Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/akt inhibitors with reduced hypotension

Article abstract of DOI:10.1021/jm0701019

Compound 7 was identified as a potent (IC₅₀ = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC₅₀ = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

Full text of DOI:10.1021/jm0701019

2990
J. Med. Chem. 2007, 50, 2990-3003
Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein
Kinase B/Akt Inhibitors with Reduced Hypotension
Gui-Dong Zhu,*,† Viraj B. Gandhi,† Jianchun Gong,† Sheela Thomas,† Keith W. Woods,† Xiaohong Song,† Tongmei Li,†
R. Bruce Diebold,† Yan Luo,† Xuesong Liu,† Ran Guan,† Vered Klinghofer,† Eric F. Johnson,† Jennifer Bouska,†
Amanda Olson,† Kennan C. Marsh,‡ Vincent S. Stoll,§ Mulugeta Mamo,§ James Polakowski,| Thomas J. Campbell,|
Ruth L. Martin,| Gary A. Gintant,| Thomas D. Penning,† Qun Li,† Saul H. Rosenberg,† and Vincent L. Giranda†
Cancer Research, Preclinical Safety, Structural Biology, IntegratiVe Pharmacology, GPRD, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6101
ReceiVed January 25, 2007
Compound 7 was identified as a potent (IC50 ) 14 nM), selective, and orally bioavailable (F ) 70% in
mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound
showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided
by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase
domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in
an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient
synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated
aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other
protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position
of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater
potency (IC50 ) 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs,
pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
Introduction
mutated or overexpressed signaling abnormality in human
cancers.4 A plethora of evidence has demonstrated frequent
hyperactivation of Akt kinase in a wide assortment of human
solid tumors and hematological malignancies.5 Akt signaling
inactivates a number of proapoptotic proteins, including BAD,
procaspase-9, and Forkhead (FOXO) transcription factors.6 Akt
also activates transcription factors that upregulate anti-apoptotic
genes, such as cyclic-AMP response element-binding protein
(CREB). Akt can inactivate tumor suppressor protein p53
through mdm2, leading to centrosome hyperamplification and
chromosome instability in cancer. Furthermore, in genetically
modified mouse models, aberrant Akt signaling contributes to
malignancy, either alone or in cooperation with other genetic
alterations.7 Therefore, inhibition of Akt alone, or in combination
with other standard cancer chemotherapeutics, is widely con-
sidered as an example of targeted molecular therapeutics for
the treatment of cancers. There have been more than 20
companies and academic centers declaring active programs that
target the PI3K/Akt signaling pathways.6 Because a number of
the downstream targets of Akt kinase are important for normal
cellular functions and, in particular, signaling by insulin, a
sufficient therapeutic index is required to warrant clinical
implementation.8
Protein kinase B, also known as Akt, comprises three closely
related, highly conserved cellular homologues, namely, PKBR
(Akt1), PKBâ (Akt2), and PKBγ (Akt3).1 All three mammalian
isoforms of the 57 kDa serine/threonine kinase are composed
of an N-terminal pleckstrin homology (PHa) domain, a highly
homologous kinase domain and a C-regulatory domain. In
unstimulated cells, the inactive PKB/Akt is not phosphorylated
on T308 and S473 and resides mainly in the cytosol.2 After
activation of receptor tyrosine kinases (RTK) by growth factor
(GF) and/or other extracellular stimuli, phosphatidylinositol
3-kinase (PI3K) is recruited and activated to generate, through
a cascade of biological interactions,3 its lipid product phos-
phatidylinositol (3,4,5) trisphosphate (PIP3). The binding of
PIP3 to the PH domain of Akt causes a conformational change
of the protein and facilitates its translocation to the plasma
membrane. On the surface of membrane, Akt is phosphorylated
on T308 by PDK-1 and on S473 by an uncharacterized protein
kinase (also referred to PDK-2). The fully activated kinase then
translocates to subcellular compartments where it phosphorylates
an increasing number of downstream substrates that are key
elements of diverse cellular processes including proliferation
and survival.
Protein kinase B/Akt is a central node of the PI3K/Akt
signaling pathway that is believed to be the most frequently
Many small molecule inhibitors of Akt have been developed
and described in detail in several review articles.2,9,10 Some of
these Akt inhibitors have been shown to sensitize tumor cells
to apoptotic stimuli and to slow tumor growth in vivo. Figure
1 shows the compound progression at Abbott in search for small
molecule inhibitors of Akt. High-throughput screening of the
Abbott compound collections identified a 5 µM hit 1. The
structure-activity relationship (SAR) studies at the trans-3,4′-
bispyridinylethylene of 1 and derivatization of the alkylamine
led to a double-digit nanomolar Akt inhibitor 2.11 Several
conformationally locked structures of 1 at the stilbene double
bond were evaluated, providing compound 3 with a 10-fold
* To whom correspondence should be addressed. Phone: 847-935-1305.
Fax: 847-935-5165. E-mail: gui-dong.zhu@abbott.com.
† Cancer Research.
‡ Preclinical Safety.
§ Structural Biology.
| Integrative Pharmacology.
a Abbreviations: CV, cardiovascular; SAR, structure-activity relation-
ship; RTK, receptor tyrosine kinase; GF, growth factor; PI3K, phosphati-
dylinositol 3-kinase; PIP3, phosphatidylinositol (3,4,5) trisphosphate; PH,
pleckstrin homology; CREB, cyclic-AMP response element-binding protein;
TFA, trifluoroacetic acid; Boc, tert-butoxycarbonyl; DEAD, diethyl azo-
carboxylate; DBAD, di-t-butyl azocarboxylate; ADP, Action Potential
Duration.
10.1021/jm0701019 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2991
Figure 1. Abbott compound progression of Akt inhibitors.
boost in potency against Akt.12 Further SAR studies13 at the
isoquinoline scaffold, as well as the pyridine ring of 3, afforded
analogues that significantly slowed the tumor growth in vivo,
but were accompanied by toxicity. Metabolism at the C-1
position of the isoquinoline was found to be responsible for
the poor pharmacokinetic profile of this series of Akt inhibitors,
however, blocking this site failed to provide potency against
Akt. Investigations on alternative heterocyclic pharmacophores
for the metabolically labile isoquinoline led to the discovery of
indazole-pyridine based Akt inhibitors 4,14 oxindole-pyridine
based 5,15 and pyrazolopyridine-pyridine derivative 6.16 The
selected inhibitors displayed excellent selectivity over a majority
of families of protein kinases and showed significant in vivo
efficacy in a number of mouse xenograft models. More recently,
an orally available analog 7 (F ) 70% in mice) was also
identified17 by replacing the indole moiety in 4 with a phenyl
group. Despite a nearly 100-fold loss in potency as compared
to 4, compound 7 showed a comparable efficacy in vivo as 4 at
higher doses.14a However, compound 7 displayed an IC50 of
13.4 µM in a patch clamp assay for hERG and showed
prominent effect on Purkinje fiber repolarization at 20 µM. In
both unconscious rats and unconscious dogs, 7 caused acute
hypotension. In this report, we disclose our progress on
identifying a drug-like Akt inhibitor with reduced hypotensive
effect.
Scheme 1. Method Aa
Chemistry. The Akt inhibitors with a general structure 13
were prepared by three alternative synthetic routes. Outlined in
Scheme 1 is the first and general protocol (method A). The ether
linkage in compound 10 was constructed via a Mitsunobu
reaction between bromopyridinol 8 and t-butylcarboxyaminoal-
cohol 9. A Stille reaction of the bromide 10 with trimethyl-
stannane 12, which was prepared from the known bromoinda-
zole 11,14b afforded, after Boc-deprotection with TFA, Akt
inhibitors 13. The yield in each step of method A was generally
high, but synthesis of the final compounds from 9 required three
chemical transformations and was limited by the commercial
availability of Boc-aminoalcohols.
Scheme 2 illustrates an alternate approach to compound 13
from the same starting materials (method B). Bromide 8 was
first coupled with trimethylstannane 12 through a Stille reaction,
providing phenol 14. Mitsunobu coupling of 14 with a Boc-
protected aminoalcohol 9 in the presence of diethyl azocar-
boxylate (DEAD) frequently failed to afford 15, but a replace-
a Reagents and conditions: (i) DEAD, Ph3P, THF; (ii) Me3SnSnMe3,
Pd(PPh3)4, 80 °C, 80%; (iii) (a) Pd2(dba)3, (o-tol)3P, TEA, 80 °C, 5 h; (b)
TFA, CH2Cl2, rt, 1 h.
ment with di-t-butyl azocarboxylate (DBAD) provided the
desired product, although in poor to modest yields. Finally,
removal of the Boc-protecting group under acid conditions
yielded 13. Method B allowed quicker access to 13 from the
shared intermediate 14, but the yield for the Mitsunobu step
was significantly lower, averaging 20%.
Shown in Scheme 3 is a novel and more diversified synthetic
route to 13, utilizing a copper-mediated aziridine ring-opening
reaction as the key step. Mitsunobu reaction of 8 with an
optically pure and protected aminoalcohol 16,18 followed by
silyl deprotection with TBAF, afforded ether-alcohol 17. A ring-
closure reaction of 17 proceeded smoothly under Mitsunobu
conditions to provide aziridine 18. All dialkyl azodicarboxylates
worked in the Mitsunobu step, but for easier purification, DEAD

2992 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Scheme 2. Method Ba
Zhu et al.
Table 2. Enzyme and Cellular Assay Results for Compounds 13
Akt1 IC50,a
nM
MTT (MiaPaCa)
cmpds
R
EC50,a µM
7
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
13p
13q
13r
13s
13t
13u
13v
13w
13x
H
3-F
14
0.64
0.26
0.18
0.93
ndb
8.4
8.5
21.0
65.5
12
31
29
5.9
11
23
2.1
5.0
0.9
3.1
3.6
5.6
1.8
20.7
10.0
1.3
49
3.9
2.5
11
6.0
2.4
39
2,3-F2
2,4-F2
2,6-F2
2,3,4-F3
2,4,6-F3
2-Cl
3-Cl
4-Cl
2-Br
3-Br
0.29
nd
0.38
0.45
0.44
0.34
0.37
0.7
0.81
0.67
0.27
0.21
0.49
1.0
4-Br
3-I
a Reagents and conditions: (i) Pd2(dba)3, (o-tol)3P, TEA, 72%; (ii)
DBAD, Ph3P, THF, ∼20%.
Scheme 3. Method Ca
3-Cl-4-F
4-Cl-3-F
2,3-(Cl)2
3,4-(Cl)2
3,5-(Cl)2
4-Br-2-F
4-Br-3-F
2-Br-4,6-F2
5-F-2-Me
4-Br-3-Me
4-F-3-Me
4-F-2-Me
3-F-4-Me
2,4,6-(Me)3
5-F-2-OMe
3-CF3
0.9
0.43
nd
0.24
1.26
1.07
0.34
0.33
1.61
0.23
0.6
nd
nd
0.6
1.38
0.97
1.43
2.9
0.23
0.83
1.7
13y
13z
13aa
13ab
13ac
13ad
13ae
13af
13ag
13ah
13ai
13aj
13ak
13al
13am
13an
13ao
13ap
13aq
7.7
1.2
18
4-CF3
3,5-(CF3)2
3-CF3, 4-F
3-CF3, 5-F
3-CF3, 6-F
4-CF3, 3-F
4-CF3, 2-F
2-OCF3
3-OCF3
4-OCF3
3-Ph
57
1.8
13.3
1.2
3.1
12.1
15.3
3.3
20.3
126
42
a Reagents and conditions: (i) (a) DEAD, Ph3P, THF, 99%; (b) TBAF,
THF, 93%; (ii) DEAD, Ph3P, THF, 92%; (iii) Pd2(dba)3, (o-tol)3P, DMF,
65%; (iv) CuBr-SMe2, THF, -78 °C to 0 °C; (v) CF3CO2H, CH2Cl2.
nd
Table 1. Comparison of Akt1 Enzyme Assay and Pharmacokinetic
Profile in Mice for Compounds 4, 7, and 34-36
3,4-OCH2O-
2,3-OCF2O-
3,4-OCF2CF2O-
0.58
0.68
3.7
14
13
PO auc
(µM‚h,
10 mg/kg)
Akt1 IC50,a
nM
IV t1/2
(h, 3 mg/kg)
PO F
(%, 10 mg/kg)
13ar
13as
13at
751
13
cmpd
4
7
34
35
36
0.16
14
2650
16
0.6
1
0
70
ndb
0
0
2.0
ndb
0
290
6.8
2.74
0.25
ndb
0.5
1.15
1.4
0
0
a Values are means of two or more experiments; all assays generated
data within 2-fold of the mean. All compounds were tested under 5 µM
ATP. b Not determined.
13au
13av
13aw
1360
78
16.5
1.25
4.8
was considered to be superior. A Stille reaction of 18 with
trimethylstannane 12, under the catalysis of Pd2(dba)3 and tri-
o-tolylphosphine, afforded compound 19 in an average of 65%
yield. Other catalytic systems, including Pd(PPh3)4 and Pd-
(dppf)2Cl2, were also explored, but gave lower yields. Treatment
of the aziridine 19 with an arylmagnesium bromide in the
presence of CuBr-SMe2 afforded, after Boc-deprotection, 13
in modest to excellent yields. The Grignard reagents were
prepared from bromides by classical Mg/I2 protocol or from
iodides by an exchange methodology with isopropylmagnesium
chloride. In the latter cases, an ester functionality is compatible
in the reaction.
47
a Values are means of two or more experiments; all assays generated
data within 2-fold of the mean. Enzyme assays were conducted under 5
µM ATP. b Not determined.
deprotection of TBDMS, intermediate alcohol 23. Compound
21 was in turn prepared from 3-bromophenol 20 through
alkylation. The Mitsunobu reaction of 23 with hydroxypyridine
8, followed by Stille reaction with trimethylstannane 12, as
described in Scheme 1, furnished 24. Removal of the benzyl
protecting group in 24 under hydrogenation conditions provided
phenol 25, that was coupled with appropriate alcohols under
Mitsunobu conditions, followed by acidic hydrolysis, to give
13ar-13aw.
The synthesis of aryl ether analogues (13ar-13aw of Table
2) are described in Scheme 4. A copper-mediated opening of
aziridine 2218 with a Grignard reagent of 21 afforded, after

