Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.12.004

Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable w

Full text of DOI:10.1016/j.bmc.2015.12.004

Accepted Manuscript
Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK in-
hibitors
Raghavendra Achary, Jeong In Yun, Chi Min Park, Gangadhar Rao Mathi, Joo
Yun Lee, Jae Du Ha, Chong Hak Chae, Sunjoo Ahn, Chi Hoon Park, Chong
Ock Lee, Jong Yeon Hwang, Chang-Soo Yun, Hee Jung Jung, Sung Yun Cho,
Hyoung Rae Kim, Pilho Kim
PII:
S0968-0896(15)30172-3
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.12.004
BMC 12697
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
8 October 2015
18 November 2015
2 December 2015
Please cite this article as: Achary, R., Yun, J.I., Park, C.M., Mathi, G.R., Lee, J.Y., Ha, J.D., Chae, C.H., Ahn, S.,
Park, C.H., Lee, C.O., Hwang, J.Y., Yun, C-S., Jung, H.J., Cho, S.Y., Kim, H.R., Kim, P., Discovery of novel
tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors, Bioorganic & Medicinal Chemistry (2015), doi:
http://dx.doi.org/10.1016/j.bmc.2015.12.004
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Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors
a,b
a,c
a
a,b
a
Raghavendra Achary , Jeong In Yun , Chi Min Park , Gangadhar Rao Mathi , Joo Yun Lee , Jae Du
a
a
a,b
a,b
a
a,b
Ha , Chong Hak Chae , Sunjoo Ahn , Chi Hoon Park , Chong Ock Lee , Jong Yeon Hwang , Chang-
a,b
a,b
a,b
a,*
a,b,*
Soo Yun , Hee Jung Jung , Sung Yun Cho , Hyoung Rae Kim , Pilho Kim
a
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600,
Korea
b
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon
3
05-550, Korea
c
College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea
*
Corresponding author: Tel.: +82-42-860-7541; fax: +82-42-860-7160
E-mail address: pkim@krict.re.kr (P. Kim).
Tel.: +82-42-860-7054; fax: +82-42-860-7160
E-mail address: hyungrk@krict.re.kr (H. Kim).
Abstract
Exploration of the 2-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs)
led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in
vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o
and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant
inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of
compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found
from crizotinib and LDK378.

1
. Introduction
Anaplastic lymphoma kinase (ALK) is one of the receptor tyrosine kinases (RTK) belonging to the
insulin receptor family [1]. Among various oncogenic fusion genes, ALK has obtained tremendous
attention due to ALK-positive tumors found in various cancer types, such as anaplastic large cell
lymphoma (ALCL) [2], diffuse large B-cell lymphoma (DLBCL) [1], and non-small-cell lung cancer
(
NSCLC) [3]. Nucleophosmin (NPM)-ALK and echinoderm microtubule-associated protein-like-4
EML4)-ALK are most abundant fusion genes identified in ALCL and NSCLC, respectively. In 2011,
(
crizotinib was first approved as an ALK inhibitor drug to treat ALK-positive NSCLC (Figure 1). Since
the advent of crizotinib in clinics, crizotinib resistant mutants have been developed among patients treated
with crizotinib within one to two years [4]. Thus, discovery efforts for second-generation ALK inhibitors
which could overcome crizotinib-resistant issues have been pursued comprehensively, resulting in
development of a few cornerstone compounds, such as TAE684, LDK378 (ceritinib), and CH5424802
(
alectinib). Although TAE684 was discovered as a potent NPM-ALK inhibitor [5], labile nature of
TAE684 under metabolic oxidation rendered its clinical trials discontinued. It was speculated that the
toxicity profiles of TAE684 could be structurally originated from 1,4-diaminophenyl substitutent at the 2-
position of pyrimidine [6]. To circumvent this issue, extensive modification efforts of the 2-position
substituent of pyrimidine eventually produced LDK378, where metabolically unfavorable 1,4-
diaminophenyl was modified by introducing 4-piperidinyl substituent [6]. LDK378 is known to be 3 to 6-
fold more active than crizotinib in cell cytotoxicity assays. In terms of crizotinib resistance issues,
LDK378 turned out to be active against most of the resistant mutants, such as L1196M, G1269A, I1171T,
and S1206Y, but ineffective against G1202R and F1174C [4].
Recently, various discovery programs of ALK inhibitors have focused on modification of the 2-
position substituent of pyrimidine in LDK378. For example, replacement of the 2-position substituent of
pyrimidine in LDK378 with mono- or bicyclic 2-aminothiazole was investigated as A in Figure 1, leading

into discovery of highly selective tetrahydro-4H-thiazolo[4,5-d]azepine analogs [7]. Wang et al. reported
phosphamides and carbamate analogs constructed by modifying the secondary amine of terminal
piperidine in LDK378 [8]. One of the carbamates (B) showed efficacies as potent as LDK378 in a rat
xenograft H2228 model, suggesting that modification of the terminal secondary amine could be tolerable
to maintain ALK inhibitory efficacies. Analogs of 1,3-diaminophenyl connected with flexible amino acids
at the terminal amine such as C showed potencies against both wild-type and mutant ALK kinases [9].
Figure 1. Known ALK inhibitors.
As our ongoing efforts to discover novel ALK inhibitors, our exploration started from modification of
the 2-position substituent of pyrimidine in LDK378. Among diverse structural options, we opted to
investigate bicyclic amines as the 2-position substituent of pyrimidine [10]. Thus, the bicyclic amines we
designed have the following structural features: i) non-1,4-diaminophenyl, ii) more compact structure
than that of LDK, and iii) alkyl groups at the para position of alkoxy groups [6]. Lately, we have reported
that discovery of aminobenzazepines (D), one of the bicyclic amines we explored, as ALK inhibitors [11].
In the same context, our research also focused on THIQ analogs, which are non-1,4-diaminophenyl, at the
2
-postion of pyrimidine rather than the lengthy substituents as in TAE684 or LDK378. THIQ could be
considered a cyclized form of the 2-position substituent of LDK378, specifically, ring formation between

the methyl group and the terminal amine of piperidine (Figure 2). Interestingly, alkoxy substituted THIQs
have been reported in just a few precedent reports such as for discovery of IGF-1R and IR receptor
tyrosine kinase [12] and ALK inhibitors [13], the former coupled with pyrrolo[2,3-d]pyrimidine, the latter
with pyrido[2,3-d]pyridazin-5-one. Herein, we report synthesis and structure-activity relationships of
KRCA compounds as in Figure 2, bearing alkoxy substituted THIQ groups at the 2-position of
pyrimidine.
Figure 2. Design strategies.
2
. Chemistry
With a view to obtaining compound 8, preparation of THIQ 5 started from commercially available 4-
methoxyphenethylamine 1 (Scheme 1). Amine of 1 was protected with trifluoroacetyl to give amide 2.
Nitration of 2 gave rise to nitroamide 3 regioselectively [14]. Cyclization of 3 with paraformaldehyde
under acidic heating conditions afforded N-protected THIQ 4 [15]. Reduction of nitro group in 4 was
accomplished with Pd/C hydrogenation to facilitate amine 5. While 5 was prepared in four steps in our
hands, synthesis of Boc-protected version of 5, instead of trifluoroacetyl, was reported in six steps starting
from conversion of 1 to carbamate [13]. Coupling of 5 and commercially available compound 6 was
achieved under acidic heating conditions to furnish 7 [16]. Subsequent deprotection of trifluoroacetyl
2
group in 7 under LiOH·H O conditions gave rise to 8.

