ACS Medicinal Chemistry Letters
Letter
profile (Table 4). In line with the in vitro data, the clearance of
9 was significantly lower than 2 leading to an increase in both
half-life and oral bioavailability.
previously established methodology,35 alkylation of the amine
was followed by Buchwald amination with benzophenone
imine, which gave the required diamine 31 after acidic
hydrolysis. Cyclization occurred through a Pictet−Spengler
reaction with 5-bromopicolinaldehyde under slightly modified
conditions. In order to achieve reaction turnover the reaction
was performed in AcOH with H2O present as an additive.
Without the addition of H2O the initial product arose from
condensation of the free aniline onto the aldehyde. This
intermediate appeared to undergo subsequent Pictet−Spengler
cyclization very slowly; it was thus hypothesized that the
presence of a small amount of H2O would keep enough free
aniline in equilibrium to allow cyclization to occur more
readily. Pleasingly this was observed to be the case, and
diamine 31 formed the desired cyclization product after
heating with excess aldehyde. A major byproduct observed was
the desired cyclization product where the free aniline had
recondensed onto the excess aldehyde; thus, the product was
treated with NH2OH·HCl and KOAc to hydrolyze the imine
back to the free aniline. With the cyclization product in hand
the tricyclic indazole 32 was formed by treatment of the aniline
with NaNO2 in propionic acid. After the free alcohol was
oxidized to the aldehyde, the indazole was protected with a
THP group and the aldehyde was converted to difluoromethyl
by treatment with DAST. Finally, the amino-azetidine was
installed in the usual manner through Buchwald amination to
afford 11 after cleavage of the THP group.
a
Table 4. Rat Pharmacokinetic Parameters for 2 and 9
a
Clp
Vdss
IV half-
life (h)
PO AUC
(μM.h)
Bioavailability
F (%)
Cpd (mL/min/kg) (L/kg)
2
9
65
24
7.7
17
1.9
9.6
0.22
0.76
34
60
a
Compound was dosed intravenously at 0.5 mg/kg in 5%
DMSO:95% hydroxylpropyl β-cyclodextrin or 10% DMA:90%
Captisol and orally as 1 mg/kg using a 0.1% HMPC/tween
suspension or 10% DMSO:90% cyclodextrin solution. The data
shown is the mean of the data generated in two male rats.
Turning our attention to ring C, fluorination of the methyl
substituent was examined as a way to modulate the pKa of the
piperidine ring nitrogen (Scheme 5). Previously the chiral
Scheme 5. Synthesis of C-Ring Difluoromethyl Analogue
a
11
Once again, fluorination was tolerated resulting in 11 being a
subnanomolar degrader of ERα (Table 5). However, the
a
Table 5. C-Ring Substitution
a
Reagents and conditions: (a) n-BuLi, THF, DMF, then NaBH4,
MeOH, RT, 100%; (b) CBr4, PPh3, DCM, RT, 90%; (c) tert-butyl 2-
((diphenylmethylene)amino)acetate, [PTC]* (see SI for details), aq
KOH, toluene, 0 °C, 80%, 98:2 ratio of enantiomers as determined by
chiral HPLC; (d) aq HCl, EtOAc, RT, 84%; (e) LiBH4, THF, 40 °C,
100%; (f) 2,2-difluoroethyl trifluoromethanesulfonate, DIPEA, 1,4-
dioxane, RT, 91%; (g) benzophenone imine, NaOtBu, Pd2(dba)3, rac-
BINAP, toluene, 90 °C, then aq HCl, 78%; (h) 5-bromopicolinalde-
hyde, AcOH, H2O, then NH2OH·HCl, KOAc, 63%; (i) NaNO2,
propionic acid, H2O, −15 °C, 34%; (j) SO3·Py, Et3N, DCM, DMSO,
5 °C, 64%; (k) 3,4-dihydro-2H-pyran, PTSA, DCM, then DAST,
40%; (l) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third gen-
eration precatalyst, NaOtBu, 1,4-dioxane, 70 °C, then TFA, DCM,
RT, 53%.
ER bind
pIC50
ER DR
pIC50
LogD
Hu % Rat heps Hu mics
Cpd
(LLE)
Free
Clint
Clint
10
11
8.4
8.6
9.5 (99%)
9.3 (97%)
2.4 (7.1)
2.7 (6.6)
40
28
22
32
28
34
a
Legend as Table 1.
associated rise in lipophilicity resulted in a drop in LLE relative
to 1018 and there were no beneficial effects in terms of
physicochemical parameters to justify the additional synthetic
complexity.
methyl group had been incorporated by ring-opening of the
enantiopure cyclic sulfamidate. We initially attempted to
transfer this methodology; however, we were unable to
successfully access the required difluoromethylated cyclic
sulfamidate. Instead, an asymmetric alkylation methodology
was investigated. 1,3-Dibromotoluene was treated with n-BuLi
and quenched with DMF to install the aldehyde, which was
directly reduced to the benzyl alcohol by treatment with
NaBH4. An Appel reaction then produced the required benzyl
bromide 28. Asymmetric phase-transfer catalyzed alkylation of
the glycine imine Schiff base33 with the Corey-Lygo type
cinchona alkaloid derived phase transfer catalytst34 afforded 29
in good yield and as a 98:2 ratio of enantiomers (see SI for
details). Hydrolysis of the imine and reduction of the ester
then gave the chiral amino-alcohol 30. Following our
As a final area of exploration, we turned our attention to the
alkyl chain. The concept of “motif reorganization” has been
proposed as a way to smuggle carbon atoms into fluoroalkyl
chains without adding to the lipophilic burden.36 In order to
access this substitution pattern we envisaged that a late-stage
fluorine replacement of a terminal hydroxy moiety on the alkyl
chain might be possible (Scheme 6). N-Alkylated indazole 33
was synthesized according to previously established procedures
(see SI for details). From here, Pictet−Spengler cyclization and
subsequent protection of the indazole with a THP afforded 34.
Next, the silyl protecting group was selectively cleaved and the
alcohol 35 was activated as the triflate. Treatment of the alkyl
D
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX