Discovery and preliminary structure-activity relationship studies of novel benzotriazine based compounds as Src inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.08.035

We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kina

Full text of DOI:10.1016/j.bmcl.2006.08.035

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5546–5550
Discovery and preliminary structure–activity relationship studies
of novel benzotriazine based compounds as Src inhibitors
Glenn Noronha,a,* Kathy Barrett,a Jianguo Cao,a Elena Dneprovskaia,a Richard Fine,b
Xianchang Gong,a Colleen Gritzen,a John Hood,a Xinshan Kang,b Boris Klebansky,b
G. Li,c W. Liao,c Dan Lohse,a Chi Ching Mak,a Andrew McPherson,a
Moorthy S. S. Palanki,a Ved P. Pathak,a Joel Renick,a Richard Soll,a
Ute Splittgerber,a Wolfgang Wrasidlo,a Binqi Zeng,a Ningning Zhaoa and Y. Zhouc
aTargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA
bBioPredict, Inc., 660 Kinderkamack Road, Oradell, NJ 07649, USA
cWuXi PharmaTech Ltd, Shanghai, PR China
Received 17 July 2006; revised 4 August 2006; accepted 7 August 2006
Available online 22 August 2006
Abstract—We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small mol-
ecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as
kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyl analogue (43) was identified as one of the most potent inhibitors of Src
kinase.
Ó 2006 Elsevier Ltd. All rights reserved.
Src is the prototype member of the Src-family of tyro-
sine kinases, which comprises eleven highly homologous
proteins including Src, Yes, Fyn, Lyn, Hck, Blk, Brk,
Fgr, Frk, Srm, and Yrk.1 Src is dysregulated in several
types of cancer and involved in metastases and tumor
progression, particularly those of breast, metastatic
colorectal,2 ovarian,3 and pancreatic cancers.4–6 Src
plays a role in myocardial infarction, osteoporosis,
stroke, and neurodegeneration.7 Under basal condi-
tions, Src is tightly regulated by keeping it in an inactive
conformation. However, different physiological stimuli
lead to up-regulation of Src resulting in adhesion and
cytoskeletal changes, altered gene expression, and in-
creased cell proliferation. Due to the involvement of
Src in several diseases, inhibitors of Src have potential
utility in myocardial infarction,8 aggressive forms of
cancer, osteoporosis, and stroke.9,10 Several Src inhibi-
tors have been reported recently.11–17
pounds as a new class of Src inhibitors. To the best
of our knowledge, benzotriazine template based com-
pounds have not been reported as kinase inhibitors.
Our screening efforts using recombinant human Src
resulted in the identification of novel core template 1
(Table 1).18 Compound 1 displayed low micromolar
activity against Src (IC50 = 3.6 lM). Computational
studies suggested that compound 1 was binding at
the ATP-pocket and the ring nitrogen at the 2-position
is involved as a hydrogen bond acceptor, while the
3-amino group is involved as a hydrogen bond donor
at the hinge region. Compound 1 binds in the ATP
pocket of Src in a manner similar to that seen with
compound 42 depicted in Figure 1. Both compounds
orient the 7-phenyl ring orthogonal to the benzotri-
azine core,19 positioning this ring deep within the
hydrophobic pocket. The pocket has enough space to
accommodate small substituents on the phenyl moiety.
The 3-amino group is oriented toward the solvent
accessible hydrophobic channel. This latter portion of
the binding pocket displays a greater tolerance towards
various groups in the benzotriazine series as we will
demonstrate. Based on this binding mode, we have
designed, synthesized, and tested several analogues of
7-phenyl-3-amino-1,2,4-benzotriazine by substituting
As part of our drug discovery efforts, we have identi-
fied and developed novel benzotriazine based com-
Keywords: Src inhibitor; Cancer; Kinase inhibitor; Benzotriazines.
*
Corresponding author. Tel.: +1 858 678 0760; fax: +1 858 678
0762; e-mail: noronha@targegen.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.035

G. Noronha et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5546–5550
5547
Table 1. Inhibition of Src kinase activity by the 3-aminobenzo-
[1,2,4]triazine analogs with R1 through R4 modifications
1
N
R1
R3
2
7
N
N
4
NHR4
5
R2
Compound R1
R2
R3
R4 IC50
(lM)
1
6
2,6-Cl2 Ph
Ph
3-OH Ph
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
3.6
>50
Scheme 1. Reagents and conditions: (a) NH2CN, 37% aq HCl, 110 °C,
1.5 h; (b) 30% aq NaOH, 110 °C, 0.5 h, 65% over two steps; (c) 10%
Raney Ni, H2, EtOH, rt, 4 h, 80%; (d) R1B(OH)2, Pd(PPh3)4, K2CO3,
DME/EtOH/H2O (4:1:1), D, 3 h, 80%; (e) R4Br, Pd2(dba)3, xantphos,
Cs2CO3, dioxane, D, 12 h, 70%.
7
H
12
12
8
3,4-Methylenedioxy Ph
2-Naphthyl
2,6-Me2 Ph
H
9
H
5.2
2.2
>50
10
11
12
13
14
15
16
17
H
2-Cl Ph
2,6-Me2 Ph
Me
Me
Me
H
7.4
1.5
dines were cyclized with sodium hydroxide to give
1-oxobenzotriazines (3).20,21 N-Oxides (3) were reduced
using Raney nickel to give 3-amino-7-bromobenzotria-
zines (4) in good yield. Various aryl substituted
benzotriazines (5) were prepared by treating 3-amino-
7-bromobenzotriazines (4) with aryl boronic acids under
Suzuki coupling conditions.22 The final compounds
(6–56) were prepared from 5 in good yield by Buch-
wald–Hartwig cross-coupling reactions using palladium
and xantphos.23
2-Cl-5-OH Ph
2,6-Me2 Ph
2,6-Me2 Ph
1.5
Me
0.41
0.13
2,6-Me2 Ph
2,4,6-Me3 Ph
Me Me Ph
Me
H
Ph >50
Tables 1–3 summarize the structure–activity relation-
ships for the inhibition of Src for a series of analogues
with modifications at R1 through R4. These compounds
were evaluated using recombinant human Src, PTK2 (a
tyrosine kinase substrate), and ATP. The initial SAR ef-
forts were focused on the modifications of the 7-phenyl
group. The removal of a methyl group on the benzotri-
azine resulted in a compound with comparable potency
to 1 (data not shown). However, the removal of a chlo-
rine atom (11) or two chlorine atoms (data not shown)
and removal of the two chlorine atoms and the methyl
group on the core (6) from 1 resulted in complete loss
of potency (Table 1). The ortho substitutions on the
phenyl ring orient this group perpendicular to the plane
of the benzotriazine, facilitating the binding of the moi-
ety deep within the hydrophobic pocket. Our observa-
tions in Src are consistent with the previous findings
that showed 2,6-disubstitutions on analogous phenyl
rings play a key role in enhancing the binding within
the hydrophobic pocket of Src24 and Lck.25,26 The intro-
duction of a 3-hydroxyl group (7) or 3,4-methylenedioxy
group (8) on the 7-phenyl ring did not improve the
potency when compared to 1. 2,6-Dimethylphenyl
substituted compounds without a methyl group at the
5-position (10) or with a 5-methyl group (12) resulted
in compounds with comparable potency to 1. The intro-
duction of a third methyl group on the 7-phenyl group
resulted in compound 17 with loss of potency. These
findings are consistent with the homology model that
shows tolerances in hydrophobic pocket are restricted
to small, specifically positioned groups.
Figure 1. Compound 42 in the ATP binding pocket of Src kinase.
different groups both on the left side (5-, 6-, and 7-po-
sitions) and the right side (3-position) of this
compound.
The benzotriazines studied were synthesized as shown in
Scheme 1. Appropriately substituted 3-bromo-2-nitro-
anilines (2) were reacted with cyanamide under acidic
conditions to give intermediate guanidines. These guani-
A phenyl substitution on the 3-amino group of 10 and
12 resulted in compounds 14 and 15 with improved
potency. Compound 15 was approximately 10-fold
more potent than 1. Methyl groups both at the 5- and

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G. Noronha et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5546–5550
Table 2. Inhibition of Src kinase activity by the 3-aminobenzo-
[1,2,4]triazine analogs with R4 modifications
the 5-methyl group more effectively enhances filling
hydrophobic space, or facilitates more optimal hinge
binding interactions by eliminating alternative binding
modes, or tilts the terminal phenyl ring for proper en-
trance into the hydrophobic pocket thus enhancing
potency.