o
o
Scheme 1. Reagents and conditions: (a) TFAA, Et
3
N, DCM, 0 C to rt, 3 h (97%); (b) HNO
(g), MeOH, rt, 12 h (78%); (e) 6,
O/MeOH, rt, 2 h (60%).
3
, TFA, 0 C,
o
2
0
h (81%); (c) (CH
2
O)
n
, AcOH, H
2
SO
4
, 50 C, 3.5 h (58%); (d) Pd/C, H
2
o
2 2
.08 M HCl in EtOEtOH, 80 C, 12 h (65%); (f) LiOH·H O, THF/H
Compound 17, tetrahydroisoquinolin-7-yl version of 8, was synthesized with similar methods as
described in Scheme 1. 3-Methoxyphenethylamine 9 was protected with methyl chloroformate to give
carbamate 10 (Scheme 2). Bicyclic lactam 11 [17] was obtained by heating 10 in polyphosphoric acid
[
4
16]. Lactam carbonyl reduction of 11 was achieved in the presence of LiAlH to facilitate THIQ 12 [18,
1
9]. Amine of 12 was protected with trifluoroacetyl to provide 13. Nitration of 13 gave rise to 14a as a
major product and 14b as a minor. Subsequently, nitro reduction of 14a, coupling, and deprotection
afforded 15, 16, and 17, respectively [13].
o
o
Scheme 2. Reagents and conditions: (a) ClCO
2
Me, K
2
CO
3
, DCM, 0 C to rt, 4 h (87%); (b) PPA, 120 C
o
o
to rt, 6 h (76%); (c) LiAlH
4
, THF, 0 C to 70 C, 12 h (86%); (d) TFAA, Et
3
N, DCM, rt, 3 h (65%); (e)

o
HNO
3
, TFA, 0 C, 3 h, 14a (55%), 14b (24%); (f) Pd/C, H
2
(g), MeOH, rt, 12 h (80%); (g) 6, 0.08 M HCl
o
in EtOEtOH, 80 C, 12 h (68%); (h) LiOH·H
2
O, THF/H
2
O/MeOH, rt, 2 h (64%).
With tetraisoquinolines 8 and 17 in hand, the terminal secondary amines of THIQs were transformed
to various functional groups to give 8a-i and 17a-i (Scheme 3).
Scheme 3. Reagents and conditions:
Yield (%)
conditions
R
8
17
a
b
c
d
e
f
MeI, DIPEA, EtOH, rt, 18 h
EtI, DIPEA, EtOH, rt, 18 h
Me
Et
8a (75%) 17a (84%)
8b (45%) 17b (30%)
Br(CH
Cl(CH N(Me)
ClCH CON(Me)
Ac O, Et
H, EDCI, DMAP, Et
EtNCO, Et N, DCM, rt, 18 h
NH , Et N, 1,4-dioxane, reflux, 18 h
2
)
2
OH, Cs
·HCl, Et
, K CO
N, DCM, rt, 18 h
N, DCM, rt, 18 h
2
CO
3
, DMF, rt, 18 h
(CH
(CH
CH
2
)
2
OH
8c (94%)
8d (9%)
8e (13%)
8f (43%)
17c (75%)
17d (11%)
17e (20%)
17f (89%)
o
2
)
2
2
3
N, DMF, 60 C, 16 h
2
)
2
N(Me)
2
2
2
2
3
, CH
3
CN, reflux, 18 h
2
CON(Me)
Ac
2
2
3
g
h
i
HOCH
2
CO
2
3
COCH
CONHEt
SO NH
2
OH
8g (51%) 17g (17%)
8h (61%) 17h (55%)
3
NH
2
SO
2
2
3
2
2
8i (48%)
17i (56%)
In order to study substitution effects of various alkoxy groups in 8, at first methoxy group of 4 was
transformed to alcohol 4a under heating conditions with TfOH (Scheme 4) [20]. Compound 4a was
subsequently alkylated under Mitsunobu conditions with three different alcohols to give 4b-d [21].
Typical nitro group reduction, coupling, and deprotection gave rise to 5a-c, 7a-c, and 8j-l, respectively.

o
Scheme 4. Reagents and conditions: (a) TfOH, DCM, 70 C, 10 h (42%); (b) ROH, DIAD, PPh
2 h (47-55%); (c) Pd/C, H
53-83%); (e) K CO , EtOH/H
3
, DCM, rt,
o
1
2
(g), MeOH, rt, 2 h (55-98%); (d) 6, 0.08 M HCl in EtOEtOH, 80 C, 12 h
o
(
2
3
2
O, 90 C, 2 h (55-79%).
To investigate modification effects of the secondary amine in THIQ 8, compounds 8m-o were
designed and synthesized (Scheme 5). Quaternary ammonium salt 8m was prepared from 8 under heating
conditions with MeI. Dihydroisoquinoline 8n was obtained by tandem bromination and
dehydrobromination using NBS and NaOH conditions, respectively [22]. Oxidation of 8 with Fremy’s
salt gave rise to isoquinoline 8o [23].
o
Scheme 5. Reagents and conditions: (a) MeI, THF, 70 C, 18 h (35%); (b) i) NBS, DCM, rt, 1 h; ii) 30%
3 2 2 3
NaOH (aq), rt, 1 h (51%); (c) (KSO ) NO, 4% Na CO (aq), rt, 48 h (10%).

3
3
. Biological results and discussion
.1. In vitro biological evaluations
All the compounds prepared were screened against not only ALK wild type and crizotinib-resistant
L1196M mutant enzymes, but also three different cells having EML4-ALK fusion genes (Table 1). While
THIQs 8 and 17 exhibit similar activities each other, overall, they are more active than LDK378 based on
both enzyme and cell assay results. However, attempts were unfruitful to improve activities by
constructing THIQ N-analogs, such as 8a-i and 17a-i. Replacing the methoxy group of 8 with bulky
alkoxy groups as in 8j-l results in almost similar enzyme activities as those of 8, but cell activities tend to
be getting lower. In case of quaternary ammonium salt 8m, although enzyme activities are seemingly
maintained, cell activities are abolished. While dihydroisoquinoline 8n is slightly less active than 8 in
enzyme assays, isoquinoline 8o turns out to be completely inactive.
Table 1. ALK inhibitory activities against enzymes and cells.
enzymes
cells
ALK
L1196M
IC50 (M)
Ba/F3
L1196M
CC50 (M)
compounds
R
ALK (wt)
IC50 (M)
H2228
CC50 (M)
H3122
CC50 (M)
LDK378
-
0.014
0.001
0.04
0.029
0.01
0.71
0.02
0.01
1.18
0.054
0.03
0.01
0.025
0.01
0.038
0.008
>10
0.075
0.036
>10
8
H
a
8
8
a
Me
Et
ND
b
0.003
0.001
0.018
0.003
0.002
0.001
0.03
0.24
0.41
0.22
0.03
0.009
0.06
0.53
0.24
0.54
0.09
0.03
0.07
1.1
8
c
(CH
(CH
CH
2
)
2
OH
8
d
2
)
2
N(Me)
2
0.28
0.12
0.09
0.04
8
e
2
CON(Me)
2
8
f
Ac
8
g
2
COCH OH

8
h
CONHEt
SO NH
0.002
0.007
0.00054
0.0012
0.0012
0.0015
0.0078
0.13
0.05
0.07
0.05
0.04
0.053
1.71
0.63
0.13
0.1
0.1
0.1
8
i
2
2
8
j
i-Pr
i-Bu
s-Bu
-
0.013
0.0012
0.0023
0.0033
0.039
0.05
0.54
0.27
2.2
0.023
0.12
0.1
8
k
8
l
a
8
m
ND
>10
1.5
a
8
n
o
7
-
ND
0.15
1.1
a
a
8
-
ND
ND
>10
0.010
8
1
H
0.001
0.003
0.001
0.002
0.016
0.003
0.005
0.004
0.01
0.007
0.03
0.01
0.01
0.072
0.034
0.05
0.03
0.15
0.05
0.010
ND
0.0047
1.5
1
7a
7b
Me
Et
1
0.01
0.007
0.58
0.04
0.03
0.01
0.08
0.02
0.02
0.04
0.21
0.11
0.08
0.04
0.23
0.1
0.04
0.03
0.17
0.26
0.08
0.05
0.3
1
7c
7d
7e
7f
(CH
(CH
CH
2
)
2
OH
1
2
)
2
N(Me)
2
1
2
CON(Me)
2
1
Ac
17g
COCH
CONHEt
SO NH
ND: not determined
2
OH
1
7h
1
7i
2
2
0.008
0.11
a
The activities of highly active compounds 8 and 17 were further evaluated using crizotinib-resistant
ALK mutant enzymes (Table 2). Compound 8 showed similar activities as those of LDK378 against the
mutants tested, except G1202R where 8 appeared to be 3-fold more active. In case of 17, activities were
5
-15 times better than those of LDK378 against all the mutant enzymes tested. In particular, both 8 and 17
apparently exhibited high activity against G1202R, which is known to be an essential mutant to overcome
among patients treated with crizotinib or LDK378 [4, 24].
Table 2. Inhibitory activities against ALK mutant enzymes.
G1202R
M)
G1269A
(M)
T1151-L1152
insT (M)
C1156Y
(M)
compounds
F1174L (M)
(
LDK378
0.020
0.0021
0.0017
0.00024
0.0017
0.0023
0.00033
0.0024
0.0021
0.00046
0.0042
0.0030
0.00045
8
0.0059
0.0013
1
7

