer A

Conformer B

Cmpd -X

-R³

C-H

H^a

N-H

H^b

Fig. 3. Conformational isomerism resulting from the rotation around the C⁸-N^1’bond

of N⁷-substituted 7-amino-1,2,3-triazolo[4,5-d]pyrimidines.

H^a’

H^b’

7a

7d

7i

-SCH₃

-SCH₂CH₃

-SCH₂CH₂CH₃-C₅H₆(OH)₃

-CH₃

-CH₂CH₃

3.76 3.15 8.96 9.34

3.77 3.16 8.96 9.37

3.78 3.16 8.93 9.35

2.2. Biological evaluation

1

-SCH₂CH₂CH₃-C₅H₆(OH)₂OCH₂CH₂OH 3.79 3.16 8.94 9.36

7u

7v

-H

-Cl

-C₅H₆(OH)₃

3.82 3.29 9.04 9.34

3.82 3.14 9.53 9.81

Table 1 reports the biological results (antiplatelet and antibac-

terial activity) obtained with ticagrelor (1), several of its metabo-

lites (7i, 7n-t) and simpliﬁed analogues of ticagrelor bearing a short

alkyl group at the 3-position and/or a short alkylsulfanyl group at

the 5-position and/or a simpliﬁed aralkylamino group at the 7-

position (7a-h, 7j-m, 7u-v). The aim was to examine the anti-

platelet versus antibacterial activity of other known ticagrelor

metabolites as well as a series of original simpliﬁed analogues.

The antiplatelet activity of the tested molecules was analyzed by

light transmission aggregometry upon platelet stimulation with

ADP in citrated platelet-rich-plasma using a drug concentration

equal to ticagrelor IC₅₀(1.8

mM) (Fig. 4). The antibacterial activity

against methicillin-resistant Staphylococcus aureus (MRSA, ATCC

BAA-1556) was determined by the broth microdilution method as

recommended by EUCAST guidelines.

Only ticagrelor (1) and its main metabolite AR-C124910 (7i)

showed antibacterial activity against MRSA. The other compounds

revealed absence of activity against bacteria up to a concentration

Table 1

Antiplatelet activity of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor; antibacterial activity established on methicillin-resistant S. aureus.

Cpd

-X

-R²

-R³

Antiplatelet activity (Fold-inhibition vs vehicle^a)

Antibacterial activity (MIC^b,

mM)

7a

7b

7c

7d

7e

7f

7g

7h

7i

7j

7k

7l

7m

1

7n

7o

7p

7q

7r

7s

7t

-SCH₃

-SCH₂CH₃

-CH(CH₂)CH-C₆H₃F₂

H

-CH(CH₂)CH-C₆H₃F₂

H

-CH(CH₂)₂

-CH(CH₂)CH-C₆H₅

-CH₂CH₂-C₆H₃F₂

-CH(CH₂)CH-C₆H₃F₂

H

-CH₃

-CH₂CH₃

-CH₃

-CH₂CH₃

-CH₃

-CH₂CH₃

-C₅H₉

-C₅H₆(OH)₃

0.94 0.09

0.87 0.04

0.97 0.08

0.91 0.15

1.08 0.05

0.97 0.06

1.00 0.09

1.10 0.09

4.80 2.50#

1.10 0.13

2.60 0.65

3.10 0.65#

1.10 0.07

4.30 2.20#

1.00 0.17

1.00 0.09

2.70 0.99*#

6.20 3.70#

2.00 0.72#

1.70 0.24

1.00 0.02

1.00 0.04

1.10 0.12

>200

25

>200

25

>200

-SCH₂CH₂CH₃

-SCH₂CH(OH)CH₃

-SCH₂CH₂CH₂OH

ReSCH₂CH(OH)CH₃

S-SCH₂CH(OH)CH₃

-SCH₂CH(OH)CH₃

-SCH₂CH₂CH₂OH

-H

-C₅H₆(OH)₃

-C₅H₆(OH)₂OCH₂CH₂OH

-C₅H₆(OH)₃

H

-CH(CH₂)CH-C₆H₃F₂

-C₅H₆(OH)₂OCH₂CH₂OH

-C₅H₆(OH)₃

7u

7v

-Cl

-C₅H₆(OH)₃

a

Vehicle: 1% DMSO.

b

MIC: minimal inhibitory concentration. Antiplatelet activity is presented as fold-inhibition vs. vehicle of area under the curve values of ADP-induced platelet aggregation

(mean S.D., n ¼ 4e21). # indicates P < 0.05 vs. vehicle; * indicates P < 0.05 vs. antiplatelet activity of compound 1 (wilcoxon matched-pairs signed rank test).

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

5

4. Experimental section

4.1. General procedures

Melting points were determined on a Stuart SMP3 capillary

apparatus and are uncorrected. The ¹H and ¹³C NMR spectra were

recorded on Bruker instruments equipped with a TCI cryoprobe

(Bruker Avance HD 500 MHz for ¹H; 125 MHz for ¹³C/Bruker Avance

III HD 700 MHz for ¹H; 176 MHz for ¹³C) using deuterated dimethyl

sulfoxide (DMSO‑d₆) or deuterated chloroform (CDCl₃) as the sol-

vent with tetramethylsilane (TMS) as an internal standard; chem-

ical shifts are reported in

d values (ppm) relative to that of internal

TMS. The abbreviations s ¼ singlet, d ¼ doublet, t ¼ triplet,

q ¼ quadruplet, p ¼ pentuplet, h ¼ hexuplet, m ¼ multiplet,

dd ¼ doublet of doublet, td ¼ triplet of doublet, qd ¼ quadruplet of

doublet, dt ¼ doublet of triplet, dq ¼ doublet of quadruplet,

tt ¼ triplet of triplet, tq ¼ triplet of quadruplet, ddd ¼ doublet of

doublet of doublets, ddt ¼ doublet of doublet of triplets and

bs ¼ broad singlet are used throughout. The compounds bearing an

aralkylamino group at the 7-position shows existence of two

isomeric forms, resulting in the duplication of several proton sig-

nals described as major and minor in the NMR data. Elemental

analyses (C, H, N, S) were realized on a Thermo Scientiﬁc Flash EA

1112 elemental analyzer and were within 0.4% of the theoretical

values for carbon, hydrogen and nitrogen; a higher tolerance

( 0.75%) was admitted for sulfur, considering its corresponding

peak shape. This analytical method certiﬁed a purity of ꢁ95% for

each tested compound. All reactions were routinely checked by TLC

on silica gel Merck 60 F254.

Fig. 4. Representative ADP-induced platelet aggregation curves performed in human

citrated PRP after 10-min pre-incubation with the indicated molecules (1.8

vehicle (1% DMSO). The arrow depicts the time of agonist addition.

mM) or

of 200 mM. On the contrary, ﬁve ticagrelor analogues (7i, 7l, 7p, 7q,

7r), among which the active metabolite AR-C124910 (7i), displayed

antiplatelet activity. The antiplatelet activity of molecules 7i, 7l, 7q

and 7r was similar to that of the reference compound 1 while it was

weaker than the reference compound for molecule 7p (P ¼ 0.016).

Interestingly, the antiplatelet activity of the R-isomer 7q was

found to be more pronounced than that of its counterpart, the S-

isomer 7r (P ¼ 0.03), both of them being possible metabolites of

ticagrelor and resulting from the hydroxylation at the 2-position of

the propylsulfanyl side chain of the active metabolite 7i [22]. Hy-

droxylation at the 3-position of the same side chain of 7i also

provided another known metabolite [22], compound 7p, which

also showed antiplatelet activity.

The antiplatelet activity, but not the antibacterial activity, was

maintained when the nature of the aralkylamino side chain at the

7-position was simpliﬁed. The ticagrelor analogue 7l devoid of the

two ﬂuorine atoms at the 3,4-positions of the phenyl ring was

equipotent to the reference compound 1. The presence of a single

cyclopropyl chain instead of a phenylcyclopropyl moiety (com-

pound 7k) was sufﬁcient to maintain a marked antiplatelet activity.

Surprisingly, the replacement of the cyclopropyl group of 1 with an

ethylene moiety (compound 7m) dramatically suppressed the an-

tiplatelet activity. The absence of the aralkyl group on the nitrogen

atom at the 7-position of 1 (providing compound 7j) also generated

the similar results.

4.2. Materials

2-Thiobarbituric acid 8, 4,6-dichloro-2-(propylthio)pyrimidin-

5-amine 12b.3 (R¹¼ propyl), 4,6-dichloropyrimidin-5-amine 12c,

2,4,6-trichloro-5-nitropyrimidine 11a, (1R,2S)-2-(3,4- diﬂuor-

ophenyl)cyclopropanamine and 2-(((3aR,4S,6R,6aS)-6-amino-2,2-

dimethyltetrahydro-

3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)

ethanol were purchased from Fluorochem. (3aR,4S,6R,6aS)-6-

Amino-2,2-dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol was

purchased from Spirochem. 3-mercapto-1-propanol and 1-

mercaptopropan-2-ol were purchased from Aldrich. Both enan-

tiomers of 1-mercaptopropan-2-ol were purchased from

Chemspace.

4.3. 2-(Methylthio)pyrimidine-4,6-diol (9.1)

2-Thiobarbituric acid 8 (2,50 g, 17.4 mmol) was dissolved in KOH

10% (25 mL) and supplemented with methyl iodide (1.25 mL,

20.0 mmol). The reaction mixture was introduced in a sealed vessel

and heated at 80 ^ꢀC for 1 h. After cooling on an ice bath to 5 ^ꢀC, the

mixture was acidiﬁed by addition of hydrochloric acid 6 N and the

resulting precipitate was ﬁltered off and washed with diethyl ether

to give 9.1 (2,10 g, 77% yield, m.p.: >300 ^ꢀC). ¹H NMR (DMSO‑d₆):

3. Conclusion

d

2.46 (s, 3H, SCH 3), 5.13 (s, 1H, CH), 11.71 (bs, 2H, OH). ¹³C NMR

(DMSO‑d₆): 12.7, 85.5, 158.6, 163.5.

d

A series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related

to ticagrelor were synthesized and examined as putative anti-

platelet and antibacterial agents. Slight modiﬁcations of the

structure of ticagrelor dramatically led to a loss of the antibacterial

activity against methicillin-resistant Staphylococcus aureus, while

the antiplatelet activity was maintained with some simpliﬁed

ticagrelor analogues. Our results indicated that the antiplatelet and

antibacterial activity of 1,2,3-triazolo[4,5-d]pyrimidines were not

necessarily linked supporting the view that the observed effects

involve distinct mechanisms and unrelated biological targets.

4.4. 2-(Ethylthio)pyrimidine-4,6-diol (9.2)

2-Thiobarbituric acid 8 (2.50 g, 17.4 mmol) was dissolved in KOH

10% (25 mL) and supplemented with ethyl iodide (1.63 mL,

20.0 mmol). The reaction mixture was introduced in a sealed vessel

and heated at 80 ^ꢀC for 1 h. After cooling on an ice bath to 5 ^ꢀC, the

mixture was acidiﬁed by addition of hydrochloric acid 6 N and the

resulting precipitate was ﬁltered off and washed with diethyl ether

to give 9.2 (2.05 g, 69% yield, m.p.: >300 ^ꢀC). ¹H NMR (DMSO‑d₆):

6

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

d

1.28 (t, J ¼ 7.3 Hz, 3H, CH₃), 3.08 (q, J ¼ 7.3 Hz, 2H, SCH 2), 5.12 (s,

and acetic acid (4 mL) was added iron powder (1,07 g, 19.5 mmol).

1H, CH), 11.68 (bs, 2H, OH). ¹³C NMR (DMSO‑d₆):

d

14.6, 24.0, 85.6,

After 1 h stirring at room temperature, ethyl acetate (50 mL) was

added and the suspension was ﬁltered. The ﬁltrate was washed

with water and with an aqueous saturated solution of sodium

hydrogenocarbonate and the organic layer was evaporated to

dryness under vacuum. Water was added on the residue and the

resulting precipitate was ﬁltered off to give 12b.1 (0.83 g, 95% yield,

158.1, 162.8.

4.5. 2-(Methylthio)-5-nitropyrimidine-4,6-diol (10.1)

To 6 mL of acetic acid cooled at 5 ^ꢀC on an ice bath were added

fuming nitric acid (2.5 mL) and (9.1) (2.0 g, 12.6 mmol). After 1 h

stirring at room temperature, the mixture was cooled at 5 ^ꢀC on an

ice bath, water (50 mL) was added and the resulting precipitate was

ﬁltered off to give 10.1 (1,72 g, 67% yield, m.p.: 220e221 ^ꢀC (dec.)).

m.p.: 105e108 ^ꢀC). ¹H NMR (DMSO‑d₆):

2H, NH₂). ¹³C NMR (DMSO‑d₆):

13.8, 133.4, 143.7, 154.4.

d 2.45 (s, 3H, SCH 3), 5.90 (s,

d

¹H NMR (DMSO‑d₆) 2.56 (s, 3H, SCH 3). ¹³C NMR (DMSO‑d₆)

d d 13.2,

4.11. 4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (12b.2.)

117.4, 158.7, 164.6.

To a solution of (11b.2) (1.0 g, 3.9 mmol) in methanol (10 mL)

and acetic acid (4 mL) was added iron powder (1.07 g, 19.5 mmol).

After 1 h stirring at room temperature, ethyl acetate (50 mL) was

added and the suspension was ﬁltered. The ﬁltrate was washed

with water and with an aqueous saturated solution of sodium

hydrogenocarbonate and the organic layer was evaporated to

dryness under vacuum. Water was added on the residue and the

resulting precipitate was ﬁltered off to give 12b.2 (0.76 g, 86% yield,

4.6. 2-(Ethylthio)-5-nitropyrimidine-4,6-diol (10.2)

To 6 mL of acetic acid cooled at 5 ^ꢀC on an ice bath were added

fuming nitric acid (2.5 mL) and (9.2) (1.80 g, 10.5 mmol). After 1 h

stirring at room temperature, the mixture was cooled at 5 ^ꢀC on an

ice bath, water (50 mL) was added and the resulting precipitate was

ﬁltered off to give 10.2 (1.57 g, 69% yield, m.p.: 210e213 ^ꢀC (dec.)).

¹H NMR (DMSO‑d₆):

2H, SCH 2). ¹³C NMR (DMSO‑d₆):

d

1.31 (t, J ¼ 7.3 Hz, 3H, CH₃), 3.17 (q, J ¼ 7.3 Hz,

m.p.: 48e50 ^ꢀC). ¹H NMR (DMSO‑d₆):

d

1.28 (t, J ¼ 7.3 Hz, 3H, CH₃),

3.02 (q, J ¼ 7.3 Hz, 2H, SCH 2), 5.90 (s, 2H, NH₂). ¹³C NMR

d

14.4, 24.7, 117.4, 158.9, 164.0.

(DMSO‑d₆):

d 14.3, 24.9, 133.5, 143.7, 153.8.

4.7. 4,6-Dichloro-2-(methylthio)-5-nitropyrimidine (11b.1)

To a solution of (10.1) (1.5 g, 7.4 mmol) in POCl₃(10 mL) cooled at

5 ^ꢀC on an ice bath was added dropwise 2,6-lutidine (2.5 mL). After

2 h stirring at 80 ^ꢀC, the mixture was poured on crushed ice and the

resulting precipitate was ﬁltered off to give 11b.1 (1.63 g, 92% yield,

4.12. (3aR,4S,6R,6aS)-6-[(5-amino-6-chloropyrimidin-4-yl)amino]-

2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (13c.1)

m.p.: 63e64 ^ꢀC).¹H NMR (DMSO‑d₆):

d

2.56 (s, 3H, SCH 3). ¹³C NMR

The mixture of 4,6-dichloropyrimidin-5-amine (1.0 g,

6.1

mmol),

(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro

(DMSO‑d₆): 13.5, 149.0, 154.5, 166.1.

d

cyclopenta[d][1,3]dioxol-4-ol (1.34 g, 7.8 mmol) and triethylamine

(0.85 mL, 6.1 mmol) in acetonitrile (10 mL) was placed in a sealed

vessel and heated overnight at 110 ^ꢀC. After evaporation of the

solvent, the residue was puriﬁed by column chromatography on

silica gel using 100% ethyl acetate to give 13c.1 as a white solid

4.8. 4,6-Dichloro-2-(ethylthio)-5-nitropyrimidine (11b.2)

To a solution of (10.2) (1.5 g, 6.9 mmol) in POCl₃(10 mL) cooled

at 5 ^ꢀC on an ice bath was added dropwise 2,6-lutidine (2.5 mL).

After 2 h stirring at 80 ^ꢀC, the mixture was poured on crushed ice

and extracted with ethyl acetate (3 ꢂ 50 mL). The organic layers

were washed with water and with an aqueous saturated solution of

sodium hydrogenocarbonate and ethyl acetate was evaporated to

dryness under vacuum. The resulting oily residue 11b.2 (1.76 g, 85%

yield) was used without further puriﬁcation in the next step

(1.43 g, 78% yield). ¹H NMR (DMSO‑d₆):

d 1.21 (s, 3H, CH₃), 1.36 (s,

3H, CH₃), 1.70 (d, J ¼ 13.7 Hz,1H, 5⁰-Ha), 2.22 (m,1H, 5⁰-Hb), 4.07 (m,

1H, 4⁰-H), 4.29 (t, J ¼ 5.9 Hz, 1H, 6⁰-H), 4.41 (d, J ¼ 6.0 Hz, 1H, 3a⁰-H),

4.51 (d, J ¼ 6.0 Hz, 1H, 6a⁰-H), 4.97 (s, 2H, NH₂), 5.25 (d, J ¼ 3.1 Hz,

1H, OH), 6.49 (d, J ¼ 7.2 Hz, 1H, NH), 7.79 (s, 1H, 2-H). ¹³C NMR

(DMSO‑d₆):

d 24.1, 26.5, 36.0, 57.0, 75.3, 84.4, 85.7, 109.7, 123.5,

(12b.2). ¹H NMR (DMSO‑d₆)

d

1.35 (t, J ¼ 7.3 Hz, 3H, CH₃), 3.18 (q,

137.6, 146.1, 151.7.

J ¼ 7.3 Hz, 2H, SCH 2). ¹³C NMR (DMSO‑d₆)

d 14.0, 25.3, 149.1, 154.5,

165.4.

