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
good PI3Kδ inhibitory activity and selectivity.12,14,18 More importantly,
the benzo[d]imidazole motif could also significantly attenuate CYP3A4
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