3
.2. Docking studies
Docking studies were performed to elucidate binding modes of 8, 17, and LDK378, to ALK. Binding
modes of 8 and 17 turned out to be similar to that of LDK378 as shown in Figure 3 [4]. In particular,
protonated secondary amines on THIQs of 8 and 17 have an identical electrostatic interaction with
Asp1203 despite their different puckers of THIQ (Figures 3a and 3b), which mimics a charge-charge
interaction between protonated piperidine of LDK378 and Glu1210 (Figure 3c) [6]. These key
interactions could provide a rationale to comprehend similar ALK activity results between THIQs (8 and
1
7) and LDK378. On the other hand, the G1202R mutation leads to bulkier residues around the binding
pocket, which could cause more steric interference in binding modes of ALK inhibitors (Figures 3d and
e) [25]. As 8 and 17 have more compact THIQ side chains than that of LDK378, 8 and 17 could be
3
affected by less steric interference than LDK378, consistent with high activities of THIQs against
G1202R mutant.
Figure 3. Binding modes of 8 (a), 17 (b), and LDK378 (c) in wild-type ALK and surface delineation of
wild-type (d) and G1202R mutant (e) ALKs with ALK inhibitors. ALK is represented by ribbons with the

interacting residues as sticks. Hydrogen bonds and electrostatic interactions are drawn as dashed black
lines. Blue and red colors on surface represent positively charged and negatively charged residues,
respectively.
3
.3. Stability and pharmacokinetic profiles
NADPH-dependent oxidative metabolism of compounds 8 and 17 in liver microsomes of different
o
species were evaluated after 30 min incubation of each sample at 30 C (Table 3). Compared with
LDK378, 8 and 17 seem to be slightly less stable. In vivo pharmacokinetics (PK) of compounds 8 and 17
was examined in male rats with a dose of 10 or 20 mpk. Cmax and AUC of 8 and 17 are significantly
improved, compared with those of LDK378.

Table 3. Metabolic stability and PK data.
rat PO AUC
rat liver
microsomes
remaining
human liver
microsomes
% remaining
rat PO Cmax
(g/mL)
compounds
(g·h/mL)
%
(10 mpk)
(
10 mpk)
1.400a
15.900
4.63
LDK378
98
81
81
88
79
59
0.090a
1.120
0.325
8
1
7
a
20 mpk
3
.4. In vivo xenograft evaluations
For in vivo xenograft study, H3122 cells were implanted subcutaneously into the right flanks of
3
female nude mice. Drug treatment was initiated right after tumor volumes reached about 190 mm . 50
mpk of each LDK378, 8, and 17 was administered by oral administration for 14 days (Figure 4). Overall,
it turned out that 8 and 17 were as active as LDK378, suggesting that in vitro assay results could be
correlated with in vivo xenograft model data in this series of compounds. In addition, there are no
significant body weight changes detected among LDK378, 8, and 17 (Supplementary data).
Figure 4. Antitumor activities of compounds in H3122 murine xenograft model.
*
p < 0.01 versus control group on the final day using Student’s t-test.
3
.5. Kinase profiling

Out of the two promising THIQ compounds (8 and 17), the kinase profiling assay of compound 8 was
performed against 96 kinases at 1 M (Supplementary data). While LDK378 inhibits only 9 kinases at a
level of over 90% inhibition, compound 8 apparently inhibits about one-third of 96 kinases tested,
suggesting THIQ-containing ALK inhibitors could be multi-targeting kinase inhibitors.
4
. Conclusion
THIQ-containing pyrimidine analogs 8 and 17 were discovered as highly potent ALK inhibitors,
showing their in vitro and in vivo efficacies comparable with those of LDK378. However, in case of
THIQ analogs (8a-o and 17a-i), the activities were dramatically diminished, compared with their parent
compounds. These data and docking results suggest that in this series of compounds the terminal
secondary amine on THIQ may play a significant role in binding the ALK enzyme. This is also concurred
with a recent docking study report where the terminal piperidine amine of LDK378 interacts with
Glu1210 of ALK by forming a salt bridge [6]. It is notable to mention that compounds 8 and 17 have
significant inhibitory activities against five different ALK mutant enzymes including G1202R. Since both
crizotinib and LDK378 cannot overcome the resistance issues related to G1202R mutant, this THIQ
scaffold could be useful to develop ALK inhibitors circumventing the resistance issues [4, 26].
Encouraged by these promising results, further optimization efforts of both 8 and 17 are underway and the
progress will be reported in due course.
5
5
. Experimental
.1. Chemistry
Solvents and reagents were obtained from commercial vendors and used as received. Compound 6
was purchased from Chemlin (Nanjing, China). TLC was carried out on precoated silica gel F254 plate
Merck, art. 5715) and column chromatography was performed using silica gel (Merck, mesh 230-400
(
1
13
μm). H and C NMR spectra were recorded with Bruker Avance 300 and Bruker Avance, using TMS or

the solvent peak as an internal standard. LC/MS analysis was conducted on the Waters Acquity UPLC
system with electrospray ionization in positive ion mode. EI/MS data was obtained with Varian 1200L.
HRMS was conducted on the JMS-700 (JEOL, Tokyo, Japan).
5
.1.1. 2,2,2-Trifluoro-N-(4-methoxyphenethyl)acetamide (2)
To a solution of 4-methoxyphenethylamine (1, 12.0 g, 79.4 mmol) in DCM (100 mL) was added
trifluoroacetic anhydride (13.5 mL, 95.3 mmol) followed by dropwise addition of Et
3
N (27.6 mL, 198
O and extracted
and the solvent was removed under
o
mmol) at 0 C. The reaction mixture was allowed to stir at rt for 3 h, quenched with H
2
with EtOAc. The combined organic layers were dried over Na
2
SO
4
vacuum. The crude mixture was purified by silica gel column chromatography using EtOAc/Hexanes (1/2)
1
as an eluent to afford 2 (19.0 g, 76.9 mmol, 97%) as a white solid. H NMR (300 MHz, DMSO-d
6
) δ 9.46
(s, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.39-3.35 (m, 2H), 2.72 (t, J = 7.2
+
Hz, 2H); LC/MS m/z 248.30 [M + H ].
5
.1.2. 2,2,2-Trifluoro-N-(4-methoxy-3-nitrophenethyl)acetamide (3)
To a solution of 2 (20.0 g, 80. 9 mmol) in TFA (206 mL) was added conc. HNO
3
(8.49 g, 80.89 mmol) at
C. The reaction mixture was stirred at 0 C for 2 h, concentrated under vacuum to remove TFA and
extracted with EtOAc. The organic layers were washed with H O and saturated NaCl (aq), dried over
Na SO , and the solvent was removed under vacuum. The crude product was purified by silica gel
o
o
0
2
2
4
column chromatography using EtOAc/Hexanes (1/2) as an eluent to afford 3 (19.2 g, 65.7 mmol, 81%) as
1
a white solid. H NMR (300 MHz, DMSO-d
6
) δ 9.46 (s, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 1.8,
8
.4 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H), 3.42 (q, J = 6.9 Hz, 2H), 2.82 (t, J = 6.9 Hz, 2H);
+
+
LC/MS m/z 293.28 [M + H ], 585.44 [2M + H ].