4.13. (3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)

amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol

(13a.1)

4.9. 2,4,6-Trichloropyrimidin-5-amine (12a)

To a solution of 2,4,6-trichloro-5-nitropyrimidine 11a (1.0 g,

4.38 mmol) in methanol (10 mL) and acetic acid (4 mL) was added

iron powder (1.0 g, 17.9 mmol) under vigorous agitation. After 1 h at

room temperature, the mixture was diluted with methanol (30 mL)

and ﬁltered. The precipitate was washed with methanol (30 mL)

and the ﬁltrate was then concentrated under reduced pressure. The

residue was taken up with water (50 mL) and extracted with

dichloromethane (3 ꢂ 50 mL). The combined organic layers were

dried over MgSO₄, evaporated and puriﬁed by column chroma-

tography on silica gel using hexane/ethyl acetate gradient to give

12a as a white solid (0.77 g, 89% yield, m.p.: 107e109 ^ꢀC). ¹H NMR

The mixture of 2,4,6-trichloropyrimidin-5-amine 12a (1.0 g,

5.0

mmol),

(3aR,4S,6R,6aS)-6-

amino-2,2-

dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol (1.1 g, 6.4 mmol)

and triethylamine (0.7 mL, 5.0 mmol) in acetonitrile (10 mL) was

placed in a sealed vessel and heated overnight at 110 ^ꢀC. After

evaporation of the solvent, the residue was puriﬁed by column

chromatography on silica gel using 100% ethyl acetate to give 13a.1

as a white solid (1.48 g, 88% yield, m.p.: 105 ^ꢀC (dec.)). ¹H NMR

(CDCl₃):

d

1.29 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 1.82 (d, J ¼ 14.5 Hz, 1H,

5⁰-Ha), 2.17 (d, J ¼ 2.0 Hz, 1H, OH), 2.36 (dt, J ¼ 14.5 Hz/5.2 Hz, 1H,

5⁰-Hb), 3.28 (s, 2H, NH₂), 4.40 (d, J ¼ 2.0 Hz, 1H, 4⁰-H), 4.54 (d,

J ¼ 5.3 Hz, 1H, 3a⁰-H), 4.57 (d, J ¼ 5.3 Hz, 1H, 6a⁰-H), 4.71 (dd,

J ¼ 8.4 Hz/6.6 Hz, 1H, 6⁰-H), 6.11 (d, J ¼ 8.7 Hz, 1H, NH). ¹³C NMR

(CDCl₃):

d d 134.7, 145.1, 145.4.

4.51 (bs, 2H, NH₂). ¹³C NMR (CDCl₃):

4.10. 4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (12b.1)

To a solution of (11b.1) (1.0 g, 4.2 mmol) in methanol (10 mL)

(CDCl₃):

d 23.8, 26.2, 35.0, 57.0, 78.1, 85.2, 86.1, 110.6, 120.3, 142.8,

150.2, 155.1.

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

7

4.14. 2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)

amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)

4.18. 6-Chloro-N⁴-ethyl-2-(ethylthio)pyrimidine-4,5-diamine

(13b.4)

oxy)ethanol (13a.2)

4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (12b.2) (0.5 g,

2.2 mmol) was dissolved in a solution of ethylamine 2.0 M in

methanol (3.3 mL, 6.6 mmol). The reaction mixture was introduced

in a sealed vessel and heated at 100 ^ꢀC for 1 h. After concentration

of the reaction mixture to dryness under vacuum, the residue was

puriﬁed by silica gel column chromatography to give 13b.4 (0.47 g,

The mixture of 2,4,6-trichloropyrimidin-5-amine 12a (1.0 g,

5.0 mmol), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-

3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (1.4 g, 6.4 mmol)

and triethylamine (0.7 mL, 5.0 mmol) in acetonitrile (10 mL) was

placed in a sealed vessel and heated overnight at 110 ^ꢀC. After

evaporation of the solvent, the residue was puriﬁed by column

chromatography on silica gel using 100% ethyl acetate to give 13a.2

91% yield, m.p.: 93e95 ^ꢀC). ¹H NMR (DMSO‑d₆):

d

1.16 (t, J ¼ 7.2 Hz,

3H, NHCH₂CH₃), 1.27 (t, J ¼ 7.2 Hz, 3H, SCH₂CH₃), 2.96 (q, J ¼ 7.2 Hz,

2H, SCH₂CH₃), 3.38 (p, J ¼ 6.1 Hz, 2H, NHCH₂CH₃), 4.74 (s, 2H, NH₂),

as an oily residue (1.59 g, 83% yield). ¹H NMR (DMSO‑d₆):

d 1.23 (s,

3H, CH₃), 1.39 (s, 3H, CH₃), 1.86 (d, J ¼ 14.0 Hz, 1H, 5⁰-Ha), 2.22 (m,

1H, 5‘-Hb), 3.51 (m, 4H, OCH₂CH₂OH), 3.90 (s, 1H, 4’-H), 4.30 (s, 1H,

6.93 (s, 1H, NH). ¹³C NMR (DMSO‑d₆):

d 14.4, 15.0, 24.5, 35.8, 119.9,

137.3, 152.6, 155.2.

6⁰-H), 4.50 (s, 1H, 6a⁰-H), 4.54 (s, 1H, 3a⁰-H), 5.04 (s, 1H, OCH₂

-

CH₂OH), 5.17 (s, 2H, NH₂), 6.83 (d, J ¼ 6.7 Hz, 1H, NH). ¹³C NMR

4.19. 6-Chloro-N⁴-methyl-2-(propylthio)pyrimidine-4,5-diamine

(13b.5)

(DMSO‑d₆): d 24.1, 26.3, 32.9, 56.6, 60.3, 70.3, 83.2, 83.5, 83.9, 110.2,

112.8, 136.5, 144.6, 152.7.

4,6-Dichloro-2-(propylthio)pyrimidin-5-amine 12b.3 (0.5 g,

2.1 mmol) was dissolved in methanol (2 mL) and supplemented

with a solution of methylamine 33% w/w in methanol (0.76 mL,

6.3 mmol). The reaction mixture was introduced in a sealed vessel

and heated at 100 ^ꢀC for 1 h. After concentration of the reaction

mixture to dryness under vacuum, the residue was puriﬁed by silica

gel column chromatography to give 13b.5 (0.47 g, 96% yield, m.p.:

4.15. 6-Chloro-N⁴-methyl-2-(methylthio)pyrimidine-4,5-diamine

(13b.1)

4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (12b.1) (0.5 g,

2.4 mmol) was dissolved in methanol (2 mL) and supplemented

with a solution of methylamine 33% w/w in methanol (0.87 mL,

7.2 mmol). The reaction mixture was introduced in a sealed vessel

and heated at 100 ^ꢀC for 1 h. After concentration of the reaction

mixture to dryness under vacuum, the residue was puriﬁed by silica

gel column chromatography to give 13b.1 (0.4 g, 82% yield, m.p.:

119e121 ^ꢀC). ¹H NMR (DMSO‑d₆):

d

0.95 (t, J ¼ 7.4 Hz, 3H,

SCH₂CH₂CH₃), 1.64 (h, J ¼ 7.3 Hz, 2H, SCH₂CH₂CH₃), 2.87 (d,

J ¼ 4.5 Hz, 3H, NHCH₃), 2.96 (t, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃), 4.71 (s,

2H, NH₂), 7.01 (q, J ¼ 4.4 Hz, 1H, NHCH₃). ¹³C NMR (DMSO‑d₆):

d

13.3, 22.6, 27.8, 32.1, 120.0, 137.1, 153.2, 155.4.

141e143 ^ꢀC). ¹H NMR (DMSO‑d₆):

d 2.38 (s, 3H, SCH 3), 2.88 (d,

J ¼ 3.0 Hz, 3H, NHCH₃), 4.70 (s, 2H, NH₂), 7.01 (s, 1H, NH). ¹³C NMR

(DMSO‑d₆):

d

13.5, 27.8, 120.1, 137.2, 153.3, 155.9.

4.20. 6-Chloro-N⁴-ethyl-2-(propylthio)pyrimidine-4,5-diamine

(13b.6)

4.16. 6-Chloro-N⁴-ethyl-2-(methylthio)pyrimidine-4,5-diamine

(13b.2)

4,6-Dichloro-2-(propylthio)pyrimidin-5-amine 12b.3 (0.5 g,

2.1 mmol) was dissolved in a solution of ethylamine 2.0 M in

methanol (3.2 mL, 6.4 mmol). The reaction mixture was introduced

in a sealed vessel and heated at 100 ^ꢀC for 1 h. After concentration

of the reaction mixture to dryness under vacuum, the residue was

puriﬁed by silica gel column chromatography to give 13b.6 (0.4 g,

4,6-Dichloro-2-(methylthio)pyrimidin-5-amine (12b.1) (0.5 g,

2.4 mmol) was dissolved in a solution of ethylamine 2.0 M in

methanol (3.6 mL, 7.2 mmol). The reaction mixture was introduced

in a sealed vessel and heated at 100 ^ꢀC for 1 h. After concentration

of the reaction mixture to dryness under vacuum, the residue was

puriﬁed by silica gel column chromatography to give 13b.2 (0.45 g,

77% yield, m.p.: 96e98 ^ꢀC). ¹H NMR (DMSO‑d₆):

d

0.95 (t, J ¼ 7.4 Hz,

3H, SCH₂CH₂CH₃), 1.16 (t, J ¼ 7.2 Hz, 3H, NHCH₂CH₃), 1.63 (h,

J ¼ 7.3 Hz, 2H, SCH₂CH₂CH₃), 2.94 (t, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃),

3.37 (m, 2H, NHCH₂CH₃), 4.75 (s, 2H, NH₂), 6.95 (t, J ¼ 4.8 Hz, 1H,

86% yield, m.p.:120e122 ^ꢀC). ¹H NMR (DMSO‑d₆):

d 1.16 (t,

NHCH₂CH₃). ¹³C NMR (DMSO‑d₆):

d 13.3, 14.3, 22.7, 32.1, 35.7, 119.8,

J ¼ 7.2 Hz, 3H, NHCH₂CH₃), 2.37 (s, 3H, SCH 3), 3.38 (qd, J ¼ 7.2 Hz/

137.3, 152.5, 155.3.

5.3 Hz, 2H, NHCH₂CH₃), 4.76 (s, 2H, NH₂), 6.94 (t, J ¼ 4.8 Hz, 1H, NH).

¹³C NMR (DMSO‑d₆):

d 13.5, 14.3, 35.7, 119.8, 137.2, 152.4, 155.7.

4.21. 6-Chloro-N⁴-cyclopentyl-2-(propylthio)pyrimidine-4,5-

diamine (13b.7)

4.17. 6-Chloro-2-(ethylthio)-N⁴-methylpyrimidine-4,5-diamine

(13b.3)

4,6-Dichloro-2-(propylthio)pyrimidin-5-amine 12b.3 (0.5 g,

2.1 mmol) was dissolved in methanol (2 mL) and supplemented

with cyclopentylamine (536.0 mg, 6.3 mmol). The reaction mixture

was introduced in a sealed vessel and heated at 100 ^ꢀC for 2 h. After

concentration of the reaction mixture to dryness under vacuum,

the residue was puriﬁed by silica gel column chromatography to

4,6-Dichloro-2-(ethylthio)pyrimidin-5-amine (12b.2) (0.5 g,

2.2 mmol) was dissolved in methanol (2 mL) and supplemented

with a solution of methylamine 33% w/w in methanol (0.80 mL,

6.6 mmol). The reaction mixture was introduced in a sealed vessel

and heated at 100 ^ꢀC for 1 h. After concentration of the reaction

mixture to dryness under vacuum, the residue was puriﬁed by silica

gel column chromatography to give 13b.3 (0.43 g, 87% yield, m.p.:

give 13b.7 (0.57 g, 95% yield, oil). ¹H NMR (DMSO‑d₆):

d 0.95 (t,

J ¼ 7.4 Hz, 3H, SCH₂CH₂CH₃), 1.49 (m, 2H, 2⁰-Ha/5⁰-Ha), 1.55 (m, 2H,

3⁰-Ha/4⁰-Ha), 1.64 (m, 2H, SCH₂CH₂CH₃), 1.70 (m, 2H, 3⁰-Hb/4⁰-Hb),

1.96 (m, 2H, 2⁰-Hb/5⁰-Hb), 2.94 (t, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃), 4.25

(h, J ¼ 6.7 Hz, 1H,1⁰-H), 4.83 (s, 2H, NH₂), 6.76 (d, J ¼ 6.3 Hz,1H, NH).

112e114 ^ꢀC). ¹H NMR (DMSO‑d₆):

d

1.27 (t, J ¼ 7.2 Hz, 3H, SCH₂CH₃),

2.87 (d, J ¼ 3.8 Hz, 3H, NHCH₃), 2.97 (q, J ¼ 7.2 Hz, 2H, SCH₂CH₃),

4.70 (s, 2H, NH₂), 7.00 (s, 1H, NH). ¹³C NMR (DMSO‑d₆):

d

14.9, 24.5,

¹³C NMR (DMSO‑d₆):

d 13.3, 22.9, 23.5, 32.1, 32.2, 52.7, 119.9, 137.2,

27.8, 120.1, 137.2, 153.3, 155.4.

152.0, 155.0.

8

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

4.22. (3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)

pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d]

[1,3]dioxol-4-ol (13b.8)

4.25. (3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-ol (14a.1)

The mixture of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine

12b.3 (1.0 g, 4.2 mmol), (3aR,4S,6R,6aS)-6-amino-2,2-

To a solution of 13a.1 (1.0 g, 3.0 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(275 mg, 4.0 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14a.1 as a white solid (0.61 g, 59% yield,

dimethyltetrahydrocyclopenta[d][1,3]dioxol-4-ol

(0.93

g,

5.4 mmol) and triethylamine (0.6 mL, 4.2 mmol) in acetonitrile

(10 mL) was introduced in a sealed vessel and heated overnight at

110 ^ꢀC. After evaporation of the solvent, the residue was puriﬁed by

column chromatography on silica gel using 100% ethyl acetate to

give 13b.8 as a brown oil (1.40 g, 89% yield, oil). ¹H NMR (CDCl₃):

decomposition at 280 ^ꢀC). ¹H NMR (CDCl₃)

d 1.34 (s, 3H, CH₃), 1.54

(s, 3H, CH₃), 2.41 (d, J ¼ 15.2 Hz, 1H, 5⁰-Ha), 2.90 (ddd, J ¼ 15.1 Hz/

8.0 Hz/5.7 Hz,1H, 5⁰-Hb), 3.23 (d, J ¼ 5.2 Hz,1H, OH), 4.46 (bs,1H, 4⁰-

H), 4.81 (d, J ¼ 5.7 Hz, 1H, 3a⁰-H), 5.17 (d, J ¼ 5.7 Hz, 1H, 6a⁰-H), 5.39

d

1.03 (t, J ¼ 7.4 Hz, 3H, SCH₂CH₂CH₃), 1.26 (s, 3H, CH₃), 1.43 (s, 3H,

CH₃), 1.76 (m, 2H, SCH₂CH₂CH₃), 1.83 (d, J ¼ 14.5 Hz, 1H, 5⁰-Ha), 2.14

(s, 1H, OH), 2.36 (m, 1H, 5⁰-Hb), 3.01 (ddd, J ¼ 13.4 Hz/8.3 Hz/6.4 Hz,

1H, SCHa), 3.09 (s, 2H, NH₂), 3.13 (ddd, J ¼ 13.5 Hz/8.3 Hz/6.4 Hz,1H,

SCHb), 4.38 (s, 1H, 4⁰-H), 4.51 (dd, J ¼ 5.4 Hz/1.7 Hz, 1H, 3a⁰-H), 4.57

(dd, J ¼ 5.4 Hz/1.2 Hz, 1H, 6a⁰-H), 4.62 (t, J ¼ 7.4 Hz, 1H, 6⁰-H), 5.93

(d, J ¼ 7.2 Hz,1H, 6⁰-H). ¹³C NMR (CDCl₃)

d 24.2, 26.6, 37.2, 64.7, 76.6,

84.9, 87.3, 112.0, 133.6, 150.8, 155.6, 157.9.

4.26. 2-(((3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-yl)oxy)ethanol (14a.2)

(d, J ¼ 8.4 Hz,1H, NH). ¹³C NMR (CDCl₃):

d 13.5, 23.2, 23.8, 26.2, 33.2,

35.0, 57.2, 78.1, 85.2, 86.2, 110.3, 117.2, 144.4, 154.5, 162.0.

To a solution of 13a.2 (1.0 g, 2.6 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(240 mg, 3.5 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The resulting mixture was extracted

with ethyl acetate (3 ꢂ 50 mL) and the combined organic layers

were dried over MgSO₄and evaporated to give 14a.2 as an oily

4.23. 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)

pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d]

[1,3]dioxol-4-yl)oxy)ethanol (13b.9)

residue (0.92 g, 89% yield). ¹H NMR (DMSO‑d₆)

d 1.27 (s, 3H, CH₃),

The mixture of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine

12b.3 (1.0 g, 4.2 mmol), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-

dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)

ethanol (1.17 g, 5.4 mmol) and triethylamine (0.6 mL, 4.2 mmol) in

acetonitrile (10 mL) was introduced in a sealed vessel and heated

overnight at 110 ^ꢀC. After evaporation of the solvent, the residue

was puriﬁed by column chromatography on silica gel using 100%

ethyl acetate to give 13b.9 (1.36 g, 77% yield, m.p.: 112e114 ^ꢀC). ¹H

1.48 (s, 3H, CH₃), 2.44 (m, 1H, 5⁰-Ha), 2.90 (dt, J ¼ 13.1 Hz/6.0 Hz, 1H,

5⁰-Hb), 3.39e3.51 (m, 4H, OCH₂CH₂OH), 4.01 (m, 1H, 4⁰-H), 4.32 (bs,

12H, OCH₂CH₂OH/H₂O), 4.69 (dd, J ¼ 7.2 Hz/2.9 Hz, 1H, 3a⁰-H), 5.01

(m, 1H, 6⁰-H), 5.17 (dd, J ¼ 7.1 Hz/4.7 Hz, 1H, 6a⁰-H). ¹³C NMR

(DMSO‑d₆)

d 24.7, 26.8, 35.8, 60.0, 61.8, 70.8, 82.0, 82.1, 83.7, 112.6,

129.3, 148.3, 155.4.

4.27. 7-Chloro-3-methyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]

NMR (CDCl₃)

d

1.03 (t, J ¼ 7.4 Hz, 3H, SCH₂CH₂CH₃), 1.26 (s, 3H, CH₃),

pyrimidine (14b.1)

1.43 (s, 3H, CH₃), 1.75 (m, 2H, SCH₂CH₂CH₃), 1.92 (d, J ¼ 14.5 Hz, 1H,

5⁰-Ha), 2.28 (ddd, J ¼ 14.5 Hz/5.9 Hz/4.4 Hz, 1H, 5⁰-Hb), 2.59 (bs, 1H,

OH), 2.99 (ddd, J ¼ 13.4 Hz/8.2 Hz/6.4 Hz, 1H, SCHa), 3.14 (ddd,

J ¼ 13.5 Hz/8.2 Hz/6.4 Hz, 1H, SCHb), 3.38 (bs, 2H, NH₂), 3.60 (ddd,

J ¼ 9.9 Hz/6.1 Hz/2.6 Hz, 1H, OCHa), 3.70 (ddd, J ¼ 9.9 Hz/5.8 Hz/

2.5 Hz, 1H, OCHb), 3.79 (m, 2H, OCH₂CH₂OH), 3.97 (d, J ¼ 4.1 Hz, 1H,

4⁰-H), 4.53 (dd, J ¼ 5.4 Hz/1.2 Hz, 1H, 3a⁰-H), 4.59 (m, 1H, 6⁰-H), 4.61

(dd, J ¼ 5.5 Hz/1.8 Hz, 1H, 6a⁰-H), 6.17 (d, J ¼ 8.4 Hz, 1H, NH). ¹³C

To a solution of 13b.1 (1.0 g, 4.9 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(450 mg, 6.5 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.1 as a beige solid (1.0 g, 95% yield).

¹H NMR (DMSO‑d₆)

d

2.66 (s, 3H, SCH 3), 4.23 (s, 3H, NCH₃). ¹³C

NMR (DMSO‑d₆) 14.2, 33.3, 131.2, 150.8, 151.7, 170.3.

d

NMR (CDCl₃) d 13.5, 23.2, 23.8, 26.2, 32.5, 33.2, 56.8, 61.9, 70.4, 82.8,

84.5, 85.3, 110.3, 116.9, 144.5, 154.4, 162.0.

4.28. 7-Chloro-3-ethyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidine (14b.2)

To a solution of 13b.2 (1.0 g, 4.6 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(415 mg, 6.0 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.2 as a beige solid (0.92 g, 87% yield).

4.24. (3aR,4S,6R,6aS)-6-(7-chloro-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-ol (14c.1)

To a solution of 13c.1 (1.0 g, 3.1 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(275 mg, 4.0 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The resulting mixture was extracted

with ethyl acetate (3 ꢂ 50 mL) and the combined organic layers

were dried over MgSO₄and evaporated to give 14c.1 as an oily

¹H NMR (DMSO‑d₆)

d

1.56 (t, J ¼ 7.3 Hz, 3H, NCH₂CH₃), 2.65 (s, 3H,

SCH 3), 4.66 (q, J ¼ 7.3 Hz, 2H, NCH₂CH₃). ¹³C NMR (DMSO‑d₆)

d 14.2,

42.4, 131.4, 150.4, 151.7, 170.2.

4.29. 7-Chloro-5-(ethylthio)-3-methyl-3H-[1,2,3]triazolo[4,5-d]

pyrimidine (14b.3)

residue (0.95 g, 92% yield). ¹H NMR (DMSO‑d₆)

d 1.23 (s, 3H, CH₃),

1.48 (s, 3H, CH₃), 2.59 (m, 2H, 5⁰-H), 4.17 (td, J ¼ 6.1 Hz/2.6 Hz,1H, 4⁰-

H), 4.61 (dd, J ¼ 6.8 Hz/2.6 Hz, 1H, 3a⁰-H), 5.20 (bs, 1H, OH), 5.25 (dd,

J ¼ 7.3 Hz/3.6 Hz, 1H, 6⁰-H), 5.42 (dd, J ¼ 6.8 Hz/3.6 Hz, 1H, 6a⁰-H),

To a solution of 13b.3 (1.0 g, 4.6 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(415 mg, 6.0 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.3 as a beige solid (0.70 g, 87% yield).

9.11 (s, 1H, 2-H). ¹³C NMR (DMSO)

d 24.7, 26.9, 38.1, 62.1, 74.2, 82.3,

86.0, 112.1, 129.9, 148.4, 149.6, 155.3.

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

9

¹H NMR (DMSO‑d₆)

d

1.39 (t, J ¼ 7.3 Hz, 3H, SCH₂CH₃), 3.25 (q,

water (40 mL) was then added. The resulting mixture was extracted

with ethyl acetate (3 ꢂ 50 mL) and the combined organic layers

were dried over MgSO₄and evaporated to give 14b.8 as an oily

J ¼ 7.3 Hz, 2H, SCH₂CH₃), 4.22 (s, 3H, NCH₃). ¹³C NMR (DMSO‑d₆)

d

14.0, 25.5, 33.3, 131.3, 150.8, 151.8, 169.7.

residue (0.88 g, 85% yield). ¹H NMR (CDCl₃)

d

1.10 (t, J ¼ 7.4 Hz, 3H,

4.30. 7-Chloro-3-ethyl-5-(ethylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidine (14b.4)

SCH₂CH₂CH₃), 1.33 (s, 3H, CH₃), 1.54 (s, 3H, CH₃), 1.83 (h, J ¼ 7.3 Hz,

2H, SCH₂CH₂CH₃), 2.38 (d, J ¼ 15.3 Hz, 1H, 5⁰-Ha), 2.90 (m, 1H, 5⁰-

Hb), 3.24 (td, J ¼ 7.1 Hz/1.7 Hz, 2H, SCH₂CH₂CH₃), 3.76 (d, J ¼ 8.8 Hz,

1H, OH), 4.44 (m, 1H, 4⁰-H), 4.80 (d, J ¼ 5.6 Hz, 1H, 3a⁰-H), 5.04 (d,

J ¼ 5.7 Hz, 1H, 6a⁰-H), 5.34 (d, J ¼ 7.7 Hz, 1H, 6⁰-H). ¹³C NMR (CDCl₃)

To a solution of 13b.4 (1.0 g, 4.3 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(395 mg, 5.7 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.4 as a beige solid (0.88 g, 87% yield).

d

13.5, 22.1, 24.1, 26.6, 33.8, 37.0, 64.1, 76.7, 85.3, 87.6, 111.6, 132.0,

150.2, 153.7, 172.5.

¹H NMR (DMSO‑d₆)

d

1.39 (t, J ¼ 7.3 Hz, 3H, SCH₂CH₃), 1.56 (t,

4.35. 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (14b.9)

J ¼ 7.3 Hz, 3H, NCH₂CH₃), 3.24 (q, J ¼ 7.3 Hz, 2H, SCH₂CH₃), 4.66 (q,

J ¼ 7.3 Hz, 2H, NCH₂CH₃). ¹³C NMR (DMSO‑d₆)

d 13.9,14.2, 25.5, 42.5,

131.5, 150.4, 151.8, 169.6.

To a solution of 13b.9 (1.0 g, 2.4 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(225 mg, 3.2 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The resulting mixture was extracted

with ethyl acetate (3 ꢂ 50 mL) and the combined organic layers

were dried over MgSO₄and evaporated to give 14b.9 as an oily

4.31. 7-Chloro-3-methyl-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidine (14b.5)

To a solution of 13b.5 (1.0 g, 4.3 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(395 mg, 5.7 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.5 as an orange solid (0.87 g, 84%

residue (0.96 g, 94% yield). ¹H NMR (CDCl₃)

d

1.09 (t, J ¼ 7.4 Hz, 3H,

SCH₂CH₂CH₃), 1.37 (s, 3H, CH₃), 1.55 (s, 3H, CH₃), 1.83 (h, J ¼ 7.4 Hz,

2H, SCH₂CH₂CH₃), 2.14 (t, J ¼ 6.0 Hz, 1H, OH), 2.54 (m, 1H, 5⁰-Ha),

2.70 (m, 1H, 5⁰-Hb), 3.21 (t, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃), 3.49e3.65

(m, 4H, OCH₂CH₂OH), 4.05 (m, 1H, 4⁰-H), 4.88 (d, J ¼ 6.3 Hz, 1H, 3a⁰-

H), 5.21 (td, J ¼ 7.4 Hz/6.4 Hz/2.5 Hz, 1H, 6⁰-H), 5.53 (dd, J ¼ 6.3 Hz/

yield). ¹H NMR (DMSO‑d₆)

d

1.03 (t, J ¼ 7.1 Hz, 3H, SCH₂CH₂CH₃),

1.76 (h, J ¼ 7.0 Hz, 2H, SCH₂CH₂CH₃), 3.23 (t, J ¼ 7.1 Hz, 2H,

SCH₂CH₂CH₃), 4.22 (s, 3H, NCH₃). ¹³C NMR (DMSO‑d₆)

d 13.2, 21.7,

32.8, 33.2, 131.3, 150.8, 151.7, 169.8.

2.1 Hz,1H, 6a⁰-H). ¹³C NMR (CDCl₃)

d 13.6, 22.3, 24.5, 26.8, 33.9, 35.9,

61.8, 63.4, 70.7, 82.9, 83.6, 84.0, 112.4, 132.2, 150.7, 153.4, 171.8.

4.32. 7-Chloro-3-ethyl-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidine (14b.6)

4.36. (3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-

dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (15c.1)

To a solution of 13b.6 (1.0 g, 4.0 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(375 mg, 5.4 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.6 as an orange solid (0.90 g, 86%

The mixture of 14c.1 (0.5 g, 1.6 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.41 g, 2.4 mmol) and triethyl-

amine (0.29 mL, 2.05 mmol) in acetonitrile (10 mL) was left to react

at room temperature for 2 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 15c.1 as a white solid (0.67 g,

yield). ¹H NMR (DMSO‑d₆)

d

1.02 (t, J ¼ 7.4 Hz, 3H, SCH₂CH₂CH₃),

1.56 (t, J ¼ 7.3 Hz, 3H, NCH₂CH₃), 1.76 (h, J ¼ 7.4 Hz, 2H,

SCH₂CH₂CH₃), 3.24 (t, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃), 4.66 (q,

J ¼ 7.3 Hz, 2H, NCH₂CH₃). ¹³C NMR (DMSO‑d₆)

d

13.3, 14.2, 21.7, 32.9,

94% yield). ¹H NMR (DMSO‑d₆)

d

1.26 (s, 3H, CH₃), 1.37 (q, J ¼ 6.0 Hz,

42.5, 131.5, 150.3, 151.8, 169.7.

0.8H, 3⁰-Ha major), 1.42 (m, 0.2H, 3⁰-Ha minor), 1.47 (m, 3.2H, CH₃/

3⁰-Hb minor), 1.54 (dt, J ¼ 9.9 Hz/5.3 Hz, 0.8H, 3⁰-Hb major), 2.18

(ddd, J ¼ 9.4 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.26 (m, 0.2H, 2⁰-H

minor), 2.45e2.60 (m, 2H, 5⁰⁰⁰-H), 3.28 (dd, J ¼ 7.7 Hz/3.6 Hz, 0.8H,

1⁰-H major), 3.78 (m, 0.2H, 1⁰-H minor), 4.14 (m, 1H, 4⁰⁰⁰-H), 4.57 (dd,

J ¼ 7.1 Hz/2.8 Hz, 1H, 3a’’’-H), 5.08 (td, J ¼ 7.9 Hz/4.4 Hz, 1H, 6⁰⁰⁰-H),

5.22 (m, 0.2H, 6a’’’-H minor), 5.29 (m, 1.8H, 6a’’’-H major/OH), 7.03

(m, 0.2H, 2⁰⁰-H minor), 7.09 (m, 0.8H, 6⁰⁰-H major), 7.27e7.37 (m, 2H,

2⁰⁰-H/5⁰⁰-H), 8.32 (s, 0.2H, 2-H minor), 8.42 (s, 0.8H, 2-H minor), 9.01

(d, J ¼ 3.7 Hz, 0.2H, NH minor), 9.34 (d, J ¼ 4.0 Hz, 0.8H, NH major).

4.33. 7-Chloro-3-cyclopentyl-5-(propylthio)-3H-[1,2,3]triazolo[4,5-

d]pyrimidine (14b.7)

To a solution of 13b.7 (1.0 g, 3.5 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(320 mg, 4.6 mmol). The

mixture was allowed to reach room temperature within 1 h and

water (40 mL) was then added. The precipitate was ﬁltered and

washed with water to give 14b.7 as an orange solid (0.70 g, 67%

yield). ¹H NMR (DMSO‑d₆)

d

1.03 (t, J ¼ 7.3 Hz, 3H, SCH₂CH₂CH₃),

¹³C NMR (DMSO‑d₆)

d 15.2, 23.7, 24.7, 26.9, 33.9, 37.9, 62.1, 74.3,

1.76 (m, 4H, 3⁰-Ha/4⁰-Ha/SCH₂CH₂CH₃), 1.93 (m, 2H, 3⁰-Hb/4⁰-Hb),

2.24 (m, 4H, 2⁰-H₂/5⁰-H₂), 3.21 (t, J ¼ 7.1 Hz, 2H, SCH₂CH₂CH₃), 5.35

82.2, 86.0, 112.0, 114.8, 117.1, 122.9, 124.6, 139.2, 146.8, 148.1, 148.4,

148.7, 150.3, 155.0, 156.4, 156.5.

(p, J ¼ 7.1 Hz, 1H, 1⁰-H). ¹³C NMR (DMSO‑d₆)

d 13.2, 21.8, 24.3, 31.8,

32.8, 59.7, 131.8, 150.1, 151.7, 169.3.

4.37. (3aR,4S,6R,6aS)-6-(7-amino-5-chloro-3H-[1,2,3]triazolo[4,5-

d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-ol (15a.1)

4.34. (3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (14b.8)

The solution of 14a.1 (0.5 g, 1.45 mmol) in THF (10 mL) was

saturated with ammonia gas in a sealed vessel and left to react at

room temperature for 1 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 15a.1 as a white solid (0.45 g,

To a solution of 13b.8 (1.0 g, 2.7 mmol) in acetic acid (10 mL)

cooled on an ice bath was added NaNO₂(250 mg, 3.6 mmol). The

mixture was allowed to reach room temperature within 1 h and

10

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

95% yield). ¹H NMR (DMSO‑d₆)

d

1.26 (s, 3H, CH₃), 1.47 (s, 3H, CH₃),

156.9, 157.8.

2.42 (m, 1H, 5⁰-Ha), 2.55 (m, 1H, 5⁰-Hb), 4.13 (m, 1H, 4⁰-H), 4.56 (dd,

J ¼ 7.0 Hz/3.0 Hz, 1H, 3a⁰-H), 4.98 (ddd, J ¼ 8.6 Hz/7.0 Hz/4.2 Hz, 1H,

6⁰-H), 5.25 (m, 2H, OH/6a⁰-H), 8.64 (bs, 1H, NHa), 8.96 (bs, 1H, NHb).

4.40. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-3-methyl-5-

(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7a)

¹³C NMR (DMSO‑d₆)

d 24.7, 26.8, 37.8, 61.9, 74.2, 82.1, 85.9, 112.0,

123.6, 150.0, 156.5, 157.6.

The mixture of 14b.1 (0.5 g, 2.3 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.59 g, 3.45 mmol) and trie-

thylamine (0.42 mL, 2.95 mmol) in acetonitrile (10 mL) was left to

react at room temperature for 2 h. After evaporation of the solvent,

the residue was puriﬁed by column chromatography on silica gel

using hexane/ethyl acetate gradient to give 7a as a white solid

4.38. (3aR,4S,6R,6aS)-6-(5-chloro-7-(((1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-ol (15a.2)

(0.69 g, 86% yield, m.p.: 213e216 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.37 (q,

The mixture of 14a.1 (0.5 g, 1.45 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.37 g, 2.2 mmol) and triethyl-

amine (0.26 mL, 1.86 mmol) in acetonitrile (10 mL) was left to react

at room temperature for 30 min. After evaporation of the solvent,

the residue was puriﬁed by column chromatography on silica gel

using hexane/ethyl acetate gradient to give 15a.2 as a white solid

(0.59 g, 85% yield, decomposition at 85 ^ꢀC). ¹H NMR (DMSO‑d₆)

J ¼ 6.2 Hz, 0.8H, 3⁰-Ha major), 1.44 (m, 0.4H, 3⁰-H minor), 1.52 (m,

0.8H, 3⁰-Hb major), 2.14 (ddd, J ¼ 9.5 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H

major), 2.23 (m, 0.2H, 2⁰-H minor), 2.34 (s, 2.4H, SCH 3 major), 2.52

(s, 0.6H, SCH 3 minor), 3.15 (m, 0.8H,1⁰-H major), 3.76 (m, 0.2H,1⁰-H

minor), 4.04 (s, 0.6H, NCH₃minor), 4.06 (s, 2.4H, NCH₃major), 7.02

(m, 0.2H, 6⁰⁰-H minor), 7.09 (m, 0.8H, 6⁰⁰-H major), 7.22e7.36 (m, 2H,

2⁰⁰-H/5⁰⁰-H), 8.96 (d, J ¼ 4.6 Hz, 0.2H, NH minor), 9.34 (d, J ¼ 3.6 Hz,

d

1.25 (s, 0.9H, CH₃minor), 1.26 (s, 2.1H, CH₃major), 1.41e1.50 (m,

0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.6, 15.0, 24.0, 33.0, 33.9,

5H, CH₃/3⁰-H₂), 2.23 (ddd, J ¼ 9.7 Hz/6.6 Hz/3.3 Hz, 0.7H, 2⁰-H

major), 2.29 (ddd, J ¼ 9.5 Hz/6.5 Hz/3.2 Hz, 0.3H, 2⁰-H minor),

2.35e2.44 (m, 1H, 5⁰⁰⁰-Ha), 2.56 (m, 1H, 5⁰⁰⁰-Hb), 3.13 (dt, J ¼ 7.7 Hz/

3.9 Hz, 0., 1⁰-H major), 3.79 (m, 0.3H, 1⁰-H minor), 4.14 (m, 1H, 4⁰⁰⁰-

H), 4.54 (dd, J ¼ 7.0 Hz/2.8 Hz, 0.3H, 3a’’’-H minor), 4.57 (dd,

J ¼ 7.0 Hz/2.8 Hz, 0.7H, 3a’’’-H major), 4.97 (td, J ¼ 8.3 Hz/4.3 Hz,

0.3H, 6⁰⁰⁰-H minor), 5.00 (td, J ¼ 7.9 Hz/4.1 Hz, 0.7H, 6⁰⁰⁰-H major),

5.21 (dd, J ¼ 6.9 Hz/4.2 Hz, 0.3H, 6a’’’-H minor), 5.23 (d, J ¼ 4.6 Hz,

1H, OH), 5.27 (dd, J ¼ 6.9 Hz/4.1 Hz, 0.7H, 6a’’’-H major), 7.03 (bs,

0.3H, 6⁰⁰-H minor), 7.14 (bs, 0.7H, 6⁰⁰-H major), 7.25 (m, 0.3H, 2⁰⁰-H

minor), 7.31e7.37 (m,1H, 5⁰⁰-H), 7.40 (m, 0.7H, 2⁰⁰-H major), 9.55 (bs,

0.3H, NH minor), 9.81 (bs, 0.7H, NH major). ¹³C NMR (DMSO‑d₆)

115.0, 117.0, 122.6, 122.9, 139.2, 146.8, 148.4, 148.7, 148.9, 150.3,

153.9, 169.8. Anal. (C₁₅H₁₄F₂N₆S) theoretical: C, 51.71; H, 4.05; N,

24.12; S, 9.20. Found: C, 51.86; H, 4.27; N, 24.33, S, 9.13.

4.41. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-3-ethyl-5-

(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7b)

The mixture of 14b.2 (0.5 g, 2.2 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.56 g, 3.3 mmol) and triethyl-

amine (0.4 mL, 2.8 mmol) in acetonitrile (10 mL) was left to react at

room temperature for 2 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 7b as a white solid (0.58 g,

d

14.5, 23.7, 24.7, 26.9, 33.6, 37.9, 62.2, 74.3, 82.2, 86.0, 112.0, 117.1,

123.4, 124.1, 138.6, 146.9, 148.4, 149.5, 150.4, 151.1, 155.4, 156.2,

156.8, 157.7.

