Note: Descriptions are shown in the official language in which they were submitted.
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
ORALLY ACTIVE PURINE-BASED INHIBITORS OF HEAT SHOCK PROTEIN 90
FIELD OF THE INVENTION
[0001] The invention relates in general to purine analogs and their use in
inhibiting heat shock protein 90's
(fISP90's) to thereby treat or prevent HSP90-dependent diseases, e.g.,
proliferative disorders such as breast
cancer.
CROSS-REFERENCE
(0002] This application claims the benefit of U.S. Provisional Application No.
60/753,636, filed December 22,
2005, Provisional Application No. 60/753,448, filed December 22, 2005 and
Provisional Application
No. 60/753,69 8, also filed December 22, 2005.
(0003] This application also relates to US Application Serial No. 10/494,4I4,
filed April 30, 2004 which is a US
national phase application of International Application PCTUS02/35069 filed
October 30, 2002, which in
turn claims priority to US provisional application 60/335,391 filed October
30, 2001.
[0004] The contents of all the above applications are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0005] The following description includes information that may be useful in
understanding the present invention.
It is not an admission that any of the information provided herein is prior
art or relevant to the presently
claimed inventions, or that any publication specifically or implicitly
referenced is prior art.
[0006] Heat Shock Protein 90's (Hsp90s) are ubiquitous chaperone proteins that
maintain the proper conformation
of many "client" proteins (see Kanial et. al. Trends Mol. Med. 2004, 10, 283-
290; Dymock et. al. Expert
Opin. Ther. Patents 2004, 14, 837-847; Isaacs et. al. Cancer Cell, 2003, 3,
213; Maloney et. al. Expert
Opin. Biol. Ther. 2002, 2, 3-24 and Richter et. al. J. Cell. Physiol. 2001,
188, 281-290), and are involved
in folding, activation and assembly of a wide range of proteins, including key
proteins involved in signal
transduction, cell cycle control and transcriptional regulation. Researchers
have reported that HSP90
chaperone proteins are associated with important signaling proteins, such as
steroid hormone receptors and
protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and
ErbB-2 (Buchner, TIBS,
1999, 24, 136-141; Stepanova et. al., Genes Dev. 1996, 10, 1491-502; Dai et.
al., J Biol. Chem. 1996, 271,
22030-4). Studies further indicate that certain co-chaperones, e.g., Hsp70,
p60/Hop/Stil, Hip, Bagl,
HSP40/Hdj2/Hsj 1, immunophilins, p23, and p50, may assist HSP90 in its
function (see for example
Caplan, Trends in Cell Biol., 1999, 9, 262-268). Inhibition of Hsp90 causes
these client proteins to adopt
abenrant conformations, and these abnormally folded proteins are rapidly
eliminated by the cell via
ubiquitinylation and proteasome degradation. Interestingly, the list of Hsp90
client proteins includes a
series of notorious oncogenes. Four of them are clinically validated cancer
targets: HER-2/neu (Herceptin
(trastuzumab)), Bcr-Abl (Gleevec (imatinib mesylate)), the estrogen receptor
(tamoxifen), and the
androgen receptor (Casodex (bicalutamide)), while the others play a critical
role in the development of
cancer. Some of the most sensitive Hsp90 clients are involved in growth
signalling (Raf-1, Akt, cdk4, Src,
Bcr-Abl, etc). In contrast, few tumor suppressor genes, if any, seem to be
clients of Hsp90 (for lists of
client proteins see Pratt et. al. Exp. Biol. Med. 2003, 228, 111-133; Workman
et. al. Cancer Lett. 2004,
206, 149-157 and Zhang et. al. J. Mol. Med. 2004, 82, 488-499.), and
consequently, inhibition of Hsp90
1
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
has an overall anti-proliferative effect. In addition, some client proteins
are involved in other fundamental
.processes of tumorigenesis, namely apoptosis evasion (e.g. Apaf-1, RIP, Akt),
imrnortality (e.g. hTert),
angiogenesis (e.g. VEGFR, Flt-3, FAK, HIF-1), and metastasis (c-Met).
[0007] The various client proteins are not equally responsive to Hsp90
irihibitors, and some undergo degradation at
lower concentrations of the inhibitor, or with faster kinetics, depending on
the cell line. The more sensitive
clients are usually those involved in growth signaling, but some mutated
proteins found in tumor cells
(mutant p53, Gleevec-resistant Bcr-Abl, see Gorre et. al. Blood, 2002, 100,
3041-3044) are particularly
dependent on Hsp90 to preserve their conformation and function. This unique
feature sensitizes tumor cells
to Hsp90 inhibitors, and when these factors converge, they confer on Hsp90
inhibitors notable anti-cancer
properties in vitro and in vivo.
(00081 A remarkable advantage of targeting Hsp90 lies in the simultaneous
depletion of multiple oncogenic
proteins, thereby attacking several pathways necessary for cancer development,
and reducing the likelihood
of the tumor acquiring resistance to the Hsp90 inhibitor. Another striking
feature of Hsp90 is that it occurs
in an activated form in cancer cells, and in a latent form in normal cells
(Kamal et. al. Nature, 2003, 425,
407-410 and Workman et. al. Trends Mol. Med. 2004, 10, 47-51.) This provides
an opportunity to
specifically target cancer cells with inhibitors selective for the activated
form What distinguishes the
activated and latent forms of Hsp90 at a molecular level is not well
understood. It is clear, however, that the
activity of Hsp90 is regulated by a highly sophisticated process involving at
a minimum (1) Hsp90
dimerization, (2) formation of multi-protein complexes with numerous co-
chaperones, and (3) ATP/ADP
binding, ATP hydrolysis being essential for the chaperone cycle and function.
[0009] The chaperoning function of Hsp90 can be "switched off ' by inhibiting
its ATP-ase activity. The
nucleotides ADP and ATP can bind to two sites, one located close to the N-
terminal, the other close to the
C-terminal. Geldanamycin, isolated from the microorganism Streptomyces
hygroscopicus, was originally
identified for its antiprotozoal, herbicidal and anti fungal activities.
Ansamycin antibiotics, such as
geldanamycin (GM), herbimycin A (HA), and 17-AAG are thought to exert their
anticancerous effects by
tight binding of the N-terminus pocket of HSP90, (while for example novobiocin
binds to the C-terminal
domain, see Yun et. al. Biochemistry, 2004, 43, 8217-8229), thereby
destabilizing substrates that normally
interact with HSP90 (Stebbins et al. Cell, 1997, 89, 239-250). This pocket is
highly conserved and has
weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al.,
supra; Grenert, J.P. et al.,
1997, J. Biol. Chem., 272:23843-50). Further, ATP and ADP have both been shown
to bind this pocket
with low affinity and to have weak ATPase activity (Proromou, et. al., Cell,
1997, 90, 65-75 and Panaretou,
et. al., EMBC J., 1998, 17, 4829-36). In vitro and in vivo studies have
demonstrated that occupancy of this
N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90
function and inhibits protein
folding. At high concentrations, ansamycins and other HSP90 inhibitors have
been shown to prevent
binding of protein substrates to HSP90 (Scheibel, T., H. et al., 1999, Proc.
Natl. Acad. Sci. U S A 96:1297-
302; Schulte, T. W. et al., 1995, J. Biol. Chem. 270:24585-8; Whitesell, L.,
et al., 1994, Proc. Natl. Acad.
Sci. U S A 91:8324-8328). Ansamycins have also been demonstrated to inhibit
the ATP-dependent release
of chaperone-associated protein substrates (Schneider, C., L. et al., 1996,
Proc. Natl. Acad. Sci. U S A,
93:14536-41; Sepp-Lorenzino et al., 1995, J. Biol. Chem. 270:16580-16587). In
either event, the
substrates are degraded by a ubiquitin-dependent process in the proteasome
(Schneider, C., L., supra; Sepp-
Lorenzino, L., et al., 1995, J. Biol. Chem., 270:16580-16587; Whitesell, L. et
al., 1994, Proc. Natl. Acad.
Sci. USA, 91: 8324-8328).
2
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
100101 HSP90 substrate destabilization occurs in tumor and non-transformed
cells alike and has been shown to be
especially effective on a subset of signaling regulators, e.g., Raf (Schulte,
T. W. et al., 1997, Biochem.
Biophys. Res. Commun. 239:655-9; Schulte, T. W., et al., 1995, J. Biol. Chem.
270:24585-8), nuclear
steroid receptors (Segnitz, B., and U. Gehring. 1997, J. Biol. Chem. 272:18694-
18701; Smith, D. F. et al.,
1995, Mol. Cell. Biol. 15:6804-12 ), v-src (Whitesell, L., et al., 1994, Proc.
Natl. Acad. Sci. U S A
91:8324-8328) and certain transmembrane tyrosine kinases (Sepp-Lorenzino, L.
et al.,. 1995, J. Biol.
Chem. 270:16580-16587) such as EGF receptor (EGFR) and Her2/Neu (Hartmann, F.,
et al., 1997, Int. J.
Cancer 70:221-9; Miller, P. et al., 1994, Cancer Res. 54:2724-2730; Mimnaugh,
E. G., et al., 1996, J. Biol.
Chem. 271:22796-801; Schnur, R. et al., 1995, J. Med. Chem. 38:3806-3812),
CDK4, and mutant p53.
Erlichman et al., Proc. AACR (2001), 42, abstract 4474. The ansamycin-induced
loss of these proteins
leads to the selective disruption of certain regulatory pathways and results
in growth arrest at specific
phases of the cell cycle (Muise-Heinmericks, R. C. et al., 1998, J. Biol.
Chem. 273:29864-72), and
apoptsosis, and/or differentiation of cells so treated (Vasilevskaya, A. et
al., 1999, Cancer Res., 59:3935-
40).
[0011] In addition to anti-cancer and antitumorgenic activity, HSP90
inhibitors have also been implicated in a
wide variety of ofher utilities, including use as anti-inflammation agents,
anti-infectious disease agents,
agents for treating autoimmunity, agents for treating ischemia, and agents
useful in promoting nerve
regeneration (See, e.g., Rosen et al., WO 02/09696; PCT/(JSO1/23640; Degranco
et al., WO 99/51223;
PCT/US99/07242; Gold, U.S. Patent 6,210,974 B1). There are reports in the
literature that fibrogenetic
disorders including but not.limited to scleroderma, polymyositis, systemic
lupus, rheumatoid arthritis, liver
cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis
may be treatable. (Strehlow, WO
02/02123; PCT/US01/20578).
100121 Ansamycins and other HSP90 inhibitors thus hold great proniise for the
treatment and/or prevention of
many types of disorders. However, many of the natural-product derived Hsp90
inhibitors exhibit
pharmaceutical deficiencies; their relative insolubility makes them difficult
to formulate and administer,
and they are not easily synthesized and currently must, at least in part, be
generated through fermentation.
Further, the dose limiting toxicity of ansamyins is hepatic. For example, the
semi-synthetic inhibitor 17-
allylamino, 17-desmethoxy-geldanamycin (17-AAG), currently in phase II
clinical trials, is expensive to
manufacture, difficult to formulate (the NCI clinical protocol consists of
injecting a DMSO solution of 17-
AAG) and at present administered only parenterally. Although the 17-
dimethylaminoethylamino analog
(17-DMAG) is more soluble, it exhibits all of the side effects of 17-AAG as
well as gastrointestinal
hemorrhaging in preclinical toxicity studies (Glaze et. al. Proc. Am. Assoc.
Cancer. Res. 2003, 44, 162-162
and Eiseman et. al. Cancer Chemother. Pharmacol. 2005, 55, 21-32). Radicicol
(RC), another natural
product Hsp90 inhibitor, is poorly water-soluble and is inactive in tumor
xenograft models. Semi-synthetic
oxime derivatives of radicicol provide better solubility and substantially
improved the pharmacological
profile in murine models, but are still limited to intravenous administration
(Ikuina et. al. J. Med. Chem.
2003, 46, 2534-2541. Furthermore, radicicol and its oximes contain an oxirane
ring which has been viewed
as a liability for stability and toxicity, prompting the synthesis of
cycloproparadicicol: Yang et. al. J. Am.
Chen:. Soc. 2004, 126, 7881 and 2003, 125, 9602-9603) Despite the potential of
ansamycins, alternative
HSP90 inhibitors are therefore needed.
[0013] Fully synthetic, orally active inhibitors of Hsp90 have been sought in
order to provide more flexible dosing
schedule options, and to possibly avoid the side-effects of the natural
product inhibitors. Chiosis et al.
3
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
described the design and synthesis of purine analogs that mimic geldanamycin
and other ansamycins in
their ability to bind the ATP binding pocket of, and thus inhibit, HSP90. See
International Patent
Application PCT/USO1/46303 (WO 02/36075; Chemistry & Biology 8:289-299 (2001).
The specific
compounds that Chiosis et al. described included a trimethoxybenzyl entity
substituted at positions 3, 4,
and S. Using gel-binding assays, these were shown to bind HSP90 approximately
20-fold less avidly than
17-AAG. Chiosis et al. did not attempt a quinone mimic for the methoxybenzyl
entitx, speculating that to
do so would lead to hepatoxicity. Id., )g. 290, col. 1, 4. Nor did Chiosis
et al. teach, suggest, or
otherwise report the use of sulfides, sulfoxides, and sulfones as described
herein.
[0014] More recently, other novel non-natural product Hsp90 inhibitors have
been reported (e.g. PU3 and
CCT018159; see Chiosis et. al. Bioorg. Med. Chem. Lett. 2002, 10, 3555-3564;
Vilenchik et. al. Chern.
Bi 1. 2004, 11, 787-797; Chiosis et. al. WO 0236075, 2002; Drysdale et. al. WO
03/055860 Al, 2003;
Wright et. al. Chem. Biol. 2004, 11, 775-785; Dymock et. al. Bioorg. Med.
Chem. Lett. 2004, 14, 325-328;
Dymock et. al. J. Med. Cliem. 2005, 48, 4212-4215. Structure of Hsp90 in
complex with PU3 pdb code
1UY6, and with PU24FCI: pdb code lUYF and Clevenger et. al. Org. Lett. 2004,
6, 4459-4462). The
structures of these inhibitors were designed using the crystal structures of
Hsp90 in complex with ATP,
geldanamycin, or radicicol. The 8-benzyladenines such as PU3 were designed to
adopt the same C-shaped
conformation as geldanamycin (Chiosis et. al. Current Cancer Drug Targets,
2003, 3, 371-376) with the
adenine ring pointing to the adenine-binding site (hinge region), and the
trimethoxybenzene ring emulating
the H-bond accepting nature of the quinone ring of geldanamycin. (The benzene
ring of PU3 was not
designed to have exactly the same orientation as the quinone ring of
geldanamycin. Rather, the
trimethoxybenzene moiety was designed to point in the same general direction
and form a hydrogen bond
with Lys112, an amino acid which forms a hydrogen bond with the quinone ring
of geldanamycin.) The
recently obtained crystal structure of Hsp90 in complex with PU3 confirmed
that the purine ring occupies
the position normally occupied by ADP/ATP, but the benzene ring points in a
direction opposite to the
predicted one, to form a v-stacking interaction with Phe138. Nevertheless, PU3
inhibits Hsp90 (HER-2
degradation assay, HER-2 ICSo = 40 M) and afforded a valuable starting point
for further optimization.
Structure-activity studies based on PU3 led to the more active PU24FCI (HER-2
ICso = 1.7 M) which was
subsequently also co-crystallized with Hsp90. When PU24FCI was formulated in
DMSO/EtOH/phosphate-
buffered saline 1:1:1 and administered intraperitoneally to mice bearing MCF-7
xenogra$ tumors, it
induced at 100-300 mg/kg down-regulation of HER-2 and Raf-1, a pharmacodynamic
response consistent
with Hsp90 inhibition, and at 200 mg/kg it significantly repressed tumor
growth. Very high doses (500-
1000 mglkg) of PU24FCI were required to observe a similar pharmacodynamic
response upon oral
administration, and no 8-benzyladenine has been reported to inhibit tumor
growth by the oral route. In our
hands, PU24FCI proved to be too insoluble to be effectively formulated and
delivered orally. So far,
despite extensive SAR studies to improve potency and pharmaceutics properties,
Hsp90 inhibitors have not
demonstrated activity in animal models of human cancer (xenografts) when
administered orally.
[0015] The discovery of the 8-benzyladenines led to the design of 8-
sulfanyladenines (Kasibhatla et. al. WO
3037860, 2003 and Llauger et. al. J. Med. Chem. 2005, 48, 2892 2905),
exemplified by 8-(2-iodo-5-
methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine, which exhibited
excellent potency in several
cell-based assays, but was poorly soluble in water and did not have sufficient
oral bioavailability in
clinically acceptable formulations.
4
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
100161 The present invention provides water-soluble, orally bioavailable
purine analogs, and their use in inhibiting
heat shock protein 90's to thereby treat or prevent Hsp90-dependent diseases
as demonstrated by their oral
efficacy in tumor xenograft models.
0 H 0 Me2N H 0
Meol I /NI 1 N
I oHO
H ~ N N ..
I O
\~~.. O I I, O H I F{
~~~OH O ~~OH O \O
CI O
Me0 Me0 Me0 .~~OH O I HO(
~~~~ / OCONHZ OCONH2 OCONHZ
Getdanamycin (GM) 17AAG 17DMAG Radicicol (RC)
HO O MeO OMe MeO OMe
~ NHZ ~ ~ OMe
_ O NHa OMe NH2 CI ~~ OMe N N
HO Ni N Ni N' - j S
N, \ N N N N F N
H
CCT018159 PU3 PU24FCI 8-(2-iodo-5-methoxy-phenyisulfanyl)
-8-pent-4-ynyl-9H-purin-6-yiamine
SUMMARY OF THE INVENTION
In one embodiment, the invention provides a compound of Formula I:
NH2
N~ N
I ~>--S Ra
RsN N ~ ~ b
Rx R
~
Ry
~ Rd Rc
Formula I
or tautomer or pharmaceutically acceptable salt thereof, wherein
Rs is independently selected from H and F;
each R. Rb, R', and Rd is independently selected from H, halo, lower alkyl,
OR3, SR3, C(O)N(R4)2i NRaRa,
C(O)Rz, and -C(O)OR4;
R" is independently selected from optionally substituted CI-C6 alkyl,
optionally substituted C2-C6 alkenyl
and optionally substituted C2-C6 alkynyl;
R'' is independently selected from 0, NR' and a bond;
RZ is independently selected from H, Cj-Cg alkyl, C2-C6 alkenyl, C2-C6
alkynyl, -P(O)(OR4)Z and C(O)RZ;
R' is independently selected from H, optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally substituted
heteroalkyl, optionally substituted aryl,
optionally substituted heterocyclyl, C(O)RZ, -C(O)OR2, C(O)NR42i C(S)OR2,
C(S)NR 2, P(0)(OR )Z, and SOZRa;
5
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
RZ is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR4Z,
C(O)RZ, and -C(O)ORa; and
R4 is independently selected from H, optionally substituted allcyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, and
optionally substituted heterocyclyl. The invention
also provides the following embodiments:
-compounds of Formula I wherein R , R6, R , and Ra are independently selected
from halo and OR3;
-compounds of Formula I wherein at least two of R, Rb, R , and Ra are
independently selected from halo
and methoxy;
-compounds of Formula I wherein at least three of Ra, Rb, R , and Rd are
independently selected from halo
and OR3;
-compounds of Formula I wherein at least three of Ra, Rb, R , and Ra are
independently selected from halo
and methoxy;
-compounds of Formula I wherein Ra is halo, and Rd is OW;
-compounds of Formula I wherein R" is optionally substituted C2-C3 alkyl,
optionally substituted C2-C3
alkenyl or optionally substituted C2-C3 alkynyl, R}' is NR1; and RZ is C1-C6
alkyl;
-compounds of Formula I wherein R" is optionally substituted C2-C3 allcyl,
optionally substituted C2-C3
alkenyl or optionally substituted C2-C3 alkynyl; RI is a bond; and Rz is H;
-compounds of Formula I wherein R" is optionally substituted C2-C3 alkyl,
optionally substituted C2-C3
alkenyl or optionally substituted C2-C3 alkynyl; R'' is NR1; and W is C(O)R2.
-compounds of Formula I wherein R" is optionally substituted C2-C3 alkyl,
optionally substituted C2-C3
alkenyl or optionally substituted C2-C3 alkynyl; Rs' is NH; and RZ is H.
-compounds of Formula I wherein R" is optionally substituted C2-C3 alkyl,
optionally substituted C2-C3
alkenyl or optionally substituted C2-C3 alkynyl; Ry is NH; and RZ is Cl -C6
alkyl; and
-compounds of Formula I wherein R' is optionally substituted C2-C3 alkyl; RY
is NH; and RZ is CI-C6 alkyl.
In a finther embodiment, the invention provides a compound of formula 11:
ANHa
~ / NN~_S
Rs N N N
~x S / Ra
Ry I
Rz Rd Rb
Rc
Formula II
or tautomer or pharmaceutically acceptable salt thereof, wherein
RS is independently selected from H and F;
each Ra, Rb, R', and Ra is independently selected from H, halo, lower alkyl,
OR3, SR3, C(O)N(R )2a NR R ,
C(O)R2, and -C(O)OR4;
6
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
R" is independently selected from optionally substituted C2-C6 alkyl,
optionally substituted C2-C6 allkenyl
and optionally substituted C2-C6 alkynyl;
Ry is independently selected from 0, NR' or a bond;
RZ is independently selected from H, Q-C6 alkyl, C2-C6 alkenyl, CZ-Cr6
alkynyl, -P(O)(ORd)Z and C(O)R2;
R' is independently selected from H, optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally substituted
heteroalkyl, optionally substituted aryl,
optionally substituted heterocyclyl, C(O)Ra, -C(O)ORa, C(O)NR"2a C(S)ORZ,
C(S)NRaa, P(O)(OR4)2, and SO2RZ;
Ra is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR42,
C(O)Rz, and -C(O)ORZ; and
R4 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, and
optionally substituted heterocyclyl.
The invention also provides the following embodiments:
-conipounds of Formula II wherein at least one of Ra, Rb, R', and Rd is halo;
R' is optionally substituted C2-
C3 alkyl; Ry is a bond; and RZ is H;
-compounds of Formula II wherein at least one of Ra, Rb, R', and Rd is halo;
R" is optionally substituted C2-
C3 alkyl; Ry is NR1; and RZ is H;
-compounds of Formula II wherein at least one of R8, Rb, r, and Rd is halo; R'
is optionally substituted C2-
C3 alkyl; Ry is NR1; and RZ is CX6 alkyl;
-compounds of Formula II wherein at least one of R, Rb, R', and Ra is halo; R"
is optionally substituted C2-
C3 alkyl; Ry is a bond; and V is -P(O)(OR4)Z; and
-compounds of Formula II wherein at least one of Ra, Rb, R', and Rd is
methoxy; R" is optionally
substituted C2-C3 alkyl; R'' is a bond; and RZ is H.
In yet another embodiment, the invention provides a compound of formula III:
NH2
~ N
Rs N N
' iM S / Ra
T I
Rz Rd ~ N
Rc
Formula III
or tautomer or phannaceutically acceptable salt thereof, wherein
Rs is independently selected from H and F;
each Ra, R' and Ra is independently selected from H, halo, lower alkyl, OR3,
SR3, C(O)N(R)2, NR R4,
C(O)R2, and -C(O)OR ;
R" is independently selected from optionally substituted C2-C4 alkyl,
optionally substituted CZ-C4 alkenyl
and optionally substituted C2-C4 alkynyl;
7
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
R'' is independently selected from 0, NR' and a bond; and
RZ is independently selected from H, CI-C6 alkyl, C2-C6 alkenyl, CZ-C6
alkynyl, -P(O)(OR4)a and C(O)Rz;
R' is independently selected from H, optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally substituted
heteroalkyl, optionally substituted aryl,
optionally substituted heterocyclyl, C(O)RZ, -C(O)ORz, C(O)NR4Z, C(S)OR2,
C(S)NR4Z, P(O)(OR")a, and SOZRz;
R2 is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR42,
C(O)RZ, and -C(O)ORZ; and
R4 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, and
optionally substituted heterocyclyl.
The invention also provides the following embodiments:
-compounds of Formula III wherein at least one of Ra, R , and Rd is halo; R"
is optionally substituted CZ-C3
alkyl; R'' is a bond; and RZ is H;
-compounds of Formula III wherein at least one of Ra, R , and Rd is halo; R'
is optionally substituted C2-C3
alkyl; Ry is NR'; and RZ is H;
-compounds of Formula III wherein at least one of Ra, R', and Ra is halo; R"
is optionally substituted C2-C3
alkyl; R'' is a bond; and Rz is CI-C6 alkyl; and
-compounds of Formula III wherein at least one of Ra, R , and Ra is halo;
R" is optionally substituted C2-C3 alkyl; R'' is a bond; and Rz is -
P(O)(OR4)Z.
In yet a further embodiment, the invention provides a conlpound of formula IV:
NH2
I N
~>---S
Y
Z~=N N X
Formula IV
or tautomer or pharmaceutically acceptable salt thereof, wherein
X is independently selected from H, halo, CN, N3, N(R')a, NR'S(O)ZR2, OR3, SW,
lower alkyl,
C(O)N(R4)2, perhaloalkyl, C(O)R2, and -C(O)OR4;
Y is independently selected from optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally substituted
alicyclic, optionally substituted araalkyl,
optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl,
optionally substituted heterocyclyl,
optionally substituted alkylaminoalkyl (-(CHZ)n NHRZ), optionally substituted
alkylaminodialkyl (-(CH2),j-NRzR),
optionally substituted alkylcazbonylaminoalkyl, (-(CH2).-C(O)-NR R4),
optionally substituted
alkylcarbonyloxylalkyl (-(CHZ)o C(O)-O-R4), hydroxyalkyl (-(CHa)õOH),
haloalkyl (-(CHz)õhalo), perhaloalkyl,
aminoalkyl (-(CH2).-NH2), C(O)R2, S(O)ZRZ, C(O)NR42, and C(O)OR2;
Z is independently selected from H and halogen;
8
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
R' is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)Rz, -
C(O)OR2, C(O)NR4Z, C(S)ORZ, C(S)NWZ, P(O)(OR4)2i and S02R2;
R2 is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
beterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR42,
C(O)R2, and -C(O)ORa;
R4 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally'substituted aryl, and
optionally substituted heterocyclyl; and
nisfrom1to3.