5
.1.3. 2,2,2-Trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (4)
To a mixture of H
2
SO
4
(150 mL) and AcOH (100 mL) was added 3 (25.0 g, 85.6 mmol) followed by
o
paraformaldehyde (14.5 g, mmol). The reaction mixture was heated at 50 C for 3.5 h, quenched with ice
2
cold water, and extracted with EtOAc. The combined organic layers were dried over Na SO and the
solvent was removed under vacuum. The crude product was purified by silica gel column
chromatography using EtOAc/Hexanes (1/1) as an eluent to afford 4 (15.1 g, 49.6 mmol, 58%) as a white
1
solid. H NMR (300 MHz, DMSO-d
6
) δ 7.76 (s, 1H), 7.38 (s, 0.4H), 7.33 (s, 0.6H), 4.85 (s, 0.7H), 4.81 (s,
+
1
.3H), 3.88 (s, 3H), 3.80-3.78 (m, 2H), 2.86-2.92 (m, 2H); LC/MS m/z 305.40 [M + H ].
5
.1.4. 2,2,2-Trifluoro-1-(7-hydroxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (4a)
To a solution of 4 (1.00 g, 3.29 mmol) in DCM (10 mL) was added triflic acid (3.00 mL, 32.9 mmol). The
o
reaction mixture was heated at 70 C for 10 h, allowed to cool rt, and quenched with ice cold water. This
mixture was basified with NaHCO
3
(aq) and extracted with EtOAc (2 x 50 mL). The organic layers were
O. The combined organic layers were dried over Na SO
4
washed with saturated NaCl (aq) followed by H
2
2
and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel
column chromatography using EtOAc/Hexanes (1/1) as an eluent to afford 4a (400 mg, 1.38 mmol, 42%)
1
as a yellow solid. H NMR (300 MHz, CDCl
3
) δ 10.41 (br, s, 1H), 7.96 (s, 1H), 6.98 (s, 0.7H), 6.95 (s,
+
0
.3H), 4.82 (s, 1.4H), 4.76 (s, 0.6H), 4.13-3.82 (m, 2H), 2.99-2.96 (m, 2H); LC/MS m/z 290.8 [M + H ].
5
.1.5. General procedure for the preparation of 4b-d
To a solution of 4a (140 mg, 0.480 mmol) in DCM (2.0 mL) was added an appropriate alcohol (0.62
o
mmol). Ph
and the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with H
extracted with DCM. The organic layers were washed with brine solution followed by H O. The
3
P (194 mg, 0.720 mmol) and DIAD (146 mg, 0.720 mmol) were added to this mixture at 0 C
2
O and
2

2 4
combined organic layers were dried over Na SO and the solvent was removed under vacuum. The crude
product was purified by silica gel column chromatography using EtOAc/Hexanes (1/2) as an eluent to
afford 4b-d, respectively.
5
.1.5.1. 2,2,2-Trifluoro-1-(7-isopropoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (4b)
Isopropanol (37 mg, 0.62 mmol) was used and 4b (75.0 mg, 0.226 mmol, 47%) was obtained as a pale
1
yellow solid. H NMR (300 MHz, CDCl
3
) δ 7.63 (s, 1H), 6.85 (s, 0.7H), 6.81 (s, 0.3H), 4.81 (s, 1.4H),
4
.75 (s, 0.6H), 4.63 (sept, J = 6.0 Hz, 1H), 3.93-3.85 (m, 2H), 2.96-2.92 (m, 2H), 1.39 (d, J = 6.0 Hz, 6H);
+
LC/MS m/z 333.2 [M + H ].
5
.1.5.2. 2,2,2-Trifluoro-1-(7-isobutoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (4c)
Isobutanol (46 mg, 0.62 mmol) was used and 4c (95.0 mg, 0.274 mmol, 53%) was obtained as a pale
1
yellow solid. H NMR (300 MHz, CDCl
3
) δ 7.68 (s, 1H), 6.86 (s, 0.6H), 6.83 (s, 0.4H), 4.82 (s, 1.3H),
4
.77 (s, 0.7H), 3.91-3.83 (m, 4H), 2.95-2.94 (m, 2H), 2.19-2.11 (m, 1H), 1.05 (d, J = 6.6 Hz, 6H); LC/MS
+
m/z 345.9 [M + H ].
5
.1.5.3. 1-(7-(sec-Butoxy)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (4d)
2
-Butanol (46 mg, 0.62 mmol) was used and 4d (98.1 mg, 0.283 mmol, 55%) was obtained as a pale
1
yellow solid. H NMR (300 MHz, CDCl
3
) δ 7.63 (s, 1H), 6.85 (s, 0.7H), 6.82 (s, 0.3H), 4.82 (s, 1.3H),
4
5
.76 (s, 0.7H), 4.43-4.39 (m, 1H), 3.93-3.86 (m, 2H), 2.97-2.93 (m, 2H), 1.82-1.65 (m, 2H), 1.35 (d, J =
+
.70 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); LC/MS m/z 345.0 [M + H ].
5
.1.6. Representative procedure for the preparation of 5, 5a-c: 1-(6-Amino-7-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (5)

To a solution of 4 (3.04 g, 10.0 mmol) in MeOH (50 mL) was added Pd/C (304 mg, 10% wt/wt) and the
mixture was stirred under H (g) at rt for 12 h. The reaction mixture was filtered through a celite bed and
2
washed with MeOH. The filtrate was evaporated under reduced pressure and purified by silica gel column
chromatography using EtOAc/Hexanes (1/1) to afford 5 (2.14 g, 7.80 mmol, 78%) as a slightly yellow
1
solid. H NMR (300 MHz, DMSO-d
6
) δ 6.69 (s, 0.4H), 6.66 (s, 0.6H), 6.41 (s, 1H), 4.65 (br, s, 2H), 4.61-
+
4
.46 (m, 2H), 3.79-3.70 (m, 2H), 3.72 (s, 3H), 2.66-2.72 (m, 2H); LC/MS m/z 274.7 [M + H ].
5
4
5
6
.1.6.1. 1-(6-Amino-7-isopropoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (5a)
b (50 mg, 0.15 mmol) in MeOH (1 mL), Pd/C (10 mg, 10% wt/wt), and 2 h reaction time were used and
1
a (41.2 mg, 0.136 mmol, 91%) was obtained as a slightly yellow solid. H NMR (300 MHz, CDCl
3
) δ
.55-6.49 (m, 2H), 4.67 (s, 1.3H), 4.62 (s, 0.7H), 4.81 (sept, J = 4.8 Hz, 1H), 3.85-3.79 (m, 2H), 3.63 (br,
+
s, 2H), 2.80 (br, s, 2H), 1.34 (d, J = 4.8 Hz, 6H); LC/MS m/z 302.8 [M + H ].
5
4
5
.1.6.2. 1-(6-Amino-7-isobutoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (5b)
c (90 mg 0.26 mmol) in MeOH (1 mL), Pd/C (9 mg, 10% wt/wt), and 2 h reaction time were used and
1
b (80 mg, 0.25 mmol, 98%) was obtained as a slightly yellow solid. H NMR (300 MHz, CDCl
3
) δ 6.51
(s, 1H), 6.48 (s, 1H), 4.67 (s, 1.2H), 4.62 (s, 0.8H), 3.83-3.79 (m, 4H), 3.72 (br, s, 2H), 2.79 (br, s, 2H),
+
+
2
.14-2.09 (m, 1H), 1.04 (d, J = 6.6 Hz, 6H); LC/MS m/z 316.7 [M + H ], 631.2 [2M + H ].
5
4
5
6
2
.1.6.3. 1-(6-Amino-7-(sec-butoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1 (5c)
d (90 mg 0.26 mmol) in MeOH (1 mL), Pd/C (9 mg, 10% wt/wt), and 2 h reaction time were used and
1
c (45.0 mg, 0.142 mmol, 55%) was obtained as a slightly yellow solid. H NMR (300 MHz, CDCl
3
) δ
.53-6.49 (m, 2H), 4.67 (s, 1.3H), 4.62 (s, 0.7H), 4.26-4.25 (m, 1H), 3.83-3.79 (m, 4H), 2.79-2.78 (m,
+
H), 1.81-1.64 (m, 2H), 1.30 (d, J = 5.7 Hz, 3H), 0.99 (t, J = 6.9 Hz, 3H); LC/MS m/z 316.8 [M + H ],