73% yield, m.p.: 164e165 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.37 (q,

J ¼ 6.2 Hz, 1H, 3⁰-Ha), 1.49 (m, 4H, 3⁰-Hb/NCH₂CH₃), 2.13 (ddd,

J ¼ 9.4 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.25 (m, 0.2H, 2⁰-H

minor), 2.33 (s, 2.4H, SCH 3 major), 2.52 (s, 0.6H, SCH 3 minor), 3.14

(m, 0.8H, 1⁰-H major), 3.78 (m, 0.2H, 1⁰-H minor), 4.49 (q, J ¼ 7.3 Hz,

2H, NCH₂CH₃), 7.02 (m, 0.2H, 6⁰⁰-H minor), 7.09 (m, 0.8H, 6⁰⁰-H

major), 7.22e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.95 (d, J ¼ 4.6 Hz, 0.2H, NH

minor), 9.35 (d, J ¼ 3.7 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

4.39. 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-yl)oxy)ethanol (15a.3)

The mixture of 14a.2 (0.5 g, 1.28 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.33 g, 1.9 mmol) and triethyl-

amine (0.23 mL, 1.64 mmol) in acetonitrile (10 mL) was left to react

at room temperature for 30 min. After evaporation of the solvent,

the residue was puriﬁed by column chromatography on silica gel

using hexane/ethyl acetate gradient to give 15a.3 as a yellowish

d 13.6, 14.5, 15.0, 24.0, 33.9, 41.3, 115.0, 117.0, 122.8, 123.0, 139.2,

146.8, 148.3, 148.7, 148.8, 150.3, 153.9, 169.8. Anal. (C₁₆H₁₆F₂N₆S)

theoretical: C, 53.03; H, 4.45; N, 23.19; S, 8.85. Found: C, 52.94; H,

4.75; N, 23.30, S, 8.64.

4.42. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-5-(ethylthio)-

3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7c)

solid (0.62 g, 92% yield). ¹H NMR (DMSO‑d₆)

d 1.26 (s, 0.9H, CH₃

minor), 1.27 (s, 2.1H, CH₃major), 1.42e1.50 (m, 5H, CH₃/3⁰-H₂), 2.24

(ddd, J ¼ 9.7 Hz/6.5 Hz/3.4 Hz, 0.7H, 2⁰-H major), 2.29 (ddd,

J ¼ 9.6 Hz/6.5 Hz/3.2 Hz, 0.3H, 2⁰-H minor), 2.5 (m, 1H, 5⁰⁰⁰-Ha), 2.66

(m, 1H, 5⁰⁰⁰-Hb), 3.14 (dt, J ¼ 7.8 Hz/3.9 Hz, 0.7H, 1⁰-H major),

3.38e3.51 (m, 4H, OCH₂CH₂OH), 3.77 (m, 0.3H, 1⁰-H minor), 4.00

(m, 1H, 4⁰⁰⁰-H), 4.56 (m, 1H, OH), 4.67 (dd, J ¼ 7.3 Hz/3.1 Hz, 0.3H,

3a’’’-H minor), 4.70 (dd, J ¼ 7.3 Hz/3.1 Hz, 0.7H, 3a’’’-H major), 5.01

(ddd, J ¼ 10.1 Hz/6.8 Hz/5.0 Hz, 0.3H, 6⁰⁰⁰-H minor), 5.04 (ddd,

J ¼ 9.7 Hz/6.8 Hz/4.7 Hz, 0.7H, 6⁰⁰⁰-H major), 5.17 (dd, J ¼ 7.3 Hz/

4.8 Hz, 0.3H, 6a’’’-H minor), 5.22 (dd, J ¼ 7.3 Hz/4.6 Hz, 0.7H, 6a’’’-H

major), 7.03 (d, J ¼ 8.3 Hz, 0.3H, 6⁰⁰-H minor), 7.14 (d, J ¼ 8.3 Hz,

0.7H, 6⁰⁰-H major), 7.25 (ddd, J ¼ 12.0 Hz/7.8 Hz/2.0 Hz, 0.3H, 2⁰⁰-H

minor), 7.31e7.37 (m,1H, 5⁰⁰-H), 7.40 (ddd, J ¼ 12.0 Hz/7.8 Hz/2.0 Hz,

0.7H, 2⁰⁰-H major), 9.56 (d, J ¼ 4.9 Hz, 0.3H, NH minor), 9.83 (d,

The mixture of 14b.3 (0.5 g, 2.2 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.56 g, 3.3 mmol) and triethyl-

amine (0.4 mL, 2.8 mmol) in acetonitrile (10 mL) was left to react at

room temperature for 2 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 7c as a white solid (0.45 g, 58%

yield, m.p.: 210e212 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

1.09 (t, J ¼ 7.3 Hz,

2.5 Hz, SCH₂CH₃major),1.35 (m,1.4H, 3⁰-Ha major/SCH₂CH₃minor),

1.44 (m, 0.4H, 3⁰-H minor), 1.56 (m, 0.8H, 3⁰-Hb major), 2.13 (ddd,

J ¼ 9.5 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.24 (m, 0.2H, 2⁰-H

minor), 2.89 (m, 1.6H, SCH₂CH₃major), 3.12 (m, 0.4H, SCH₂CH₃

minor), 3.17 (m, 0.8H, 1⁰-H major), 3.75 (m, 0.2H, 1⁰-H minor), 4.03

(s, 0.6H, NCH₃minor), 4.05 (s, 2.4H, NCH₃major), 7.01 (m, 0.2H, 6⁰⁰-

H minor), 7.07 (m, 0.8H, 6⁰⁰-H major), 7.21e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H),

8.96 (d, J ¼ 4.7 Hz, 0.2H, NH minor), 9.36 (d, J ¼ 3.8 Hz, 0.8H, NH

J ¼ 3.4 Hz, 0.7H, NH major). ¹³C NMR (DMSO‑d₆)

d 14.5, 23.7, 24.7,

26.8, 33.6, 35.5, 60.0, 61.7, 70.7, 81.9, 83.7, 112.5, 114.9, 115.6, 117.0,

123.4, 124.1, 138.6, 147.2, 148.6, 149.5, 150.0, 151.2, 155.4, 156.6,

major). ¹³C NMR (DMSO‑d₆)

d 14.6, 15.2, 24.0, 24.8, 32.4, 34.1, 114.7,

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

11

117.0, 122.7, 122.8, 139.4, 147.0, 148.4, 148.7, 149.4, 150.0, 153.9,

169.3. Anal. (C₁₆H₁₆F₂N₆S) theoretical: C, 53.03; H, 4.45; N, 23.19; S,

8.85. Found: C, 53.05; H, 4.65; N, 23.27, S, 8.41.

4.8H, 3⁰-Hb minor/SCH₂CH₂CH₃major/NCH₂CH₃), 1.56 (m, 0.8H, 3⁰-

Hb major), 1.70 (h, J ¼ 7.1 Hz, 0.4H, SCH₂CH₂CH₃minor), 2.13 (ddd,

J ¼ 9.5 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.25 (ddd, J ¼ 9.1 Hz/

6.2 Hz/3.2 Hz, 0.2H, 2⁰-H minor), 2.88 (m, 1.6H, SCH₂CH₂CH₃major),

3.10 (t, J ¼ 7.0 Hz, 0.4H, SCH₂CH₂CH₃minor), 3.16 (m, 0.8H, 1⁰-H

major), 3.76 (m, 0.2H, 1⁰-H minor), 4.48 (q, J ¼ 7.3 Hz, 2H, NCH₂CH₃),

7.02 (m, 0.2H, 2⁰⁰-H minor), 7.07 (m, 0.8H, 6⁰⁰-H major), 7.23e7.36

(m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.94 (d, J ¼ 4.0 Hz, 0.2H, NH minor), 9.35 (s,

4.43. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-5-(ethylthio)-

3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7d)

The mixture of 14b.4 (0.5 g, 2.05 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.52 g, 3.1 mmol) and triethyl-

amine (0.37 mL, 2.6 mmol) in acetonitrile (10 mL) was left to react

at room temperature for 2 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 7d as a white solid (0.69 g,

0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.0, 14.5, 15.0, 22.3, 24.0,

32.3, 34.1, 41.3, 114.8, 117.0, 122.8, 122.9, 139.4, 147.0, 148.4, 148.7,

148.8, 150.1, 153.9, 169.6. Anal. (C₁₈H₂₀F₂N₆S) theoretical: C, 55.37;

H, 5.16; N, 21.52; S, 8.21. Found: C, 55.30; H, 5.41; N, 21.64, S, 8.03.

90% yield, m.p.: 145e146.5 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

1.09 (t,

4.46. 3-Cyclopentyl-N-((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-

amine (7g)

J ¼ 7.3 Hz, 2.4H, SCH₂CH₃major), 1.35 (m, 1.4H, 3⁰-Ha major/

SCH₂CH₃minor), 1.44 (m, 0.2H, 3⁰-Ha minor), 1.47 (t, J ¼ 7.3 Hz,

3.2H, NCH₂CH₃/3⁰-Hb minor), 1.56 (m, 0.8H, 3⁰-Hb major), 2.12 (ddd,

J ¼ 9.5 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.24 (m, 0.2H, 2⁰-H

minor), 2.88 (m, 1.6H, SCH₂CH₃major), 3.11 (m, 0.4H, SCH₂CH₃

minor), 3.16 (m, 0.8H, 1⁰-H major), 3.77 (m, 0.2H, 1⁰-H minor), 4.48

(q, J ¼ 7.3 Hz, 2H, NCH₂CH₃), 7.02 (m, 0.2H, 6⁰⁰-H minor), 7.07 (m,

0.8H, 6⁰⁰-H major), 7.23e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.96 (d, J ¼ 3.9 Hz,

0.2H, NH minor), 9.37 (s, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

The mixture of 14b.7 (0.5 g, 1.67 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.42 g, 2.5 mmol) and triethyl-

amine (0.3 mL, 2.1 mmol) in acetonitrile (10 mL) was heated at

50 ^ꢀC for 2 h. After evaporation of the solvent, the residue was

puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 7g as a white solid (0.53 g, 74% yield,

d

14.5,14.6,15.2, 24.0, 24.8, 34.1, 41.3,114.8,117.0,122.8,122.9,139.4,

m.p.: 113.5e115 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.82 (t, J ¼ 7.2 Hz, 2.4H,

147.0, 148.4, 148.7, 148.9, 150.0, 154.0, 169.2. Anal. (C₁₇H₁₈F₂N₆S)

theoretical: C, 54.24; H, 4.82; N, 22.33; S, 8.52. Found: C, 54.25; H,

5.13; N, 22.48, S, 8.43.

SCH₂CH₂CH₃major), 0.99 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor),

1.38 (m, 1H, 3⁰-Ha), 1.44e1.55 (m, 2.6H, 3⁰-Hb/SCH₂CH₂CH₃major),

1.72 (m, 2.4H, SCH₂CH₂CH₃minor/3⁰⁰⁰-Ha/4⁰⁰⁰-Ha), 1.90 (m, 2H, 3⁰⁰⁰-

Hb/4⁰⁰⁰-Hb), 2.12e2.19 (m, 5H, 2⁰-H/2⁰⁰⁰-H₂/5⁰⁰⁰-H₂), 2.89 (m, 1.6H,

SCH₂CH₂CH₃major), 3.10 (m, 0.4H, SCH₂CH₂CH₃minor), 3.14 (m,

0.8H, 1⁰-H major), 3.78 (m, 0.2H, 1⁰-H minor), 5.15 (p, J ¼ 7.2 Hz, 1H,

1⁰⁰⁰-H), 7.02 (m, 0.2H, 6⁰⁰-H minor), 7.08 (m, 0.8H, 6⁰⁰-H major),

7.22e7.37 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.94 (bs, 0.2H, NH minor), 9.33 (bs,

4.44. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-3-methyl-5-

(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7e)

The mixture of 14b.5 (0.5 g, 2.05 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.52 g, 3.1 mmol) and triethyl-

amine (0.37 mL, 2.6 mmol) in acetonitrile (10 mL) was heated at

50 ^ꢀC for 2 h. After evaporation of the solvent, the residue was

puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 7e as a white solid (0.53 g, 69% yield,

0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.0, 15.0, 22.3, 24.0, 24.2,

31.8, 32.3, 34.0, 58.3, 114.8, 117.0, 122.8, 123.1, 139.3, 146.8, 148.4,

148.6, 148.7, 150.3, 153.9, 169.0. Anal. (C₂₁H₂₄F₂N₆S) theoretical: C,

58.59; H, 5.62; N, 19.52; S, 7.45. Found: C, 58.44; H, 5.62; N, 19.71, S,

7.49.

m.p.: 185e187 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.80 (t, J ¼ 7.4 Hz, 2.4H,

SCH₂CH₂CH₃major), 1.00 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor),

1.37 (m, 0.8H, 3⁰-Ha major), 1.43 (m, 0.2H, 3⁰-Ha minor), 1.49 (m,

1.8H, 3⁰-Hb minor/SCH₂CH₂CH₃major), 1.56 (m, 0.8H, 3⁰-Hb major),

1.70 (h, J ¼ 7.3 Hz, 0.4H, SCH₂CH₂CH₃minor), 2.13 (ddd, J ¼ 9.5 Hz/

6.3 Hz/3.2 Hz, 0.8H, 2⁰-H major), 2.23 (m, 0.2H, 2⁰-H minor), 2.88 (m,

1.6H, SCH₂CH₂CH₃major), 3.11 (t, J ¼ 7.2 Hz, 0.4H, SCH₂CH₂CH₃

minor), 3.17 (m, 0.8H, 1⁰-H major), 3.75 (m, 0.2H, 1⁰-H minor), 4.03

(s, 0.6H, NCH₃minor), 4.05 (s, 2.4H, NCH₃major), 7.02 (m, 0.2H, 6⁰⁰-

H minor), 7.07 (m, 0.8H, 6⁰⁰-H major), 7.22e7.37 (m, 2H, 2⁰⁰-H/5⁰⁰-H),

8.96 (s, 0.2H, NH minor), 9.36 (s, 0.8H, NH major). ¹³C NMR

4.47. (3aR,4S,6R,6aS)-6-(7-amino-5-(propylthio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (16a)

The solution of 14b.8 (0.5 g, 1.3 mmol) in THF (10 mL) was

saturated with ammonia gas in a sealed vessel and left to react at

room temperature for 1 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 16a as a white solid (0.38 g,

79% yield). ¹H NMR (DMSO‑d₆)

d

1.00 (t,

J

¼

7.4 Hz, 3H,

(DMSO‑d₆)

d

12.9, 15.1, 22.2, 24.0, 32.3, 32.4, 34.2, 117.0, 122.6, 122.7,

SCH₂CH₂CH₃), 1.26 (s, 3H, CH₃), 1.47 (s, 3H, CH₃), 1.71 (h, J ¼ 7.3 Hz,

2H, SCH₂CH₂CH₃), 2.47 (m, 1H, 5⁰-Ha), 2.56 (m, 1H, 5⁰-Hb), 3.08 (m,

2H, SCH₂CH₂CH₃), 4.13 (m, 1H, 4⁰-H), 4.54 (dd, J ¼ 7.0 Hz/3.0 Hz, 1H,

3a⁰-H), 4.99 (ddd, J ¼ 9.1 Hz/7.0 Hz/4.4 Hz, 1H, 6⁰-H), 5.25 (dd,

J ¼ 7.0 Hz/4.4 Hz,1H, 6a⁰-H), 5.28 (d, J ¼ 4.7 Hz,1H, OH), 8.09 (bs,1H,

139.4, 146.7, 148.4, 148.7, 149.3, 150.3, 153.8, 169.3. Anal.

(C₁₇H₁₈F₂N₆S) theoretical: C, 54.24; H, 4.82; N, 22.33; S, 8.52.

Found: C, 54.25; H, 4.87; N, 22.38, S, 7.89.

4.45. N-((1R,2S)-2-(3,4-diﬂuorophenyl)cyclopropyl)-3-ethyl-5-

(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (7f)

NHa), 8.43 (bs, 1H, NHb). ¹³C NMR (DMSO‑d₆)

d 13.4, 22.6, 24.7, 26.9,

32.2, 37.7, 61.9, 74.2, 82.1, 86.1, 111.9, 122.8, 149.4, 155.1, 169.3.

The mixture of 14b.6 (0.5 g, 1.95 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.50 g, 2.95 mmol) and trie-

thylamine (0.35 mL, 2.5 mmol) in acetonitrile (10 mL) was heated at

50 ^ꢀC for 2 h. After evaporation of the solvent, the residue was

puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 7f as a white solid (0.45 g, 59% yield,

4.48. (3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-ol (16b)

The mixture of 14b.8 (0.5 g, 1.3 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.33 g, 1.95 mmol) and trie-

thylamine (0.23 mL, 1.6 mmol) in acetonitrile (10 mL) was heated at

80 ^ꢀC for 2 h. After evaporation of the solvent, the residue was

m.p.: 136e138 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.81 (t, J ¼ 7.4 Hz, 2.4H,

SCH₂CH₂CH₃major), 0.99 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor),

1.37 (m, 0.8H, 3⁰-Ha major), 1.41 (m, 0.2H, 3⁰-Ha minor), 1.49 (m,

12

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 16b as a white solid (0.62 g, 92%

phenylcyclopropanamine hydrochloride (0.3 g, 1.74 mmol) and

triethylamine (0.21 mL, 1.45 mmol) in acetonitrile (10 mL) was

heated at 80 ^ꢀC for 2 h. After evaporation of the solvent, the residue

was puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 16e as a white solid (0.54 g, 88% yield).

yield). ¹H NMR (DMSO‑d₆)

d

0.84 (t, J ¼ 7.3 Hz, 2.4H, SCH₂CH₂CH₃

major), 1.00 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor), 1.26 (s, 3H,

CH₃), 1.38 (m, 1H, 3⁰-Ha), 1.47 (s, 3H, CH₃), 1.53 (m, 2.6H, 3⁰-Hb/

SCH₂CH₂CH₃major), 1.71 (h, J ¼ 7.1 Hz, 0.4H, SCH₂CH₂CH₃minor),

2.13 (m, 0.8H, 2⁰-H major), 2.25 (m, 0.2H, 2⁰-H minor), 2.45 (m, 1H,

5⁰⁰⁰-Ha), 2.54 (m, 1H, 5⁰⁰⁰-Hb), 2.88 (dt, J ¼ 13.6 Hz/7.2 Hz, 0.8H, SCHa

major), 2.94 (dt, J ¼ 14.2 Hz/7.2 Hz, 0.8H, SCHb major), 3.09 (m,

0.4H, SCH 2 minor), 3.15 (m, 0.8H, 1⁰-H major), 3.75 (m, 0.2H, 1⁰-H

minor), 4.13 (m, 1H, 4⁰⁰⁰-H), 4.55 (m, 1H, 3a’’’-H), 4.98 (m, 1H, 6⁰⁰⁰-H),

5.21 (m, 0.2H, 6a’’’-H minor), 5.25 (m, 1.8H, 6a’’’-H major/OH), 7.02

(bs, 0.2H, 6⁰⁰-H minor), 7.07 (bs, 0.8H, 6⁰⁰-H major), 7.22e7.36 (m,

2H, 2⁰⁰-H/5⁰⁰-H), 8.99 (d, J ¼ 4.7 Hz, 0.2H, NH minor), 9.38 (d,

¹H NMR (DMSO‑d₆)

d

0.83 (t, J ¼ 7.3 Hz, 2.4H, SCH₂CH₂CH₃major),

1.00 (m, 0.6H, SCH₂CH₂CH₃minor), 1.27 (s, 3H, CH₃), 1.33 (m, 1H, 3⁰-

Ha), 1.40 (m, 0.2H, 3⁰-Hb minor), 1.50 (m, 5.4H, CH₃/3⁰-Hb major/

SCH₂CH₂CH₃major), 1.71 (h, J ¼ 7.1 Hz, 0.4H, SCH₂CH₂CH₃minor),

2.14 (m, 0.8H, 2⁰-H major), 2.26 (m, 0.2H, 2⁰-H minor), 2.51 (m, 1H,

5⁰⁰⁰-Ha), 2.66 (m, 1H, 5⁰⁰⁰-Hb), 2.91 (m, 1.6H, SCH₂CH₂CH₃major),

3.09 (m, 0.4H, SCH₂CH₂CH₃minor), 3.20 (m, 0.8H, 1⁰-H major),

3.39e3.50 (m, 4H, OCH₂CH₂OH), 3.82 (m, 0.2H, 1⁰-H minor), 4.00

(m, 1H, 4⁰⁰⁰-H), 4.57 (t, J ¼ 4.6 Hz, 1H, OH), 4.67 (m, z, 1H, 6a’’’-H),

5.01 (m, 1H, 6⁰⁰⁰-H), 5,20 (m, 1H, 3a’’’-H), 7.19 (m, 3H, 2⁰⁰-H/4⁰⁰-H/6⁰⁰-

H), 7.29 (t, J ¼ 7.5 Hz, 2H, 3⁰⁰-H/5⁰⁰-H), 8.99 (d, J ¼ 4.4 Hz, 0.2H, NH

minor), 9.37 (d, J ¼ 3.6 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

J ¼ 4.0 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.1, 15.0, 22.4,

24.1, 24.8, 27.0, 32.4, 34.1, 37.9, 61.9, 74.3, 82.2, 86.2, 112.0, 114.9,

117.1, 122.9, 123.2, 139.4, 146.9, 148.5, 148.8, 149.1, 150.4, 154.0,

169.4.

d

13.1, 15.0, 22.4, 24.4, 24.8, 26.9, 32.5, 33.8, 35.4, 60.1, 61.4, 70.7,

81.9, 82.0, 83.7, 122.5, 125.7, 126.0, 128.2, 141.2, 149.1, 153.9, 169.5.