In still a further embodiment, the invention provides a compound of formula V:
NH2
N
~' ~ ~-S
Z N N }=N
Y S
X
Formula V
or tautomer or pharmaceutically acceptable salt thereof, wherein
X is independently selected from H, halo, CN, N3, N(R')2, NR'S(O)aRz, OR3,
SR3, lower alkyl,
C(O)N(R4)2, perhaloallcyl, C(O)R2, and -C(O)OR4;
Y is independently selected from optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally substituted
alicyclic, optionally substituted araalkyl,
optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl,
optionally substituted heterocyclyl,
optionally substituted al.kylaminoalkyl (-(CHa)o-NHRZ), optionally substituted
alkylaminodialkyl (-(CH2)n NRaR),
optionally substituted alkylcarbonylaminoalkyl, (-(CHz)a C(O)-NR4R4),
optionally substituted
alkylcarbonyloxylalkyl (-(CHa)o C(O)-O R4), hydroxyalkyl (-(CHZ)n OH),
haloalkyl (-(CHZ),,-halo), perhaloalkyl,
aminoalkyl (-(CH2
.)n NHa), C(O)Ra, S(O)zRz, C(O)NR42, and C(O)ORa;
Z is independently selected from H and halogen;
RI is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, = optionally
substituted heterocyclyl, C(O)R2, -
C(O)ORa, C(O)NR 2a C(S)ORz, C(S)NR~z, P(O)(OR4)2, and SOZR2;
R2 is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR4a,
C(O)R2, and -C(O)ORa;
9
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
R4 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, and
optionally substituted heterocyclyl; and
n is from l to 3.
In a further embodiment, the invention provides a compound of formula VI:
NH2
N-S~
N
Z N N
Y S
X
N
Formula VI
or tautomer or pharmaceutically acceptable salt thereof, wherein
X is independently selected from H, halo, CN, N3, N(R')2, NR'S(O)ZRa, OR3,
SR3, lower alkyl,
C(O)N(R4)2, perhaloalkyl, C(O)Ra, and -C(O)OR4;
Y is independently selected from optionally substituted alkyl, optionally
substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally substituted
alicyclic, optionally substituted araalkyl,
optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl,
optionally substituted heterocyclyl,
optionally substituted alkylaminoalkyl (-(CHZ)õ-NHRz), optionally substituted
alkylanrinodialkyl (-(CHa)o NR.ZRZ),
optionally substituted allcylcarbonylaminoaIlcyl, (-(CH2)o C(O) NR4R4),
optionally substituted
alkylcarbonyloxylalkyl (-{CH2)n-C(O)-O-R4), hydroxyalkyl (-(CHZ)n OH),
haloalkyl (-(CH2),,-halo), perhaloalkyl,
aminoalkyl (-(CH2)a NH2), C(O)Ra, S(O)ZR2, C(O)NR Z, and C(O)OR2;
Z is independently selected from H and halogen;
R' is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)R2, -
C(O)OR2, C(O)NR42, C(S)OR2, C(S)NR'2, P(O)(OR)2i and S02Ra;
R2 is independently selected from optionally substituted alkyl, optionally
substituted cycloalkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heterocyclyl and optionally substituted
heteroaryl;
R3 is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heterocyclyl, C(O)NR42,
C(O)R2, and -C(O)ORx;
R" is independently selected from H, optionally substituted alkyl, optionally
substituted cycloalkyl,
optionally substituted heteroalkyl, optionally substituted aryl, and
optionally substituted heterocyclyl; and
n is from 1 to 3.
In yet another embodiment, the invention provides a compound selected from the
group consisting of:
9-(tert-Butyl-dimethyl-silanyloxymethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine; 9=(2-
Chloro-ethyl)-8-(2-iodo-5-methoxy-phenytsulfanyl)-9H-purin-6-ylamine; 9-(3-
chloro-propyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H purin-6-ylamine; 9-(4-Chloro-butyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine;
8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-[3-(4-methyl-piperazin-1-yl)-propyl]-9H-
purin-6-ylarnine; 9-(3-
Dimethylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine;
8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-(3-piperidin-l-yl-propyl)-9H-purin-6-ylamine; 9-(3-
Cyclopropylamino-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-ylamine; 8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-(3-morpholin-4-yl-propyl)-
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
9H-purin-6-ylamine; 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-methylamino-
propyl)-9H-purin-6-ylamine; 9-(3-
Ethylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylaznine; 8-
(2-Iodo-5-methoxy-
phenylsulfanyl)-9-[2-(4-methyl piperazin-1-yl)-ethyl]-9H-purin-6-ylamine; 8-(2-
Iodo-5-methoxy-phenylsulfanyl)-9-
(2-piperidin-1-yl-ethyl)-9H-purin-6-ylamine; 8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-(2-propylamino-ethyl)-9H-
purin-6-ylamine; 8-(2,5-Dimethoxy-phenylsulfanyl)-9-(3-dimethylamino-propyl)-
9H-purin-6-ylamine; 8-(2-Iodo-5-
methoxy-phenylsulfanyl)-9-(2-isopropylamino-ethyl)-9H-purin-6-ylamine; 9-(2-
Butylamino-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-ylamine; 9-(2-sec-Butylamino-ethyl)-8-(2-
iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine; 9-[2-(1-Ethyl-propylarnino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine;
9-(2-Cyclopropylami.no-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine; 8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-[2-(3-methyl-butylamino)-ethyl]-9H-purin-6-ylamine; 9-[2-
(3,3-Dimethyl-butylamino)-ethyl]-8-
(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; {2-[6-Amino-8-(2-iodo-5-
methoxy-phenylsulfanyl)-purin-
9-yl]-ethylamino}-acetonitrile; 2-{2-[6-Amino-8-(2-iodo-5-methoxy-
phenylsulfanyl)-purin-9-yl]-ethylamino}-
ethanol; 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-[2-(2-methoxy-ethylamino)-
ethyl]-9H-purin-6-ylamine; 9-(2-
Cyclopentylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine; 9-(2-Cyclohexylamino-ethyl)-
8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; 9-(2-Cycloheptylamino-
ethyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H purin-6-ylamine; 9-(2-Cyclooctylamino-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-
6-ylamine; 9-[2-(Cyclopropylmethyl-anuno)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine; 8-
(2-Iodo-5-methoxy-phenylsulfanyl)-9-[2-(2-rnethyl-allylamino)-ethyl]-9H-purin-