+
6
31.1 [2M + H ].
5
.1.7. Representative procedure for the preparation of 7, 7a-c: 1-(6-((5-Chloro-4-((2-
(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-
yl)-2,2,2-trifluoroethan-1-one (7)
To a solution of 5 (100 mg, 0.37 mmol) in 0.08 M HCl in ethoxyethanol (1.0 mL) was added 2,5-
o
dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (6, 152 mg, 0.44 mmol) and heated at 80 C
for 12 h. The reaction mixture was allowed to cool rt and solid precipitated was filtered, and washed with
1
EtOH and dried under vacuum to afford 7 (138 mg, 0.236 mmol, 65%) as a white solid. H NMR (300
3
MHz, CDCl ) δ 9.56 (s, 1H), 8.54 (t, J = 7.9 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 0.4H), 8.13 (s, 0.6H), 7.95 (d,
J = 6.6 Hz, 1H), 7.67-7.58 (m, 2H), 7.33-7.28 (m, 1H), 6.66 (s, 0.4H), 6.63 (s, 0.4H), 4.76 (s, 1.3H), 4.72
(s, 0.7H), 3.85 (s, 3H), 3.84-3.78 (m, 2H), 3.27 (sept, J = 6.9 Hz, 1H), 2.83-2.74 (m, 2H), 1.33 (d, J = 6.9
+
Hz, 6H); LC/MS m/z 584.1 [M + H ].
5
3
.1.7.1. 1-(6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-isopropoxy-
,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (7a)
The same method as 7 was used except replacing 5 with 5a (50 mg, 0.17 mmol) to afford 7a (61 mg, 0.10
1
mmol, 53%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.53 (s, 1H), 8.52 (t, J = 7.8 Hz, 1H), 8.18 (s,
1
0
H), 8.09 (d, J = 9.9 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.62-7.58 (m, 2H), 7.32-7.26 (m, 1H) 6.65 (s,
.4H), 6.62 (s, 0.6H), 4.73 (s, 1H), 4.68 (s, 1H), 4.58 (sept, J = 6.0 Hz, 1H), 3.88-3.79 (m, 2H), 3.26 (sept
J = 6.9 Hz, 1H), 2.76-2.69 (m, 2H), 1.58 (d, J = 6.0 Hz, 6H), 1.32 (d, J = 6.9 Hz, 6H); LC/MS m/z 612.0
+
[
M + H ].
5
.1.7.2. 1-(6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-isobutoxy-

3
,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (7b)
The same method as 7 was used except replacing 5 with 5b (65 mg, 0.21 mmol) to afford 7b (97 mg, 0.16
1
mmol, 83%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.55 (s, 1H), 8.57-8.52 (m, 1H), 8.19 (s, 1H),
8
6
2
.19 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.62-7.58 (m, 2H), 7.31-7.26 (m, 1H) 6.64 (s, 0.6H),
.61 (s, 0.4H), 4.73 (s, 1H), 4.69 (s, 1H), 3.79-3.86 (m, 4H), 3.25 (sept, J = 6.9 Hz, 1H), 2.77 (br, s, 2H),
+
.21-2.14 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H), 1.08 (d, J = 6.6 Hz, 6H); LC/MS m/z 626.0 [M + H ].
5
.1.7.3.
1-(7-(sec-Butoxy)-6-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-
yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (7c)
The same method as 7 was used except replacing 5 with 5c (45 mg, 0.14 mmol) to afford 7c (50 mg,
1
0
.079 mmol, 62%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.53 (s, 1H), 8.55-8.52 (m, 1H), 8.18
(s, 1H), 8.09 (d, J = 9.3 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.66-7.61 (m, 2H), 7.31-7.26 (m, 1H) 6.64 (s,
0
.7H), 6.61 (s, 0.3H), 4.72 (s, 1H), 4.68 (s, 1H), 4.35-4.34 (m, 1H), 3.85-3.81 (m, 2H), 3.26 (sept, J = 6.6
Hz, 1H), 2.75 (br, s, 2H), 1.82-1.69 (m, 2H), 1.34 (d, J = 5.4 Hz, 3H), 1.32 (d, J = 6.6 Hz, 6H), 1.02 (t, J
+
=
7.5 Hz, 3H); LC/MS m/z 626.0 [M + H ].
4
2
5
.1.8.
5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-
yl)pyrimidine-2,4-diamine (8)
To a solution of 7 (130 mg, 0.220 mmol) in THF (1.0 mL) was added a solution of LiOH·H
.11 mmol) in H O (0.5 mL) followed by MeOH (0.25 mL). The reaction mixture was stirred at rt for 2 h.
The solvents were evaporated under vacuum and extracted with EtOAc. The organic layers were washed
with H O and saturated NaCl (aq). The combined organic layers were dried over Na SO , filtered, and
2
O (47.0 mg,
1
2
2
2
4
concentrated under vacuum to get a crude product which was purified through silica gel column
chromatography using MeOH/DCM (1:9) as an eluent to afford 8 (64 mg, 0.13 mmol, 60%) as a white

1
solid. H NMR (300 MHz, CDCl
dd, 1.5, 8.1 Hz, 1H), 7.66 (dt, J = 1.5, 8.7 Hz, 1H), 7.55 (s, 1H), 7.32-7.26 (m, 1H), 6.55 (s, 1H), 4.04 (br,
s, 2H), 3.88 (s, 3H), 3.25 (sept, J = 6.9 Hz, 1H), 3.18 (br, s, 2H), 2.67 (br, s, 2H), 2.45 (br, s, 1H), 1.33 (d,
3
) δ 9.52 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.94
(
1
3
J = 6.9 Hz, 6H); C NMR (125 MHz, CDCl
3
) δ 157.5, 155.4, 155.3, 146.5, 138.4, 134.6, 131.3, 128.9,
1
4
27.0, 126.3, 124.9, 123.6, 123.2, 119.2, 107.7, 106.0, 55.8, 55.5, 48.0, 44.0, 28.8, 15.4; LC/MS m/z
+
+
88.2 [M + H ]; HRMS (EI) calcd for C23
H26ClN
5
O
3
S [M ] 487.1445, found 487.1432.
4
2
5
.1.9.
5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(7-methoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine (8a)
To a solution of 8 (50 mg, 0.10 mmol) in EtOH (1 mL) was added DIPEA (0.040 mL, 0.25 mmol) and
o
MeI (0.010 mL, 0.15 mmol) at 0 C. The reaction mixture was stirred at rt for 18 h, quenched with water,
2 4
and extracted with DCM. The combined organic layers were dried over Na SO , and the solvent was
removed under vacuum. The crude mixture was purified by silica gel column chromatography using
1
MeOH/DCM (1/10) as an eluent to afford 8a (38 mg, 0.075 mmol, 75%) as a yellow solid. H NMR (300
MHz, CDCl
3
) δ 9.56 (s, 1H), 8.50 (d, J = 9.0 Hz, 1H), 8.14 (s, 1H), 7.95-7.80 (m, 2H), 7.53 (s, 1H), 7.37
(t, J = 7.6 Hz, 1H), 7.28-7.27 (m, 1H), 6.75 (s, 1H), 4.60 (s, 2H), 4.14 (t, J = 6.1 Hz, 2H), 3.92 (s, 3H),
+
3
.30-3.15 (m, 6H), 1.30 (d, J = 6.8 Hz, 6H); LC/MS m/z 502.1 [M + H ].
2
4
5
.1.10.
5-Chloro-N -(2-ethyl-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-N -(2-
(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (8b)
The same method as 8a was used except replacing MeI with EtI (0.020 mL, 0.15 mmol) to afford 8b (23
1
mg, 0.045 mmol, 45%) as a yellow solid. H NMR (300 MHz, CDCl
3
) δ 9.46 (s, 1H), 8.50 (d, J = 8.5 Hz,
1
3
2
H), 8.15 (s, 1H), 7.99-7.90 (m, 2H), 7.73-7.59 (m, 1H), 7.53 (s, 1H), 7.34-7.22 (m, 1H), 6.54 (s, 1H),
.85 (s, 3H), 3.68-3.54 (m, 2H), 3.23-3.08 (m, 1H), 2.90 (dd, J = 15.9, 5.1 Hz, 4H), 2.59 (q, J = 6.8 Hz,
+
H), 1.38-1.16 (m, 9H); LC/MS m/z 516.2 [M + H ].
5
3
.1.11.
2-(6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-
,4-dihydroisoquinolin-2(1H)-yl)ethan-1-ol (8c)

To a solution of 8 (50 mg, 0.10 mmol) in DMF (1 mL) was added 2-bromoethanol (0.010 mL, 0.15 mmol)
o
and Cs
2
CO
3
(81 mg, 0.25 mmol) at 0 C. The reaction mixture was stirred at rt for 18 h, quenched with
2 4
water, and extracted with DCM. The combined organic layers were dried over Na SO , and the solvent
was removed under vacuum. The crude mixture was purified by silica gel column chromatography using
1
MeOH/DCM (1/10) as an eluent to afford 8c (50 mg, 0.094 mmol, 94%) as a slightly yellow solid. H
NMR (300 MHz, CDCl
3
) δ 9.56 (s, 1H), 8.48 (q, J = 3.8 Hz, 1H), 8.15 (d, J = 10.1 Hz, 2H), 7.90 (d, J =
7
4
.4 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.36-7.28 (m, 1H), 6.71 (s, 1H), 4.21 (s, 2H), 4.21 (s,
H), 4.05-3.77 (m, 8H), 3.31-3.16 (m, 1H), 3.06 (s, 1H), 1.30 (d, J = 6.6 Hz, 6H); LC/MS m/z 532.1 [M +
+
H ].
2
4
5
.1.12. 5-Chloro-N -(2-(2-(dimethylamino)ethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-N -
2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (8d)
To a solution of 8 (50 mg, 0.10 mmol) in DMF (1 mL) was added Et
(
3
N (0.030 ml, 0.22 mmol) at rt. The
mixture was stirred for 15 min at rt, and then 2-chloro-N,N-dimethylethanamine hydrochloride (18 mg,
o
0
.13 mmol) was added to the mixture at rt. The reaction mixture was stirred at 60 C for 16 h, quenched
with water, acidified with 1 N HCl (aq), and extracted with EtOAc. The combined organic layers were
dried over Na SO , and the solvent was removed under vacuum. The crude mixture was purified by silica
2
4
gel column chromatography using MeOH/DCM (1/7) as an eluent to afford 8d (5.0 mg, 0.0090 mmol, 9%)
1
as a yellow solid. H NMR (300 MHz, CDCl
3
) δ 9.53 (s, 1H), 8.56-8.50 (m, 1H), 8.27-8.18 (m, 2H), 8.07
(d, J = 6.9 Hz, 1H), 7.95-7.93 (m, 1H), 7.66-7.55 (m, 2H), 6.62 (d, J = 6.9 Hz, 1H), 4.64-4.51 (m, 2H),
3
2
.89 (s, 3H), 3.79-3.74 (m, 1H), 3.68-3.63 (m, 4H), 3.28-3.23 (m, 1H), 3.13-3.10 (m, 1H), 2.73-2.67 (m,
+
H), 1.33 (d, J = 6.9 Hz, 6H), 1.26 (s, 6H); LC/MS m/z 559.1 [M + H ].
5
3
.1.13.
2-(6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-
,4-dihydroisoquinolin-2(1H)-yl)-N,N-dimethylacetamide (8e)

To a solution of 8 (50 mg, 0.10 mmol) in CH
0.02 mL, 0.15 mmol) and K CO (35 mg, 0.35 mmol) at rt. The reaction mixture was refluxed for 18 h,
quenched with water, and extracted with EtOAc. The combined organic layers were dried over MgSO
3
CN (1 mL) was added 2-chloro-N,N-dimethylacetamide
(
2
3
4
,
and the solvent was removed under vacuum. The crude mixture was purified by silica gel column
chromatography using MeOH/DCM (1/10) as an eluent to afford 8e (7.6 mg, 0.013 mmol, 13%) as a
1
yellow solid. H NMR (300 MHz, CDCl
3
) 9.58 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H),
7
5
2
.94 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.61 (s, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.66 (s, 1H), 5.47-
.23 (m, 4H), 5.10 (d, J = 16.1 Hz, 2H), 4.78-4.60 (m, 2H), 3.91 (s, 3H), 3.35-3.20 (m, 1H), 3.09 (s, 3H),
+
.98 (s, 3H), 1.33 (d, J = 6.8 Hz, 6H); LC/MS m/z 573.1 [M + H ].
5
3
.1.14.
1-(6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-
,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (8f)
3
To a solution of 8 (50 mg, 0.10 mmol) in DCM (1 mL) was added Et N (0.030 ml, 0.22 mmol) and acetic
o
anhydride (0.020 mL, 0.15 mmol) at 0 C. The mixture was stirred for 18 h at rt, quenched with water,
2 4
and extracted with DCM. The combined organic layers were dried over Na SO , and the solvent was
removed under vacuum. The crude mixture was purified by silica gel column chromatography using
1
MeOH/DCM (1/10) as an eluent to afford 8f (23 mg, 0.043 mmol, 43%) as a yellow solid. H NMR (300
MHz, CDCl
3
) δ 9.52 (s, 1H), 8.56-8.49 (m, 1H), 8.17 (s, 1H), 8.06 (s, 0.4H), 8.05 (s, 0.6H), 7.93 (d, J =
7
1
1
5
.9 Hz, 1H), 7.70-750 (m, 2H), 7.35-7.26 (m, 1H), 6.65 (s, 0.6H), 6.61 (s, 0.4H), 4.68 (s, 1H), 4.58 (s,
H), 3.89 (s, 1.2H), 3.87 (s, 1.8H), 3.79 (t, J = 5.6 Hz, 1H), 3.65 (t, J = 5.6 Hz, 1H), 3.25 (sept, J = 6.8 Hz,
H), 2.73 (t, J = 5.4 Hz, 1H), 2.64 (t, J = 5.4 Hz, 1H), 2.18 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H); LC/MS m/z
+
30.2 [M + H ].
5
.1.15. 1-(6-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-2-hydroxyethan-1-one (8g)
To a solution of 8 (50 mg, 0.10 mmol) in DCM (1 mL) was added glycolic acid (11 mg, 0.15 mmol),

EDCI (23 mg, 0.15 mmol), DMAP (20 mg, 0.15 mmol), and Et
mixture was stirred for 18 h at rt, quenched with water, and extracted with DCM. The combined organic
layers were dried over Na SO , and the solvent was removed under vacuum. The crude mixture was
3
N (0.010 ml, 0.072 mmol) at rt. The
2
4
purified by silica gel column chromatography using MeOH/DCM (1/10) as an eluent to afford 8g (28 mg,
1
0
8
.051 mmol, 51%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.53 (s, 1H), 8.53 (t, J = 8.5 Hz, 1H),
.17 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.68-7.3 (m, 2H), 7.35-7.34 (m, 1H), 6.62
(d, J = 18.1 Hz, 1H), 4.73 (s, 1H), 4.39 (s, 1H), 4.25 (s, 2H), 3.89 (s, 3H), 3.80-3.56 (m, 2H), 3.48 (t, J =
5
.6 Hz, 1H), 3.24 (q, J = 6.9 Hz, 1H), 2.80-2.62 (m, 2H), 1.31 (d, J = 6.0 Hz, 6H); LC/MS m/z 546.1 [M
+
+
H ].
5
.1.16.
6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-N-ethyl-7-
methoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (8h)
To a solution of 8 (50 mg, 0.10 mmol) in DCM (1 mL) was added ethylisocyanate (0.010 mL, 0.15 mmol)
o
and Et
3
N (0.010 ml, 0.072 mmol) at 0 C. The mixture was stirred for 18 h at rt, quenched with water, and
2 4
extracted with DCM. The combined organic layers were dried over Na SO , and the solvent was removed
under vacuum. The crude mixture was purified by silica gel column chromatography using MeOH/DCM
1
(
1/10) as an eluent to afford 8h (34 mg, 0.061 mmol, 61%) as a brown solid. H NMR (300 MHz, CDCl
3
)
δ 9.52 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.62 (t, J =
7
2
.7 Hz, 1H), 7.56 (s, 1H), 7.36-7.20 (m, 1H), 6.64 (s, 1H), 4.55-4.37 (m, 2H), 3.87 (s, 3H), 3.70-3.53 (m,
H), 3.40-3.16 (m, 3H), 2.67 (t, J = 5.5 Hz, 2H), 1.31 (d, J = 6.8 Hz, 6H), 1.18 (t, J = 7.2 Hz, 3H);
+
LC/MS m/z 559.1 [M + H ].
5
.1.17. 6-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-7-methoxy-3,4-
dihydroisoquinoline-2(1H)-sulfonamide (8i)
To a solution of 8 (50 mg, 0.10 mmol) in 1,4-dioxane (1 mL) was added sulfamide (14 mg, 0.15 mmol)
3
and Et N (0.010 ml, 0.072 mmol) at rt. The mixture was refluxed for 18 h, quenched with water, and