N
N
N
NHR4
Compound
R4
IC50 (lM)
The SAR studies on the left side of the molecule resulted
in the identification of the 2,6-dimethylphenyl group at
the 7-position and a methyl group at the 5-or 6-position
on the benzotriazine ring as preferred for the potency.
While keeping the above groups constant, we explored
several different groups on the 3-amino moiety (R4 in
Table 2). While a phenyl group on the 3-amino group
(15) is beneficial, a quinolinyl group on the 3-amino
(18) results in loss of potency. The 2-methoxyphenyl
(22) substitution results in a loss of potency. The
4-methoxyphenyl substituted compound (23) and 4-eth-
oxy substituted compound (24) result in compounds
with potency comparable to 15, both 10-fold better than
1. Modeling studies suggested that the groups at the 2-
position in the above compounds might create steric
clashes that are also reflected in data from compounds
22 and 26–28. While the substitution of a 2-pyridyl
group (31) results in a complete loss of potency, 4-pyr-
idyl group substitution results in a compound (32) with
10-fold improvement in potency over 15. The substitu-
tion of an acyl group (33) results in severe loss of poten-
cy, while a benzoyl group (34) on the 3-amino moiety
results only in a 4-fold loss in potency. In the pyri-
do[2,3-d]pyrimidin-7(8H)-ones series,27 a large number
of aliphatic and aromatic amino groups on the right side
are tolerated and show low nM potency. However, in
the benzotriazine series, we have discovered that the aro-
matic group proximal to the 3-amino position is essen-
tial for activity. Additionally either 3- or 4-substitution
on the 3-amino N-phenyl group is preferred for potency
thus showing the benzotriazine series displays unique
characteristics that differ significantly from the other
structurally related series in its tolerance toward 3-ami-
no substituents.
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
8-Quinolinyl
4-nBuPh
3-ClPh
>50
>50
0.13
0.24
>50
0.14
0.11
0.18
>50
>50
>50
0.96
0.14
>50
0.04
>50
1.8
4-N(Me)2Ph
2-MeOPh
4-MeOPh
4-EtOPh
3-Me Ph
2,3-Me2Ph
2,4-Me2Ph
2,5-Me2Ph
3,4-Me2Ph
3-SO2NH2Ph
2-Pyridyl
4-Pyridyl
COMe
COPh
Table 3. Inhibition of Src kinase activity by the 3-aminobenzo-[1,2,4]
triazine analogs with R4 modifications
0
N
N
4
N
R4'
3
N
H
0
Compound R4
IC50
(lM)
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
4-(2-Diethyl amino) ethoxy
3-(2-Diethyl amino) ethoxy
4-(4-(2-Ethoxy) morpholino)
0.010
0.010
0.032
0.021
0.036
0.041
0.040
0.007
0.006
0.009
0.026
0.008
0.018
0.320
0.137
0.480
0.128
0.013
0.019
0.041
4-(1-(2-Ethoxy)-4-methylpiperazino)
4-(1-(2-Propoxy)-4-methylpiperazino)
3-(1-(2-Ethoxy)-4-methylpiperazino)
3-(1-(2-Propoxy)-4-methylpiperazino)
4-(2-(1-Pyrrolidinyl) ethoxy)
Modeling studies indicated that the substitution of large
groups either at the 3- or 4-position of the phenyl ring
would be tolerated since these groups are extended into
a solvent accessible area. We introduced several water-
soluble groups at both the 4- and 3-positions to improve
the aqueous solubility of these compounds. Further
modeling suggested that a positively charged ionizable
group in the solvent accessible area might potentially
interact favorably with Asp-348 and improve the poten-
cy. Several compounds were prepared to address both
the solubility and the interaction of such analogues with
the aspartic acid. The introduction of the 2-(diethylami-
no)ethoxyphenyl group at the 4-position (35) resulted in
a compound with improved potency (IC50 = 0.01 lM).