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2993
Scheme 4a
deprotection, provided 34-36, while the reaction of 27 and 29
with 3316 in the presence of bis(tri-tert-butylphosphine)palla-
dium(0) provided 37.
Results and Discussion
When the side chain indole moiety of 4 was replaced with a
phenyl group, the resulting Akt inhibitor 7 displayed an
improved pharmacokinetic profile in several species (mouse,
rat, and dog).17 Despite a relatively short half-life (IV t1/2 ) 1
h in mouse), as shown in Table 1, compound 7 showed 70%
oral bioavailability in mice with respectable plasma drug
exposure (PO auc ) 2.0 µM‚h, 10 mg/kg). Encouraged by this
initial success, we next adopted the same strategy into other
interesting series of Akt inhibitors. The indole moiety in three
oxindole-pyridine based Akt inhibitors (e.g., 515) was replaced
with a phenyl group, leading to 34-36. As shown in Table 1,
the modification to 34 demonstrated a 1000-fold drop in potency
against Akt1, while 35 and 36 retained good activities. PK
screening of 35 and 36 in mice, however, revealed lack of oral
bioavailability for both compounds.
There were several limitations with the orally bioavailable 7
as a clinically useful agent. Despite significant efficacy in
multiple animal models,14a this compound showed a relatively
poor therapeutic index. In an in vitro assay, compound 7 caused
depolarization of Purkinje fibers at 20 µM, which is less than
10-fold of the plasma concentration at therapeutic dose.
Compound 7 also induced severe hypotension at 4-fold effica-
cious Cmax in both dog and rat. In addition, 7 is 100-fold less
active than 4 against Akt1 and significantly less selective over
other protein kinases. Therefore, our initial goals were, through
substitutions of the phenyl group in 7, to identify an orally
bioavailable Akt inhibitor with (i) reduced hypotension, (ii) less
activity in the Purkinje assay, and (iii) improved in vitro potency
against Akt, as well as selectivity over other protein kinases.
Armed with an X-ray structure of 4 bound to PKA,14a which
is a closely related analogue of Akt in the same AGC family of
protein kinases and has only three different amino acid residues
in the kinase domain, we initially planned to modify the phenyl
group of 7 in a way to mimic indole. The indole scaffold of 4
lies nicely underneath the glycine-rich loop in PKA and results
up to 100-fold higher potency against Akt1 (Figure 2, right).
An X-ray structure of 7 bound to PKA, however, displayed
relatively low electron density of the phenyl group, suggesting
a less tightly bound phenyl moiety in the ligand-protein
complex. An overlap of 4 (green) and 7 (blue) in the protein,
as shown on the left of Figure 2, reveals the phenyl group (blue)
positioned away from the glycine-rich loop. Thus, it seems
difficult to predict patterns of substitutions helpful in locking
the loosely bound phenyl group into the same position as the
indole. Due to this challenge, we decided to synthesize a number
of diversely substituted phenyl derivatives of 7 to screen for
more potent and selective analogs with reduced hypotension.
Accordingly, we developed a novel and efficient synthetic route
(Scheme 3/method C), with which diversified analogs of 7 could
be synthesized in two steps from intermediate 19 and readily
available aryl halides.
a Reagents and conditions: (i) 4-MeOBnCl, Cs2CO3, DMF, 80%; (ii)
(a) Mg, THF, I2; (b) CuBr-SMe2, THF, -78 °C to 0 °C; (c) TBAF, THF,
91%; (iii) Ph3P, DEAD, THF, 75%; (iv) Pd2(dba)3, (o-tol)3P, DMF, 76%;
(v) 10% Pd/C, H2, MeOH, 83%; (vi) HOCH2R′′, DBAD, Ph3P, THF; (vii)
CF3CO2H, CH2Cl2.
Scheme 5a
a Reagents and conditions: (i) Me3SnSnMe3, Pd(PPh3)4, 115 °C; (ii) (a)
Pd2(dba)3, (o-tol)3P, TEA, 80 °C, 5 h; (b) TFA, CH2Cl2, rt, 1 h; (iii) (a)
Pd[P(t-Bu)3]2, CsF, dioxane, 80 °C, 15 h; (b) TFA, CH2Cl2, rt, 1 h.
Table 2 summarizes selected data of compound 13 in an Akt
enzymatic assay, as well as in an MTT assay as an indication
of their cytotoxicity in MiaPaCa cells. As predicted from the
X-ray structure of 7 bound to PKA, there was no clear trend of
SAR observed for the phenyl group with a wide variety of
substituents. Substitutions by one, two, or three fluorines on
the phenyl ring had minimal impact (13a, 13b, and 13e) unless
both hydrogen atoms ortho to the C-1 position were replaced
Outlined in Scheme 5 are the syntheses of Akt inhibitors 34-
37. Bromide 10 in which R is hydrogen, 3-trifluoromethyl, or
2,3-difluorophenyl groups, were prepared as described in
Scheme 1 via Mitsunobu protocol. Palladium-catalyzed reaction
of the bromides 10 with hexamethylditin furnished trimethyl-
stannanes 27-29. Stille coupling of 28 with bromides 30-3215
under the catalysis of Pd2(dba)3 and (o-tol)3P, followed by Boc-

2994 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Zhu et al.
Figure 2. X-ray structures of 4 bound to PKA (right) and an overlap with 7 in the protein complex (left).19
Figure 3. Left: overlap of the X-ray structures of Akt inhibitor 7 (blue) in protein kinase A with 13l (purple) and 13au (yellow). Right: overlap
of 4 (green) with 13l (purple) and 13au (yellow).
(13d vs 13a-13e). For other halides, substitution at the meta-
position was statistically more potent (13h, 13k, 13m), while
ortho-substituted analogues showed reduced potency (13g, 13j).
The Akt1 potency of 3-substituted derivatives correlated well
with the size of the halides (I > Br > Cl > F), with the iodo-
analog 13m being the most active (Akt1 IC50 ) 0.9 nM). As
demonstrated with compounds 13n, 13o, 13q, and 13t, 3,4-bis-
halogen-substituted analogues with at least one nonfluorine,
showed higher Akt potency than other substitution patterns, with
IC50 values of low single-digit nanomolar. Again, bis-substitu-
tions ortho to methylene (e.g., 13u) were detrimental. Likewise,
bis-halogen/methyl-substituted analogues showed a similar
pattern of activity, with C-3,4 analogs (13w, 13z) being more
potent and 2,6-substitutions (13aa) being the least active.
2-Methoxy analogue 13ab showed a similar profile of activity
as compared to the corresponding methyl derivative (13v). It is
interesting that meta-trifluoromethyl analogue 13ac is 10-fold
more active than the para-derivative 13ad, showing an IC50 of
1.2 nM against Akt1. While addition of fluorine to 13ac at the
4- (13af) or 6-position (13ah) showed little impact, 5-fluoro-
3-trifluoromethyl analogue 13ag displayed an order of magni-
tude diminished binding affinity to Akt1. As observed for mono-
halogen compounds, C-3 substitution (13al) showed highest Akt
activity among the three mono-trifluoromethoxy-analogs (13ak-
13am). A phenyl group seems to be too bulky at the C-3 position
of the phenyl group (13an). A bicyclic structure as indicated in
compounds 13ao-13aq appeared to be detrimental as well.
Compounds 13ar-13aw demonstrate our efforts toward
incorporation of a chemical functionality to interact with the
protein through hydrogen bonding. SAR studies on the phenyl
group of 7 have shown the C-3 position optimal for attachment
of a linker. Further encouraged by the high potency of
3-trifluoromethoxy analogue 13al (Akt1 IC50 ) 3.3 nM), a
straight or branched alkoxy group was considered to be an
appropriate tether. Thus, a morpholine group, in which both
nitrogen and oxygen can be hydrogen bond acceptors, was
attached to the C-3 position of the phenyl group with a
methylene-ether linkage. As shown in Table 2, compound 13ar
was a rather weak Akt inhibitor, suggesting a limited space in
this area of the protein. An amino group, as exemplified by
13as, appeared to be slightly beneficial. Interestingly, compound
13at, with one methylene shorter linkage, showed a 2 orders
of magnitude boost in Akt potency. Removal (13au) or
methylation (13av) of the piperidine nitrogen in 13at showed
much diminished potency. A shorter tether between the amino
and the phenyl group, as illustrated with compound 13aw, was
also detrimental. Despite a lack of structural confirmation, the
sum of the above data implies formation of a hydrogen bond
between the piperidine nitrogen of 13at and the protein.
Through the synthesis of a wide variety of substituted phenyl
analogues, we have identified a number of Akt inhibitors with
an order of magnitude improved potency with respect to 7.
However, little is known about the structural requirements for
even more potent compounds. Figure 3 shows a comparison of
the crystal structures of selected Akt inhibitors in PKA,
attempting to illustrate conformational requirement for a higher
binding affinity to Akt. On the left of the figure is an overlap
of the X-ray structures of 7 (blue) bound to PKA, with 13l
(purple) and 13au (yellow). Despite large variations in the
potency (PKA IC50 ) 16 nM for 7, 15 nM for 13l, and >3µM
for 13au), the indazole, pyridine ring, and primary amino group
overlap quite well for all three Akt inhibitors. The major
difference appears on the orientations of the phenyl group, with
an unsubstituted ring (7) hovering away from, and the 4-bromo
analog (13l) underneath, the glycine-rich loop. The 3-cyclo-
hexylmethoxy group in 13au seems to be too bulky for this
area, extending into a deeper binding cavity. Together with the
lost potency of 13au, the hydrophobic interaction with the
glycine-rich loop is thus considered to be critical for a higher
binding affinity to PKA.

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2995
Figure 4. Effect of 13o on mean arterial pressure in conscious mice
following oral administration. Compound 13o induced a slight effect
at 300 mg/kg.
Figure 5. Dog pharmacokinetics of compound 13o at 2.5 mg/kg.
As shown on the right of Figure 3, the 4-bromophenyl group
of 13l is in the proximity of the indole pharmacophore of the
more potent 4 (green, PKA IC50 ) 6 nM). After a comparison
of their Akt (4 . 13l > 7 . 13au) and PKA activity (4 > 13l
) 7 . 13au), along with their side chain orientations in the
X-ray structures, it is reasonable to conclude (1) the space
underneath the glycine-rich loop of PKA is limited but big
enough to accommodate small substituents to a phenyl group
without significant impact on the activity, (2) the hydrophobic
interaction with the glycine-rich loop is critical for a higher
binding affinity, and (3) cocrystallization of this series of Akt
inhibitors with PKA has limited utility in predicting structures
of highly potent Akt inhibitors.
Also included in Table 2 are the MTT data of our Akt
inhibitors in MiaPaCa-2 human pancreatic cancer cells as an
indication of their antiproliferative activity. The majority of these
compounds showed correlations between Akt activity and
cytotoxicity, while a few displayed either unexpectly strong
(13b) or weak (13m, 13w, and 13ai) cytoxicity. A combination
of factors including cell penetration and selectivity profile would
complicate the direct comparison of enzyme and cellular
potency.
We next needed to assess the hypotensive effect of these
phenyl analogues of 7. Due to limited throughput and the high
cost of in vivo dog cardiovascular evaluation, an in vitro assay,
namely, femoral artery relaxation assay (FAR), was evaluated
as an initial screening assay for reduced risk of in vivo CV
toxicity (i.e., hypotension). In this assay, isolated slices of dog
femoral artery were placed on a strain gauge. Relaxations under
eight concentrations of Akt inhibitor or vehicle were then
assessed. However, little correlation between the FAR data and
the later in vivo dog cardiovascular risk was observed.
Compounds that had little or no effect on the isolated femoral
arteries, such as 35 (EC50 ) 354 µM), showed acute hypotension
in unconscious dog (30 mmHg at IV 25 mg/kg). On the other
hand, compounds that showed profound effects in the isolated
arteries, for example 13o (EC50 ) 6.0 µM), had modest in vivo
toxicity (12 mmHg at IV 30 mg/kg), particularly when
administered orally (Figure 4). Therefore, we turned to a more
reliable in vivo model with reasonable throughput, cost, and
compound requirements. After evaluation of several practical
models in literature, we initiated studies in telemetry-instru-
mented rats and later to telemetry-instrumented mice as they
became available. As demonstrated in Figure 4, 13o caused
minimal hypotension in conscious mice after an oral administra-
tion up to 300 mg/kg, correlating with the unconscious dog
results.
Table 3. Fold Selectivity of Selected Akt Inhibitors over Other Selected
Protein Kinasesa
family
AGC
kinase
4
7
13o
37c
Akt1
1
1
1
1
PKA
40
1.4
2.4
22
PKCγ
PKCδ
CDK2
ERK2
GSK3â
MAPK
CK2
KDR
Flt1
cKIT
SRC
150
200
150
2100
260
21 000
15 000
19 000
22 000
7300
16 000
15 000
68
110
32
4.2
24
10
100
490
>330
>200
>530
1200
235
53
250
320
5.3
6.0
27
360
400
>1500
>880
>2300
1600
1000
3000
130
120
110
620
9000
3100
4200
>1800
>7900
>2900
3000
7400
57
CMGC
TK
CAMK
Chk1
RSK2
a All compounds were tested at 5 µM ATP.
Table 4. Enzyme and Cellular Assay Results for Compounds 37
Akt1 IC50,a PKA IC50,a MTT (MiaPaCa)
cmpds
R′
R
nM
nM
EC50,a µM
37a
37b
37c
13ac
37d
13b
H
Cl
3-CF3
3-CF3
7.2
2.9
0.6
1.2
5
78
15
13
5
7
9
2.39
1.38
0.37
0.6
0.26
0.18
CH3 3-CF3
NAb 3-CF3
CH3 2,3-F2
NAb 2,3-F2
8.5
a Values are means of two or more experiments; all assays generated
data within 2-fold of the mean. Kinase assays were conducted under 5 µM
ATP. b Not applicable.
respectable plasma drug exposure in dog with 40% bioavail-
ability. A similar type of pharmacokinetic properties for this
compound were also observed in other species such as mouse
(PO F ) 84%) and rat (PO F ) 38%).
As shown in a head-to-head comparison in Table 3, com-
pound 13o displayed a similar type of selectivity profile as 7,
which is relatively less selective as compared to compound 4
against the majority of protein kinase.
Thus, through the synthesis of a number of phenyl derivatives
of our lead Akt inhibitor 7, we have identified 13o as a next
generation lead with better in vitro potency and improved
pharmacokinetic and CV safety profiles. Higher selectivity,
however, still remained as one of major criteria to be further
improved for a potentially wider therapeutic window. In a
previous report,16 we have discribed that incorporation of a
nitrogen atom into the C-6 position of the indazole scaffold may
increase the selectivity profile, especially against PKA. Table
4 summarizes our further investigation of this modification. We
Illustrated in Figure 5 is a dog pharmacokinetic profile of
13o. After oral administration, this compound showed a

