Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127479

Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.

Full text of DOI:10.1016/j.bmcl.2020.127479

Bioorganic&MedicinalChemistryLetters30(2020)127479
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and structure-activity relationship study of piperazinone-
containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors
⁎
Ning-Yu Wanga, ,1, Wei-Qiong Zuob,1, Rong Hua, Wan-Li Wanga, Yong-Xia Zhub, Ying Xub,
⁎
Luo-Ting Yub, Zhi-Hao Liub,
a School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
b Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ
inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of
thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be
more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several
potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin
lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ
inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
PI3Kδ
SAR
Thieno[3,2-d]pyrimidine
Piperazinone
Antiproliferative activity
The phosphatidylinositol 3-kinases (PI3Ks) family contains a panel
of lipid kinases which regulate many physiological functions and cel-
lular processes, including cell proliferation, survival and metabolism.1
The amplification or mutation of PI3Ks are always associated with
different diseases, including various cancers2 and autoimmune dis-
eases,3 implying that PI3K pathways would be promising drug targets.
Up to now, a number of small molecules targeted at PI3Ks have been
developed4 and their clinical benefit for cancer patients have been ex-
tensively validated.5 Current reported PI3K inhibitors could be divided
into two classes: pan PI3K inhibitors and isoform-selective PI3K in-
hibitors.4 Although the former class, including pan-class I PI3K in-
hibitors and pan‑PI3K/mTOR inhibitors, have demonstrated remark-
able anticancer activity in preclinical models of solid tumor and
leukemia, most cancer patients cannot achieve satisfactory clinical ef-
ficiency from them owing to their dose-limiting toxicities or inadequate
responses in the clinic.6,7 While isoform-selective PI3K inhibitors,
which only target at one or several PI3K isoforms closely related to
specific cancer types, have achieved impressive efficiency in clinical,
including PI3Kδ inhibitors in B cell malignancies and PI3Kα inhibitors
in advanced breast cancer.8
some of them have entered advanced clinical trials or even been ap-
proved, such as idelalisib, duvelisib and umbralisib (Fig. 1a). However,
several disadvantages, including significant toxicity, poor target se-
lectivity as well as unsatisfactory pharmacokinetic profiles, have pre-
vented their wide application or clinical development. More potent
PI3Kδ inhibitors with new chemotypes are thus needed to be developed
to provide us more drug candidates.
Thienopyrimidine derivatives have represented a classical chemo-
type of PI3K inhibitors, including pan-PI3K inhibitors as well as iso-
forms selective PI3K inhibitors (Fig. 1b).11 Previous reports have de-
monstrated that the substituent at 6-position of thienopyrimidine core
is important for the PI3Kδ isoform selectivity, mainly due to the
“tryptophan shelf” effect that a small amino acid, threonine, at position
750 in PI3Kδ is substituted by a larger, charged amino acid, lysine or
arginine, in the other three Class I isoforms (Fig. 2).12–15 This subtle
difference in residues results in the substantial different drug-target
interactions between the piperazine ring of GDC-0941 and PI3Kδ as
well as other PI3K isoforms,16 and thus makes it possible to develop
selective PI3Kδ inhibitors by minor structural modifications from a pan-
PI3K inhibitor. In this study, a series of thienopyrimidine derivatives
implanting two kinds of piperazinone motifs at 6-position were de-
signed as novel PI3Kδ inhibitors. We thought that the relative rigid and
tortuous feature of piperazinone would facilitate the terminal fragment
accessing the tryptophan shelf of PI3Kδ while impair its binding with
The PI3Kδ isoform mainly expresses in leukocytes and is crucial for
the survival of leukocytes as well as their malignant counterpart.9 It was
thus thought to be a promising target for the treatment of lymphomas.
A number of PI3Kδ inhibitors have been disclosed in recent years,10 and
⁎ Corresponding authors.
E-mail addresses: wangny-swjtu@swjtu.edu.cn (N.-Y. Wang), liuzhihao@scu.edu.cn (Z.-H. Liu).
1 These authors contributed equally to this work.
https://doi.org/10.1016/j.bmcl.2020.127479
Received 21 April 2020; Received in revised form 25 July 2020; Accepted 6 August 2020
Availableonline09August2020
0960-894X/©2020ElsevierLtd.Allrightsreserved.