6-ylamine; 9-(2-tert-Butylamino-
ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; 9-(3-Amino-
propyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine; 9-(2-Cyclopropylamino-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-
purin-6-ylamine; 9-(2-Allylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine; 8-(2-Iodo-5-
methoxy-phenylsulfanyl)-9-(2-morpholin-4-yl-ethyl)-9H-purin-6-ylamine; 8-(2-
Iodo-5-methoxy-phenylsulfanyl)-9-
(3-propylamino-propyl)-9H-purin-6-ylamine; 9-(3-Heptylamino-propyl)-8-(2-iodo-
5-methoxy-phenylsulfanyl)-9H-
puri.n-6-ylamine; 9-(3-Cyclopentylamino-propyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-puri.n-6-ylamine; 9-(3-
Cyclooctylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine; 8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-(3-isobutylamino-propyl)-9H-purin-6-ylamine; 8-(2-lodo-5-
methoxy-phenylsulfanyl)-9-[3-(1,2,2-
trimethyl-propylamino)-propyl]-9H-purin-6-ylamine; 4-{3-[6-Amino-8-(2-iodo-5-
methoxy-phenylsulfanyl)-purin-9-
yl]-propylamino}-piperidine-1-carboxylic acid tert-butyl ester; 9-(2-
Benzylamino-ethyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine; 9-[3-(1,1-Dimethyl-propylamino)-propyl]-8-
(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine; 9-(3-Cyclobutylarnino-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-
purin-6-ylamine; 9-(3-Amino-propyl)-S-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine; {2-[6-Amino-8-
(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl}-carbamic acid tert-butyl
ester; 9-(2-Anuno-ethyl)-8-(2-iodo-
5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine; 2-[6-Amino-8-(2-iodo-5-methoxy-
phenylsulfanyl)-purin-9-yl]-
acetamide; 1-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl] propan-2-
one; N-{2-[6-Amino-8-(2-iodo-
5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl}-acetamide; N-{2-[6-Amino-8-(2-
iodo-5-methoxy-phenyIsulfanyl)-
purin-9-yl]-ethyl}-methanesulfonamide; N-{2-[6-Amino-8-(2-iodo-5-methoxy-
phenylsulfanyl)-purin-9-yl]-ethyl}-
N-isobutyl-acetamide; N-{2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-
9-yl]-ethyl}-N-isobutyl-
methanesulfonamide; 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9-(4-methyl-pent-
3-enyl)-9H-purin-6-ylaznine; 8-
(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; 8-
(2,5-Dimethoxy-biphenyl-3-
ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; 9-(4-Methyl-pent-3-enyl)-8-
(thiazol-2-ylsulfanyl)-9H-purin-6-
ylamine; 8-(Benzothiazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-
ylamine; 8-(1H-Benzoiniidazol-2-
ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; Acetic acid 2-[6-
amino-8-(naphthalen-2-ylsulfanyl)-
11
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
purin-9-yl]-ethyl ester; Acetic acid 2-[6-anzino-8-(naphthalen-l-ylsulfanyl)-
purin-9-yl]-ethyl ester; Acetic acid 2-[6-
amino-8-(quinolin-8-ylsulfanyl)-purin-9-yl]-ethyl ester; Acetic acid 2-[6-
amino-8-(IH-indol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester; Acetic acid 2-[6-amino-8-(2,5-dimethoxy-phenylsulfanyl)-purin-
9-y1]-ethyl ester; Acetic acid 2-[6-
amino-8-(benzo[b]thiophen-2-ylsulfanyl)-purin-9-yl]-ethyl ester; 8-
(Benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-
5' purin-6-ylamine; 9-Pent-4-ynyl-8-(quinolin-2-ylsulfanyl)-9H-purin-6-
ylamine; 8-(1-Allyl-IH-benzoimidazol-2-
ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine; 8-(1-Methyl-lH-
benzoimitdazol-2-ylsulfanyl)-9-(4-
methyl-pent-3-enyl)-9H-purin-6-ylamine ; 2-[6-Amino-8-(naphthalen-2-
ylsulfanyl)-purin-9-yl]-ethanol; 2-[6-
Amino-8-(naphthalen-1-ylsulfanyl)-purin-9-yl]-ethanol; 2-[6-Amino-8-(quinolin-
8-ylsulfanyl)-purin-9-yl]-ethanol;
Acetic acid 2-[6-amino-8-(3-chloro-lH-indol-2-ylsulfanyl)-purin-9-yl]-ethyl
ester; Acetic acid 2-[6-amino-8-(3-
brorno-lH-indol-2-ylsulfany])-purin-9-yl]-ethyl ester; Acetic acid 2-[6-amino-
8-(3-iodo-lH-indol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester ; Acetic acid 2-[6-amino-8-(1-propyl-lH-indol-2-
ylsulfanyl)-purin-9-yl]-ethyl ester; Acetic
acid 2-[6-arnino-8-(3-iodo-l-propyl-lH-indol-2-ylsulfanyl)-purin-9-yl]-ethyl
ester; Acetic acid 2-[6-amino-8-(1,4-
dimethoxy-naphthalen-2-ylsulfanyl)-purin-9-yl]-ethyl ester; 3-[6-Amino-8-
(benzo[1,3]dioxol-5-ylsulfanyl)-purin-9-
yl]-propan-l-ol; 3-[6-Amino-8-(2,3-dihydro-benzo[1,4]dioxin-6-ylsulfanyl)-
purin-9-yl]-propan-l-ol; 9-Butyl-B-(7-
chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 9-ethyl-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-9H-purine-
6-ylamine; 9-Propyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylanune; 9-Pentyl-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 8-(7-Bromo-benzothiazol-2-
ylsulfanyl)-9-butyl-9H-purine-6-
ylamine; 9-Butyl-8-(7-methyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 9-
Butyl-8-(7-methoxy-
benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 9-Butyl-B-(7-ethoxy-
benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine; 9-Butyl-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylanvne; 9-
Butyl-B-(7-trifluoromethyl-
benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 8-(Benzothiazol-2-ylsulfanyl)-
9-butyl-9H-purine-6-ylamine; 9-
Butyl-8-(6-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 9-Butyl-8-(5-
chloro-benzothiazol-2-ylsulfanyl)-
9H-purine-6-ylamine; 9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-
6-ylam.ine; 9-Butyl-8-(4-chloro-
benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methoxy-ethyl)-9H-purin-6-
ylamine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-(2-vinyloxy-ethyl)-9H purin-6-ylamine; 9-Butyl-8-
(thiazolo[5,4-b]pyridin-2-
ylsulfanyl)-9H-purine-6-ylamine; Acetic acid 4-[6-amino-8-(7-fluoro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-butyl
ester; 8-(4-Bromo-6,7-difluoro benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-
ylamine; 9-Butyl-8-(6,7-dichloro-
benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine; 9-Butyl-8-(6,7-difluoro-
benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine; 8-(6,7-Dichloro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine; Acetic acid 3-[6-amino-8-
(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester; 9-But-3-
enyl-8-(7-chloro-benzothoazol-2-
ylsulfanyl)-9H-purine-6-ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-pent-
4-ynyl-9H-purin-6-ylamine; 8-(7-
Methoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; 8-(7-
Methyl-benzothiazol-2-ylsulfanyl)-9-
pent-4-ynyl-9H-purin-6-ylarnine; 9-Butyl-8-(7-methoxymethoxymethyl-
benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine; Acetic acid 3-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-
9-yl]-propyl ester; Acetic acid 3-
[6-amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester; 8-(4-
Amino-7-fluorol-benzothiazol-2-
ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; 8-(7-Ethoxy-benzothiazol-2-
ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine; Acetic acid 2-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-
9-yl]-ethyl ester; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-ethyl-9H-purine-6-ylamine; 2-Chloro-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-9-
methyl-9H-purine-6-ylamine; 8-(7-Bromo-thiazolo[5,4-b]pyridin-2-y1sulfanyl)-9-
butyl-9H-purine-6-ylamine; 8-(7-
Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-2-chloro-9-methyl-9H-purin-6-
ylamine; Acetic acid 2-[6-amino-8-(7-
bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-ethyl ester; 8-(7-Bromo-
thiazolo[5,4-b]pyridin-2-ylsulfanyl)-
12
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
9-butyl-9H-purine-6-ylamine; Acetic acid 3-[6-amino-8-(7-bromo-thiazoie[4,5-
c]pyridin-2-ylsulfanyl)-purin-9-yl]-
propyl ester; 8-(7-Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-9-(4-methyl-pent-
3-enyl)-9H-purin-6-ylamine; Acetic
acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-
ethyl ester; 8-(7-Bromo-thiazolo[5,4-
b]pyridin-2-y1sulfanyl)-2-chloro-9-methyl-9H-purine-6-ylamine; Acetic acid 3-
[6-amino-8-(7-chloro-thiazolo[4,5-
c]pyridin-2-ylsulfanyl)-purin-9-yl]-propyl ester; 9-Butyl-8-(7-chloro-
benzooxazol-2-ylsulfanyl)-9H-purine-6-
ylamine; Acetic acid 2-[6-amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester; Acetic acid 3-[6-
amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-9-y1]-propyl ester; 9-Butyl-
8-(7-fluoro-benzooxazol-2-
ylsulfanyl)-9H-purine-6-ylamine ; Acetic acid 2-[6-amino-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethyl
ester; Acetic acid 2-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester; Acetic acid 4-[6-amino-
8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butyl ester; Acetic acid 3-
[6-amino-8-(7-fluoro-benzothiazol-2-
ylsulfanyl)-purin-9-yl]-propyl ester; Acetic acid 3-[6-amino-8-(7-bromo-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propyl ester; 2-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-
ethanol; 2-[6-Amino-8-(7-fuloro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethanol; 2-[6-Amino-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-l-ol; 4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
butan-l-ol; 4-[6-amino-8-(7-fluoro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-butan-l-ol; 3-[6-amino-8-(7-fluoro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-ol; 3-[6-Amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-l-ol; 3-[6-Amino-8- (7-
bromo-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-ol; 3-[6-Amino-8- (7-
methoxy-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-propan-ol; 2-[6-Amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethanol; 3-[6-Amino-8-(7-
methyl-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-ol; 2-[6-amino-8-(7-bromo-
thiazolo[4,5-c]pyridin-2-
ylsulfanyl) purin-9-yl]-ethanol; 2-[6-Amino-8-(7-cliloro-thiazolo[5,4-
b]pyridin-2-ylsulfanyl)-purin-9-yl]-ethanol; 8-
(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(1-ethyl-propylamino)-propyl]-9H-
purin-6-yl amine; 9-(3-tert-
Butylamino-propyl)-8-(7-chloro benzothiazol-2-ylsulfanyl)- 9H- purin-6-yl
amine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-(3-isobutylamino-propyl)- 9H- purin-6-yl amine; 9-(3-sec-
Butylamino-propyl)-8-(7-Chloro-
benzothiazol-2-ylsulfanyl)- 9H- purin-6-yl amine; 9-[2-(2,2-Dimethyl-
propylamino)-ethyl]-8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9H- purin-6-yl amine; 9-[2-Isopropylamino-ethyl]-8-
(7-methoxy-benzothiazol-2-
ylsulfanyl)-9H-purin-6-yl amine ; 9-[2-tert-Butylamino-ethyl]-8-(7-methoxy-
benzothiazol-2-ylsulfanyl)-9H-purin-6-
yl amine; 9-(2-Isobutylamino-ethyl)-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-
purin-6-yl amine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-[3-(2,2-dimethyl-propylaniino)-propyl]-9H- purin-
6-yl amine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-(2-prop-2-ynylanuno-ethyl)-9H-purin-6-yl amine; 8-
(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-(2-cyclopentylamino-ethyl)-9H-purin-6-yl amine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-[2-(3-
methyl-butylamino)-ethyl]-9H-purin-6-yl amine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-[2-(1,1-dimethyl-
propylamino)-ethyl]-9H-purin-6-yl amine; 9-(2-A1lylamino-ethyl)-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-9H-purin-
6-ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-isopropylamino-propyl)
9H- purin-6-yl amine; 8-(7-
Chlorol-benzothiazol-2-ylsulfanyl)-9-(3-pyrrol-1-yl-propyl.)-9H-purine-6-
ylamine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-[2-(3,3-dimethyl-butylamino)-ethyl]-9H- purin-6-yl amine; 8-(7-
Chloro-benzothiazol-2-ylsulfanyl)-9-
(3-morpholin-4-yl-propyl)-9H-purin-6-ylamine; 8-(7-Chloro-benzothiazoI-2-
ylsulfanyl)-9-(2-morpholin-4-yl-ethyl)-
9H-purin-6-ylanzine; 9-(2-Bromo-ethyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
9H-purine-6-ylanune; 8-(7-Fluoro-
benzothiazol-2-ylsulfanyl)-9-(2-vinyloxy-ethyl)-9H-purin-6-ylamine; 8-(7-
Fluoro-benzothiazol-2-ylsulfanyl)-9-
pent-4-ynyl-9H-purin-6-ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-
chloro-ethyl)-9H-purine-6-ylamine;