2996 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Table 5. Comparison of Important Akt Inhibitors
Zhu et al.
PK in mouse (10 mg/kg)
toxicity
mouse MAP
MTT (MiaPaCa)
selectivity vs
other kinase
PO F,
PO auc,
mouse
skin
canine purkinje
cmpds
Akt1 IC50,a nM
0.16
EC50,a µM
t1/2, h
%
µM‚h
decrease (mmHg)
(APD prolongation)c
4
0.082
0.64
0.27
0.37
excellent
good
0.6
0
70
84
25
0
severe
no
60 (infusion at
0.48 mg/kg/min)b
31 (PO at
150 mg/kg)
clean (PO at
150 mg/kg)
clean (PO at
150 mg/kg)
2.4% at 20 µM
7
14
1.0
2.0
2.3
1.7
severe depolarization
at 20 µM
-1.3% at 20 µM
13o
37c
3.6
0.6
good
2.1
no
excellent
1.84
no
-4% at 20 µM
a Values are means of two or more experiments. Kinase assays were conducted under 5 µM ATP. b Dog study. c APD: action potential duration.
and 75/100/125 MHz for 13C) with deuteriochloroform as solvent
and internal standard unless otherwise indicated. The chemical shifts
are given in delta (δ) values, and the coupling constants (J) are
given in hertz (Hz). When peak multiplicities are given, the
following abbreviations are used: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broadened. Mass spectra were performed
as follows: ESI (electrospray ionization) was performed on a
Finnigan SSQ7000 MS run as a flow injection acquisition; DCI
(desorption chemical ionization) was performed on a Finnigan
SSQ7000 MS using a direct exposure probe with ammonia gas;
and APCI (atmospheric pressure chemical ionization) was per-
formed on a Finnigan Navigator MS run as flow injection
acquisition. Elemental analyses were performed by Quantitative
Technologies, Inc., Whitehouse, New Jersey. All manipulations
were performed under nitrogen atmosphere unless otherwise
mentioned. All solvents and other reagents were obtained from
commercial sources and used without further purification, except
where noted. Flash column chromatography was performed on silica
gel 60 (Merck, 230-400 mesh) using the indicated solvent. For
routine aqueous workup, the reaction mixture was partitioned
between brine and EtOAc, and the organic layer was washed with
brine and dried over MgSO4.
chose to incorporate a nitrogen atom into a more potent analog
13ac and a more cytotoxic 13b identified in Table 2.
As demonstrated in Tables 3 and 4, incorporation of a
nitrogen atom into the C-6 position of the indazole moiety of
13ac led to the identification of compound 37c with improved
potency against Akt (IC50 ) 0.6 nM). A 5-fold boost on the
selectivity over PKA was also observed. Screening of 37c in
selected protein kinases across several different families, as
shown in Table 3, revealed a comparable selectivity profile to
our highly selective benchmark 4. The 3-methyl group of the
aza-indazole seemed to be important; elimination (37a) or
replacement with a chlorine (37b) resulted in reduced potency,
as well as selectivity. No significant improvement over Akt
selectivity was observed, however, for incorporation of a
nitrogen atom into 13b at the same position.
Table 5 summarizes selected properties of our representative
Akt inhibitors. Compound 4 was highly potent in both enzyme
and cellular assays, but lacked both oral bioavailability and
sufficient cardiovascular safety. Compound 7 improved the
pharmacokinetic property but with a sacrifice of potency and
selectivity. In addition, the CV toxicity issue remained unsolved.
The SAR studies on the phenyl group of 7 resulted in the more
potent and orally bioavailable 13o with reduced hypotension.
Further improvement on selectivity by introducing a nitrogen
atom at the C-6 position of the indazole led to the discovery of
37c. Compound 37c displayed excellent potency against Akt1
with an IC50 of 0.6 nM and improved selectivity over other
protein kinases. Compound 37c was orally bioavailable in mice
(F ) 25%), with a longer half-life (t1/2 ) 1.8h) and similar
plasma exposure (auc ) 1.7 µM‚h) at 10 mg/pk as compared
to 7. As was observed for 13o, no statistically meaningful
hypotension was observed for compound 37c when dosed orally
in conscious mice up to 150 mg/kg. Both compounds were
negative in a dog Purkinje assay, indicating relatively less risk
of cardiovascular QT prolongation.
tert-Butyl 3-Methyl-5-(trimethylstannyl)-1H-indazole-1-car-
boxylate (12). A 250 mL round-bottom flask (RBF) was charged
with bromide 11 (10.0 g, 32.14 mmol)14b and Pd(PPh3)4 (3.7 g,
3.21 mmol) and was purged with N2. Toluene (120 mL) and
hexamethylditin (15.8 g, 48.20 mmol) were added, and the reaction
mixture was heated under N2 at 115 °C for 3 h. After cooling, solid
material was filtered off and the filtrate was concentrated. The
residue was separated by flash chromatography (8-20% gradient
EtOAc in hexane) to give 12 as a white solid. Yield: 10.1 g (80%).
1H NMR (300 MHz, CDCl3): δ 0.35 (s, 9H), 1.72 (s, 9H), 2.61 (s,
3H), 7.60 (d, J ) 8.14 Hz, 1H), 7.75 (s, 1H), 8.08 (d, J ) 8.14 Hz,
1H). MS (DCI): m/z 397 (M + H)+.
General Procedure for Synthesis of Compound 13 through
the Stille Reaction of Aryl Bromide 10 with Trimethylstannane
12 (Method 1). Step A. A 1 L RBF was charged with 3-bromo-
5-hydroxypyridine (8, 79.6 mmol),20 a Boc-protected amino-alcohol
9 (79.6 mmol), and Ph3P (25.05 g, 95.52 mmol) and was purged
with nitrogen. THF (250 mL) was added at 0 °C. After stirring at
the same temperature for 10 min, diethyl azodicarboxylate (DEAD,
15.04 mL, 95.52 mmol) was added via syringe. The reaction mixture
was stirred at 0 °C for 1 h and at rt overnight. Volatiles were
removed by rotary evaporator, and the residue was separated by
flash chromatography to provide product 10.
In summary, we have developed a facile synthesis of
substituted arylether-indazole-pyridine based protein kinase
B/Akt inhibitors utilizing a novel copper-mediated aziridine ring
opening methodology. This new synthetic protocol enabled a
convergent synthesis of a wide variety of substituted aryl ether
analogues and resulted in the discovery of our next generation
lead 13o and 13ac. Compound 13ac was further optimized into
37c through incorporation of a nitrogen into the benzene ring
of the methyl indazole scaffold. Compound 37c demonstrated
significant improvement in potency, selectivity, and cardiovas-
cular safety as compared to the previous Akt inhibitors of this
series.
Step B. A RBF equipped with a septum was charged with
bromide 10 (0.395 mmol), trimethylstannane 12 (0.395 mmol), Pd2-
(dba)3 (36 mg, 0.0395 mmol), and (o-tol)3P (36 mg, 0.118 mmol)
and was purged with N2. Anhydrous DMF (10 mL) and Et3N (165
µL, 1.18 mmol) were added via syringe. The solution was purged
with N2 again and was heated at 70 °C overnight. After cooling,
the reaction mixture was partitioned between ethyl acetate and brine.
The organic phase was washed with brine and concentrated. The
residue was separated by flash chromatography to afford the coupled
product 15.
Experimental Section
General Procedure. The NMR spectra were obtained on Varian
M-300, Bruker AMX-400, Varian U-400, and Varian Unity Inova
1
500 magnetic resonance spectrometers (300/400/500 MHz for H