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Fig. 1. Structure of representative PI3K inhibitors. (a). The structure of PI3Kδ inhibitors idelalisib, duvelisib and umbralisib; (b). The structure of thienopyrimidine
PI3K inhibitors, including pan-PI3K inhibitor GDC-0941 and PI3Kδ inhibitor PI-3065.
Fig. 2. Cocrystal structure of PI3Kγ + GDC-0941 (left, PDB ID: 3DBS)15 and PI3Kδ + GDC-0941 (right, PDB ID: 2WXP)16 demonstrate the “tryptophan shelf” formed
in PI3Kδ.
other PI3K isoforms. Here we report the synthesis, structure-activity
relationship (SAR) study and the preliminary biological evaluation with
respect to this kind of PI3Kδ inhibitors to validate their potential as
anticancer agents.
provide the critical common intermediates 5a. 5a reacted with different
1-substituted piperazin-2-ones (6a-6l, Supplementary data Table 1) or
1-substituted piperazines in the presence of N,N-diisopropylethylamine
to provide 7a-7l and 9a-9c, or it underwent nucleophilic substitution
with 4-methylpiperazin-2-one or tert-butyl 3-oxopiperazine-1-carbox-
ylate to produce the title compounds 8a and 8x(Scheme 2).
The synthesis route of thienopyrimidine derivatives 7a-7l, 8a-8ab
and 9a-9c is shown in Scheme 1 and Scheme 2. To prepare the two
kinds of piperazinone-containing thieno[3,2-d]pyrimidines reported in
our study, an alternative synthesis route was designed based on pre-
vious studies.17–18 Briefly, compound 1 underwent nucleophilic sub-
stitution with morpholine and formylation with dimethylformamide to
afford aldehyde 2, which was reduced by sodium borohydride to pro-
vide alcohol 3. Then CeN coupling of compound 3 and 2-ethylbenzo[d]
imidazole afford 4, which was then chloridized with thionyl chloride to
The Boc group of 8x was removed by trifluoroacetic acid in di-
chloromethane to provide 5b, which was nucleophilic substituted with
2,2,2-trifluoroethyl methanesulfonate in acetonitrile to produce 8b.
And reduction amination of 5b with different aldehydes or ketones in
dichloromethane by sodium triacetoxyborohydride produced 8c-8k. 8k
was then underwent deprotection of ethylene glycol with concentrated
hydrochloric acid to afford ketone 8l, which was reduced by sodium
2