4
extracted with DCM. The combined organic layers were dried over MgSO , and the solvent was removed
under vacuum. The crude mixture was purified by silica gel column chromatography using MeOH/DCM
1
(
1/10) as an eluent to afford 8i (27 mg, 0.048 mmol, 48%) as a brown solid. H NMR (300 MHz, CDCl
3
)
δ 9.52 (s, 1H), 8.52 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 8.06(s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.8
Hz, 1H), 7.55 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 4.48 (s, 2H), 4.37 (s, 2H), 3.87 (s, 3H), 3.50
(t, J = 5.8 Hz, 2H), 3.26 (sept, J = 6.8 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 1.31 (d, J = 6.8 Hz, 6H); LC/MS
+
m/z 567.1 [M + H ].
2
4
5
.1.18.
5-Chloro-N -(7-isopropoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-N -(2-
(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (8j)
2 3
To a solution of 7a (50 mg, 0.08 mmol) in EtOH (2.0 mL) was added a solution of K CO (45 mg, 0.33
o
mmol) in H
2
O (1.0 mL) and heated at 100 C for 1 h. The reaction mixture was evaporated, extracted with
2 4
EtOAc, and washed with saturated NaCl (aq). The combined organic layers were dried over Na SO and
the solvent was removed under vacuum. The crude product was purified by silica gel column
chromatography using MeOH/DCM (1:9) as an eluent to afford 8j (16 mg, 0.032 mmol, 55%) as a white
1
solid. H NMR (300 MHz, CDCl
3
) δ 9.48 (br, s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 7.96-7.92 (m,
1
H), 7.66-7.59 (m, 2H), 7.29-7.24 (m, 1H), 6.54 (s, 1H), 4.54 (sept, J = 6.3 Hz, 1H), 3.95 (s, 2H), 3.26
(sept, J = 6.9 Hz, 1H), 3.13-3.08 (m, 2H), 2.59-2.55 (m, 2H), 1.93 (br, s, 1H), 1.37 (d, J = 6.3 Hz, 6H),
+
1
.31 (d, J = 6.9 Hz, 6H); LC/MS m/z 516.0 [M + H ].
2
4
5
.1.19.
5-Chloro-N -(7-isobutoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-N -(2-
(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (8k)
The same method as 8j was used except replacing 7a with 7b (75 mg, 0.12 mmol) to afford 8k (44 mg,
1
0
.083 mmol, 70%) as a white solid. HNMR (300 MHz, CDCl
3
) δ 9.49 (br, s, 1H), 8.56 (d, J = 8.4 Hz,

1
3
1
H), 8.16 (s, 1H), 7.94-7.91 (m, 2H), 7.64-7.56 (m, 2H), 7.26-7.24 (m, 1H), 6.52 (s, 1H), 3.96 (s, 2H),
.76 (d, J = 6.3 Hz, 2H), 3.26 (sept, J = 6.6 Hz, 1H), 3.10 (br, s, 2H), 2.59 (br, s, 2H), 2.18-2.14 (m, 1H),
+
.71 (br, s, 1H), 1.31 (d, J = 6.6 Hz, 6H), 1.06 (d, J = 6.6 Hz, 6H); LC/MS m/z 530.0 [M + H ].
2
4
5
.1.20.
N -(7-(sec-Butoxy)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-chloro-N -(2-
(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (8l)
The same method as 8j was used except replacing 7a with 7c (35 mg, 0.06 mmol) to afford 8l (23 mg,
1
0
1
1
.043 mmol, 79%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.46 (br, s, 1H), 8.53 (d, J = 8.4 Hz,
H), 8.15 (s, 1H), 7.95-7.90 (m, 2H), 7.64-7.59 (m, 2H), 7.28-7.23 (m, 1H), 6.52 (s, 1H), 4.31-4.29 (m,
H), 3.95 (s, 2H), 3.24 (sept, J = 6.6 Hz, 1H), 3.10 (br, s, 2H), 2.57 (br, s, 2H), 2.25 (br, s, 1H), 1.83-1.61
+
(
m, 2H), 1.30 (d, J = 6.6 Hz, 9H), 0.99 (t, J = 7.2 Hz, 3H); LC/MS m/z 530.0 [M + H ].
4
2
5
.1.21. 5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydro-
4
2
λ -isoquinolin-6-yl)pyrimidine-2,4-diamine, iodide salt (8m)
o
A solution of 8 (50 mg, 0.10 mmol) and MeI (0.031 mL, 0.50 mmol) in THF (1 mL) was stirred at 70 C
for 18 h. The reaction mixture was concentrated and purified by silica gel column chromatography using
1
MeOH/DCM (1/9) as an eluent to afford 8m (23 mg, 0.036 mmol, 35%) as a white solid. H NMR (300
MHz, CDCl
3
) δ 9.59 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H),
7
.73 (t, J = 7.3 Hz, 1H), 7.62 (s, 1H), 7.35 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 4.85 (s, 2H), 4.00 (t, J = 6.1
Hz, 2H), 3.91 (s, 3H), 3.61 (s, 6H), 3.32-3.16 (m, 1H), 3.08 (t, J = 6.5 Hz, 2H), 1.32 (d, J = 6.8 Hz, 6H);
-
LC/MS m/z 516.2 [M - I ].
4
2
5
.1.22.
5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(7-methoxy-3,4-dihydroisoquinolin-6-
yl)pyrimidine-2,4-diamine (8n)

To a solution of 8 (50 mg, 0.10 mmol) in DCM (0.5 mL) was added NBS (20 mg, 0.11 mmol) and stirred
at rt for 1 h. To the mixture was added 30% NaOH (aq) and stirred for 1h. The reaction mixture was
4
extracted with EtOAc and organic layers were washed with brine, dried over MgSO , concentrated, and
purified by silica gel column chromatography using MeOH/DCM (1/9) as an eluent to afford 8n (25 mg,
1
0
1
.051 mmol, 51%) as a dark orange gel. H NMR (300 MHz, CDCl
3
) δ 9.54 (s, 1H), 8.49 (d, J = 8.2 Hz,
H), 8.28 – 8.10 (m, 3H), 7.92 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.62 (t, J = 7.1 Hz, 1H), 7.29 (d, J = 7.4
Hz, 1H), 6.79 (s, 1H), 3.91 (s, 3H), 3.71 (t, J = 7.7 Hz, 2H), 3.31-3.16 (m, 1H), 2.55 (t, J = 7.7 Hz, 2H),
+
1
.29 (d, J = 6.8 Hz, 6H); LC/MS m/z 486.3 [M + H ].
4
2
5
.1.23.
5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(7-methoxyisoquinolin-6-yl)pyrimidine-2,4-
diamine (8o)
To a solution of (KSO
3
)
2
2 3
NO (304 mg, 1.13 mmol) in 4% Na CO (aq) (4.6 mL) was added 8 (50 mg,
0
.102 mmol) and stirred at rt for 48 h. The reaction mixture was extracted with DCM and organic layers
were washed with brine, dried over MgSO , concentrated, and purified by silica gel column
4
chromatography using MeOH/DCM (1/9) as an eluent to afford 8o (6.3 mg, 0.13 mmol, 10%) as a yellow
1
solid. H NMR (300 MHz, acetone-d
6
) δ 9.64 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H),
8
7
.38 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.88-7.76 (m, 1H), 7.58-7.46 (m, 2H),
+
.43-7.31 (m, 1H), 4.13 (s, 3H), 3.57-3.39 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); LC/MS m/z 484.1 [M + H ].
5
.1.24. Methyl 3-methoxyphenethylcarbamate (10)
2 3
To a solution of 3-methoxyphenethylamine (9, 50.0 g, 331 mmol) in DCM (500 mL) was added Na CO
o
(
70.1 g, 661 mmol) and methyl chloroformate (18.6 mL, 238.08 mmol) at 0 C. The reaction mixture was
stirred at rt for 4 h, quenched with water, and extracted with DCM. The combined organic layers were
dried with Na SO , filtered, and concentrated. The crude mixture was purified by silica gel column
2
4