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2997
Step C. Compound 15 (0.2 mmol) was dissolved in CH2Cl2 (5
mL) and was treated with trifluoroacetic acid (1 mL) at 0 °C. After
stirring at 0 °C for 5 min, the solution was allowed to warm up to
rt for 1 h. CH3CN (10 mL) was added, and the solution was
concentrated. The residue was purified by HPLC (Zorbax, C-18,
250 × 2.54 column; mobile phase A, 0.1% TFA in H2O; B, 0.1%
TFA in CH3CN; 0-100% gradient) to provide compound 13 as
TFA salt. A HCl salt of compound 13 was obtained by dissolving
the TFA salt in a mixture of methylene chloride and methanol and
precipitating with 1 M HCl solution in ether. Removal of the
volatiles afforded 13 as HCl salt.
(19). A 100 mL RBF was charged with aziridine 18 (950 mg, 2.88
mmol), trimethylstannane 12 (1.14 g, 2.88 mmol), Pd2(dba)3 (263
mg, 0.288 mmol), and tri-o-tolylphosphine (263 mg) and was
purged with N2. Anhydrous DMF (35 mL) and Et3N (1.2 mL) were
added via syringe. The solution was purged with N2 again and was
heated at 72 °C for 4 h. After cooling, ethyl acetate (150 mL) was
added. The mixture was washed with brine (200 mL) and water
(200 mL). The ethyl acetate solution was concentrated and the
residual oil was separated by flash chromatography (50-80%
1
gradient EtOAc in hexane) to give 19 (634 mg, 65%). H NMR
(300 MHz, CDCl3): δ 1.44 (s, 9H), 1.74 (s, 9H), 2.28 (d, J ) 3.73
Hz, 1H), 2.44 (d, J ) 6.44 Hz, 1H), 2.65 (s, 3H), 2.88 (dd, J )
6.10, 3.73 Hz, 1H), 4.23 (d, J ) 4.75 Hz, 2H), 7.49-7.51 (m, 1H),
7.73 (dd, J ) 8.82, 1.70 Hz, 1H), 7.82 (s, 1H), 8.20 (d, J ) 8.48
Hz, 1H), 8.33 (d, J ) 2.37 Hz, 1H), 8.53 (s, 1H). MS (APCI): m/z
481 (M + 1)+.
General Synthesis of 13 through Opening of Aziridine 19
(Method 3). To a suspension of CuBr-SMe2 (25 mg, 0.12 mmol)
and aziridine 19 (100 mg, 0.21 mmol) in THF (6 mL) was added
substituted phenylmagnesium bromide (0.8 mmol) at approximately
-35 °C. The formed clear solution was allowed to warm up to
-20 °C within 40 min and was quenched with water. The mixture
was partitioned between EtOAc and brine. The organic layer was
concentrated and the residue was separated by flash chromatography
to provide a Boc-protected 13, which was deprotected as described
in method 1/step C to afford 13.
tert-Butyl 5-(5-Hydroxypyridin-3-yl)-3-methyl-1H-indazole-
1-carboxylate (14). A 1 L RBF equipped with a septum was
charged with bromide 8 (5.2 g, 30.3 mmol), trimethylstannane 12
(10.0 g, 25.2 mmol), Pd2(dba)3 (2.3 g, 2.52 mmol), and (o-tol)3P
(2.3 g, 7.6 mmol) and was purged with N2. Anhydrous DMF (250
mL) and Et3N (7 mL, 50 mmol) were added via syringe. The
solution was purged with N2 again and was heated at 80 °C for 3
h. After cooling, the reaction mixture was partitioned between ethyl
acetate and brine. The organic phase was washed with brine and
concentrated. The residue was separated by flash chromatography
(30-100% gradient EtOAc in hexane) to afford 14. Yield: 5.9 g
1
(72%). H NMR (300 MHz, DMSO-d6): δ 1.66 (s, 9H), 2.59 (s,
3H), 7.50 (d, J ) 2.37 Hz, 1H), 7.88-7.93 (m, 1H), 8.12 (d, J )
8.82 Hz, 1H), 8.15-8.18 (m, 2H), 8.46 (d, J ) 1.70 Hz, 1H), 10.07
(br s, 1H). MS (DCI): m/z 326 (M + 1)+.
(1S)-1-(3-Fluoro-benzyl)-2-(5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy)-ethylamine (13a). The title compound was synthe-
sized as 2× TFA salt by method A. 1H NMR (500 MHz, DMSO-
d6): δ 2.55 (s, 3H), 3.08 (m, 2H), 3.91 (s, 1H), 4.15 (dd, J ) 10.61,
5.93 Hz, 1H), 4.32 (dd, J ) 10.61, 3.12 Hz, 1H), 7.12 (m, 1H),
7.20 (m, 2H), 7.40 (m, 1H), 7.57 (d, J ) 8.73 Hz, 1H), 7.69 (dd,
J ) 8.42, 1.56 Hz, 1H), 7.71 (d, J ) 1.87 Hz, 1H), 8.07 (s, 1H),
8.29 (s, 3H), 8.31 (d, J ) 2.81 Hz, 1H), 8.62 (s, 1H). MS (ESI):
m/z 377 (M + H)+.
General Synthesis of Compound 13 through Mitsunobu
Reaction of 14 (Method 2). A 100 mL RBF was charged with 14
(101 mg, 0.31 mmol), an appropriate alcohol 9 (0.31 mmol), and
Ph3P (199 mg, 0.76 mmol) and was purged with N2. THF (10 mL)
was added at 0 °C. After stirring at the same temperature for 10
min, di-t-butyl azodicarboxylate (DBAD, 175 mg, 0.76 mmol) was
added. The reaction mixture was stirred at rt overnight. Volatiles
were removed by rotary evaporator, and the residue was separated
by flash chromatography to provide product 15. Boc-deprotection
of 15, as described in method 1/step C, provided Akt inhibitor 13.
(1S)-[2-(5-Bromo-pyridin-3-yloxy)-1-hydroxymethyl-ethyl]-
carbamic Acid tert-Butyl Ester (17). A 100 mL RBF was charged
with 3-bromo-5-hydroxypyridine (8, 1.20 g, 6.87 mmol),20 (R)-[1-
(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl]-carbam-
ic acid tert-butyl ester (16, 2.1 g, 6.87 mmol),18 and Ph3P (2.34 g,
8.93 mmol) and was purged with N2. THF (30 mL) was added at
0 °C. After stirring at 0 °C for 10 min, diethyl azodicarboxylate
(DEAD, 1.41 mL, 8.93 mmol) was added via syringe. The reaction
mixture was stirred at 0 °C for 0.5 h and at rt for 2 h. The reaction
mixture was concentrated, and the residue was separated by flash
chromatography (5-25% gradient EtOAc in hexane) to provide
the coupled product (3.14 g, 99%). This product (3.14 g, 6.8 mmol)
was dissolved in THF (40 mL) and was treated with TBAF (7.14
mL, 7.14 mmol) at rt for 1 h. Solvent was removed and the residual
oil was purified by flash chromatography (40-80% gradient EtOAc
in hexane) to give alcohol 17 (2.19 g, 93%). 1H NMR (300 MHz,
CDCl3): δ 1.46 (s, 9H), 3.77-3.95 (m, 2H), 3.98-4.20 (m, 3H),
5.09 (br s, 1H), 7.40 (t, J ) 2.20 Hz, 1H), 8.25 (d, J ) 2.37 Hz,
1H), 8.30 (d, J ) 1.36 Hz, 1H). MS (DCI): m/z 347, 349 (M +
1)+.
(1S)-1-(2,3-Difluoro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13b). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (300 MHz,
CD3OD): δ 2.62 (s, 3H), 3.30 (m, 2H), 4.03 (m, 1H), 4.32 (dd, J
) 10.8, 4.5 Hz, 1H), 4.48 (dd, J ) 10.8, 3.0 Hz, 1H), 7.19 (m,
3H), 7.62 (d, J ) 8.4 Hz, 1H), 7.74 (d, J ) 8.4 Hz, 1H), 8.12 (s,
2H), 8.44 (s, 1H), 8.74(s, 1H). MS (DCI/NH3): m/e 395 (M +
1)+.
(1S)-1-(2,4-Difluoro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13c). The title compound was
1
synthesized as TFA salt by method A. H NMR (300 MHz, CD3-
OD): δ 2.62 (s, 3H), 3.10 (m, 2H), 3.96 (m, 1H), 4.27 (dd, J )
10.8, 4.5 Hz, 1H), 4.43 (dd, J ) 10.8, 3.0 Hz, 1H), 7.01 (m, 2H),
7.40 (m, 1H), 7.61 (d, J ) 8.4 Hz, 1H), 7.71 (d, J ) 8.4 Hz, 1H),
7.94 (s, 1H), 8.08 (s, 1H), 8.37 (s, 1H), 8.67 (s, 1H). MS (DCI/
NH3): m/e 395 (M + 1)+.
(1S)-1-(2,6-Difluoro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13d). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (300 MHz,
CD3OD): δ 2.62 (s, 3H), 3.31 (m, 2H), 3.97 (m, 1H), 4.24 (dd, J
) 10.8, 4.5 Hz, 1H), 4.42 (dd, J ) 10.8, 3.0 Hz), 7.06 (m, 2H),
7.40(m, 1H), 7.60 (d, J ) 8.4 Hz, 1H), 7.70 (d, J ) 8.4 Hz, 1H),
7.84 (s, 1H), 8.04 (s, 1H), 8.31 (s, 1H), 8.41 (s, 1H). MS (DCI/
NH3): m/e 395 (M + 1)+.
(2S)-2-(5-Bromo-pyridin-3-yloxymethyl)-aziridine-1-carboxyl-
ic Acid tert-Butyl Ester (18). Ph3P (15.95 g, 60.82 mmol) was
dissolved in 9:1 THF/CH3CN (300 mL) and cooled to 4 °C with
an ice/water bath. DEAD (9.58 mL, 60.82 mmol) was added slowly.
After stirring for 15 min at the same temperature, a solution of 17
(17.6 g, 50.68 mmol) in THF (60 mL) was added slowly. The
solution was allowed to warm to rt and stirred overnight. The
solution was concentrated and the residual oil was purified by flash
chromatography (20-40% gradient EtOAc in hexane) to give
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2,3,4-
trifluoro-benzyl)-ethylamine (13e). The title compound was
1
synthesized as 2× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.62 (s, 3H), 3.23 (m, 2H), 4.00 (m, 1H), 4.31 (dd, J
) 10.61, 5.30 Hz, 1H), 4.46 (dd, J ) 10.61, 3.12 Hz, 1H), 7.17
(m, 2H), 7.62 (d, J ) 8.73 Hz, 1H), 7.73 (dd, J ) 8.74, 1.56 Hz,
1H), 8.02 (s, 1H), 8.08 (s, 1H), 8.40 (s, 1H), 8.69 (s, 1H). MS
(DCI/NH3): m/e 413 (M + 1)+. Anal. (C22H19F3N4O‚2.8TFA) C,
H, N.
1
aziridine 18 (15.4 g, 92%). H NMR (300 MHz, CDCl3): δ 1.44
(s, 9H), 2.22 (d, J ) 3.73 Hz, 1H), 2.41 (d, J ) 6.10 Hz, 1H),
2.78-2.84 (m, 1H), 4.05-4.17 (m, 2H), 7.42-7.44 (m, 1H), 8.27
(s, 1H), 8.31 (s, 1H). MS (DCI): m/z 329, 331 (M + 1)+.
5-[5-((2S)-1-tert-Butoxycarbonyl-aziridin-2-ylmethoxy)-pyri-
din-3-yl]-3-methyl-indazole-1-carboxylic Acid tert-Butyl Ester
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2,4,6-
trifluoro-benzyl)-ethylamine (13f). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (500 MHz,