4.49. 2-(((3aR,4S,6R,6aS)-6-(7-amino-5-(propylthio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (16c)

4.52. 2-(((3aR,4S,6R,6aS)-6-(7-((3,4-diﬂuorophenethyl)amino)-5-

(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-

dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol

(16f)

The solution of 14b.9 (0.5 g, 1.16 mmol) in THF (10 mL) was

saturated with ammonia gas in a sealed vessel and left to react at

room temperature for 1 h. After evaporation of the solvent, the

residue was puriﬁed by column chromatography on silica gel using

hexane/ethyl acetate gradient to give 16c as a white solid (0.36 g,

The mixture of 14b.9 (0.5 g, 1.16 mmol), 2-(3,4-diﬂuorophenyl)

ethanamine (0.27 g, 1.74 mmol) and triethylamine (0.21 mL,

1.45 mmol) in acetonitrile (10 mL) was heated at 80 ^ꢀC for 2 h. After

evaporation of the solvent, the residue was puriﬁed by column

chromatography on silica gel using hexane/ethyl acetate gradient to

give 16f as a white solid (0.53 g, 83% yield). ¹H NMR (DMSO‑d₆)

75% yield). ¹H NMR (DMSO‑d₆)

d

1.00 (t,

J

¼

7.3 Hz, 3H,

SCH₂CH₂CH₃), 1.27 (s, 3H, CH₃), 1.49 (s, 3H, CH₃), 1.71 (h, J ¼ 7.2 Hz,

2H, SCH₂CH₂CH₃), 2.56 (dt, J ¼ 13.0 Hz/9.7 Hz, 1H, 5⁰-Ha), 2.67 (dt,

J ¼ 13.0 Hz/6.6 Hz, 1H, 5⁰-Hb), 3.08 (m, 2H, SCH₂CH₂CH₃), 3.40e3.51

(m, 4H, OCH₂CH₂OH), 4.01 (m, 1H, 4⁰-H), 4.56 (t, J ¼ 5.2 Hz, 1H, OH),

4.67 (dd, J ¼ 7.3 Hz/3.1 Hz, 1H, 3a⁰-H), 5.02 (m, 1H, 6⁰-H), 5.22 (dd,

J ¼ 7.2 Hz/4.9 Hz, 1H, 6a⁰-H), 8.10 (bs, 1H, NHa), 8.44 (bs, 1H, NHb).

d

0.99 (t, J ¼ 7.1 Hz, 3H, SCH₂CH₂CH₃), 1.26 (s, 3H, CH₃), 1.48 (s, 3H,

CH₃), 1.70 (h, J ¼ 7.3 Hz, 2H, SCH₂CH₂CH₃), 2.50 (m, 1H, 5⁰⁰⁰-Ha), 2.65

(m, 1H, 5⁰⁰⁰-Hb), 2.95 (m, 2H, 2⁰-H₂), 3.07 (m, 2H, SCH₂CH₂CH₃),

3.40e3.51 (m, 4H, OCH₂CH₂OH), 3.73 (q, J ¼ 6.8 Hz, 1.6H, 1⁰-H₂

major), 4.00 (m, 1H, 4⁰⁰⁰-H), 4.10 (q, J ¼ 6.9 Hz, 0.4H, 1⁰-H₂minor),

4.58 (t, J ¼ 5.0 Hz, 1H, OH), 4.67 (dd, J ¼ 7.3 Hz/3.2 Hz, 1H, 3a’’’-H),

5.01 (m, 1H, 6⁰⁰⁰-H), 5.19 (m, 0.2H, 6a’’’-H), 7.07 (m, 0.8H, 6⁰⁰-H ma-

jor), 7.15 (m, 0.2H, 6⁰⁰-H minor), 7.29e7.41 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.74

(t, J ¼ 6.3 Hz, 0.2H, NH minor), 9.09 (d, J ¼ 5.6 Hz, 0.8H, NH major).

¹³C NMR (DMSO‑d₆)

d 13.4, 22.6, 24.8, 26.9, 32.2, 35.3, 60.0, 61.4,

70.7, 81.9, 82.0, 83.8, 112.4, 122.8, 149.4, 155.1, 169.4.

4.50. 2-(((3aR,4S,6R,6aS)-6-(7-(Cyclopropylamino)-5-(propylthio)-

3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-

3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (16d)

¹³C NMR (DMSO‑d₆)

d 13.3, 22.7, 24.7, 26.9, 32.4, 33.5, 35.4, 41.1,

60.0, 61.3, 70.7, 81.8, 83.7, 112.5, 117.0, 117.6, 123.0, 125.4, 137.1, 147.0,

148.2, 149.0, 149.1, 150.4, 153.0, 169.4.

The mixture of 14b.9 (0.5 g, 1.16 mmol), cyclopropylamine

(0.12 g, 1.74 mmol) and triethylamine (0.21 mL, 1.45 mmol) in

acetonitrile (10 mL) was heated at 80 ^ꢀC for 2 h. After evaporation of

the solvent, the residue was puriﬁed by column chromatography on

silica gel using hexane/ethyl acetate gradient to give 16d as a white

4.53. 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]

dioxol-4-yl)oxy)ethanol (16g)

solid (0.48 g, 91% yield). ¹H NMR (DMSO‑d₆) 0.68 (m, 2H, 2⁰-Ha/3⁰-

d

Ha), 0.76 (m, 1.4H, 2⁰-Hb major/3⁰-Hb major), 0.87 (m, 0.6H, 2⁰-Hb

minor/3⁰-Hb minor),1.00 (t, J ¼ 7.3 Hz, 3H, SCH₂CH₂CH₃),1.26 (s, 3H,

CH₃), 1.49 (s, 3H, CH₃), 1.73 (m, 2H, SCH₂CH₂CH₃), 2.54 (m, 1H, 5⁰⁰-

Ha), 2.65 (m, 1H, 5⁰⁰-Hb), 3.05 (m, 0.7H, 1⁰-H major), 3.10 (m, 2H,

SCH₂CH₂CH₃), 3.39e3.51 (m, 4.3H, 1⁰-H minor/OCH₂CH₂OH), 4.00

(m, 1H, 4⁰⁰-H), 4.57 (bs, 1H, OH), 4.67 (dd, J ¼ 7.3 Hz/3.2 Hz, 1H, 6a’’-

H), 5.01 (m, 1H, 6⁰⁰-H), 5.20 (m, 1H, 3a’’-H), 8.83 (d, J ¼ 4.1 Hz, 0.3H,

NH minor), 9.11 (d, J ¼ 4.3 Hz, 0.7H, NH major). ¹³C NMR (DMSO‑d₆)

The mixture of 14b.9 (0.5 g, 1.16 mmol), (1R,2S)-2-(3,4-

diﬂuorophenyl)cyclopropanamine (0.3 g, 1.74 mmol) and triethyl-

amine (0.21 mL, 1.45 mmol) in acetonitrile (10 mL) was heated at

80 ^ꢀC for 2 h. After evaporation of the solvent, the residue was

puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 16g as a white solid (0.56 g, 86% yield).

¹H NMR (DMSO‑d₆)

d

0.84 (t, J ¼ 7.4 Hz, 2.4H, SCH₂CH₂CH₃major),

d

5.9, 7.5, 13.6, 22.7, 23.7, 24.7, 26.9, 32.5, 35.4, 60.0, 61.3, 70.7, 81.8,

1.00 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor), 1.26 (s, 3H, CH₃), 1.38

(m, 1H, 3⁰-Ha), 1.48 (s, 3H, CH₃), 1.53 (m, 2.6H, 3⁰-Hb/SCH₂CH₂CH₃

major), 1.71 (h, J ¼ 7.2 Hz, 0.4H, SCH₂CH₂CH₃minor), 2.13 (m, 0.8H,

2⁰-H major), 2.24 (m, 0.2H, 2⁰-H minor), 2.50 (m, 1H, 5⁰⁰⁰-Ha), 2.65

(m, 1H, 5⁰⁰⁰-Hb), 2.89 (m, 0.8H, SCHa major), 2.93 (m, 0.8H, SCHb

major), 3.08 (m, 0.4H, SCH 2 minor), 3.15 (m, 0.8H, 1⁰-H major),

3.39e3.51 (m, 4H, OCH₂CH₂OH), 3.75 (m, 0.2H,1⁰-H minor), 4.01 (m,

1H, 4⁰⁰⁰-H), 4.56 (t, J ¼ 5.2 Hz, 1H, OH), 4.64 (dd, J ¼ 7.3 Hz/3.2 Hz,

0.2H, 3a’’’-H minor), 4.68 (dd, J ¼ 7.3 Hz/3.2 Hz, 0.8H, 3a’’’-H major),

82.0, 83.7, 112.5, 148.9, 154.1, 169.4.

4.51. 2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(7-(((1R,2S)-2-

phenylcyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)

ethanol (16e)

The mixture of 14b.9 (0.5 g, 1.16 mmol), (1R,2S)-2-

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

13

5.01 (m, 1H, 6⁰⁰⁰-H), 5.17 (m, 0.2H, 6a’’’-H minor), 5.21 (m, 0.8H, 6a’’’-

H major), 7.02 (bs, 0.2H, 6⁰⁰-H minor), 7.08 (bs, 0.8H, 6⁰⁰-H major),

7.22e7.37 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 9.00 (d, J ¼ 4.7 Hz, 0.2H, NH minor),

1.6H, SCH₂CH₂CH₂OH major), 1.84 (p,

J

¼

6.7 Hz, 0.4H,

SCH₂CH₂CH₂OH minor), 2.14 (m, 0.8H, 2⁰-H major), 2.25 (m, 0.2H,

2⁰-H minor), 2.44 (m, 1H, 5⁰⁰⁰-Ha), 2.54 (m, 1H, 5⁰⁰⁰-Hb), 2.97 (dt,

J ¼ 13.8 Hz/7.1 Hz, 0.8H, SCHa major), 3.03 (dt, J ¼ 13.9 Hz/7.0 Hz,

0.8H, SCHb major), 3.16 (m, 1.2H, SCH 2 minor/1⁰-H major), 3.40 (q,

J ¼ 6.0 Hz, 1.6H, CH₂OH major), 3.53 (q, J ¼ 5.6 Hz, 0.4H, CH₂OH

minor), 3.76 (m, 0.2H, 1⁰-H minor), 4.13 (m, 1H, 4⁰⁰⁰-H), 4.49 (t,

J ¼ 5.1 Hz, 0.8H, CH₂OH major), 4.55 (m, 1.2H, CH₂OH minor/3a’’’-H),

4.98 (m, 1H, 6⁰⁰⁰-H), 5.22 (m, 0.2H, 6a’’’-H minor), 5.26 (m, 1.8H, 6a’’’-

H major/4⁰⁰⁰-OH), 7.02 (bs, 0.2H, 6⁰⁰-H minor), 7.08 (bs, 0.8H, 6⁰⁰-H

major), 7.22e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.99 (d, J ¼ 4.6 Hz, 0.2H, NH

minor), 9.37 (d, J ¼ 3.9 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

9.39 (d, J ¼ 3.9 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.1, 15.0,

22.4, 24.0, 24.8, 26.9, 32.4, 34.0, 35.5, 59.8, 60.0, 61.4, 70.7, 81.9, 83.7,

112.5, 114.9, 117.0, 122.9, 123.1, 139.3,146.9,148.5, 148.8, 149.1, 150.5,

153.9, 169.5.

4.54. (3aR,4S,6R,6aS)-6-(7-amino-5-((2-hydroxypropyl)thio)-3H-

[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (16h)

The mixture of 15a.1 (0.3 g, 0.92 mmol), 1-mercaptopropan-2-ol

(0.12 mL, 1.38 mmol) and K₂CO₃(0.19 g, 1.38 mmol) in acetonitrile

(3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h. After evap-

oration of the solvent, the residue was taken up with water (25 mL)

and extracted with dichloromethane (3 ꢂ 25 mL). The combined

organic layers were dried over MgSO₄, evaporated and puriﬁed by

column chromatography on silica gel using hexane/ethyl acetate

gradient to give 16h as an oily residue (0.27 g, 77% yield). ¹H NMR

d 15.0, 23.9, 24.7, 26.9, 27.3, 32.2, 33.9, 37.8, 59.3, 61.9, 74.3, 82.1,

86.1, 111.9, 115.0, 117.0, 122.9, 123.2, 139.2, 146.9, 148.4, 149.0, 150.4,

154.0, 169.4.

4.57. (3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(((R)-2-hydroxypropyl)thio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (16k)

(DMSO‑d₆)

d

1.18 (d, J ¼ 6.2 Hz, 3H, CHOHCH₃), 1.26 (s, 3H, CH₃), 1.47

(s, 3H, CH₃), 2.46 (m, 1H, 5⁰-Ha), 2.57 (m, 1H, 5⁰-Hb), 3.10 (ddd,

J ¼ 13.4 Hz/6.6 Hz/4.3 Hz, 1H, SCHa), 3.22 (dt, J ¼ 13.3 Hz/5.4 Hz, 1H,

SCHb), 3.89 (ddt, J ¼ 11.6 Hz/8.6 Hz/4.1 Hz, 1H, CHOHCH₃), 4.13 (m,

1H, 4⁰-H), 4.55 (m, 1H, 3a⁰-H), 4.86 (dd, J ¼ 4.9 Hz/1.4 Hz, 1H, 4⁰-OH),

4.98 (ddd, J ¼ 9.0 Hz/7.0 Hz/4.3 Hz, 1H, 6⁰-H), 5.25 (m, 1H, 6a⁰-H),

5.27 (d, J ¼ 4.8 Hz, 1H, CHOHCH₃), 8.10 (bs, 1H, NHa), 8.43 (bs, 1H,

The mixture of 15a.2 (0.3 g, 0.63 mmol), (R)-1-mercaptopropan-

2-ol (0.08 mL, 0.96 mmol) and K₂CO₃(0.13 g, 0.96 mmol) in

acetonitrile (3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h.

After evaporation of the solvent, the residue was taken up with

water (25 mL) and extracted with dichloromethane (3 ꢂ 25 mL).

The combined organic layers were dried over MgSO₄, evaporated

and puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 16k as a white solid (0.25 g, 75%

NHb). ¹³C NMR (DMSO‑d₆)

d 22.7, 24.8, 26.9, 37.8, 47.8, 61.8, 65.4,

74.2, 82.1, 86.1, 111.9, 122.8, 149.3, 155.1, 169.5.

yield). ¹H NMR (DMSO‑d₆)

d

1.01 (d, J ¼ 6.1 Hz, 2.4H, CHOHCH₃

4.55. (3aR,4S,6R,6aS)-6-(7-amino-5-((3-hydroxypropyl)thio)-3H-

[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (16i)

major), 1.18 (d, J ¼ 6.0 Hz, 0.6H, CHOHCH₃minor), 1.26 (s, 3H, CH₃),

1.38 (m, 1H, 3⁰-Ha), 1.47 (s, 3H, CH₃), 1.53 (m, 1H, 3⁰-Hb), 2.13 (m,

0.8H, 2⁰-H major), 2.24 (m, 0.2H, 2⁰-H minor), 2.43 (m, 1H, 5⁰⁰⁰-Ha),

2.55 (m, 1H, 5⁰⁰⁰-Hb), 2.88 (dd, J ¼ 13.4 Hz/7.0 Hz, 0.8H, SCHa major),

3.10e3.18 (m, 1.8H, SCHa minor/SCHb major/1⁰-H major), 3.23 (dd,

J ¼ 13.3 Hz/5.2 Hz, 0.2H, SCHb minor), 3.78 (m,1H, CHOHCH₃major/

1⁰-H minor), 3.90 (m, 0.2H, CHOHCH₃minor), 4.14 (bs, 1H, 4⁰⁰⁰-H),

4.56 (m, 1H, 3a’’’-H), 4.79 (d, J ¼ 4.8 Hz, 0.8H, CHOHCH₃major), 4.87

(d, J ¼ 4.2 Hz, 0.2H, CHOHCH₃minor), 4.99 (m, 1H, 6⁰⁰⁰-H), 5.22 (m,

0.2H, 6a’’’-H minor), 5.26 (m, 1.8H, 6a’’’-H major/4⁰⁰⁰-OH), 7.02 (bs,

0.2H, 6⁰⁰-H minor), 7.09 (bs, 0.8H, 6⁰⁰-H major), 7.22e7.36 (m, 2H, 2⁰⁰-

H/5⁰⁰-H), 9.00 (d, J ¼ 4.8 Hz, 0.2H, NH minor), 9.37 (d, J ¼ 4.0 Hz,

The mixture of 15a.1 (0.3 g, 0.92 mmol), 3-mercapto-1-propanol

(0.12 mL, 1.38 mmol) and K₂CO₃(0.19 g, 1.38 mmol) in acetonitrile

(3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h. After evap-

oration of the solvent, the residue was taken up with water (25 mL)

and extracted with dichloromethane (3 ꢂ 25 mL). The combined

organic layers were dried over MgSO₄, evaporated and puriﬁed by

column chromatography on silica gel using hexane/ethyl acetate

gradient to give 16i as an oily residue (0.25 g, 71% yield). ¹H NMR

(DMSO‑d₆)

d

1.26 (s, 3H, CH₃), 1.47 (s, 3H, CH₃), 1.84 (m, 2H,

0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 15.0, 22.5, 24.0, 24.7, 26.9,

SCH₂CH₂CH₂OH), 2.48 (m, 1H, 5⁰-Ha), 2.55 (m, 1H, 5⁰-Hb), 3.14 (t,

J ¼ 7.2 Hz, 2H, SCH 2), 3.52 (t, J ¼ 6.2 Hz, 1H, CH₂OH), 4.13 (m, 1H, 4⁰-

H), 4.55 (m, 2H, 3a⁰-H/CH₂OH), 4.98 (ddd, J ¼ 9.1 Hz/7.0 Hz/4.4 Hz,

1H, 6⁰-H), 5.26 (m, 2H, 6a⁰-H/4⁰-OH), 8.09 (bs, 1H, NHa), 8.43 (bs, 1H,

d 24.7, 26.9, 27.2, 32.3, 37.7, 59.5, 61.9,

74.2, 82.0, 86.1, 111.9, 122.8, 149.4, 155.1, 169.3.