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Scheme 1. Synthesis of thieno[3,2-d]pyrimidine derivatives 7a-7l and 9a-9c. Reagents and conditions: a. (i) Morpholine, MeOH, rt; (ii) n-BuLi, DMF, THF, −78 °C;
b. NaBH4, MeOH; c. Pd2(dba)3, XPhos, Cs2CO3, 1,4-Dioxane, 110 °C; d. SOCl2, DCM; e. DIPEA, i-PrOH, reflux.
borohydride to provide alcohol 8m, or underwent reduction amination
with dimethylamine hydrochloride or pyrrolidine to provide 8n and 8o.
The acetamide 8p was prepared by nucleophilic substitution of 5b with
iodoacetamide in acetonitrile, while 8q was got by condensation re-
action of 5b with L-lactic acid. Finally, 5b underwent acylation with
different acyl chlorides or sulfonylation with different sulfonyl chlor-
ides to produce 8r-8w, 8y-8ab.
demonstrated the possibility to develop PI3Kδ inhibitors based on pi-
perazinone motifs.
The lactam nitrogen in 4-(thieno[3,2-d]pyrimidin-6-ylmethyl)pi-
perazin-2-one series (7a-7l) prevent its modification for extensive SAR
study. We thus designed the 1-(thieno[3,2-d]pyrimidin-6-ylmethyl)pi-
perazin-2-one series (8a-8ab) which allowed the introduction of more
diverse fragments to optimize the potency and selectivity. When alkyls
or cycloalkyls were introduced to the 4-position of piperazinone (8a-
8f), all compounds exhibited excellent potency for PI3Kδ with moderate
to good δ/α selectivity. And an alkyl or cycloalkyl with 3–5 carbons
also seemed to be the best substituent for both the PI3Kδ potency and
the δ/α selectivity, which was consistent with the 4-(thieno[3,2-d]
pyrimidin-6-ylmethyl)piperazin-2-one series. The replacement of cy-
clohexyl in 8f with hexatomic heterocycles (8g-8i) resulted in negli-
gible to moderate improvement in both PI3Kδ potency and δ/α se-
lectivity, while the introduction of substituents with hydrogen receptors
(8j-8m) at the para-position of cyclohexyl substantially benefit the
PI3Kδ potency. We speculated that these four compounds might form
an additional hydrogen bond with PI3Kδ via this fragment to contribute
the PI3Kδ potency but only 8k and 8m could form a hydrogen bond
with PI3Kα, which resulted in a better δ/α selectivity for 8j and 8l. A
basic substituent at the para-position of cyclohexyl (8n, 8o) would be
harmful to the PI3Kδ potency, which could also be validated by 8g. The
position of the piperazinone carbonyl seemed to be inessential for the
PI3Kδ potency or the δ/α selectivity (7b&8a, 7e&8d, 7f&8e, 7g&8m,
7h&8p), though the presence of this carbonyl seemed to be critical for
both PI3Kδ potency and selectivity (7f, 8e&9c).
Previous studies have demonstrated that a benzo[d]imidazole
fragment substituted at 2-position of thieno[3,2-d]pyrimidine core
could fit well into the affinity pocket of PI3Kδ to achieve moderate to
good PI3Kδ inhibitory activity and selectivity.12,14,18 More importantly,
the benzo[d]imidazole motif could also significantly attenuate CYP3A4
time-dependent inhibition to avoid the drug-drug interactions (DDI)
risk,12 which makes benzo[d]imidazoles an preferred class of sub-
stituents for 2-position of thieno[3,2-d]pyrimidine core. 2-Ethylbenzo
[d]imidazole motif was thus selected to incorporate in the 2-position of
thieno[3,2-d]pyrimidine core in this study. Several 4-(thieno[3,2-d]
pyrimidin-6-ylmethyl)piperazin-2-ones (7a-7l) harboring alkyls or aryls
in the 1-position of piperazinone with different size were firstly pre-
pared, And the potency of these compounds for PI3Kδ and PI3Kα were
tested to evaluate their potency and PI3Kδ selectivity. As shown in
Table 1, a hydrophobic alkyl group on 1-position of piperazinone (7b-
7g VS 7h-7i) seemed to be essential for the potency against PI3Kδ and
the increase in the size would benefit the potency and the δ/α se-
lectivity as well. An alkyl or cycloalkyl with 3–5 carbons seemed to be
the best substituent for both the PI3Kδ potency and the δ/α selectivity.
When an aryl was introduced to this position, a substantial loss of po-
tency for PI3Kδ as well as the δ/α selectivity was observed. This could
be partly attributed to the high rigidity of 1-aryl-piperazin-2-one motif
that might compromise the fitness of these compounds for PI3Kδ. The
preliminary SAR study yielded several potent PI3Kδ inhibitors with low
nanomolar IC50 and moderate to good δ/α selectivity, which
Next, a series of acyls and sulfonyls were introduced to the 4-posi-
tion of piperazinone. Almost all of these acyl and sulfonyl derivatives
exhibited excellent PI3Kδ potency with single-digit nanomolar IC50s,
while the acyl panel displayed much better δ/α selectivity as compared
with the sulfonyl panel. A possible explanation for this phenomenon
3