2998 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Zhu et al.
CD3OD): δ 2.63 (s, 3H), 3.19 (m, 2H), 3.97 (m, 1H), 4.32 (dd, J
) 10.61, 4.99 Hz, 1H), 4.49 (dd, J ) 10.61, 3.12 Hz, 1H), 6.95 (t,
J ) 8.27 Hz, 2H), 7.63 (d, J ) 8.73 Hz, 1H), 7.74 (dd, J ) 8.74,
1.56 Hz, 1H), 8.08 (d, J ) 2.18 Hz, 1H), 8.10 (s, 1H), 8.41 (s,
1H), 8.72 (s, 1H). MS (APCI): m/z 411 (M - 1)+. Anal.
(C22H19F3N4O‚3.0TFA) C, H, N.
(1S)-1-(2-Chloro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy]-ethylamine (13g). The title compound was synthe-
sized as 2× TFA salt by method A. 1H NMR (300 MHz, DMSO-
d6): δ 2.55 (s, 3H), 3.22 (m, 2H), 3.89 (m, 1H), 4.15 (m, 1H),
4.31 (m, 1H), 7.35 (m, 2H), 7.48 (m, 3H), 7.58 (d, J ) 8.82 Hz,
1H), 7.70 (m, 2H), 8.08 (s, 1H), 8.31 (d, J ) 2.71 Hz, 2H), 8.64
(d, J ) 1.70 Hz, 1H), 12.84 (br s, 1H). MS (ESI): m/e 393 (M +
H)+.
2.03 Hz, 1H), 7.62 (d, J ) 8.81 Hz, 1H), 7.72 (dd, J ) 8.48, 1.36
Hz, 1H), 7.99 (s, 1H), 8.08 (s, 1H), 8.39 (s, 1H), 8.68 (s, 1H). MS
(APCI): m/z 411 (M + 1)+. Anal. (C22H20ClFN4O‚2.7TFA) C, H,
N.
(1S)-1-(4-Chloro-3-fluoro-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13o). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (300 MHz,
CD3OD): δ 2.63 (s, 3H), 3.17 (t, J ) 6.95 Hz, 2H), 4.00 (m, 1H),
4.28 (dd, J ) 10.51, 5.43 Hz, 1H), 4.44 (dd, J ) 10.51, 3.05 Hz,
1H), 7.17 (dd, J ) 8.14, 1.70 Hz, 1H), 7.29 (dd, J ) 10.00, 1.87
Hz, 1H), 7.49 (t, J ) 7.97 Hz, 1H), 7.62 (d, J ) 8.82 Hz, 1H),
7.73 (d, J ) 7.12 Hz, 1H), 8.01 (m, 1H), 8.09 (s, 1H), 8.40 (d, J
) 2.37 Hz, 1H), 8.68 (d, J ) 1.70 Hz, 1H). MS (APCI): m/z 411
(M + 1)+. Anal. (C22H20ClFN4O‚2.7TFA) C, H, N.
(1S)-1-(3-Chloro-benzyl)-2-(5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy)-ethylamine (13h). The title compound was synthe-
sized as 2× TFA salt by method A. 1H NMR (500 MHz, DMSO-
d6): δ 2.55 (s, 3H), 3.06 (d, J ) 7.49 Hz, 2H), 3.92 (m, 1H), 4.16
(m, 1H), 4.33 (dd, J ) 10.92, 3.12 Hz, 1H), 7.31 (d, J ) 7.49 Hz,
1H), 7.37 (m, 2H), 7.45 (s, 1H), 7.58 (d, J ) 8.73 Hz, 1H), 7.70
(dd, J ) 8.73, 1.56 Hz, 1H), 7.77 (s, 1H), 8.08 (s, 1H), 8.23 (s,
3H), 8.34 (d, J ) 2.50 Hz, 1H), 8.65 (s, 1H). MS (ESI): m/z 393
(M + H)+.
(1S)-1-(4-Chloro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy]-ethylamine (13i). The title compound was synthe-
sized as 3× TFA salt by method C. 1H NMR (300 MHz, CD3OD):
δ 2.63 (s, 3H), 3.16 (dd, J ) 7.63, 2.54 Hz, 2H), 3.98 (m, 1H),
4.30 (dd, J ) 10.51, 5.42 Hz, 1H), 4.45 (dd, J ) 10.51, 3.05 Hz,
1H), 7.34 (d, J ) 8.81 Hz, 2H), 7.39 (d, J ) 8.81 Hz, 2H), 7.63
(d, J ) 8.81 Hz, 1H), 7.74 (dd, J ) 8.81, 1.70 Hz, 1H), 8.11 (m,
2H), 8.43 (d, J ) 2.03 Hz, 1H), 8.73 (s, 1H). MS (APCI): m/z 393
(M + 1)+. Anal. (C22H21ClN4O‚3TFA) C, H, N.
(1S)-1-(2,3-Dichloro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13p). The title compound was
1
synthesized as 3× TFA salt by method B. H NMR (300 MHz,
CD3OD): δ 2.63 (s, 3H), 3.40 (dd, J ) 7.32, 5.13 Hz, 2H), 4.10
(m, 1H), 4.33 (dd, J ) 10.62, 4.76 Hz, 1H), 4.47 (dd, J ) 10.99,
2.93 Hz, 1H), 7.30 (t, J ) 7.69 Hz, 1H), 7.39 (d, J ) 7.32 Hz,
1H), 7.52 (d, J ) 7.69 Hz, 1H), 7.63 (d, J ) 8.79 Hz, 1H), 7.74
(d, J ) 8.79 Hz, 1H), 8.11 (s, 2H), 8.45 (s, 1H), 8.75 (s, 1H). MS
(APCI): m/z 427 (M + 1)+. Anal. (C22H20Cl2N4O‚3.5TFA) C, H,
N.
(1S)-1-(3,4-Dichloro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13q). The title compound was
1
synthesized as 3× TFA salt by method B. H NMR (300 MHz,
CD3OD): δ 2.62 (s, 3H), 3.16 (m, 2H), 3.99 (m, 1H), 4.27 (dd, J
) 10.8, 4.5 Hz, 1H), 4.43 (dd, J ) 10.8, 3.0 Hz, 1H), 7.28 (d, J )
8.4 Hz, 1H), 7.54 (d, J ) 8.4 Hz, 1H), 7.56 (s, 1H), 7.62 (d, J )
8.4 Hz, 1H), 7.72 (d, J ) 8.4 Hz, 1H), 7.98 (s, 1H), 8.08 (s, 1H),
8.39 (s, 1H), 8.68 (s, 1H). MS (DCI/NH3): m/e 428 (M + 1)+.
(1S)-1-(3,5-Dichloro-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13r). The title compound was
(1S)-Bromo-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-pyridin-
3-yloxy]-ethylamine (13j). The title compound was synthesized
1
1
as 3× TFA salt by method B. H NMR (500 MHz, CD3OD): δ
synthesized as 3× TFA salt by method B. H NMR (300 MHz,
2.62 (s, 3H), 3.37 (m, 2H), 4.10 (m, 1H), 4.30 (dd, J ) 10.61, 4.99
Hz, 1H), 4.43 (dd, J ) 10.61, 3.12 Hz, 1H), 7.25 (t, J ) 6.71 Hz,
1H), 7.37 (t, J ) 6.86 Hz, 1H), 7.42 (m, 1H), 7.63 (d, J ) 8.74
Hz, 1H), 7.66 (d, J ) 8.11 Hz, 1H), 7.73 (dd, J ) 8.73, 1.56 Hz,
1H), 8.03 (d, J ) 1.87 Hz, 1H), 8.09 (s, 1H), 8.40 (s, 1H), 8.70 (s,
1H). MS (APCI): m/z 438 (M + 1)+. Anal. (C22H21BrN4O‚2.9TFA)
C, H, N.
CD3OD): δ 2.63 (s, 3H), 3.18 (dd, J ) 7.32, 3.30 Hz, 2H), 4.02
(m, 1H), 4.32 (dd, J ) 10.44, 5.31 Hz, 1H), 4.47 (dd, J ) 10.62,
2.93 Hz, 1H), 7.37 (s, 1H), 7.39 (d, J ) 8.06 Hz, 1H), 7.63 (d, J
) 8.79 Hz, 1H), 7.74 (d, J ) 8.06 Hz, 1H), 8.10 (s, 3H), 8.44 (s,
1H), 8.73 (s, 1H). MS (APCI): m/z 427 (M + 1)+. Anal. (C22H20-
Cl2N4O‚3.2TFA) C, H, N.
(1S)-1-(4-Bromo-2-fluoro-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13s). The title compound was
(1S)-1-(3-Bromo-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy]-ethylamine (13k). The title compound was synthe-
1
synthesized as 3× TFA salt by method B. H NMR (500 MHz,
1
sized as 2× HCl salt by method A. H NMR (300 MHz, DMSO-
CD3OD): δ 2.63 (s, 3H), 3.22 (m, 2H), 4.00 (m, 1H), 4.34 (dd, J
) 10.61, 5.30 Hz, 1H), 4.49 (dd, J ) 10.61, 3.12 Hz, 1H), 7.33 (t,
J ) 8.11 Hz, 1H), 7.37 (d, J ) 1.56 Hz, 1H), 7.41 (m, 1H), 7.64
(d, J ) 8.73 Hz, 1H), 7.75 (dd, J ) 8.74, 1.56 Hz, 1H), 8.13 (s,
1H), 8.19 (s, 1H), 8.46 (s, 1H), 8.77 (s, 1H). MS (ESI): m/z 456
(M + 1)+. Anal. (C22H20BrFN4O‚2.8TFA) C, H, N.
d6): δ 2.57 (s, 3H), 3.08 (m, 2H), 4.27 (dd, J ) 10.85, 5.43 Hz,
1H), 4.43 (m, 1H), 7.34 (m, 2H), 7.49 (dt, J ) 7.54, 1.65 Hz, 1H),
7.61 (m, 2H), 7.77 (dd, J ) 8.65, 1.53 Hz, 1H), 8.14 (s, 1H), 8.22
(s, 1H), 8.49 (s, 2H), 8.82 (s, 1H). MS(DCI): m/z 437, 439 (M +
H)+.
(1S)-1-(4-Bromo-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-py-
ridin-3-yloxy]-ethylamine (13l). This compound was prepared as
(1S)-1-(4-Bromo-3-fluoro-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13t). The title compound was
1
1
2× TFA salt by general method B. H NMR (300 MHz, CF3-
synthesized as 3× TFA salt by method B. H NMR (500 MHz,
CO2D): δ 3.16 (s, 3H), 3.46 (m, 2H), 4.48 (m, 1H), 4.86 (m, 2H),
7.34 (m, 2H), 7.70 (m, 2H), 8.24 (m, 2H), 8.57 (m, 2H), 8.86 (m,
1H), 9.07 (m, 1H). MS (ESI): m/e 437 (M + 1).
CD3OD): δ 2.63 (s, 3H), 3.18 (m, 2H), 4.01 (m, 1H), 4.32 (dd, J
) 10.61, 5.62 Hz, 1H), 4.46 (dd, J ) 10.61, 2.81 Hz, 1H), 7.11
(dd, J ) 8.11, 1.56 Hz, 1H), 7.26 (dd, J ) 9.36, 1.87 Hz, 1H),
7.62 (d, J ) 7.18 Hz, 1H), 7.63 (d, J ) 8.42 Hz, 1H), 7.74 (dd, J
) 8.73, 1.56 Hz, 1H), 8.10 (d, J ) 4.06 Hz, 2H), 8.43 (s, 1H),
8.72 (s, 1H). MS (ESI): m/z 456 (M + 1)+. Anal. (C22H20BrFN4O‚
2.6TFA) C, H, N.
(1S)-1-(3-Iodo-benzyl)-2-[5-(3-methyl-1H-indazol-5-yl)-pyri-
din-3-yloxy]-ethylamine (13m). The title compound was synthe-
sized as 3× TFA salt by method B. 1H NMR (300 MHz, CD3OD):
δ 2.62 (s, 3H), 3.12 (m, 2H), 3.96 (m, 1H), 4.24 (dd, J ) 10.8, 4.5
Hz, 1H), 4.40 (dd, J ) 10.8, 3.0 Hz, 1H), 7.16 (d, J ) 7.8 Hz,
1H), 7.35 (d, J ) 7.8 Hz, 1H), 7.62 (d, J ) 8.1 Hz, 1H), 7.68 (d,
J ) 7.8 Hz, 1H), 7.72 (d, J ) 8.1 Hz, 1H), 7.75 (s, 1H), 7.92 (s,
1H), 8.07 (s, 1H), 8.36 (s, 1H), 8.65 (s, 1H). MS (DCI/NH3): m/e
485 (M + 1)+.
(1S)-1-(2-Bromo-4,6-difluoro-benzyl)-2-[5-(3-methyl-1H-inda-
zol-5-yl)-pyridin-3-yloxy]-ethylamine (13u). The title compound
was synthesized as 3× TFA salt by method B. 1H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.32 (m, 1H), 3.48 (m, 1H), 4.03 (m,
1H), 4.34 (dd, J ) 10.45, 4.84 Hz, 1H), 4.48 (dd, J ) 10.61, 3.43
Hz, 1H), 7.13 (t, J ) 8.11 Hz, 1H), 7.40 (d, J ) 8.11 Hz, 1H),
7.63 (d, J ) 8.73 Hz, 1H), 7.74 (dd, J ) 8.73, 1.56 Hz, 1H), 8.09
(s, 1H), 8.11 (s, 1H), 8.42 (s, 1H), 8.73 (s, 1H). MS (APCI): m/z
474 (M + 1)+. Anal. (C22H19BrF2N4O‚3TFA) C, H, N.
(1S)-1-(3-Chloro-4-fluoro-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13n). The title compound was
1
synthesized as 3× TFA salt by method B. H NMR (300 MHz,
CD3OD): δ 2.62 (s, 3H), 3.15 (t, J ) 7.12 Hz, 2H), 3.98 (m, 1H),
4.28 (dd, J ) 10.51, 5.42 Hz, 1H), 4.44 (dd, J ) 10.51, 3.05 Hz,
1H), 7.23 (d, J ) 8.48 Hz, 1H), 7.30 (m, 1H), 7.51 (dd, J ) 7.12,
(1S)-1-(5-Fluoro-2-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13v). The title compound was

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2999
1
synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.36 (s, 3H), 2.62 (s, 3H), 3.16 (dd, J ) 14.19, 6.71
Hz, 1H), 3.23 (m, 1H), 3.97 (m, 1H), 4.29 (dd, J ) 10.45, 4.84
Hz, 1H), 4.42 (dd, J ) 10.61, 3.12 Hz, 1H), 6.95 (td, J ) 8.42,
2.81 Hz, 1H), 7.04 (dd, J ) 9.67, 2.81 Hz, 1H), 7.25 (dd, J )
8.42, 5.93 Hz, 1H), 7.63 (d, J ) 8.74 Hz, 1H), 7.73 (dd, J ) 8.73,
1.56 Hz, 1H), 8.05 (s, 1H), 8.09 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H).
MS (APCI): m/z 391 (M + 1)+. Anal. (C23H23FN4O‚2.6TFA) C,
H, N.
3.28 Hz, 1H), 7.58 (d, J ) 8.42 Hz, 1H), 7.61 (d, J ) 7.49 Hz,
1H), 7.65 (s, 1H), 7.66 (s, 1H), 7.69 (dd, J ) 8.74, 1.56 Hz, 1H),
7.73 (s, 1H), 7.75 (m, 1H), 8.07 (s, 1H), 8.22 (s, 3H), 8.33 (d, J )
2.50 Hz, 1H), 8.64 (d, J ) 1.56 Hz, 1H). MS (ESI): m/z 427 (M
+ H)+.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(4-tri-
fluoromethyl-benzyl)-ethylamine (13ad). The title compound was
1
synthesized as 3× TFA salt by method B. H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.28 (m, 2H), 4.05 (m, 1H), 4.32 (dd, J
) 10.61, 5.30 Hz, 1H), 4.47 (dd, J ) 10.61, 2.81 Hz, 1H), 7.56 (d,
J ) 7.80 Hz, 2H), 7.63 (d, J ) 8.74 Hz, 1H), 7.69 (d, J ) 8.11
Hz, 2H), 7.74 (dd, J ) 8.74, 1.56 Hz, 1H), 8.12 (d, J ) 6.55 Hz,
2H), 8.45 (br s, 1H), 8.74 (br s, 1H). MS (APCI): m/z 428 (M +
1)+. Anal. (C23H21F3N4O‚2.7TFA) C, H, N.
(1S)-1-(4-Bromo-3-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13w). The title compound was
1
synthesized as 3× TFA salt by method B. H NMR (500 MHz,
CD3OD): δ 2.37 (s, 3H), 2.63 (s, 3H), 3.11 (m, 2H), 3.97 (m, 1H),
4.29 (dd, J ) 10.61, 5.62 Hz, 1H), 4.44 (dd, J ) 10.61, 3.12 Hz,
1H), 7.07 (dd, J ) 8.11, 1.87 Hz, 1H), 7.27 (s, 1H), 7.54 (d, J )
8.11 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.73 (d, J ) 8.73 Hz,
1H), 8.06 (s, 1H), 8.10 (s, 1H), 8.41 (s, 1H), 8.71 (s, 1H). MS
(ESI): m/z 452 (M + 1)+. Anal. (C23H23BrN4O‚2.7TFA) C, H, N.
(1S)-1-(4-Fluoro-3-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13x). The title compound was
(1S)-1-(3,5-Bis-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-in-
dazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ae). The title com-
1
pound was synthesized as 3× TFA salt by method C. H NMR
(500 MHz, CD3OD): δ 2.62 (s, 3H), 3.35 (m, 1H), 3.42 (m, 1H),
4.12 (m, 1H), 4.31 (dd, J ) 10.61, 5.30 Hz, 1H), 4.49 (dd, J )
10.61, 3.12 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.73 (dd, J )
8.74, 1.87 Hz, 1H), 7.94 (s, 1H), 8.01 (s, 2H), 8.05 (s, 1H), 8.08
(s, 1H), 8.43 (s, 1H), 8.72 (s, 1H). MS (APCI): m/z 495 (M +
1)+. Anal. (C24H20F6N4O‚2.8TFA) C, H, N.
1
synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.24 (s, 3H), 2.63 (s, 3H), 3.11 (dd, J ) 7.64, 3.90
Hz, 2H), 3.94 (m, 1H), 4.29 (dd, J ) 10.61, 5.62 Hz, 1H), 4.44
(dd, J ) 10.61, 2.81 Hz, 1H), 7.03 (m, 1H), 7.16 (m, 1H), 7.21 (d,
J ) 7.18 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.74 (d, J ) 1.87
Hz, 1H), 8.06 (s, 1H), 8.10 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H). MS
(APCI): m/z 392 (M + 1)+. Anal. (C23H23FN4O‚3TFA) C, H, N.
(1S)-1-(4-Fluoro-2-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13y). The title compound was
(1S)-1-(4-Fluoro-3-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13af). The title com-
1
pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.23 (m, 2H), 4.02 (m, 1H),
4.28 (dd, J ) 10.8, 4.5 Hz, 1H), 4.44 (dd, J ) 10.8, 3.0 Hz, 1H),
7.36 (t, J ) 9.0 Hz, 1H), 7.62 (d, J ) 8.1 Hz, 1H), 7.68 (m, 1H),
7.74 (d, J ) 8.1 Hz, 1H), 8.04 (s, 1H), 8.09 (s, 1H), 8.41 (s, 1H),
8.70 (s, 1H). MS (DCI/NH3): m/e 445 (M + 1)+.
1
synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.40 (s, 3H), 2.62 (s, 3H), 3.15 (dd, J ) 14.19, 6.40
Hz, 1H), 3.22 (m, 1H), 3.94 (m, 1H), 4.29 (dd, J ) 10.61, 4.99
Hz, 1H), 4.42 (dd, J ) 10.61, 2.81 Hz, 1H), 6.91 (td, J ) 8.42,
2.50 Hz, 1H), 7.00 (dd, J ) 9.83, 2.34 Hz, 1H), 7.26 (dd, J )
8.42, 5.93 Hz, 1H), 7.63 (d, J ) 8.74 Hz, 1H), 7.73 (dd, J ) 8.74,
1.25 Hz, 1H), 8.08 (s, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 8.72 (s, 1H).
MS (APCI): m/z 392 (M + 1)+. Anal. (C23H23FN4O‚2.8TFA) C,
H, N.
(1S)-1-(3-Fluoro-5-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ag). The title com-
1
pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.30 (m, 2H), 4.06 (m, 1H),
4.29 (dd, J ) 10.51, 5.09 Hz, 1H), 4.45 (dd, J ) 10.85, 3.05 Hz,
1H), 7.45 (dd, J ) 7.80, 5.76 Hz, 2H), 7.55 (s, 1H), 7.62 (d, J )
8.81 Hz, 1H), 7.73 (d, J ) 8.48 Hz, 1H), 7.98 (s, 1H), 8.07 (s,
1H), 8.42 (br s, 1H), 8.73 (br s, 1H). MS (APCI): m/z 445 (M +
1)+.
(1S)-1-(3-Fluoro-4-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13z). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (300 MHz,
(1S)-1-(2-Fluoro-5-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ah). The title com-
CD3OD): δ 2.24 (d, J ) 1.70 Hz, 3H), 2.63 (s, 3H), 3.11 (d, J )
8.14 Hz, 2H), 3.96 (m, 1H), 4.31 (dd, J ) 10.51, 5.76 Hz, 1H),
4.46 (dd, J ) 10.85, 3.05 Hz, 1H), 7.03 (t, J ) 8.48 Hz, 1H), 7.15
(m, 1H), 7.21 (d, J ) 7.46 Hz, 1H), 7.64 (d, J ) 8.48 Hz, 1H),
7.74 (dd, J ) 8.81, 1.70 Hz, 1H), 8.14 (m, 2H), 8.45 (d, J ) 2.37
Hz, 1H), 8.75 (d, J ) 1.36 Hz, 1H). MS (APCI): m/z 391 (M +
1)+. Anal. (C23H23FN4O‚2.9TFA) C, H, N.
1
pound was synthesized as 3× TFA salt by method C. H NMR
(500 MHz, CD3OD): δ 2.63 (s, 3H), 3.26-3.31 (m, 1H), 3.34-
3.39 (m, 1H), 4.03-4.10 (m, 1H), 4.32 (dd, J ) 10.53, 5.03 Hz,
1H), 4.49 (dd, J ) 10.68, 3.05 Hz, 1H), 7.38 (t, J ) 9.15 Hz, 1H),
7.63 (d, J ) 8.85 Hz, 1H), 7.70-7.72 (m, 1H), 7.72-7.76 (m,
1H), 7.78 (d, J ) 6.71 Hz, 1H), 8.10 (d, J ) 1.83 Hz, 1H), 8.11 (s,
1H), 8.43 (s, 1H), 8.73 (s, 1H). MS (ESI): m/z 445 (M + H)+.
Anal. (C23H20F4N4O‚2.7TFA) C, H, N.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2,4,6-
trimethyl-benzyl)-ethylamine (13aa). The title compound was
1
synthesized as 2× TFA salt by method C. H NMR (500 MHz,
(1S)-1-(3-Fluoro-4-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ai). The title com-
CD3OD): δ 2.21 (s, 3H), 2.34 (s, 6H), 2.62 (s, 3H), 3.14 (dd, J )
14.19, 5.46 Hz, 2H), 3.92 (m, J ) 8.73, 4.99 Hz, 1H), 4.26 (dd, J
) 10.45, 4.84 Hz, 1H), 4.36 (m, 1H), 6.89 (s, 2H), 7.63 (d, J )
8.74 Hz, 1H), 7.72 (dd, J ) 8.73, 1.56 Hz, 1H), 8.11 (s, 2H), 8.42
(s, 1H), 8.75 (s, 1H). MS (APCI): m/z 402 (M + 1)+. Anal.
(C25H28N4O‚2.5TFA) C, H, N.
1
pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.28 (m, 2H), 4.08 (m, 1H),
4.32 (dd, J ) 10.8, 4.5 Hz, 1H), 4.48 (dd, J ) 10.8, 3.0 Hz, 1H),
7.38 (d, J ) 8.1 Hz, 1H), 7.40 (d, J ) 12.0 Hz, 1H), 7.43 (d, J )
8.4 Hz, 1H), 7.70 (t, J ) 8.4 Hz, 1H), 7.75 (d, J ) 8.1 Hz, 1H),
8.13 (m, 2H), 8.44 (s, 1H), 8.74 (s, 1H). MS (DCI/NH3): m/e 445
(M + 1)+.
(1S)-1-(5-Fluoro-2-methoxy-benzyl)-2-[5-(3-methyl-1H-inda-
zol-5-yl)-pyridin-3-yloxy]-ethylamine (13ab). The title compound
was synthesized as 3× TFA salt by method C. 1H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.16 (d, J ) 7.18 Hz, 2H), 3.84 (s, 3H),
4.02 (m, 1H), 4.30 (dd, J ) 10.61, 5.93 Hz, 1H), 4.45 (dd, J )
10.45, 2.96 Hz, 1H), 7.04 (m, 3H), 7.64 (d, J ) 8.73 Hz, 1H), 7.74
(d, J ) 8.74 Hz, 1H), 8.12 (s, 2H), 8.43 (s, 1H), 8.74 (s, 1H). MS
(APCI): m/z 408 (M + 1)+. Anal. (C23H23FN4O2‚3.5TFA) C, H,
N.
(1S)-1-(2-Fluoro-4-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13aj). The title com-
1
pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.31 (m, 2H), 4.04 (m, 1H),
4.29 (dd, J ) 10.85, 5.09 Hz, 1H), 4.45 (dd, J ) 10.85, 3.39 Hz,
1H), 7.54 (d, J ) 8.81 Hz, 1H), 7.55 (s, 1H), 7.60 (dd, J ) 4.07,
3.39 Hz, 1H), 7.63 (s, 1H), 7.72 (dd, J ) 8.81, 1.70 Hz, 1H), 7.96
(s, 1H), 8.07 (s, 1H), 8.39 (s, 1H), 8.67 (s, 1H). MS (APCI): m/z
445 (M + 1)+.
(1S)-2-(5-(3-methyl-1H-indazol-5-yl)-pyridin-3-yloxy)-1-(3-tri-
fluoromethyl-benzyl)-ethylamine (13ac). The title compound was
1
synthesized as 2× TFA salt by method A. H NMR (500 MHz,
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2-tri-
fluoromethoxy-benzyl)-ethylamine (13ak). The title compound
was synthesized as 3× TFA salt by method C. 1H NMR (300 MHz,
DMSO-d6): δ 2.55 (s, 3H), 3.16 (dd, J ) 7.33, 2.34 Hz, 2H), 3.97
(s, 1H), 4.16 (dd, J ) 10.61, 5.62 Hz, 1H), 4.34 (dd, J ) 10.76,