33.9, 37.8, 39.3, 61.8, 65.1, 74.3, 82.1, 86.1, 111.9, 114.9, 117.1, 123.0,

123.1, 139.2, 144.5, 146.8, 148.5, 149.0, 150.3, 153.9, 155.4, 169.6.

4.58. (3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(((S)-2-hydroxypropyl)thio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-

cyclopenta[d][1,3]dioxol-4-ol (16l)

NHb). ¹³C NMR (DMSO‑d₆)

4.56. (3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-((3-hydroxypropyl)thio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d]

[1,3]dioxol-4-ol (16j)

The mixture of 15a.2 (0.3 g, 0.63 mmol), (S)-1-mercaptopropan-

2-ol (0.08 mL, 0.96 mmol) and K₂CO₃(0.13 g, 0.96 mmol) in

acetonitrile (3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h.

After evaporation of the solvent, the residue was taken up with

water (25 mL) and extracted with dichloromethane (3 ꢂ 25 mL).

The combined organic layers were dried over MgSO₄, evaporated

and puriﬁed by column chromatography on silica gel using hexane/

ethyl acetate gradient to give 16l as a white solid (0.28 g, 84% yield).

The mixture of 15a.2 (0.3 g, 0.63 mmol), 3-mercapto-1-propanol

(0.08 mL, 0.96 mmol) and K₂CO₃(0.13 g, 0.96 mmol) in acetonitrile

(3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h. After evap-

oration of the solvent, the residue was taken up with water (25 mL)

and extracted with dichloromethane (3 ꢂ 25 mL). The combined

organic layers were dried over MgSO₄, evaporated and puriﬁed by

column chromatography on silica gel using hexane/ethyl acetate

gradient to give 16j as a white solid (0.24 g, 72% yield). ¹H NMR

¹H NMR (DMSO‑d₆)

d

1.01 (d, J ¼ 6.1 Hz, 2.4H, CHOHCH₃major), 1.18

(d, J ¼ 6.0 Hz, 0.6H, CHOHCH₃minor), 1.25 (s, 3H, CH₃), 1.37 (m,

0.8H, 3⁰-Ha major), 1.40 (m, 0.2H, 3⁰-Ha minor), 1.47 (s, 3.2H, 3⁰-Hb

minor/CH₃), 1.51 (m, 0.8H, 3⁰-Hb major), 2.14 (m, 0.8H, 2⁰-H major),

2.24 (m, 0.2H, 2⁰-H minor), 2.43 (m, 1H, 4⁰⁰⁰-Ha), 2.55 (m, 1H, 4⁰⁰⁰-

Hb), 3.06 (m, 1.6H, SCH 2 major), 3.12 (m, 0.2H, SCHa minor), 3.17

(DMSO‑d₆)

d

1.26 (s, 3H, CH₃), 1.38 (q, J ¼ 6.3 Hz, 1H, 3⁰-Ha), 1.47 (s,

3H, CH₃), 1.52 (dt, J ¼ 9.9 Hz/5.4 Hz, 1H, 3⁰-Hb), 1.70 (p, J ¼ 6.6 Hz,

14

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

(m, 0.8H, 1⁰-H major), 3.23 (dd, J ¼ 13.5 Hz/5.1 Hz, 0.2H, SCHb mi-

nor), 3.77 (m, 1H, CHOHCH₃major/1⁰-H minor), 3.88 (m, 0.2H,

CHOHCH₃minor), 4.13 (bs, 1H, 4⁰⁰⁰-H), 4.56 (m, 1H, 3a’’’-H), 4.79 (d,

J ¼ 4.8 Hz, 0.8H, CHOHCH₃major), 4.86 (d, J ¼ 4.8 Hz, 0.2H,

CHOHCH₃minor), 4.99 (m, 1H, 6⁰⁰⁰-H), 5.20 (m, 0.2H, 6a’’’-H minor),

5.25 (m,1.8H, 6a’’’-H major/4⁰⁰⁰-OH), 7.02 (m, 0.2H, 6⁰⁰-H minor), 7.08

(m, 0.8H, 6⁰⁰-H major), 7.23e7.35 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.99 (d,

J ¼ 5.2 Hz, 0.2H, SCH₂CH₂CH₂OH minor), 4.58 (t, J ¼ 5.1 Hz, 1H,

OCH₂CH₂OH), 4.67 (m, 1H, 3a’’’-H), 5.02 (m, 1H, 6⁰⁰⁰-H), 5.18 (m,

0.2H, 6a’’’-H minor), 5.22 (dd, J ¼ 7.2 Hz/4.9 Hz, 0.8H, 6a’’’-H major),

7.02 (m, 0.2H, 6⁰⁰-H minor), 7.08 (m, 0.8H, 6⁰⁰-H major), 7.22e7.36

(m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.99 (d, J ¼ 4.6 Hz, 0.2H, NH minor), 9.37 (d,

J ¼ 3.8 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 15.1, 23.9, 24.8,

26.9, 27.4, 32.3, 33.9, 35.5, 59.3, 60.1, 61.5, 70.7, 81.9, 82.1, 83.7,112.5,

115.0,117.1,123.0,123.2,139.2,146.9,148.4,148.8,149.1,150.4,154.0,

169.5.

J ¼ 4.2 Hz, 0.2H, NH minor), 9.36 (d, J ¼ 3.1 Hz, 0.8H, NH major). ¹³

C

NMR (DMSO‑d₆)

d 15.0, 22.6, 23.9, 24.7, 26.9, 33.8, 37.8, 39.2, 61.8,

65.2, 74.3, 82.1, 86.1, 111.9, 115.0, 117.0, 123.0, 123.1, 139.1, 147.2,

148.5, 148.6, 148.9, 150.1, 150.3, 153.8, 155.4, 169.6.

4.61. (1S,2R,3S,4R)-4-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)

cyclopentane-1,2,3-triol (7u)

4.59. 1-((7-(((1R,2S)-2-(3,4-Diﬂuorophenyl)cyclopropyl)amino)-3-

((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-

3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-5-yl)thio)propan-2-ol (16m)

To a solution of 15c.1 (0.15 g, 0.34 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 7u as a white solid (0.12 g, 88%

The mixture of 15a.3 (0.3 g, 0.57 mmol), 1-mercaptopropan-2-ol

(0.07 mL, 0.87 mmol) and K₂CO₃(0.12 g, 0.87 mmol) in acetonitrile

(3 mL) was heated in a sealed vessel at 100 ^ꢀC for 3 h. After evap-

oration of the solvent, the residue was taken up with water (25 mL)

and extracted with dichloromethane (3 ꢂ 25 mL). The combined

organic layers were dried over MgSO₄, evaporated and puriﬁed by

column chromatography on silica gel using hexane/ethyl acetate

gradient to give 16m as a white solid (0.25 g, 74% yield). ¹H NMR

yield, m.p.: 148e152 ^ꢀC). ¹H NMR (DMSO‑d₆) 1.37 (m, 0.8H, 3⁰-Ha

d

major), 1.41 (m, 0.2H, 3⁰-Ha minor),1.49 (m, 0.2H, 3⁰-Hb minor),1.54

(m, 0.8H, 3⁰-Hb major), 1.94 (m, 1H, 5⁰⁰⁰-Ha), 2.19 (m, 0.8H, 2⁰-H

major), 2.26 (m, 0.2H, 2⁰-H minor), 2.63 (m, 1H, 5⁰⁰⁰-Hb), 3.29 (m,

0.8H, 1⁰-H major), 3.80 (m, 1H, 3⁰⁰⁰-H), 3.82 (m, 0.2H, 1⁰-H minor),

3.94 (m, 1H, 1⁰⁰⁰-H), 4.67 (m, 1H, 2⁰⁰⁰-H), 4.93 (d, J ¼ 3.6 Hz, 1H, 3⁰⁰⁰-

OH), 5.06 (m, 2H, 2⁰⁰⁰-OH, 4⁰⁰⁰-H), 5.16 (d, J ¼ 5.2 Hz, 1H, 1⁰⁰⁰-OH), 7.05

(m, 0.2H, 6⁰⁰-H minor), 7.09 (m, 0.8H, 6⁰⁰-H major), 7.27e7.36 (m, 2H,

2⁰⁰-H/5⁰⁰-H), 8.30 (s, 0.2H, 2-H minor), 8.40 (s, 0.8H, 2-H major), 8.95

(s, 0.2H, NH minor), 9.29 (d, J ¼ 4.0 Hz, 0.8H, NH major). ¹³C NMR

(DMSO‑d₆)

d

1.01 (d, J ¼ 6.1 Hz,1.2H, CHOHCH₃major R or S), 1.05 (d,

J ¼ 6.1 Hz, 1.2H, CHOHCH₃major R or S), 1.18 (m, 0.6H, CHOHCH₃

minor), 1.27 (s, 3H, CH₃), 1.38 (m, 1H, 3⁰-Ha), 1.49 (s, 3H, CH₃), 1.52

(m, 1H, 3⁰-Hb), 2.14 (m, 1H, 2⁰-H major), 2.25 (m, 1H, 2⁰-H minor),

2.50 (m, 1H, 5⁰⁰⁰-Ha), 2.66 (m, 1H, 5⁰⁰⁰-Hb), 2.88 (dd, J ¼ 13.5 Hz/

7.0 Hz, 0.4H, SCHa major R or S), 3.02 (dd, J ¼ 13.4 Hz/6.8 Hz, 0.4H,

SCHa major R or S), 3.08e3.17 (m, 2H, SCHa minor/SCHb/1⁰-H ma-

jor), 3.40e3.50 (m, 4H, OCH₂CH₂OH), 3.76 (m, 1H, CHOH major/1⁰-H

minor), 3.88 (m, 0.2H, CHOH minor), 4.00 (m, 1H, 4⁰⁰⁰-H), 4.56 (t,

J ¼ 4.5 Hz, 1H, OCH₂CH₂OH), 4.67 (m, 1H, 3a’’’-H), 4.79 (m, 0.8H,

CHOH major), 4.85 (m, 0.2H, CHOH minor), 5.02 (m, 1H, 6⁰⁰⁰-H), 5.17

(m, 0.2H, 6a’’’-H minor), 5.22 (m, 0.8H, 6a’’’-H major), 7.02 (bs, 0.2H,

6⁰⁰-H minor), 7.09 (bs, 1H, 6⁰⁰-H major), 7.22e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-

H), 9.00 (d, J ¼ 4.5 Hz, 0.2H, NH minor), 9.37 (m, 0.8H, NH major).

(DMSO‑d₆)

d 15.3, 23.7, 33.9, 36.1, 59.8, 61.2, 73.3, 74.9, 76.8, 114.9,

117.2, 123.0, 124.6, 139.3, 147.1, 148.4, 148.5, 148.7, 150.1, 154.8, 156.1,

156.2. Anal. (C₁₈H₁₈F₂N₆O₃.H₂O) theoretical: C, 51.18; H, 4.77; N,

19.90. Found: C, 51.23; H, 4.74; N, 19.60.

4.62. (1S,2R,3S,4R)-4-(5-chloro-7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)

cyclopentane-1,2,3-triol (7v)

¹³C NMR (DMSO‑d₆)

d 15.0, 22.5, 22.6, 23.9, 24.8, 26.9, 33.8, 35.5,

39.2, 60.0, 61.4, 65.1, 70.7, 81.9, 82.0, 83.7, 112.5, 115.0, 117.1, 123.0,

123.1, 139.2, 146.9, 148.5, 148.7, 149.0, 150.4, 153.9, 169.7.

To a solution of 15a.2 (0.15 g, 0.31 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 7v as a white solid (0.11 g, 80%

4.60. 3-((7-(((1R,2S)-2-(3,4-Diﬂuorophenyl)cyclopropyl)amino)-3-

((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-

3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-5-yl)thio)propan-1-ol (16n)

The mixture of 15a.3 (0.3 g, 0.57 mmol), 3-mercapto-1-propanol

(0.07 mL, 0.87 mmol) and K₂CO₃(0.12 g, 0.87 mmol) in acetonitrile

(3 mL) was heated in a sealed vessel at 100 ^ꢀC for 1 h. After evap-

oration of the solvent, the residue was taken up with water (25 mL)

and extracted with dichloromethane (3 ꢂ 25 mL). The combined

organic layers were dried over MgSO₄, evaporated and puriﬁed by

column chromatography on silica gel using hexane/ethyl acetate

gradient to give 16n as a white solid (0.22 g, 65% yield). ¹H NMR

yield, m.p.: 195e200 ^ꢀC). ¹H NMR (DMSO‑d₆) 1.42e1.50 (m, 2H, 3⁰-

d

H), 1.89 (m, 1H, 5⁰⁰⁰-Ha), 2.18 (ddd, J ¼ 9.6 Hz/6.5 Hz/3.3 Hz, 0.7H, 2⁰-

H major), 2.29 (ddd, J ¼ 9.6 Hz/6.4 Hz/3.2 Hz, 0.3H, 2⁰-H minor), 2.63

(m, 1H, 5⁰⁰⁰-Hb), 3.14 (m, 0.7H, 1⁰-H major), 3.77 (m, 1H, 3⁰⁰⁰-H), 3.82

(m, 0.3H, 1⁰-H minor), 3.94 (m, 1H, 1⁰⁰⁰-H), 4.56 (m, 0.3H, 2⁰⁰⁰-H mi-

nor), 4.61 (m, 0.7H, 2⁰⁰⁰-H major), 4.96 (m, 2H, 3⁰⁰⁰-OH/4⁰⁰⁰-H), 5.05 (d,

J ¼ 6.4 Hz, 0.3H, 2⁰⁰⁰-OH minor), 5.08 (d, J ¼ 6.4 Hz, 0.7H, 2⁰⁰⁰-OH

major), 5.13 (d, J ¼ 4.1 Hz, 0.3H, 1⁰⁰⁰-OH minor), 5.15 (d, J ¼ 4.0 Hz,

0.7H, 1⁰⁰⁰-OH major), 7.04 (m, 0.3H, 6⁰⁰-H minor), 7.14 (m, 0.7H, 6⁰⁰-H

major), 7.24e7.42 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 9.53 (d, J ¼ 5.0 Hz, 0.3H, NH

minor), 9.81 (d, J ¼ 3.9 Hz, 0.7H, NH major). ¹³C NMR (DMSO‑d₆)

(DMSO‑d₆)

d

1.27 (s, 3H, CH₃), 1.37 (q, J ¼ 6.2 Hz, 1H, 3⁰-Ha), 1.49 (s,

3H, CH₃), 1.52 (dt, J ¼ 10.4 Hz/5.5 Hz, 1H, 3⁰-Hb), 1.70 (p, J ¼ 6.7 Hz,

1.6H, SCH₂CH₂CH₂OH major), 1.84 (p,

J

¼

6.7 Hz, 0.4H,

SCH₂CH₂CH₂OH minor), 2.15 (ddd, J ¼ 9.5 Hz/6.4 Hz/3.3 Hz, 0.8H,

2⁰-H major), 2.24 (m, 0.2H, 2⁰-H minor), 2.51 (m, 1H, 5⁰⁰⁰-Ha), 2.66

(m, 1H, 5⁰⁰⁰-Hb), 3.00 (m, 1.6H, SCH₂CH₂CH₂OH major), 3.16 (m, 1.2H,

SCH₂CH₂CH₂OH minor/1⁰-H major), 3.38e3.54 (m, 6H,

SCH₂CH₂CH₂OH/OCH₂CH₂OH), 3.74 (m, 0.2H, 1⁰-H minor), 4.00 (m,

1H, 4⁰⁰⁰-H), 4.50 (t, J ¼ 5.1 Hz, 0.8H, SCH₂CH₂CH₂OH major), 4.55 (t,

d

14.6, 23.7, 24.4, 33.6, 35.6, 36.1, 36.2, 61.0, 73.2, 75.1, 76.7, 114.9,

115.6, 117.1, 122.9, 123.5, 123.6, 124.0, 138.6, 147.2, 148.6, 150.0, 150.1,

151.7, 155.4, 156.6, 156.8, 157.6. Anal. (C₁₈H₁₇ClF₂N₆O₃.H₂O) theo-

retical: C, 47.32; H, 4.19; N, 18.40. Found: C, 47.51; H, 4.07; N, 18.08.

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

15

4.63. (1S,2R,3S,4R)-4-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7h)

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7j as a white solid

To a solution of 16a (0.15 g, 0.41 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7h as a white solid

(0.09 g, 66% yield, m.p.: 180e182 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 0.99 (t,

J ¼ 7.3 Hz, 3H, SCH₂CH₂CH₃), 1.69 (h, J ¼ 7.2 Hz, 2H, SCH₂CH₂CH₃),

2.06 (ddd, J ¼ 14.3 Hz/9.8 Hz/5.0 Hz, 1H, 4⁰-Ha), 2.63 (m, 1H, 4⁰-Hb),

3.08 (m, 2H, SCH₂CH₂CH₃), 3.46e3.52 (m, 4H, OCH₂CH₂OH), 3.76 (t,

J ¼ 6.1 Hz, 1H, 5⁰-H), 3.94 (m, 1H, 1⁰-H), 4.60 (m, 2H, 2⁰-H/OCH₂

-

CH₂OH), 4.97 (q, J ¼ 9.1 Hz, 1H, 3⁰-H), 5.06 (d, J ¼ 3.9 Hz, 1H, 1⁰-OH),

5.13 (d, J ¼ 6.4 Hz,1H, 2⁰-OH), 8.07 (s, 1H, NHa), 8.42 (s,1H, NHb). ¹³C

(0.05 g, 37% yield, m.p.: 175e180 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.99 (t,

NMR (DMSO‑d₆) d 13.3, 22.4, 32.1, 33.1, 60.3, 60.7, 70.8, 73.7, 74.1,

J ¼ 7.3 Hz, 3H, SCH₂CH₂CH₃), 1.68 (h, J ¼ 7.1 Hz, 2H, SCH₂CH₂CH₃),

1.99 (ddd, J ¼ 13.5 Hz/9.1 Hz/4.4 Hz, 1H, 5⁰-Ha), 2.58 (ddd,

J ¼ 13.7 Hz/9.1 Hz/7.2 Hz, 1H, 5⁰-Hb), 3.08 (m, 2H, SCH₂CH₂CH₃),

3.78 (m, 1H, 2⁰-H), 3.93 (m, 1H, 1⁰-H), 4.68 (m, 1H, 3⁰-H), 4.96 (q,

J ¼ 9.0 Hz, 1H, 4⁰-H), 5.08 (bs, 3H, 1⁰⁰⁰-OH/2⁰⁰⁰-OH/3⁰⁰⁰-OH), 8.05 (bs,

81.7, 122.8, 149.6, 155.1, 169.0. Anal. (C₁₄H₂₂N₆O₄S) theoretical: C,

45.39; H, 5.99; N, 22.69; S, 8.66. Found: C, 45.66; H, 6.33; N, 22.53, S,

8.58.