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Scheme 2. Synthesis of thieno[3,2-d]pyrimidine derivatives 7a-7l and 9a-9c. Reagents and conditions: a. t-BuOK, THF, 0 °C; b. TFA, DCM, rt; c. 2,2,2-trifluoroethyl
methanesulfonate, K2CO3, MeCN, reflux; d. aldehydes or ketones, DCM, sodium triacetoxyborohydride; e. DCM, THF, concentrated HCl(aq); f. NaBH4, MeOH, 0 °C-
r.t.; g. dimethylamine hydrochloride(8n) or pyrrolidine(8o), DCM, sodium triacetoxyborohydride; h. iodoacetamide, MeCN, reflux; i. L-lactic acid, HOBT, EDCI, TEA,
DCM; j. acyl chlorides or sulfonyl chlorides, TEA, DCM.
would be that the bond angle of the two single bonds for sulfonyl is
significantly smaller than that for acyl, which facilitate their interaction
with PI3Kα and finally led to worse δ/α selectivity. Moreover, our
sulfonyl piperazinone derivatives also exhibited better PI3Kδ potency
and δ/α selectivity as compared with their sulfonyl piperazine coun-
terparts (8y&9a, 8ab&9b) in spite of to a less extent.
could adopt a favorable packing interaction with the indole ring of
Trp760 over its piperazine counterpart 9f via the methylene groups of
piperazinone and cyclopentyl, which would be a possible explanation
for the substantial better PI3Kδ potency of 8e than 9c.
The preliminary optimization with respect to piperazinone-con-
taining thieno[3,2-d]pyrimidines have provide us several compounds
with comparable or even better PI3Kδ potency as compared with ide-
lalisib, several potent and selective piperazinone PI3Kδ inhibitors (7f,
8e, 8l, 8s, 8t) were selected to further evaluate their PI3K isoforms
selectivity as well as the antiproliferative activity (Table 2). All of these
compounds also exhibited good δ/β and δ/γ selectivity with SI of >
100, implying that the PI3Kδ isoforms selectivity of piperazinone-
containing thieno[3,2-d]pyrimidines is not restricted to PI3Kα. Four
non-Hodgkin lymphoma (NHL) cell lines, including three diffuse large
B-cell lymphoma (DLBCL) cell lines (SU-DHL-6, OCI-LY-3, OCI-LY-10)
and one mantle cell lymphoma (MCL) cell line (JEKO-1), as well as
three normal cell lines (Vero, LO-2 and HEK-293) were selected to
evaluate the antiproliferative activity of the abovementioned PI3Kδ
inhibitors by MTS assay. All these compounds exhibited similar
Our SAR study have demonstrated that piperazinone would be a
promising motif to design new PI3Kδ inhibitors with better PI3Kδ po-
tency and δ/α selectivity, regardless of the position of the carbonyl of
piperazinone. To interpret the importance of piperazinone motif for
PI3Kδ potency and δ/α selectivity, two structurally similar compounds
8e and 9c were selected to dock into the hinge and affinity pocket of
PI3Kδ. As shown in Fig. 3, the O atom of morpholine and N atom of
benzimidazole of both compounds formed two crucial hydrogen bonds
with Val828 and Lys779 of PI3Kδ, respectively. And the piperazinone
fragment in 8e and the piperazine fragment in 9c could stack on the
“tryptophan shelf” formed by Thr750 and Trp760 in PI3Kδ, which
endow the PI3Kδ selectivity of both compounds over other PI3K iso-
forms. It seemed that the relative rigid piperazinone fragment of 8e
4

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Table 1
Biochemical assay data for the title compounds 7a-7l, 8a-8ab and 9a-9c.
Cpd
R
PI3Kδ IC50(nM)a
20
PI3Kα/δ Selectivityb
13
Cpd
R
PI3Kδ IC50(nM)
2.2
PI3Kα/δ selectivity
13
7a
H
8k
7b
7c
Me
Et
4.9
4.1
53
10
8l
1.6
1.6
184
18
8m
7d
7e
5.7
2.5
7.7
49
8n
8o
14
14
36
8
7f
2.1
2.1
119
35
8p
8q
6.2
3.6
25
49
7g
7h
7i
12
15
7.1
11
8r
8s
3.2
1.1
35
76
(continued on next page)
5