When the 2-(diethylamino)ethoxyphenyl group was
moved to the 3-position as in compound 36, the potency
did not change. Both of these compounds (35 and 36)
were 40-fold more potent than 15 suggesting the impor-
tance of the Asp-348 interaction. We observed a similar
trend with the 1-(2-ethoxy)-4-methylpiperazino group at
the 3-position (40) and at the 4-position (38) on the
3-(2-(1-Pyrrolidinyl) ethoxy)
4-(2-Pyrrolidin-1-yl-ethyl)-sulfonamido
3-(2-Pyrrolidin-1-yl-ethyl)-sulfonamido
4-(N,N-Dimethylamino)ethylcarboxamido
N-(2-Pyrrolidin-1-yl-ethyl)-benzamido
3-(4-Methyl-piperazine-1-sulfonyl)
4-(4-Methyl-piperazine-1-sulfonyl)
3-(Piperazine-1-sulfonyl)
4-(Piperazine-1-sulfonyl)
Piperazin-1-yl-methanone
4-Methylpiperazin-1-yl-methanone
3-(N,N-Dimethylaminoethyl)sulfonamido
3-(N,N-Dimethylaminopropyl)sulfonamido 0.029
4-(N,N-Dimethylaminoethyl)sulfonamido 0.015
6-positions of the benzotriazine ring help to improve the
potency (16). The role of the methyl group on the core is
not readily apparent since it does not seem to be in-
volved in any obvious binding interactions. Potentially

G. Noronha et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5546–5550
5549
Table 4. In vitro evaluation of 42 in different kinases
3. Wiener, J. R.; Windham, T. C.; Estrella, V. C.; Parikh, N.
U.; Thall, P. F.; Deavers, M. T.; Bast, R. C.; Mills, G. B.;
Gallick, G. E. Gynecol. Oncol. 2003, 88, 73.
4. Ito, H.; Gardner-Thorpe, J.; Zinner, M. J.; Ashley, S. W.;
Whang, E. E. Surgery 2003, 134, 221.
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Himes, N.; Burstein, D.; Doukas, J.; Soll, R.; Losordo, D.;
Cheresh, D. J. Clin. Invest. 2004, 113, 885.
Kinase
IC50 lM
Kinase
IC50 lM
Src
Yes
0.006
0.001
0.013
0.021
0.023
1.32
VEGFr2
Raf1-MEK1
Abl
0.555
0.069
0.020
5.99
Lck
Lyn
Fyn
Blk
Abl (T315I)
EphB4
Raf1
0.064
0.068
0.006
0.659
2.71
EGFr
FGFr1
Tie2
0.965
0.96
0.678
PDGFrb
CSK
p70S6K
9. Susva, M.; Missbach, M.; Green, J. Trends Pharmacol.
Sci. 2000, 21, 489.
10. Paul, R.; Zhang, Z. G.; Eliceiri, B. P.; Jiang, Q.; Boccia, A.
D.; Zhang, R. L.; Chopp, M.; Cheresh, D. A. Nat. Med.
2001, 7, 222.
11. Boschelli, D. H.; Wu, B.; Sosa, A. C. B.; Durutlic, H.; Ye,
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2004, 47, 6666.
12. Boschelli, D. H.; Wu, B.; Sosa, A. C. B.; Durutlic, H.;
Chen, J. J.; Wang, Y.; Golas, J. M.; Lucas, J.; Boschelli, F.
J. Med. Chem. 2005, 48, 3891.
13. Boschelli, D. H.; Wu, B.; Sosa, A. C. B.; Chen, J. J.;
Golas, J. M.; Boschelli, F. Bioorg. Med. Chem. Lett. 2005,
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3-aminophenyl ring. Similarly, the 2-(1-pyrrolidinyl)eth-
oxy group at the 3-position (43) and at the 4-position
(42) results in compounds with 60-fold improvement in
potency compared to the corresponding phenyl ana-
logue (15). Conformationally, restricted analogues
(48–51) showed weaker potency over the more flexible
analogues (44, 45, and 54–56). Earlier studies in the pyri-
dopyrimidinone series have shown that the water-solu-
ble group on the core does not play a significant role
in improving the potency.27 However, we have shown
in this benzotriazine series that a water-soluble group
plays a significant role in improving the potency of the
molecules.