4.66. (1S,2S,3R,5S)-3-(7-(Cyclopropylamino)-5-(propylthio)-3H-

[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)

cyclopentane-1,2-diol (7k)

1H, NHa), 8.40 (bs,1H, NHb). ¹³C NMR (CDCl₃)

d 13.3, 22.5, 32.1, 35.8,

61.2, 73.2, 74.3, 76.8, 122.8, 149.6, 155.1, 169.0. Anal.

(C₁₂H₁₈N₆O₃S.H₂O) theoretical: C, 41.85; H, 5.85; N, 24.40. Found: C,

41.83; H, 5.51; N, 24.18.

To a solution of 16d (0.15 g, 0.33 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7k as a white solid

4.64. (1S,2R,3S,4R)-4-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)cyclopentane-1,2,3-triol (7i)

To a solution of 16b (0.15 g, 0.29 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 7i as a white solid (0.104 g, 75%

(0.09 g, 66% yield, m.p.: 156e158 ^ꢀC). ¹H NMR (DMSO‑d₆)

2H, 2⁰-Ha/3⁰-Ha), 0.76 (m, 1.4H, 2⁰-Hb major/3⁰-Hb major), 0.87 (m,

0.6H, 2⁰-Hb minor/3⁰-Hb minor), 0.99 (t,

7.3 Hz, 3H,

d 0.69 (m,

J

¼

SCH₂CH₂CH₃), 1.71 (m, 2H, SCH₂CH₂CH₃), 2.04 (ddd, J ¼ 14.1 Hz/

9.8 Hz/5.0 Hz, 1H, 4⁰⁰-Ha), 2.65 (m, 1H, 4⁰⁰-Hb), 3.05 (m, 0.7H, 1⁰-H

major), 3.12 (m, 2H, SCH₂CH₂CH₃), 3.42e3.52 (m, 4.3H, 1⁰-H minor/

OCH₂CH₂OH), 3.75 (m,1H, 5⁰⁰-H), 3.94 (m,1H,1⁰⁰-H), 4.56 (m, 1H, 2⁰⁰-

H), 4.61 (m, 1H, OCH₂CH₂OH), 4.96 (m, 1H, 3⁰⁰-H), 5.06 (bs, 1H, 1⁰⁰-

OH), 5.13 (bs, 1H, 2⁰⁰-OH), 8.78 (d, J ¼ 2.6 Hz, 0.3H, NH minor), 9.08

yield, m.p.: 60e65 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.81 (t, J ¼ 7.4 Hz, 2.4H,

SCH₂CH₂CH₃major), 0.99 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃minor),

1.38 (dq, J ¼ 13.8 Hz/6.4 Hz, 1H, 3⁰-Ha), 1.49 (tq, J ¼ 13.6 Hz/6.9 Hz,

1.8H, SCH₂CH₂CH₃major/3⁰-Hb minor), 1.56 (dt, J ¼ 10.2 Hz/5.5 Hz,

0.8H, 3⁰-Hb major), 1.68 (h, J ¼ 7.1 Hz, 0.4H, SCH₂CH₂CH₃minor),

1.91 (ddd, J ¼ 13.6 Hz/9.0 Hz/4.3 Hz, 1H, 5⁰⁰⁰-Ha), 2.13 (ddd,

J ¼ 9.5 Hz/6.3 Hz/3.5 Hz, 0.8H, 2⁰-H major), 2.25 (m, 0.2H, 2⁰-H

minor), 2.59 (ddd, J ¼ 13.7 Hz/9.1 Hz/7.3 Hz, 1H, 5⁰⁰⁰-Hb), 2.85 (dt,

J ¼ 13.6 Hz/7.2 Hz, 0.8H, SCHa major), 2.95 (dt, J ¼ 13.9 Hz/7.1 Hz,

0.8H, SCHb major), 3.09 (m, 0.4H, SCH 2 minor), 3.16 (m, 0.8H, 1⁰-H

major), 3.78 (m, 1.2H, 1⁰-H minor/2⁰⁰⁰-H), 3.93 (dt, J ¼ 6.7 Hz/3.3 Hz,

1H, 1⁰⁰⁰-H), 4.65 (m, 1H, 3⁰⁰⁰-H), 4.91 (d, J ¼ 3.9 Hz, 1H, 2⁰⁰⁰-OH), 4.95

(q, J ¼ 9.0 Hz, 1H, 4⁰⁰⁰-H), 4.99 (d, J ¼ 6.5 Hz, 0.2H, 3⁰⁰⁰-OH minor),

5.02 (d, J ¼ 6.4 Hz, 0.8H, 3⁰⁰⁰-OH major), 5.07 (d, J ¼ 3.8 Hz, 0.2H, 1⁰⁰⁰-

OH minor), 5.10 (d, J ¼ 4.1 Hz, 0.8H,1⁰⁰⁰-OH major), 7.03 (bs, 0.2H, 6⁰⁰-

H minor), 7.07 (bs, 0.8H, 6⁰⁰-H major), 7.24e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H),

8.93 (d, J ¼ 4.7 Hz, 0.2H, NH minor), 9.35 (d, J ¼ 4.0 Hz, 0.8H, NH

(d, J ¼ 2.1 Hz, 0.7H, NH major). ¹³C NMR (DMSO‑d₆)

d 5.9, 7.5, 13.3,

22.7, 23.7, 24.7, 26.1, 32.5, 33.2, 60.3, 61.5, 70.8, 73.6, 74.0, 74.3, 81.8,

123.1, 149.2, 154.1, 169.1. Anal. (C₁₇H₂₆N₆O₄S) theoretical: C, 49.74;

H, 6.38; N, 20.47; S, 7.81. Found: C, 49.90; H, 6.44; N, 20.57, S, 7.10.

4.67. (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-phenylcyclopropyl)amino)-5-

(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-

hydroxyethoxy)-cyclopentane-1,2-diol (7l)

To a solution of 16e (0.15 g, 0.28 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 7l as a white solid (0.11 g, 79%

major). ¹³C NMR (DMSO‑d₆)

d 13.0, 15.0, 22.3, 24.0, 32.3, 34.1, 36.0,

61.0, 73.2, 74.5, 76.8, 114.8, 117.0, 122.8, 123.1, 139.3, 147.1, 148.5,

149.4, 150.1, 153.9, 169.1. Anal. (C₂₁H₂₄F₂N₆O₃S) theoretical: C,

52.71; H, 5.06; N, 17.56; S, 6.70. Found: C, 52.31; H, 5.26; N, 17.50, S,

6.28.

yield, m.p.: 174e179 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.80 (t, J ¼ 7.4 Hz,

2.4H, SCH₂CH₂CH₃major), 0.99 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃

minor), 1.32 (m, 1H, 3⁰-Ha), 1.40 (m, 0.2H, 3⁰-Hb minor), 1.50 (m,

2.4H, 3⁰-Hb major/SCH₂CH₂CH₃major), 1.69 (h, J ¼ 7.1 Hz, 0.4H,

SCH₂CH₂CH₃minor), 2.04 (ddd, J ¼ 14.1 Hz/9.7 Hz/5.0 Hz, 1H, 4⁰⁰⁰-

Ha), 2.12 (ddd, J ¼ 9.5 Hz/6.3 Hz/3.3 Hz, 0.8H, 2⁰-H major), 2.26 (m,

0.2H, 2⁰-H minor), 2.63 (m, 1H, 4⁰⁰⁰-Hb), 2.88 (m, 1.6H, SCH₂CH₂CH₃

major), 3.09 (m, 0.4H, SCH₂CH₂CH₃minor), 3.20 (dq, J ¼ 7.9 Hz/

4.4 Hz, 0.8H, 1⁰-H major), 3.45e3.53 (m, 4H, OCH₂CH₂OH), 3.75 (m,

1H, 5⁰⁰⁰-H), 3.85 (m, 0.2H, 1⁰-H minor), 3.93 (m, 1H, 1⁰⁰⁰-H), 4.54 (m,

1H, 2⁰⁰⁰-H), 4.61 (t, J ¼ 5.0 Hz, 1H, OCH₂CH₂OH), 4.96 (q, J ¼ 9.1 Hz,

4.65. (1S,2S,3R,5S)-3-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

(7j)

To a solution of 16c (0.15 g, 0.37 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

16

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

1H, 3⁰⁰⁰-H), 5.05 (d, J ¼ 4.1 Hz, 1H, 1⁰⁰⁰-OH), 5.12 (d, J ¼ 6.4 Hz, 1H, 2⁰⁰⁰-

OH), 7.18 (m, 3H, 2⁰⁰-H/4⁰⁰-H/6⁰⁰-H), 7.29 (t, J ¼ 7.6 Hz, 2H, 3⁰⁰-H/5⁰⁰-

H), 8.96 (d, J ¼ 4.9 Hz, 0.2H, NH minor), 9.35 (d, J ¼ 4.3 Hz, 0.8H, NH

22.3, 24.0, 32.3, 33.2, 34.1, 60.3, 60.5, 70.8, 73.7, 74.3, 81.8, 114.8,

117.0, 122.8, 123.2, 139.3, 146.8, 148.4, 148.7, 149.4, 150.3, 150.8,

154.0, 169.2. Anal. (C₂₃H₂₈F₂N₆O₄S) theoretical: C, 52.86; H, 5.40; N,

16.08; S, 6.13. Found: C, 52.75; H, 5.75; N, 16.06, S, 6.26.

major). ¹³C NMR (DMSO‑d₆)

d 13.0, 15.0, 22.3, 24.5, 32.4, 33.2, 33.9,

60.3, 60.4, 70.8, 73.6, 74.4, 81.7, 123.1, 125.6, 125.9, 128.2, 141.2,

149.4, 153.8, 169.1. Anal. (C₂₃H₃₀N₆O₄S) theoretical: C, 56.77; H,

6.21; N, 17.27; S, 6.59. Found: C, 56.64; H, 6.20; N, 17.08, S, 6.26.

4.70. (1S,2R,3S,4R)-4-(7-amino-5-((2-hydroxypropyl)thio)-3H-

[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7n)

4.68. (1S,2S,3R,5S)-3-(7-((3,4-diﬂuorophenethyl)amino)-5-

(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-

hydroxyethoxy)cyclopentane-1,2-diol (7m)

To a solution of 16h (0.15 g, 0.39 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7n as a white solid

To a solution of 16f (0.15 g, 0.27 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 7m as a white solid (0.10 g, 72%

(0.07 g, 52% yield, m.p.: 177e180 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.16 (d,

J ¼ 5.7 Hz, 3H, CH₃), 1.94 (ddt, J ¼ 13.2 Hz/8.5 Hz/4.1 Hz, 1H, 5⁰-Ha),

2.57 (m, 1H, 5⁰-Hb), 3.17 (m, 2H, SCH 2), 3.78 (bs, 1H, 2⁰-H), 3.87 (m,

1H, SCH₂CHOH), 3.93 (m, 1H, 1⁰-H), 4.67 (m, 1H, 3⁰-H), 4.85 (d,

J ¼ 4.6 Hz, 0.5H, S-SCH₂CHOH), 4.87 (d, J ¼ 4.8 Hz, 0.5H,

ReSCH₂CHOH), 4.95e4.98 (m, 2H, 2⁰-OH/4⁰-H), 5.04 (bs, 1H, 3⁰-OH),

5.17 (d, J ¼ 3.3 Hz, 1H, 1⁰-OH), 8.07 (s, 1H, NHa), 8.42 (s, 1H, NHb). ¹³C

yield, m.p.: 137e142 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.97 (t, J ¼ 7.3 Hz, 3H,

SCH₂CH₂CH₃), 1.69 (h, J ¼ 6.9 Hz, 2H, SCH₂CH₂CH₃), 2.03 (ddd,

J ¼ 14.0 Hz/9.7 Hz/4.9 Hz, 1H, 4⁰⁰⁰-Ha), 2.63 (m, 1H, 4⁰⁰⁰-Hb), 2.94 (t,

J ¼ 7.1 Hz, 2H, 2⁰-H₂), 3.08 (m, 2H, SCH₂CH₂CH₃), 3.45e3.52 (m, 4H,

OCH₂CH₂OH), 3.74 (m, 2.6H, 1⁰-H₂major/5⁰⁰⁰-H), 3.94 (m, 1H, 1⁰⁰⁰-H),

4.10 (m, 0.4H, 1⁰-H₂minor), 4.55 (m, 1H, 2⁰⁰⁰-H), 4.61 (t, J ¼ 5.0 Hz,

1H, OCH₂CH₂OH), 4.96 (q, J ¼ 9.2 Hz, 1H, 3⁰⁰⁰-H), 5.06 (d, J ¼ 4.1 Hz,

1H, 1⁰⁰⁰-OH), 5.12 (d, J ¼ 6.4 Hz, 1H, 2⁰⁰⁰-OH), 7.08 (m, 0.8H, 6⁰⁰-H

major), 7.17 (m, 0.2H, 6⁰⁰-H minor), 7.30e7.42 (m, 2H, 2⁰⁰-H/5⁰⁰-H),

8.70 (t, J ¼ 6.4 Hz, 0.2H, NH minor), 9.06 (d, J ¼ 5.6 Hz, 0.8H, NH

NMR (DMSO‑d₆)

d 22.6, 35.7, 38.8, 61.1, 65.4, 73.1, 74.3, 76.7, 122.8,

149.5,155.1,169.1. Anal. (C₁₂H₁₈N₆O₄S) theoretical: C, 42.10; H, 5.30;

N, 24.55; S, 9.37. Found: C, 42.17; H, 5.56; N, 24.47, S, 9.39.

4.71. (1S,2R,3S,4R)-4-(7-amino-5-((3-hydroxypropyl)thio)-3H-

[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7o)

major). ¹³C NMR (DMSO‑d₆)

d

13.3, 22.6, 32.4, 33.2, 33.5, 41.1, 60.2,

To a solution of 16i (0.15 g, 0.33 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7o as a white solid

60.5, 70.8, 73.6, 74.3, 81.7, 117.1, 117.5, 123.0, 125.4, 137.1, 147.1, 148.2,

148.9, 149.3, 150.1, 150.6, 153.0, 169.0. Anal. (C₂₂H₂₈F₂N₆O₄S) theo-

retical: C, 51.75; H, 5.53; N, 16.46; S, 6.28. Found: C, 51.35; H, 5.81;

N, 16.86, S, 6.34.

4.69. (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]

pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (1,

ticagrelor)

(0.08 g, 59% yield, m.p.: 185e187 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.82 (m,

2H, SCH₂CH₂CH₂OH), 1.94 (m, 1H, 5⁰-Ha), 2.59 (m, 1H, 5⁰-Hb), 3.14

(m, 2H, SCH₂CH₂CH₂OH), 3.52 (SCH₂CH₂CH₂OH), 3.79 (m, 1H, 2⁰-H),

3.94 (m, 1H, 1⁰-H), 4.52 (m, 1H, SCH₂CH₂CH₂OH), 4.67 (m, 1H, 3⁰-H),

4.91 (m, 1H, 2⁰-OH), 4.96 (d, J ¼ 8.4 Hz, 1H, 4⁰-H), 5.02 (m, 1H, 3⁰-

OH), 5.10 (m, 1H, 1⁰-OH), 8.04 (s, 1H, NHa), 8.40 (s, 1H, NHb). ¹³C

To a solution of 16g (0.15 g, 0.27 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate 100% to give 1 as a white solid (0.115 g, 83%

NMR (DMSO‑d₆)

d 27.1, 32.2, 35.9, 59.4, 61.1, 73.1, 74.4, 76.7, 122.8,

149.6, 155.1, 169.0. Anal. (C₁₂H₁₈N₆O₄S) theoretical: C, 42.10; H,

5.30; N, 24.55; S, 9.37. Found: C, 42.46; H, 5.61; N, 24.36, S, 9.60.

4.72. (1S,2R,3S,4R)-4-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-((3-hydroxypropyl)thio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7p)

yield, m.p.: 135e138 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

0.82 (t, J ¼ 7.3 Hz,

2.4H, SCH₂CH₂CH₃major), 0.99 (t, J ¼ 7.3 Hz, 0.6H, SCH₂CH₂CH₃

minor), 1.37 (m, 1H, 3⁰-Ha), 1.46 (m, 0.2H, 3⁰-Hb minor), 1.50 (ddt,

J ¼ 11.5 Hz/7.1 Hz/4.4 Hz, 1.6H, SCH₂CH₂CH₃major), 1.55 (dt,

J ¼ 10.3 Hz/5.4 Hz, 0.8H, 3⁰-Hb major), 1.69 (h, J ¼ 6.9 Hz, 0.4H,

SCH₂CH₂CH₃minor), 2.03 (m, 1H, 4⁰⁰⁰-Ha), 2.12 (m, 0.8H, 2⁰-H ma-

jor), 2.25 (m, 0.2H, 2⁰-H minor), 2.63 (m, 1H, 4⁰⁰⁰-Hb), 2.85 (dt,

J ¼ 13.6 Hz/7.2 Hz, 0.8H, SCHa major), 2.94 (dt, J ¼ 13.9 Hz/7.1 Hz,

0.8H, SCHb major), 3.08 (m, 0.4H, SCH 2 minor), 3.16 (m, 0.8H, 1⁰-H

major), 3.44e3.52 (m, 4H, OCH₂CH₂OH), 3.76 (t, J ¼ 5.2 Hz, 1H, 5⁰⁰⁰-

H), 3.79 (m, 0.2H, 1⁰-H minor), 3.94 (m, 1H, 1⁰⁰⁰-H), 4.56 (dt,

J ¼ 8.7 Hz/6.0 Hz, 1H, 2⁰⁰⁰-H), 4.60 (t, J ¼ 4.9 Hz, 1H, OCH₂CH₂OH),

4.96 (q, 9.1 Hz, 1H, 3⁰⁰⁰-H), 5.05 (d, J ¼ 4.0 Hz, 1H, 1⁰⁰⁰-OH), 5.12 (m,

1H, 2⁰⁰⁰-OH), 7.04 (bs, 0.2H, 6⁰⁰-H minor), 7.07 (bs, 0.8H, 6⁰⁰-H major),

7.23e7.37 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.94 (d, J ¼ 4.6 Hz, 0.2H, NH minor),

To a solution of 16j (0.15 g, 0.28 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7p as a white solid

(0.11 g, 79% yield, m.p.: 147e149 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.37 (q,

J ¼ 6.4 Hz, 0.8H, 3⁰-Ha major), 1.40 (q, J ¼ 6.7 Hz, 0.2H, 3⁰-Ha minor),

1.46 (m, 0.2H, 3⁰-Hb minor), 1.52 (dt, J ¼ 10.0 Hz/5.3 Hz, 0.8H, 3⁰-Hb

major), 1.66 (p, J ¼ 6.6 Hz, 1.6H, SCH₂CH₂CH₂OH major), 1.81 (p,

J ¼ 6.3 Hz, 0.4H, SCH₂CH₂CH₂OH minor), 1.91 (ddd, J ¼ 13.3 Hz/

9.36 (d, J ¼ 3.6 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 13.0, 15.0,