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Table 1 (continued)
Cpd
R
PI3Kδ IC50(nM)a
3.4
PI3Kα/δ Selectivityb
24
Cpd
R
PI3Kδ IC50(nM)
1.4
PI3Kα/δ selectivity
84
7j
8t
7k
7l
82
13
7.7
12
8u
8v
2.0
7.9
95
43
8a
8b
Me
4.5
6.3
48
32
8w
8x
2.9
12
47
52
8c
8d
8e
2.1
2.2
2.9
53
64
84
8y
2.2
4.4
3.5
10
10
4
8z
8aa
8f
12
15
21
25
8ab
9a
1.2
4.1
38
8g
2.4
8h
6.2
61
9b
4.8
13
8i
8j
4.8
3.8
56
71
9c
42
31
Idelalisibc
4.7
> 106
aIC50 values for PI3Kδ and PI3Kα are the mean value of at least two independent measurements.
bThe PI3Kα/δ selectivity was calculated as the ratio of the IC50 values of a compound to PI3Kα and PI3Kδ.
cIdelalisib is a selective PI3Kδ inhibitor with reported IC50s of 820 nM, 565 nM, 2.5 nM and 89 nM against PI3Kα, β, δ and γ, respectively.19
antiproliferative profile that the SU-DHL-6 cells and JEKO-1 cells were
highly sensitive to our PI3Kδ inhibitors, while the OCI-LY-10 cells were
insensitive. Moreover, the five piperazinone-containing thieno[3,2-d]
pyrimidines as well as idelalisib did not display obvious cytotoxicity
against all the three normal cell lines at a concentration of 20 μM,
implying their good safety profiles.
In this study, piperazinone motif was introduced into the thieno
[3,2-d]pyrimidines core to prepare new PI3Kδ inhibitors by utilizing
the different residues surrounding the solvent exposed entrance be-
tween PI3Kδ and other PI3K isoforms. Detailed SAR study demon-
strated that both the 4-(thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-
2-one
and
1-(thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-2-one
6

N.-Y. Wang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127479
Fig. 3. Models comparing the interaction of PI3Kδ and piperazine or piperazinone-containing thieno[3,2-d]pyrimidine derivatives. (a) The flexible piperazine
fragment of 9c attenuate its interaction with the indole ring of Trp760. (b) The relative rigid piperazinone fragment of 8e would facilitate its packing interaction with
the indole ring of Trp760 via the methylene groups of piperazinone and cyclopentyl.
Table 2
The PI3K isoforms selectivity and antiproliferative activity of five potent PI3Kδ inhibitors.a
Cmpds
PI3K isoforms potency (IC50: nM)
Antiproliferative activity (IC50: μM)
PI3Kδ
PI3Kα
PI3Kβ
PI3Kγ
OCI-LY-3
OCI-LY-10
SU-DHL-6
JEKO-1
Vero
LO-2
HEK-293
Idelalisib
4.7
2.1
2.9
1.6
1.1
1.4
1.9
0.9
0.5
0.6
0.5
0.3
> 500
250
243
295
84
> 500
> 500
> 500
232
245
52
5.2
2.8
6.9
8.6
2.2
1.5
2.4
> 10
> 10
> 10
> 10
0.12
0.18
0.53
0.57
0.10
0.08
0.05
0.12
0.17
0.56
0.47
0.19
0.12
0.06
0.02
0.31
0.13
0.08
0.03
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
7f
8e
8l
8s
8t
37
54
72
> 500
370
1.5
1.7
4.6
0.9
0.3
0.07
0.39
0.16
0.04
0.02
65
73
43
81
61
24
12
266
13
137
185
7.6
4.2
117
26
165
303
> 10
aIC50 values for PI3K isoforms potency and antiproliferative activity are the mean of three independent measurements and represent as mean
SD.
derivatives would be more potent and selective for PI3Kδ than their
piperazine counterparts, which led to the discovery of several highly
selective PI3Kδ inhibitors with single-digit nanomolar of IC50s. And the
molecular modeling results further confirmed that the relative rigid
piperazinone fragment indeed facilitated the interaction of PI3Kδ with
the inhibitor by favorable packing interactions. These piperazinone
PI3Kδ inhibitors also exhibited comparable antiproliferative activity
against a panel of NHL cell lines as compared with idelalisib while
without obvious cytotoxicity against normal cell lines. This study thus
provided us a start point to develop new PI3Kδ inhibitors based on
piperazinone motifs and the optimization with respect to thieno[3,2-d]
pyrimidine core as well as the benzo[d]imidazole motif would further
improve the drug-like property of this chemotype.
Acknowledgement
This work was supported by the Fundamental Research Funds for
the Central Universities (No. 2682018CX37).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.127479.
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