chromatography using EtOAc/hexanes (1/1) as an eluent to afford the title compound 10 (60.0 g, 287
1
mmol, 87 %) as a white solid. H NMR (300 MHz, CDCl
3
) δ 7.26-7.20 (m, 1H), 6.79-6.74 (m, 3H), 4.69
(br, s, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.41 (q, J = 6.6 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H); EI/MS m/z 209.1
+
[
M ].
5
.1.25. 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one (11)
o
To a preheated polyphosphoric acid (184 mL, 183.99 mmol) at 120 C was added 10 (35.0 g, 167.26
o
mmol) slowly at 120 C. The reaction mixture was stirred at rt for 6 h, quenched with ice water, basified
2 3 2 4
with K CO , and extracted with DCM. The combined organic layers were dried with Na SO , filtered, and
concentrated. The crude mixture was purified by silica gel column chromatography using EtOAc/hexanes
1
(
1/1) as an eluent to afford the title compound 11 (38.5 g, 218 mmol, 76 %) as a white solid. H NMR
(
500 MHz, CDCl
3
) δ 8.01 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.7, 2.4 Hz, 1H),
6
1
.71 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.56 (td, J = 6.6, 2.8 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H); EI/MS m/z
+
77.1 [M ].
5
.1.26. 6-Methoxy-1,2,3,4-tetrahydroisoquinoline (12)
To a solution of LiAlH
4
(8.17 g, 215 mmol) in THF (250 mL) was added a solution of 11 (38.0 g, 214
o
mmol) in THF (250 mL) at 0 ℃. The reaction mixture was stirred at 70 C for 12 h, cooled down to rt,
quenched with water and 15% NaOH (aq), and extracted with EtOAc. The combined organic layers were
2 4
dried with Na SO , filtered, and concentrated. The crude mixture was purified by silica gel column
chromatography using EtOAc/hexanes (2/1) as an eluent to afford the title compound 12 (30.0 g, 184
1
mmol, 86 %) as a yellow oil. H NMR (300 MHz, CDCl
3
) δ 6.92 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3 Hz,
1
1
H), 6.62 (s, 1H), 3.95 (s, 2H), 3.77 (s, 3H), 3.11 (t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.4 Hz, 2H), 2.20 (br, s,
+
H); EI/MS m/z 163.1 [M ].

5
.1.27. 2,2,2-Trifluoro-1-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (13)
3
To a solution of 12 (29.0 g, 178 mmol) in DCM (250 mL) was added Et N (49.6 mL, 356 mmol) and
o
trifluoroacetic anhydride (29.7 mL, 213 mmol) at 0 C. The reaction mixture was stirred at rt for 3 h,
2 4
quenched with water, and extracted with DCM. The combined organic layers were dried with Na SO ,
filtered, and concentrated. The crude mixture was purified by silica gel column chromatography using
EtOAc/hexanes (1/1) as an eluent to afford the title compound 13 (30.0 g, 115.7 mmol, 65 %) as a yellow
1
solid. H NMR (300 MHz, CDCl
3
) δ 7.08-7.02 (m, 1H), 6.82 -6.76 (m, 1H), 6.73-6.68 (m, 1H), 4.73-4.68
+
(
m, 2H), 3.88-3.82 (m, 2H), 3.80 (s, 3H), 2.95-2.93 (m, 2H); EI/MS m/z 259.0 [M ].
5
2
.1.28. 2,2,2-Trifluoro-1-(6-methoxy-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (14a) and
,2,2-trifluoro-1-(6-methoxy-5-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (14b)
To a solution of 13 (5.00 g, 30.6 mmol) in TFA (50 mL) was slowly added a solution of HNO
3
(3.5 g,
3
3.7 mmol) in TFA (10 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 3 h, The solvent was
3
evaporated under reduced pressure, neutralized with NaHCO (aq), and extracted with DCM. The
2 4
combined organic layers were dried with Na SO , filtered, and concentrated. The crude mixture was
purified by silica gel column chromatography using EtOAc/hexanes (1/2) as an eluent to afford the title
compound 14a (3.50 g, 16.8 mmol, 55%) as slightly yellow solid and 14b (1.50 g, 7.20 mmol, 24%) as
1
slightly yellow solid. 14a: H NMR (300 MHz, CDCl
3
) δ 7.69 (s, 1H), 6.91 (s, 0.4H), 6.88 (s, 0.6H), 4.77
+
(
s, 1.3H), 4.73 (s, 0.7H), 3.95 (s, 3H), 3.89-3.86 (m, 2H), 3.02-3.00 (m, 2H); LC/MS m/z 305.1 [M + H ].
1
1
4b: H NMR (300 MHz, CDCl
3
) 7.25 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.78 (s, 1.4H), 4.73
+
(
s, 0.6H), 3.90 (s, 3H), 3.87-3.85 (m, 2H), 2.90-2.86 (m, 2H); LC/MS m/z 305.1 [M + H ].
5
.1.29. 1-(7-Amino-6-methoxy-3,4-dihydisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (15)

To a solution of 14a (1.52 g, 5.00 mmol) in MeOH (25 mL) was added Pd/C (152 mg, 10% wt/wt) and
the mixture was stirred under H (g) at rt for 12 h. The reaction mixture was filtered through a celite pad
2
and washed with MeOH. The filtrate was evaporated under reduced pressure and purified by silica gel
column chromatography using EtOAc/Hexanes (1/1) to afford 15 (1.10 g, 4.00 mmol, 80%) as a slightly
1
yellow solid. H NMR (300 MHz, CDCl
3
) δ 6.56 (s, 0.4H), 6.53 (s, 0.6H), 6.47 (s, 0.6H), 6.44 (s, 0.4H),
4
.64 (s, 1.4H), 4.59 (s, 0.6H), 3.83 (s, 3H), 3.83-3.77 (m, 2H), 2.86-2.81 (m, 2H); LC/MS m/z 274.7 [M +
+
H ].
5
.1.30. 1-(7-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (16)
To a solution of 15 (100 mg, 0.370 mmol) in 0.08 M HCl in ethoxyethanol (1.0 mL) was added 6 (152 mg,
o
0
.44 mmol) and heated at 80 C for 12 h. The reaction mixture was allowed to cool rt and solid
precipitated was filtered, and washed with EtOH and dried under vacuum to afford 16 (145 mg, 0.248
1
mmol, 68%) as a white solid. H NMR (300 MHz, CDCl
3
) δ 9.47 (s, 0.6H), 9.43 (s, 0.4H), 8.44 (t, J = 8.2
Hz, 1H), 8.18 (s, 0.4H), 8.16 (s, 0.6H), 8.18 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 7.3 Hz, 0.6H),
7
4
2
.69-7.61 (m, 1.4H), 7.38 (t, J = 7.9 Hz, 0.6H), 7.31 (t, J = 7.9 Hz, 0.4H), 6.66 (s, 0.4H), 6.63 (s, 0.6H),
.57 (s, 1.3H), 4.51 (s, 0.7H), 3.89 (s, 3H), 3.86-3.81 (m, 2H), 3.24 (sept, J = 6.9 Hz, 1H), 2.85-2.92 (m,
+
H), 1.30 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H); LC/MS m/z 584.2 [M + H ].
4
2
5
.1.31. 5-Chloro-N -(2-(isopropylsulfonyl)phenyl)-N -(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-
yl)pyrimidine-2,4-diamine (17)
2
To a solution of 16 (150 mg, 0.26 mmol) in THF (1.0 mL) was added a solution of LiOH·H O (54 mg,
1
2
.25 mmol) in H O (0.5 mL) followed by MeOH (0.25 mL). The reaction mixture was stirred at rt for 2 h.
The solvents were evaporated under vacuum and extracted with EtOAc. The organic layers were washed