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

17

9.0 Hz/4.2 Hz, 1H, 5⁰⁰⁰-Ha), 2.14 (m, 0.8H, 2⁰-H major), 2.25 (m, 0.2H,

2⁰-H minor), 2.59 (m, 1H, 5⁰⁰⁰-Hb), 2.95 (dt, J ¼ 13.7 Hz/7.1 Hz, 0.8H,

SCHa major), 3.02 (dt, J ¼ 13.8 Hz/7.0 Hz, 0.8H, SCHb major), 3.16 (m,

J ¼ 6.1 Hz, 2.4H, CH₃major),1.17 (d, J ¼ 6.0 Hz, 0.6H, CH₃minor),1.38

(m, 1H, 3⁰-Ha), 1.46 (m, 0.2H, 3⁰-Hb minor), 1.52 (m, 0.8H, 3⁰-Hb

major), 1.92 (m, 1H, 5⁰⁰⁰-Ha), 2.15 (m, 0.8H, 2⁰-H major), 2.25 (m,

0.2H, 2⁰-H minor), 2.60 (m, 1H, 5⁰⁰⁰-Hb), 3.06 (m, 1.6H, SCH 2 major),

3.18 (m, 1.2H, 1⁰-H major/SCH 2 minor), 3.73e3.78 (m, 2H,

SCH₂CHOH major/1⁰-H minor/2⁰⁰⁰-H), 3.88 (m, 0.2H, SCH₂CHOH

minor), 3.93 (m, 1H, 1⁰⁰⁰-H), 4.66 (m, 1H, 3⁰⁰⁰-H), 4.76 (d, J ¼ 4.7 Hz,

0.8H, SCH₂CHOH major), 4.84 (d, 4.5 Hz, 0.2H, SCH₂CHOH minor),

4.93 (d, J ¼ 3.8 Hz,1H, 2⁰⁰⁰-OH), 4.96 (q, J ¼ 9.0 Hz,1H, 4⁰⁰⁰-H), 4.99 (d,

J ¼ 6.5 Hz, 0.2H, 3⁰⁰⁰-OH minor), 5.02 (d, J ¼ 6.4 Hz, 0.8H, 3⁰⁰⁰-OH

major), 5.16 (d, J ¼ 4.0 Hz, 1H, 1⁰⁰⁰-OH), 7.04 (bs, 0.2H, 6⁰⁰-H minor),

7.09 (bs, 0.8H, 6⁰⁰-H major), 7.24e7.35 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.94 (d,

1.2H, SCH

2

minor/1⁰-H major), 3.38 (q,

J

¼

5.9 Hz, 1.6H,

SCH₂CH₂CH₂OH major), 3.52 (q, J ¼ 5.5 Hz, 0.4H, SCH₂CH₂CH₂OH

minor), 3.78 (m, 1.2H, 1⁰-H minor/2⁰⁰⁰-H), 3.93 (m, 1H, 1⁰⁰⁰-H), 4.47 (t,

J ¼ 5.1 Hz, 0.8H, SCH₂CH₂CH₂OH major), 4.53 (t, J ¼ 4.8 Hz, 0.2H,

SCH₂CH₂CH₂OH minor), 4.65 (m, 1H, 3⁰⁰⁰-H), 4.92 (d, J ¼ 3.8 Hz, 1H,

2⁰⁰⁰-OH), 4.95 (q, J ¼ 9.0 Hz, 1H, 4⁰⁰⁰-H), 5.00 (d, J ¼ 6.5 Hz, 0.2H, 3⁰⁰⁰-

OH minor), 5.02 (d, J ¼ 6.4 Hz, 0.8H, 3⁰⁰⁰-OH major), 5.09 (d,

J ¼ 3.8 Hz, 0.2H, 1⁰⁰⁰-OH ₀m₀inor), 5.11 (d, J ¼ 4.0 Hz, 0.8H, 1⁰⁰⁰-OH

major), 7.03 (bs, 0.2H, 6 -H minor), 7.07 (bs, 0.8H, 6⁰⁰-H major),

7.24e7.35 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.94 (d, J ¼ 4.5 Hz, 0.2H, NH minor),

J ¼ 4.4 Hz, 0.2H, NH minor), 9.33 (d, J ¼ 3.9 Hz, 0.8H, NH major). ¹³

C

9.34 (d, J ¼ 3.7 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d

15.1, 23.9,

NMR (DMSO‑d₆) d 15.1, 22.4, 23.9, 33.8, 36.0, 39.1, 61.0, 65.2, 73.2,

27.2, 32.2, 33.9, 36.0, 59.2, 61.0, 73.2, 74.5, 76.7, 114.8, 117.0, 122.8,

123.1, 139.2, 147.0, 148.4, 149.3, 150.0, 153.9, 169.1. Anal.

(C₂₁H₂₄F₂N₆O₄S) theoretical: C, 51.00; H, 4.89; N, 16.99; S, 6.48.

Found: C, 50.68; H, 4.93; N, 16.56, S, 6.34.

74.5, 76.8, 114.9, 117.0, 122.9, 123.1, 139.2, 147.1, 148.7, 149.2, 153.8,

169.3. Anal. (C₂₁H₂₄F₂N₆O₄S.H₂O) theoretical: C, 49.21; H, 5.11; N,

16.40; S, 6.26. Found: C, 49.56; H, 5.05; N, 16.18, S, 5.99.

4.75. (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-((2-hydroxypropyl)thio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

(7s)

4.73. (1S,2R,3S,4R)-4-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(((R)-2-hydroxypropyl)thio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7q)

To a solution of 16k (0.15 g, 0.28 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7q as a white solid

To a solution of 16m (0.15 g, 0.26 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7s as a white solid

(0.09 g, 65% yield, m.p.: 90 ^ꢀC dec.). ¹H NMR (DMSO‑d₆)

d

1.00 (d,

(0.12 g, 86% yield, m.p.: 148e153 ^ꢀC). ¹H NMR (DMSO‑d₆)

d 1.00 (d,

J ¼ 6.0 Hz, 2.4H, CH₃major), 1.17 (d, J ¼ 6.9 Hz, 0.6H, CH₃minor),

1.38 (m, 1H, 3⁰-Ha), 1.46 (m, 0.2H, 3⁰-Hb minor), 1.53 (m, 0.8H, 3⁰-Hb

major), 1.92 (ddd, J ¼ 13.3 Hz/8.9 Hz/4.1 Hz, 1H, 5⁰⁰⁰-Ha), 2.13 (m,

0.8H, 2⁰-H major), 2.25 (m, 0.2H, 2⁰-H minor), 2.60 (m, 1H, 5⁰⁰⁰-Hb),

2.89 (dd, J ¼ 13.4 Hz/6.8 Hz, 0.8H, SCHa major), 3.14 (m, 1.8H, SCHa

minor/SCHb major/1⁰-H major), 3.21 (dd, J ¼ 13.5 Hz/5.2 Hz, 0.2H,

SCHb minor), 3.72e3.78 (m, 2H, SCH₂CHOH major/1⁰-H minor/2⁰⁰⁰-

H), 3.87 (m, 0.2H, SCH₂CHOH minor), 3.93 (m, 1H, 1⁰⁰⁰-H), 4.66 (q,

J ¼ 6.3 Hz, 1H, 3⁰⁰⁰-H), 4.80 (d, J ¼ 4.8 Hz, 0.8H, SCH₂CHOH major),

4.87 (d, J ¼ 4.5 Hz, 0.2H, SCH₂CHOH minor), 4.95 (d, J ¼ 4.3 Hz, 1H,

2⁰⁰⁰-OH), 4.98 (m, 1.2H, 4⁰⁰⁰-H/3⁰⁰⁰-OH minor), 5.04 (d, J ¼ 6.4 Hz, 0.8H,

3⁰⁰⁰-OH major), 5.17 (d, J ¼ 3.7 Hz, 1H, 1⁰⁰⁰-OH), 7.04 (bs, 0.2H, 6⁰⁰-H

minor), 7.09 (bs, 0.8H, 6⁰⁰-H major), 7.24e7.37 (m, 2H, 2⁰⁰-H/5⁰⁰-H),

8.96 (d, J ¼ 4.4 Hz, 0.2H, NH minor), 9.36 (d, J ¼ 3.9 Hz, 0.8H, NH

J ¼ 6.2 Hz,1.2H, CH₃major R or S), 1.02 (d, J ¼ 6.2 Hz,1.2H, CH₃major

R or S), 1.17 (d, J ¼ 7.1 Hz, 0.6H, CH₃minor), 1.38 (m, 1H, 3⁰-Ha), 1.47

(m, 0.2H, 3⁰-Hb minor), 1.53 (m, 0.8H, 3⁰-Hb major), 2.02 (ddt,

J ¼ 14.0 Hz/9.3 Hz/4.4 Hz, 1H, 4⁰⁰⁰-Ha), 2.14 (m, 0.8H, 2⁰-H major),

2.25 (m, 0.2H, 2⁰-H minor), 2.64 (m, 1H, 4⁰⁰⁰-Hb), 2.86 (dd,

J ¼ 13.4 Hz/7.0 Hz, 0.4H, SCHa major R or S), 3.05 (d, J ¼ 5.8 Hz, 1H,

SCHb major), 3.13e3.19 (m, 1.6H, SCHa major R or S, SCHa minor,

SCHb minor, 1⁰-H), 3.46e3.52 (m, 4H, OCH₂CH₂OH), 3.74 (m, 1.8H,

SCH₂CHOH major/5⁰⁰⁰-H), 3.88 (m, 0.2H, SCH₂CHOH minor), 3.95 (m,

1H, 1⁰⁰⁰-H), 4.56 (m, 1H, 2⁰⁰⁰-H), 4.61 (t, J ¼ 4.9 Hz, OCH₂CH₂OH), 4.78

(m, 0.8H, SCH₂CHOH major), 4.86 (m, 0.8H, SCH₂CHOH minor), 4.96

(q, J ¼ 8.7 Hz, 1H, 3⁰⁰⁰-H), 5.06 (d, J ¼ 3.8 Hz, 1H, 1⁰⁰⁰-OH), 5.09e5.12

(m, 1H, 2⁰⁰⁰-OH), 7.03 (m, 0.2H, 6⁰⁰-H minor), 7.09 (m, 0.8H, 6⁰⁰-H),

7.24e7.36 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.96 (d, J ¼ 4.5 Hz, 0.2H, NH minor),

major). ¹³C NMR (DMSO‑d₆)

d

15.0, 22.4, 24.0, 33.9, 35.9, 39.6, 61.1,

9.35 (m, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

d 15.1, 22.5, 24.0,

65.2, 73.2, 74.5, 76.7, 114.9, 117.0, 122.9, 123.1, 139.2, 147.1, 148.4,

148.7, 149.2, 150.1, 153.9, 169.2. Anal. (C₂₁H₂₄F₂N₆O₄S) theoretical:

C, 51.00; H, 4.89; N, 16.99; S, 6.48. Found: C, 50.77; H, 5.15; N, 16.64,

S, 6.99.

33.3, 33.9, 35.7, 39.4, 60.3, 60.5, 65.2, 70.9, 73.7, 74.4, 81.8, 114.9,

117.0, 122.9, 123.1, 139.2, 147.1, 148.5, 148.7, 149.4, 150.1, 153.9, 169.4.

Anal. (C₂₃H₂₈F₂N₆O₅S) theoretical: C, 51.29; H, 5.24; N, 15.60; S,

5.95. Found: C, 51.29; H, 5.49; N, 15.51, S, 5.85.

4.74. (1S,2R,3S,4R)-4-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-(((S)-2-hydroxypropyl)thio)-3H-[1,2,3]

triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (7r)

4.76. (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-diﬂuorophenyl)

cyclopropyl)amino)-5-((3-hydroxypropyl)thio)-3H-[1,2,3]triazolo

[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

(7t)

To a solution of 16l (0.15 g, 0.28 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7r as a white solid

To a solution of 16n (0.15 g, 0.26 mmol) in MeOH (3 mL), was

added HCl 12 N (1 mL). After 30 min at room temperature, meth-

anol was evaporated under reduced pressure and the resulting

residue was suspended in water (20 mL), neutralized with NaOH

10% and extracted with dichloromethane (3 ꢂ 20 mL). The com-

bined organic layers were dried over MgSO₄, concentrated under

reduced pressure and puriﬁed by column chromatography on silica

gel using ethyl acetate/methanol gradient to give 7t as a white solid

(0.10 g, 72% yield, m.p.: 90 ^ꢀC dec.). ¹H NMR (DMSO‑d₆)

d 1.02 (d,

18

E. Gofﬁn et al. / European Journal of Medicinal Chemistry 208 (2020) 112767

(0.10 g, 72% yield, m.p.: 135e137.5 ^ꢀC). ¹H NMR (DMSO‑d₆)

d

1.38 (q,

the absence of different concentrations of the tested molecules. The

vehicle was 1% DMSO. The bacterial growth in culture media was

J ¼ 6.1 Hz, 0.8H, 3⁰-Ha major), 1.40 (m, 0.2H, 3⁰-Ha minor), 1.46 (dt,

J ¼ 9.9 Hz/5.3 Hz, 0.2H, 3⁰-Hb minor), 1.53 (dt, J ¼ 11.0 Hz/5.5 Hz,

0.8H, 3⁰-Hb major), 1.66 (p, J ¼ 6.7 Hz, 1.6H, SCH₂CH₂CH₂OH major),

1.81 (p, J ¼ 6.6 Hz, 0.4H, SCH₂CH₂CH₂OH minor), 2.02 (ddd,

J ¼ 14.0 Hz/9.7 Hz/5.0 Hz, 1H, 4⁰⁰⁰-Ha), 2.14 (ddd, J ¼ 9.5 Hz/6.4 Hz/

3.3 Hz, 0.8H, 2⁰-H major), 2.25 (m, 0.2H, 2⁰-H minor), 2.64 (m, 1H,

4⁰⁰⁰-Hb), 2.93e3.03 (m, 1.6H, SCH₂CH₂CH₂OH major), 3.15e3.18 (m,

1.2H, SCH₂CH₂CH₂OH minor/1⁰-H major), 3.38 (q, J ¼ 6.1 Hz, 1.6H,

SCH₂CH₂CH₂OH major), 3.46e3.53 (m, 4.4H, SCH₂CH₂CH₂OH mi-

nor/OCH₂CH₂OH), 3.76 (m, 1H, 5⁰⁰⁰-H), 3.79 (m, 0.2H, 1⁰-H minor),

3.94 (m, 1H, 1⁰⁰⁰-H), 4.47 (t, J ¼ 5.2 Hz, 0.8H, SCH₂CH₂CH₂OH major),

4.55 (m, 1.2H, SCH₂CH₂CH₂OH minor/2⁰⁰⁰-H), 4.61 (t, J ¼ 5.2 Hz, 1H,

OCH₂CH₂OH), 4.96 (q, J ¼ 9.1 Hz, 1H, 3⁰⁰⁰-H), 5.05 (d, J ¼ 4.1 Hz, 1H,

1⁰⁰⁰-OH), 5.09 (d, J ¼ 6.5 Hz, 0.8H, 2⁰⁰⁰-OH major), 5.12 (d, J ¼ 6.4 Hz,

0.2H, 2⁰⁰⁰-OH minor), 7.03 (m, 0.2H, 6⁰⁰-H minor), 7.07 (m, 0.8H, 6⁰⁰-H

major), 7.24e7.35 (m, 2H, 2⁰⁰-H/5⁰⁰-H), 8.95 (d, J ¼ 4.8 Hz, 0.2H, NH

minor), 9.35 (d, J ¼ 4.0 Hz, 0.8H, NH major). ¹³C NMR (DMSO‑d₆)

evaluated by measuring the optical density (OD) at 600 nm (OD₆₀₀

)

by use of a spectrophotometer. The Minimal Inhibitory Concen-

tration (MIC) of each molecule tested was determined according to

the EUCAST guidelines. The MIC represents the concentration at

which there is no visible growth, i.e

DOD at 600 nm is equal to zero

wherein OD is the difference between the resulting OD in the

D

presence of the molecule and the OD of the blank (blank is the

medium with 1% DMSO).

Author contributions

The manuscript was written through contributions of all au-

thors. All authors have given approval to the ﬁnal version of the

manuscript.

Declaration of competing interest

d

15.1, 23.9, 27.3, 32.1, 33.3, 33.9, 59.2, 60.3, 60.5, 70.9, 73.7, 74.4,

81.8, 115.0, 117.1, 122.8, 123.1, 139.2, 147.1, 148.4, 148.7, 149.4, 150.1,

153.9, 169.2. Anal. (C₂₃H₂₈F₂N₆O₅S) theoretical: C, 51.29; H, 5.24; N,

15.60; S, 5.95. Found: C, 50.89; H, 5.29; N, 15.51, S, 5.99.

The authors declare that they have no known competing

ﬁnancial interests or personal relationships that could have

appeared to inﬂuence the work reported in this paper.

4.77. Biological evaluation

Acknowledgement

4.77.1. Antiplatelet activity

C. Oury is Research Director at the National Funds for Scientiﬁc

Research, Belgium (F.R.S.-FNRS). The technical assistance of S.

Counerotte is gratefully acknowledged. This work was supported by

a European Research Council (ERC)-Consolidator grant (PV- COAT

647197).

4.77.1.1. Platelet rich plasma (PRP) preparation. Venous blood was

obtained from healthy volunteers (between 20 and 40 years old)

who had not taken any drugs or medications for at least 10 days.

Procedures were approved by the institutional review committee of

ꢀ

the Universtisty of Liege (Comite d’ethique hospital-facultaire

universitaire de liege). Blood samples were collected into citrate

tubes (3.2% citrate, Greiner-BioOne) and processed within 30 min

after collection. Platelet-rich-plasma (PRP) was separated by

centrifugation of anticoagulated whole blood at 100ꢂg for

15 min at room temperature. Platelet count was measured using a

hematology analyser (Cell-dyn 3700, Abbott). Platelet poor plasma

(PPP) was obtained by centrifugation of whole blood at 800ꢂg for

Appendix A. Supplementary data

Supplementary data to this article can be found online at

https://doi.org/10.1016/j.ejmech.2020.1 12767.

Abbreviations

15 min. The platelet count in PRP was then adjusted to 250000/

by diluting PRP with autologous PPP.

ml

ADP

adenosine diphosphate

DMSO

LSD1

MRSA

NMR

TLC

dimethylsulfoxide

lysine speciﬁc demethylase 1

methicillin-resistant Staphylococcus aureus

nuclear magnetic resonance

thin layer chromatography

tetramethylsilane

4.77.1.2. Platelet aggregation. Platelet aggregation assays were

performed with PRP under stirring (1200 rpm) at 37 ^ꢀC on a

Chrono-Log Lumi-aggregometer (Kordia). PRP was pre-incubated

with ticagrelor or its analogues (1.8

ring and addition of ADP (10 M). Platelet aggregation was moni-

mM) for 10 min prior to stir-

TMS

m

tored for 10 min. The area under the curve (AUC) was recorded.

Results were expressed as fold-inhibition vs. vehicle (1% DMSO).

Data are presented as mean S.D. obtained from 4 to 21 healthy

volunteers (age: 29 (3), median (IQR); 67% males). AUC values

recorded in the presence of test molecules were compared to the

values obtained with the vehicle control (1% DMSO) or with the

reference molecule 1 (ticagrelor) by using the non-parametric

Wilcoxon signed rank test for paired samples (Prism version

8.1.2). P < 0.05 was considered signiﬁcant.

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Article Doi

Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity

DOI: 10.1016/j.ejmech.2020.112767

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