P.K. Spearing et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128193
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1
Scheme 5. Reagents and conditions: (a) TIPS-Cl, NaH, THF, 0 C to r.t.; (b) DMF, oxalyl chloride, DMF, 0 C to r.t.; (c) R benzylamine, NaBH(OAc)3, DCE, r.t.; (d)
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2
NaOH, THF, H O, 70 C; (e) HATU, DIPEA, DMF, r.t.
derived from a class of M1,3,5-preferring isatin compounds,27,28 and an
1
was found to be inactive at hM (Table 1), while thiazoles 8b and 8c
exploration of positional lactam isomers has allowed for further elabo-
displayed activities in the micromolar range. N-methylindazole com-
pound 8b was found to have superior potency within the thiazole series,
ration (Fig. 2).2
5,26
Molecules derived from the VU0453595 chemotype
are reported to have minimal ago-PAM activity, a profile that has crip-
pled the development of compounds in the alternate series.1
a trend that has been previously observed for similar indazole tail pieces
2,21,26
26
1
in related M reports. Both thiophene regioisomers (8d-k) demon-
The present work describes a novel class of 5-substituted, fused
heteroaryl-pyrrolidinones based on the VU0453595 aza-isoindolinone
structure (Fig. 2). In holding the γ-lactam moiety constant, along with
1
strated similar micromolar hM potency to 8b, and N-methylimidazole
compound 8j displayed remarkably high potency (EC50 246 nM,
although ACh Max was relatively low (40%)).
historically M
1
-preferring pendant tail pieces, we have developed a se-
Interestingly, both oxazole regioisomers (12a and 12b) were found
to be inactive, while furan (12c) was approximately equipotent to its
thiophene congener 8e. Substituted pyrroles (16a-c) and pyrazoles
(20a-j) proved even more fruitful, and compounds in these series
ries of novel 5,5-bicyclic lactams, featuring a wide variety of 5-
membered heteroaryls. Importantly, compounds in this series are
devoid of agonist activity and display robust selectivity for the M
mAChR.
1
1
consistently displayed activities in the low micromolar range for hM .
2
9
Compounds were synthesized as shown in Schemes 1–5. For
bicyclic imidazoles, thiazoles and thiophenes 8, commercially available
Within the pyrazole series, 1-substituted pyrazoles (i.e. 20a) were
generally more potent than the 2-substituted analogs (20b). Methyl
pyrrolo compound 25a was found to be inactive, further demonstrating
that subtle changes in ring substituents and/or electronics can have
2
9
aldehydes 6 were condensed with substituted benzylamines to give
intermediates 7, which were then hydrolyzed and cyclized under stan-
dard amide forming conditions to give final analogs 8 (Scheme 1). The
synthesis of substituted oxazoles and furans is shown in Scheme 2.
Commercially available esters of type 9 were brominated under radical
conditions to give intermediates 10 (oxazoles; methyl 2-(bromomethyl)
furan-3-carboxylate is available commercially). Bromides 10 were then
subjected to substitution, hydrolysis, and lactam-formation conditions
analogously to Scheme 1 to give final analogs 12. Substituted 4,5-
dihydropyrrolo[3,4-b]pyrrol-6(1H)-ones and substituted 4,5-dihy-
dropyrrolo[3,4-c]pyrazol-6(1H)-ones were synthesized in a similar
fashion (Schemes 3 and 4), with N-alkylation giving final products 16
and 20, respectively. The pyrazolo analogs (20a-j) were generally
alkylated at the beginning of the sequence, as the resulting alkyl isomers
were readily separable and identifiable by NOESY at this stage (Scheme
1
notable effects on potency for M PAMs; this kind of SAR has been
2
6
previously established in the field.
Because of their acceptable potencies, distinct chemotypes, and
relatively high ACh max values, thiazole 8b (VU6005610) and pyrazole
20a (VU6005852) were selected for further profiling. Both compounds
displayed robust selectivity for hM
(>10,000 nM hM -hM ) at the concentrations tested (Table 2). Both
compounds were also devoid of any hM agonist activity, an encour-
aging profile for the further development of this series. Additionally, 8b
displayed no species disconnect between human and rat M (rM EC50
1
over the other 4 mAChR subtypes
2
5
1
1
1
=
2080 nM). Both compounds also displayed good free fraction and low to
moderate predicted hepatic clearance across species (human and rat, see
Table 3).20 After IV administration in a rat cassette model (0.20 mg/kg,
brain sampling 0.25 h post dose), 8b (VU6005610) was also found to be
4
) (alkylations can also be conducted and separated at the end of the
sequence after deprotection of a para-methoxybenzyl intermediate, as in
the case of analog 20a (see the experimental section for further synthetic
details)). Lastly, methyl pyrazole 25a (Scheme 5) was synthesized by
route of a silyl protection-Vilsmeier-Haack reaction sequence,30 and
carried through to give final analog 25a in a similar fashion. This
chemistry generally proved quite facile, although certain ester hydro-
lyses required elevated temperatures and/or microwave irradiation to
proceed. These routes were also found to be amenable to re-ordering –
substituted tail pieces could be generated in a late-stage library format
through substitution of fluorinated (4-bromophenyl)methanamines
under standard Suzuki-Miyaura conditions.26
highly brain penetrant (K
ments)). In contrast, 20a was found to have much lower brain exposure
in this model (K
= 0.12).
In summary, we have developed a series of structurally novel and
highly mAChR subtype-selective M PAMs devoid of agonist activity.
p
= 2.1, Kp,uu = 2.2 (average of 3 experi-
p
1
Preliminary PK data for VU6005610 (8b) was particularly encouraging.
The favorable muscarinic selectivity, lack of species potency disconnect,
and high brain exposure should facilitate the use of this compound as a
1
tool to further probe M biology in rodent models. Additional synthetic
efforts within these series are underway in our laboratory and will be
reported in due course.
1
hM potency data for all analogs is listed in Table 1. Imidazole 8a
4