3000 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Zhu et al.
CD3OD): δ 2.62 (s, 3H), 3.28 (m, 2H), 4.00 (m, 1H), 4.24 (dd, J
) 10.8, 4.5 Hz, 1H), 4.40 (dd, J ) 10.8, 3.0 Hz, 1H), 7.42 (m,
4H), 7.63 (d, J ) 8.4 Hz, 1H), 7.73 (d, J ) 8.4 Hz, 1H), 8.01 (s,
1H), 8.09 (s, 1H), 8.39 (s, 1H), 8.70 (s, 1H). MS (DCI/NH3): m/e
443 (M + 1)+.
7.10-7.14 (m, 1H), 7.20-7.21 (m, 1H), 7.22-7.25 (m, 1H), 7.34-
7.37 (m, 1H), 7.37-7.40 (m, 1H). MS (DCI): m/z 294 (M + H)+.
tert-Butyl 1-Hydroxy-3-(3-(4-methoxybenzyloxy)phenyl)pro-
pan-2-ylcarbamate (23). To a suspension of magnesium turnings
(1.64 g, 68 mmol) and a crystal of iodine in anhydrous THF (80
mL) was added dropwise a solution of 21 (20 g, 68 mmol) in
anhydrous THF (56 mL) under nitrogen. The reaction mixture was
heated under reflux until all magnesium was consumed. After
cooling to rt, the formed Grignard solution was canulated into a
suspension of tert-butyl 2-((tert-butyldimethylsilyloxy)-methyl)-
aziridine-1-carboxylate (22,18 9.76 g, 34 mmol) and CuBr-SMe2
(3.5 g, 17 mmol) in anhydrous THF (60 mL) at - 30 °C. The
reaction mixture was stirred at -30 °C for 2 h and was quenched
with aq NH4Cl solution. Volatiles were removed and the residue
was partitioned between EtOAc and brine. The organic phase was
washed with water and concentrated. The residual solid was
dissolved in anhydrous THF (100 mL) and cooled to 0 °C. A 1 M
solution of TBAF in THF (100 mL) was then added, and the mixture
was allowed to be warmed up to rt for 1 h. The dark solution was
partitioned between ethyl acetate and brine. The organic phase was
washed with water and concentrated. The residual oil was separated
by flash chromatography on silica gel (60% EtOAc in hexane) to
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(3-tri-
fluoromethoxy-benzyl)-ethylamine (13al). The title compound was
1
synthesized as TFA salt by method C. H NMR (300 MHz, CD3-
OD): δ 2.62 (s, 3H), 3.22 (dd, J ) 7.29, 5.26 Hz, 2H), 4.00 (m,
1H), 4.26 (dd, J ) 10.51, 5.09 Hz, 1H), 4.43 (dd, J ) 10.85, 3.05
Hz, 1H), 7.25 (d, J ) 8.48 Hz, 1H), 7.30 (s, 1H), 7.36 (d, J ) 7.46
Hz, 1H), 7.49 (t, J ) 7.97 Hz, 1H), 7.62 (d, J ) 8.48 Hz, 1H),
7.72 (dd, J ) 8.82, 1.70 Hz, 1H), 8.00 (s, 1H), 8.08 (s, 1H), 8.40
(d, J ) 2.03 Hz, 1H), 8.68 (s, 1H). MS (APCI): m/z 444 (M +
1)+. Anal. (C23H21F3N4O2‚2.6TFA) C, H, N.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(4-tri-
fluoromethoxy-benzyl)-ethylamine (13am). The title compound
was synthesized as 2× TFA salt by method C. 1H NMR (300 MHz,
CD3OD): δ 2.62 (s, 3H), 3.20 (t, J ) 6.95 Hz, 2H), 3.98 (m, 1H),
4.28 (dd, J ) 10.51, 5.42 Hz, 1H), 4.43 (dd, J ) 10.51, 2.71 Hz,
1H), 7.30 (d, J ) 7.80 Hz, 2H), 7.45 (d, J ) 8.48 Hz, 2H), 7.62
(d, J ) 8.48 Hz, 1H), 7.73 (d, J ) 8.81 Hz, 1H), 8.00 (s, 1H), 8.08
(s, 1H), 8.40 (s, 1H), 8.68 (s, 1H). MS (APCI): m/z 443 (M +
1)+. Anal. (C23H21F3N4O2‚2.4TFA) C, H, N.
1
provide 23. Yield: 11.97 g (91%). H NMR (300 MHz, DMSO-
d6): δ 1.32 (s, 9H), 2.55 (d, J ) 8.82 Hz, 1H), 2.78 (dd, J ) 13.73,
5.26 Hz, 1H), 3.22-3.37 (m, 1H), 3.31 (s, 3H), 3.50-3.64 (m,
1H), 4.67 (t, J ) 5.59 Hz, 1H), 4.97 (s, 2H), 6.57 (d, J ) 8.48 Hz,
1H), 6.75-6.77 (m, 1H), 6.81 (br s, 1H), 6.85-6.83 (m, 1H), 6.92-
6.94 (m, 1H), 6.94-6.97 (m, 1H), 7.16 (t, J ) 7.80 Hz, 1H), 7.34
- 7.36 (m, 1H), 7.37 - 7.38 (m, 1H). MS (DCI): m/z 388 (M +
H)+.
(1S)-1-Biphenyl-3-ylmethyl-2-[5-(3-methyl-1H-indazol-5-yl)-
pyridin-3-yloxy]-ethylamine (13an). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (300 MHz,
CD3OD): δ 2.61 (s, 3H), 3.25 (d, J ) 7.69 Hz, 2H), 4.05 (m, 1H),
4.33 (dd, J ) 10.62, 5.13 Hz, 1H), 4.46 (d, J ) 10.25 Hz, 1H),
7.36 (m, 4H), 7.46 (t, J ) 7.14 Hz, 1H), 7.57 (m, 6H), 8.06 (s,
2H), 8.42 (s, 1H), 8.69 (s, 1H). MS (APCI): m/z 435 (M + 1)+.
Anal. (C28H26N4O‚3.2TFA) C, H, N.
tert-Butyl 6-(5-(2-(tert-Butoxycarbonylamino)-3-(3-(4-meth-
oxybenzyloxy)phenyl)propoxy)-pyridin-3-yl)-3-methyl-1H-inda-
zole-1-carboxylate (24). A solution of 23 (12 g, 31 mmol),
5-bromopyridin-3-ol (8, 5.4 g, 31 mmol), and triphenylphosphine
(12.2 g, 46.5 mmol) in anhydrous THF (150 mL) was cooled in an
ice bath and stirred under nitrogen for 10 min. A solution of DBAD
(10.7 g, 46.5 mmol) in anhydrous THF (100 mL) was added to the
above solution and stirred at rt for 20 h. The solution was then
concentrated and the residue was purified by flash chromatography
(15% EtOAc in hexane) to give the ether formation product. This
product was dissolved in anhydrous DMF (200 mL) and was added
trimethylstannane 12 (9.44 g, 23.9 mmol), Pd2(dba)3 (2.98 g, 3.26
mmol), (o-tol)3P (2.98 g), and triethylamine (9.1 mL). The reaction
mixture was purged with N2 and heated at 70 °C for 16 h. After
cooling, the mixture was partitioned between ethyl acetate and brine.
The organic phase was washed with water, dried over MgSO4,
filtered, and concentrated. The residual oil was purified by flash
column chromatography on silica gel (50% EtOAc in hexane) to
(1S)-1-Benzo1,3dioxol-5-ylmethyl-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13ao). The title compound was
1
synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.08 (dd, J ) 7.64, 2.65 Hz, 2H), 3.92
(m, 1H), 4.32 (dd, J ) 10.45, 5.77 Hz, 1H), 4.46 (dd, J ) 10.61,
2.81 Hz, 1H), 5.92 (d, J ) 1.87 Hz, 2H), 6.80 (d, J ) 1.87 Hz,
2H), 6.85 (s, 1H), 7.64 (d, J ) 8.73 Hz, 1H), 7.74 (dd, J ) 8.73,
1.56 Hz, 1H), 8.12 (s, 1H), 8.14 (d, J ) 1.87 Hz, 1H), 8.45 (d, J
) 1.87 Hz, 1H), 8.74 (s, 1H). MS (APCI): m/z 404 (M + 1)+.
Anal. (C23H22N4O3‚2.6TFA) C, H, N.
(1S)-1-(2,2-Difluoro-benzo1,3dioxol-4-ylmethyl)-2-[5-(3-meth-
yl-1H-indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ap). The title
compound was synthesized as 3× TFA salt by method B. 1H NMR
(500 MHz, CD3OD): δ 2.63 (s, 3H), 3.28 (m, 2H), 4.07 (m, 1H),
4.34 (dd, J ) 10.61, 4.99 Hz, 1H), 4.51 (dd, J ) 10.61, 2.81 Hz,
1H), 7.17 (m, 3H), 7.64 (d, J ) 8.73 Hz, 1H), 7.75 (d, J ) 8.73
Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.46 (s, 1H), 8.76 (s, 1H). MS
(APCI): m/z 437 (M - 1)+. Anal. (C23H20F2N4O3‚3TFA) C, H, N.
1
give 24. Yield: 11.5 g (76%). H NMR (300 MHz, CD3OD): δ
1.40 (s, 9H), 1.72 (s, 9H), 2.61 (s, 3H), 2.85-2.92 (m, 1H), 2.93-
3.01 (m, 1H), 3.74 (s, 3H), 4.08-4.19 (m, 3H), 4.85 (s, 2H), 6.78-
6.84 (m, 2H), 6.84-6.88 (m, 2H), 6.88-6.91 (m, 1H), 7.14-7.18
(m, 1H), 7.19-7.25 (m, 2H), 7.64-7.68 (m, 1H), 7.82 (dd, J )
8.65, 1.86 Hz, 1H), 8.01-8.04 (m, 1H), 8.15 (d, J ) 8.82 Hz, 1H),
8.24 (d, J ) 2.71 Hz, 1H), 8.47 (d, J ) 1.36 Hz, 1H). MS (DCI):
m/z 695 (M + H)+.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2,2,3,3-
tetrafluoro-2,3-dihydro-benzo1,4dioxin-6-ylmethyl)-ethylamine
(13aq). The title compound was synthesized as 3× TFA salt by
1
method B. H NMR (500 MHz, CD3OD): δ 2.63 (s, 3H), 3.18
(dd, J ) 14.19, 7.02 Hz, 1H), 3.24 (m, 1H), 4.02 (m, J ) 5.15,
2.65 Hz, 1H), 4.33 (dd, J ) 10.45, 5.46 Hz, 1H), 4.47 (dd, J )
10.61, 3.12 Hz, 1H), 7.29 (m, 2H), 7.34 (s, 1H), 7.63 (d, J ) 8.73
Hz, 1H), 7.74 (dd, J ) 8.74, 1.25 Hz, 1H), 8.11 (s, 2H), 8.44 (s,
1H), 8.72 (s, 1H). MS (APCI): m/z 487 (M - 1)+. Anal.
(C23H20F2N4O3‚3.1TFA) C, H, N.
tert-Butyl 6-(5-(2-(tert-Butoxycarbonylamino)-3-(3-hydroxy-
phenyl)propoxy)pyridin-3-yl)-3-methyl-1H-indazole-1-carboxylate
(25). A solution of 24 (9.4 g) in methanol (95 mL) was treated
with 10% Pd/C (2.85 g) under hydrogen of 60 psi at 50 °C for 6
h. Solid material was filtered off, and the methanol solution was
concentrated. The dark residue was purified by flash chromatog-
raphy on silica gel (50% EtOAc in hexane) to afford 25. Yield:
6.5 g (83%). 1H NMR (300 MHz, CD3OD): δ 1.38-1.41 (m, 9H),
1.72-1.73 (m, 9H), 2.63 (s, 3H), 2.84-2.96 (m, 2H), 4.09-4.15
(m, 3H), 6.60-6.66 (m, 1H), 6.69-6.75 (m, 2H), 7.08 (t, J ) 7.80
Hz, 1H), 7.67-7.71 (m, 1H), 7.86 (dd, J ) 8.82, 1.70 Hz, 1H),
8.05 (d, J ) 1.02 Hz, 1H), 8.17 (d, J ) 8.82 Hz, 1H), 8.24 (d, J )
2.71 Hz, 1H), 8.47 (d, J ) 1.70 Hz, 1H). MS (DCI): m/z 574 (M
+ H)+.
1-Bromo-3-(4-methoxybenzyloxy)benzene (21). A solution of
3-bromophenol (25 g, 144 mmol), p-methoxybenzyl chloride (22.5
g, 144 mmol), and cesium carbonate (117 g, 360 mmol) in DMF
(200 mL) was stirred at rt for 18 h. Ethyl acetate (500 mL) was
added, and the reaction mixture washed with brine (500 mL) and
water (500 mL). The organic phase was concentrated and the
residual solid was recrystallized from a 7:3 mixture of dichlo-
romethane/ethanol to provide 21 as white solid. Yield: 33.7 g
1
(80%). H NMR (300 MHz, DMSO-d6): δ 3.76 (s, 3H), 5.03 (s,
2H), 6.92-6.94 (m, 1H), 6.95-6.97 (m, 1H), 6.98-7.03 (m, 1H),

Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 3001
(S)-1-(5-(3-Methyl-1H-indazol-5-yl)pyridin-3-yloxy)-3-(3-(2-
morpholinoethoxy)phenyl)propan-2-amine (13ar). A solution of
25 (200 mg, 0.35 mmol), 4-(2-hydroxyethyl)-morpholine (91 mg,
0.70 mmol), and triphenylphosphine (182 mg, 0.70 mmol) in
anhydrous THF (8 mL) was purged with N2 and stirred in an ice-
bath for 10 min. DBAD (160 mg, 0.70 mmol) was then added, and
the reaction mixture stirred at rt for 20 h. After concentration, the
residual oil was separated by flash chromatography (10% MeOH
in EtOAc) to provide the ether product 26 (R′′ ) N-morpholino-
methy). This product was dissolved in dichloromethane (6 mL) and
was treated with trifluoroacetic acid (3 mL) at rt for 1 h. Acetonitrile
(10 mL) was added, and the mixture was concentrated. The residual
oil was purified by HPLC (Zorbax, C-18, 250 × 2.54 column;
mobile phase A, 0.1% TFA in H2O; mobile phase B, 0.1% TFA in
CH3CN; 0-100% gradient) to afford 13ar (93 mg, 55%). 1H NMR
(400 MHz, CD3OD): δ 2.62 (s, 3H), 3.16 (d, J ) 7.67 Hz, 2H),
3.35 (s, 2H), 3.38-3.50 (m, 2H), 3.58-3.62 (m, 2H), 3.86-3.98
(m, 3H), 3.99-4.04 (m, 2H), 4.30 (dd, J ) 10.74, 5.52 Hz, 1H),
4.35-4.39 (m, 2H), 4.44 (dd, J ) 10.74, 3.07 Hz, 1H), 6.94-6.98
(m, 1H), 6.98-7.02 (m, 2H), 7.34 (t, J ) 8.13 Hz, 1H), 7.61-
7.65 (m, 1H), 7.73 (dd, J ) 8.75, 1.69 Hz, 1H), 8.05-8.08 (m,
1H), 8.10 (d, J ) 0.92 Hz, 1H), 8.41 (d, J ) 1.84 Hz, 1H), 8.71 (s,
1H). MS (DCI): m/z 488 (M + H)+. Anal. (C28H33N5O3‚3.5TFA)
C, H, N.
(S)-1-(5-(3-Methyl-1H-indazol-5-yl)pyridin-3-yloxy)-3-(3-(2-
(piperidin-4-yl)ethoxy)phenyl)-propan-2-amine (13as). The title
product was prepared as 3× TFA salt according to the procedure
for 13ar substituting tert-butyl 4-(2-hydroxyethyl)piperidine-1-
carboxylate for 4-(2-hydroxyethyl)-morpholine. Yield: 158 mg
(93%). 1H NMR (500 MHz, CD3OD): δ 1.35-1.46 (m, 2H), 1.71
(q, J ) 6.34 Hz, 2H), 1.80-1.88 (m, 1H), 1.95 (d, J ) 9.36 Hz,
2H), 2.62 (s, 3H), 2.93 (t, J ) 12.79 Hz, 2H), 3.13 (d, J ) 7.49
Hz, 2H), 3.32-3.37 (m, 2H), 3.93-4.03 (m, 3H), 4.26 (dd, J )
10.76, 5.46 Hz, 1H), 4.41 (dd, J ) 10.60, 3.12 Hz, 1H), 6.84-
6.88 (m, 2H), 6.91 (d, J ) 7.80 Hz, 1H), 7.28 (t, J ) 7.80 Hz,
1H), 7.62 (d, J ) 8.73 Hz, 1H), 7.71 (dd, J ) 8.73, 1.56 Hz, 1H),
7.96-7.98 (m, 1H), 8.07 (d, J ) 0.62 Hz, 1H), 8.37 (d, J ) 1.87
Hz, 1H), 8.67 (s, 1H). MS (DCI): m/z 486 (M + H)+. Anal.
(C29H35N5O2‚3.3TFA) C, H, N.
piperidine for 4-(2-hydroxyethyl)-morpholine. Yield: 105 mg
(63%). 1H NMR (500 MHz, CD3OD): δ 1.53-1.67 (m, 2H), 1.97-
2.10 (m, 3H), 2.62 (s, 3H), 2.85 (s, 3H), 2.95-3.03 (m, 2H), 3.13
(d, J ) 7.80 Hz, 2H), 3.52 (d, J ) 12.16 Hz, 2H), 3.78-3.88 (m,
2H), 3.92-4.00 (m, 1H), 4.25 (dd, J ) 10.60, 5.30 Hz, 1H), 4.40
(dd, J ) 10.60, 2.81 Hz, 1H), 6.84-6.90 (m, 2H), 6.92 (d, J )
7.80 Hz, 1H), 7.29 (t, J ) 7.80 Hz, 1H), 7.61 (d, J ) 8.73 Hz,
1H), 7.71 (dd, J ) 8.73, 1.56 Hz, 1H), 7.95 (d, J ) 1.87 Hz, 1H),
8.06 (s, 1H), 8.36 (d, J ) 2.18 Hz, 1H), 8.66 (s, 1H). MS (ESI):
m/z 486 (M + H)+. Anal. (C29H35N5O2‚3.6TFA) C, H, N.
(S)-1-[3-(2-Amino-ethoxy)-benzyl]-2-[5-(3-methyl-1H-indazol-
6-yl)-pyridin-3-yloxy]-ethylamine (13aw). The title product was
prepared as 3× TFA salt according to the procedure for 13ar,
substituting t-butyl 2-hydroxyethylamine-1-carboxylate for 4-(2-
1
hydroxyethyl)-morpholine. Yield: 132 mg (91%). H NMR (500
MHz, CD3OD): δ 2.61 (s, 3H), 3.15 (d, J ) 7.49 Hz, 2H), 3.31-
3.35 (m, 2H), 3.95-4.02 (m, 1H), 4.17-4.22 (m, 2H), 4.27 (dd, J
) 10.60, 5.61 Hz, 1H), 4.41 (dd, J ) 10.60, 2.81 Hz, 1H), 6.96 (d,
J ) 8.42 Hz, 1H), 6.97-7.01 (m, 2H), 7.29-7.36 (m, 1H), 7.61
(d, J ) 8.73 Hz, 1H), 7.71 (dd, J ) 8.73, 1.56 Hz, 1H), 7.98 (s,
1H), 8.07 (s, 1H), 8.37 (s, 1H), 8.68 (s, 1H). MS (ESI): m/z 418
(M + H)+. Anal. (C24H27N5O2‚3.5TFA) C, H, N.
(S)-tert-Butyl 1-(3-(Trifluoromethyl)phenyl)-3-(5-(trimethyl-
stannyl)pyridin-3-yloxy)propan-2-ylcarbamate (27). A 100 mL
RBF was charged with Pd(PPh3)4 (843 mg, 0.73 mmol) and bromide
10 (R) 3-CF3, 3.47 g, 7.3 mmol) that was synthesized as described
in the general synthesis of 13 (step A). After purging with N2,
anhydrous toluene (50 mL) and hexamethylditin (4.78 g, 14.6
mmol) were added via syringe. The solution was purged with N2
again and was heated at 115 °C (oil bath) for 3 h. After cooling,
the black reaction mixture was directly loaded to a silica gel column
that was eluted with 30-70% gradient EtOAc in hexane to give
27. Yield: 3.27 g (80%). 1H NMR (300 MHz, CDCl3): δ 0.34 (s,
9H), 1.41 (s, 9H), 3.07 (d, J ) 7.46 Hz, 2H), 3.90-4.03 (m, 1H),
4.20 (m, 1H), 4.91 (m, 1H), 7.27 (d, J ) 3.05 Hz, 1H), 7.41 (d, J
) 5.09 Hz, 2H), 7.47 (s, 2H), 8.21 (d, J ) 3.05 Hz, 1H), 8.24 (s,
1H). MS (DCI): m/z 560 (M + H)+.
(S)-1-Phenyl-3-(5-(trimethylstannyl)pyridin-3-yloxy)propan-
2-amine (28). The title compound was prepared according to the
procedure for 27, substituting (S)-tert-butyl 1-phenyl-3-hydroxy-
propan-2-ylcarbamate for [1-hydroxymethyl-2-(3-trifluoromethyl-
phenyl)-ethyl]-carbamic acid tert-butyl ester. Yield: 100%. 1H
NMR (300 MHz, CDCl3): δ 0.34 (s, 9H), 1.43 (s, 9H), 3.00 (d, J
) 7.46 Hz, 2H), 3.90-3.96 (m, 2H), 4.12-4.22 (m, 1H), 4.85-
4.95 (m, 1H), 7.19-7.31 (m, 6H), 8.19-8.23 (m, 2H). MS
(APCI): m/z 492 (M + H)+.
(S)-1-(5-(3-Methyl-1H-indazol-5-yl)pyridin-3-yloxy)-3-(3-(pi-
peridin-4-ylmethoxy)phenyl)-propan-2-amine (13at). The title
product was prepared as 4× TFA salt according to the procedure
for 13ar, substituting tert-butyl 4-(hydroxymethyl)piperidine-1-
carboxylate for 4-(2-hydroxyethyl)-morpholine. Yield: 86 mg
(52%). 1H NMR (400 MHz, CD3OD): δ 1.49-1.63 (m, 1H), 2.02
(d, J ) 14.12 Hz, 2H), 2.06-2.15 (m, 1H), 2.60-2.65 (m, 3H),
2.95-3.05 (m, 2H), 3.11 (dd, J ) 20.71, 7.52 Hz, 2H), 3.41 (d, J
) 9.82 Hz, 2H), 3.79-3.88 (m, 2H), 3.90-4.03 (m, 2H), 4.23-
4.34 (m, 1H), 4.43 (dd, J ) 10.59, 5.98 Hz, 1H), 6.71-6.77 (m,
1H), 6.77-6.88 (m, 1H), 6.89-6.94 (m, 1H), 7.15-7.34 (m, 1H),
7.59-7.66 (m, 1H), 7.70-7.76 (m, 1H), 8.00-8.10 (m, 1H), 8.09-
8.13 (m, 1H), 8.38-8.46 (m, 1H), 8.71 (d, J ) 5.22 Hz, 1H). MS
(DCI): m/z 472 (M + H)+.
(S)-1-(2,3-Difluorophenyl)-3-(5-(trimethylstannyl)pyridin-3-
yloxy)propan-2-amine (29). The title compound was prepared
according to the procedure for 27, substituting (S)-tert-butyl 1-(2,3-
difluorophenyl)-3-hydroxypropan-2-ylcarbamate for [1-hydroxy-
methyl-2-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid tert-butyl
1
ester. Yield: 72%. H NMR (300 MHz, CD3OD): δ 0.25 - 0.45
(m, 9H), 1.35 (s, 9H), 2.83-2.94 (m, 1H), 3.08-3.17 (m, 1H),
4.07 (d, J ) 5.09 Hz, 2H), 4.13-4.22 (m, 1H), 7.04-7.09 (m,
2H), 7.08-7.16 (m, 1H), 7.50 (dd, J ) 3.05, 1.02 Hz, 1H), 8.12
(s, 1H), 8.14 (d, J ) 3.05 Hz, 1H). MS (DCI): m/z 528 (M + H)+.
(S)-5-(5-(2-Amino-3-phenylpropoxy)pyridin-3-yl)indolin-2-
one (34). The title compound was synthesized from 28 and 3015 as
TFA salt, according to the general synthesis of compound 13,
method 1 (steps B and C). Yield: 26%. 1H NMR (500 MHz, CD3-
OD): δ 3.15 (d, J ) 7.49 Hz, 2H), 3.61 (s, 2H), 3.91-3.99 (m,
1H), 4.26 (dd, J ) 10.61, 5.62 Hz, 1H), 4.40 (dd, J ) 10.61, 3.12
Hz, 1H), 7.04 (d, J ) 8.11 Hz, 1H), 7.28-7.34 (m, 3H), 7.35-
7.40 (m, 2H), 7.58 (d, J ) 8.11 Hz, 1H), 7.62 (s, 1H), 7.94-7.99
(m, 1H), 8.38 (d, J ) 2.50 Hz, 1H), 8.60 (d, J ) 0.94 Hz, 1H). MS
(ESI): m/z 360 (M + H)+. Anal. (C22H21N3O2‚2.3TFA) C, H, N.
(S,Z)-3-((1H-Pyrrol-2-yl)methylene)-5-(5-(2-amino-3-phenyl-
propoxy)pyridin-3-yl)indolin-2-one (35). The title compound was
synthesized from 28 and 3115 as HCl salt according to general
synthesis of compound 13, method 1 (steps B and C). Yield: 55%.
1H NMR (500 MHz, CD3OD): δ 3.22 (d, J ) 7.80 Hz, 2H), 4.01-
(S)-1-(3-Cyclohexylmethoxy-benzyl)-2-[5-(3-methyl-1H-inda-
zol-6-yl)-pyridin-3-yloxy]-ethylamine (13au). The title product
was prepared as 2× TFA salt according to the procedure for 13ar,
substituting cyclohexylmethylalcohol for 4-(2-hydroxyethyl)-mor-
1
pholine. Yield: 133 mg (81%). H NMR (400 MHz, CD3OD): δ
0.86-1.02 (m, 2H), 1.07-1.28 (m, 3H), 1.57-1.67 (m, 4H), 1.72
(d, J ) 12.58 Hz, 2H), 2.57 (s, 3H), 3.05-3.15 (m, 2H), 3.55-
3.70 (m, 2H), 3.86-3.97 (m, 1H), 4.26 (dd, J ) 10.59, 5.37 Hz,
1H), 4.41 (dd, J ) 10.59, 2.92 Hz, 1H), 6.78 (dd, J ) 8.29, 2.15
Hz, 1H), 6.81 (s, 1H), 6.84 (d, J ) 7.67 Hz, 1H), 7.21 (t, J ) 7.82
Hz, 1H), 7.55-7.59 (m, 1H), 7.67 (dd, J ) 8.90, 1.53 Hz, 1H),
8.05 (d, J ) 0.61 Hz, 1H), 8.06-8.08 (m, 1H), 8.39 (d, J ) 2.45
Hz, 1H), 8.68 (d, J ) 1.23 Hz, 1H). MS (ESI): m/z 471 (M +
H)+. Anal. (C29H34N4O2‚2.0TFA) C, H, N.
(S)-2-[5-(3-Methyl-1H-indazol-6-yl)-pyridin-3-yloxy]-1-[3-(1-
methyl-piperidin-4-ylmethoxy)-benzyl]-ethylamine (13av). The
title product was prepared as 3× TFA salt according to the
procedure for 13ar, substituting 1-methyl-4-(hydroxymethyl)-

3002 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Zhu et al.
4.09 (m, 1H), 4.45 (dd, J ) 10.29, 5.62 Hz, 1H), 4.58 (dd, J )
10.61, 2.81 Hz, 1H), 6.35-6.39 (m, 1H), 6.87 (d, J ) 2.18 Hz,
1H), 7.06 (d, J ) 8.11 Hz, 1H), 7.25 (s, 1H), 7.30-7.35 (m, 1H),
7.37-7.43 (m, 4H), 7.60 (dd, J ) 8.11, 1.56 Hz, 1H), 7.80 (s,
1H), 8.09 (d, J ) 1.25 Hz, 1H), 8.51 (d, J ) 1.25 Hz, 1H), 8.53
(d, J ) 2.18 Hz, 1H), 8.84 (s, 1H). MS (ESI): m/z 437 (M + H)+.
Anal. (C27H24N4O3‚2.8HCl) C, H, N.
(S)-5-(5-(2-Amino-3-phenylpropoxy)pyridin-3-yl)-3-(furan-2-
ylmethylene)indolin-2-one (36). The title compound was synthe-
sized from 28 and 3215 as HCl salt according to general synthesis
of compound 13, method 1 (steps B and C). Yield: 9%. 1H NMR
(500 MHz, CD3OD): δ 3.21 (d, J ) 7.80 Hz, 2H), 4.02-4.09 (m,
1H), 4.43 (dd, J ) 10.45, 5.77 Hz, 1H), 4.58 (dd, J ) 10.45, 2.96
Hz, 1H), 6.76 (dd, J ) 3.43, 1.87 Hz, 1H), 7.10 (d, J ) 8.11 Hz,
1H), 7.15 (d, J ) 3.43 Hz, 1H), 7.30-7.35 (m, 1H), 7.36-7.41
(m, 4H), 7.45 (s, 1H), 7.71 (dd, J ) 8.11, 1.87 Hz, 1H), 8.01 (d,
J ) 1.56 Hz, 1H), 8.40-8.44 (m, 1H), 8.62 (d, J ) 1.87 Hz, 1H),
8.79 (d, J ) 1.87 Hz, 1H), 8.82 (s, 1H). MS (ESI): m/z 438 (M +
H)+. Anal. (C27H23N3O3‚2.1HCl) C, H, N.
General Procedure for Synthesis of 37. A suspension of
bromide 33 (0.48 mmol), trimethylstannane 27-29 (0.48 mmol),
bis(tri-tert-butylphosphine)palladium(0) (26 mg, 0.05 mmol), and
cesium fluoride (218 mg, 1.44 mmol) in anhydrous dioxane (10
mL) was heated at 80 °C under nitrogen for 15 h. After cooling,
the reaction mixture was partitioned between EtOAc and brine. The
organic phase was washed with water, dried (MgSO4), filtered, and
concentrated. The residual oil was purified by flash column
chromatography on silica gel to provide the Stille product. This
product was dissolved in dichloromethane (6 mL), and was treated
with TFA (3 mL) at rt for 1 h. Acetonitrile (10 mL) was added
and the mixture was concentrated. The residual oil was purified
by HPLC (Zorbax, C-18, 250 × 2.54 column; mobile phase A,
0.1% TFA in H2O; mobile phase B, 0.1% TFA in CH3CN; 0-100%
gradient) to provide 37 as TFA salt.
(S)-1-(5-(1H-Pyrazolo[3,4-c]pyridin-5-yl)pyridin-3-yloxy)-3-
(3-(trifluoromethyl)phenyl)propan-2-amine (37a). Yield: 37%.
1H NMR (300 MHz, CD3OD): δ 3.23-3.28 (m, 2H), 4.05 (dd, J
) 4.58, 2.88 Hz, 1H), 4.27 (dd, J ) 10.68, 5.26 Hz, 1H), 4.45 (dd,
J ) 10.51, 3.05 Hz, 1H), 7.60-7.64 (m, 3H), 7.70 (s, 1H), 8.30 (s,
1H), 8.33-8.35 (m, 1H), 8.42-8.45 (m, 2H), 8.99 (d, J ) 1.70
Hz, 1H), 9.16 (s, 1H). MS (DCI): m/z 414 (M + H)+.
Acknowledgment. We would like to thank Dr. Milan
Bruncko for proofreading this manuscript and valuable sugges-
tions. We are very indebted to the Structural Chemistry
Department of Abbott GPRD for the spectra of all compounds
and Integrative Pharmacology for in vitro cardiovascular data.
Supporting Information Available: Full combustion data
available for the majority of final compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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pyridin-5-yl)pyridin-3-yloxy)propan-2-amine (37d). Yield: 4%.
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3.97-4.06 (m, 1H), 4.22-4.30 (m, 1H), 4.43 (dd, J ) 10.51, 3.05
Hz, 1H), 7.15-7.20 (m, 2H), 7.22-7.29 (m, 1H), 8.24 (dd, J )
2.88, 1.86 Hz, 1H), 8.36 (d, J ) 1.36 Hz, 1H), 8.39 (d, J ) 2.71
Hz, 1H), 8.96 (d, J ) 1.70 Hz, 1H), 9.06 (d, J ) 1.02 Hz, 1H).
MS (DCI): m/z 396 (M + H)+. Anal. (C21H19F2N5O‚3.0TFA) C,
H, N.
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JM0701019