The binding of 42 at the ATP pocket of Src kinase and
the key amino acid interactions with 42 are shown in
Figure 1. The 2,6-dimethyl phenyl group is positioned
deep inside the hydrophobic pocket. The ring nitrogen
at the 2-position is involved as a hydrogen bond accep-
tor with the NH of Met-341, while the 3-amino group is
involved as a hydrogen bond donor with the carbonyl of
Met-341 at the hinge region of the ATP binding pocket.
The pyrrolidine nitrogen interacts with Asp-348. We
have examined compound 42 for kinase selectivity
(Table 4). Compound 42 is equipotent against other
Src family members (Yes, Lck, Lyn, Fyn, and Blk),
PDGFrb and EphB4 receptor tyrosine kinases but has
greatly reduced activity against VEGFr2, EGFr, and
FGFr1. This benzotriazine series has significantly differ-
ent selectivity than the structurally similar Src focused
pyridopyrimidinone series,27 which has pronounced
activity against FGFr1 and reduced activity versus
PDGFrb.
15. Carraro, F.; Naldini, A.; Pucci, A.; Locatelli, G. A.;
Maga, G.; Schenone, S.; Bruno, O.; Ranise, A.; Bondav-
alli, F.; Brullo, C.; Fossa, P.; Menozzi, G.; Mosti, L.;
Modugno, M.; Tintori, C.; Manetti, F.; Botta, M. J. Med.
Chem. 2006, 49, 1549.
16. Dalgarno, D.; Stehle, T.; Narula, S.; Schelling, P.; van
Schravendijk, M.; Adams, S.; Andrade, L.; Keats, J.;
Ram, M.; Jin, L.; Grossman, T.; MacNeil, I.; Metcalf, C.;
Shakespeare, W.; Wang, Y.; Keenan, T.; Sundaramoorthi,
R.; Bohacek, R.; Weigele, M.; Sawyer, T. Chem. Biol.
Drug Des. 2006, 67, 46.
17. Wang, Y.; Metcalf, C.; Shakespeare, W.; Sundaramoorthi,
R.; Keenan, T.; Bohacek, R.; Van Schravendijk, M.;
Violette, S.; Narula, S.; Dalgarno, D.; Haraldson, C.;
Keats, J.; Liou, S.; Mani, U.; Pradeepan, S.; Ram, M.;
Adams, S.; Weigele, M.; Sawyer, T. Bioorg. Med. Chem.
Lett. 2003, 13, 3067.
18. The IC50 values for compounds were determined using a
luminescence-based kinase assay with recombinant Src
obtained from Invitrogen. In white, flat-bottomed, 96-well
plates (Nunc) parallel assays were run at room tempera-
ture at a final volume of 50 lL. Each well contained 40 lL
of buffer consisting of 40 mM Tris buffer, pH 7.4,
containing 50 mM MgCl2, 800 lM EGTA, 350 lM Triton
X-100, 2 mM b-mercaptoethanol, 250 lM peptide sub-
strate (PTK2; Promega), and an appropriate amount of
Src (75–25 ng/well) such that the assay was linear over
60 min. The final concentrations of TargeGen compounds
for IC50 value determinations ranged from 1000 to
0.01 lM by adding the appropriate amount of compound
in 2.5 lL DMSO; the DMSO present in each assay was
constant at 5%. The reaction was initiated by the addition
of 10 lL ATP to a final assay concentration of 3 lM.
After the reaction had proceeded for 60 min, 50 lL of
Kinase-Glo reagent (Promega) was added to terminate the
reaction. This solution was then allowed to proceed for an
additional 10 min to maximize the luminescence reaction.
Values were then measured using an Ultra 384 instrument
(Tecan) set for luminosity measurements. Two control
In summary, we have developed a novel benzotriazine
series as potent Src inhibitors. We have identified
the key structural requirements for improving the
activity in this series, whose SAR is distinct from that
of other structurally analogous Src-inhibitors. Future
studies will focus on further lead optimization of
this series, pharmacokinetic properties, and in vivo
pharmacology.
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G. Noronha et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5546–5550
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