9-(3-Bromo-propyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)- 9H-purine-6-
ylamine; 8-(7-Chloro-benzothoazol-2-
ylsulfanyl)-9-pent-4-enyl-9H-purine-6-ylamine; 8-(7-Chloro-benzothoazol-2-
ylsulfanyl)-9-hex-5-enyl-9H-purine-6-
ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2,(2,5-dimethoxy-phenyl)-
ethyl]- 9H-purine-6-ylamine; 9-But-
13
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
2-ynyl-8-(7-chloro-benzothiazol-2-y1sulfanyl)-913-purine-6-ylamine; 8-(7-
Chloro-benzothiazol-2-ylsulfanyl)-9-
(3,4,4-trifluoro-but-3-enyl)-9H-purin-6-ylamine; 6-[6-Amino-8-(7-
chloro=benzothiazol-2-ylsulfanyl)-purin-9-yl]-
hexanenitrile; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-methyl-but-3-enyl)-
9H-purin-6-ylamine; 4-[6-Amino-8-
(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butyronitrile; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-hex-5-
ynyl-9H-purin-6-ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-
(tetrahydro-furan-2-yl)-propyl]-9H-purin-6-
ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(tetrahydro-furan-2-
ylmethyl)-9H-purin-6-ylamine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-[2-(2-ethoxy-ethoxy)-ethyl]-9H-purin-6-ylamine; 5-
[6-Amino-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-pentanenitrile; 8-(7-Chlorol-
benzothiazol-2-ylsulfanyl)-9-(4-methoxy-3,5-
dimethyl-pyridin-2-ylmethyl)-9H-purine-6-ylamine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-prop-2-ynyl-9H-
purine-6-ylamine; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-piperidin-1-yl-
ethyl]-9H- purin-6-yl amine; 8-(7-
Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methylsulfanyl-ethyl)-9H-purin-6-
ylamine; 8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9-(2-ethylsulfanyl-ethyl)-9H-purin-6-ylamine; Phosphoric acid 3-[6-
amino-8-(7-chloro-benzothiazol-2-
ylsulfanyl)-9-yl]-propyl ester diethyl ester; Phosphoric acid 2-[6-amino-8-(7-
chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl bis-(2-chloro-ethyl) ester; {3-[6-Amino-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-purin-9-y1]-
propenyl}-phosphonic acid diethyl ester; Phosphoric acid 2-[6-amino-8-(7-
chloro-benzothiazol-2-ylsulfanyl)-9-yl]-
ethyl ester diethyl ester; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-methyl-9H-
purine-6-ylamine; 4-[6-Amino-8-(7-
chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butan-2-one; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-(2-
ethylsulfinyl-ethyl)-9H-purin-6-ylaniine; 4-[6-Amino-8-(7-chloro-benzothiazol-
2-ylsulfanyl)-purin-9-yl]-butan-2-
thione; 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethanesulfonyl-ethyl)-9H-
purin-6-ylamine; 8-(7-Chloro-
benzothiazol-2-ylsulfanyl)-9-(2-methanesulfonyl-ethyl)-9H-purin-6-ylamine; (6-
Amino-9-butyl-9H-purin-8-
ylsulfanyl)-benzothiazol-7-yl]-methanol; 9-(2-Dimethylamino-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-
purin-6-ylamine; 9-(2-Diethylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine; 8-(2-Iodo-5-
methoxy-phenylsulfanyl)-9-(2-pyrrolidin-1-yl-ethyi)-9H-purin-6-ylamine; 8-(2-
Iodo-5-methoxy-phenyisulfanyl)-9-
(2-vinyloxy-ethyl)-9H-purin-6-ylamine; 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-
(2-isopropoxy-ethyl)-9H-purin-6-
ylamine; {3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propy1}-
methyl-carbamic acid tert-butyl
ester; 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-pyrrol-l-yl-propyl)-9H-purin-6-
ylamine; (2,4-Diiodo-5-methoxy-
phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine; {3-[6-Amino-8-(2-iodo-5-
methoxy-phenylsulfanyl)-purin-9-yt]-
propyl}-carbamic acid tert-butyl ester; 8-(2-Iodo-5-trifluoromethoxy-
phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine and 8-(2-Iodo-5-trifluoromethyl-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-
6-ylamine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017) The novel features of the invention are set forth with particularity in
the appended claims. A better
understanding of the features and advantages of the present invention will be
obtained by reference to the
following detailed description that sets forth illustrative embodiments, in
which the principles of the
invention are utilized, and the accompanying drawings of which:
[0018) Fimre 1(a) represents levels of Hsp90 clients, Hsp70, and PI-3K p85 in
murine A549 tumor xenografts
following a single oral administration of 89=H3P04 at 200 mg/kg, and (b)
Levels of Hsp90 clients and PI-
3K in murine N87 tumor xenografts 24 h after a three-day course of 17-AAG
(intraperitoneally, 1 x 90
mg/kg/day) or 126-H3PO4 (orally, 2 x 200 or 2 x 100 mg/kg/day).
100191 Fi ure 2 represents tumor growth inhibition in murine N87 xenografts
models induced by (a) inhibitors
109-H3P04 and 126-H3P04 delivered orally (1 x 200 mg/kg/day, 5 days/week) or
(b) inhibitor 132-H3P04
delivered orally (2 x 100 mg/kg/day, 5 days/week). Error bars = SEM
14
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0020] Fig,ure 3 represents a pharmacokinetic study of 264 delivered at 100
mg/kg via oral gavage
[00211 Figure 4 represents a tumor growth inhibition study of 264 in the N87
xenograft model
DETAILED DESCRIPTION OF THE INVENTION
[0022] Whilc preferred exinbodiments of the present invention have been shown
and described herein, it will be
obvious to those skilled in the art that such embodiments are provided by way
of exaniple only. Numerous
variations, changes, and substitutions will now occur to those skilled in the
art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described
herein may be employed in practicing the invention. It is intended that the
following claims define the
scope of the invention and that methods and structures within the scope of
these claims and their
equivalents be covered thereby.
Definitions'
[00231 A "pharmaceutically acceptable salt" may be prepared for any compound
of the invention having a
functionality capable of forming a salt, for example an acid or base
functionality. Pharmaceutically
acceptable salts may be, derive$ from organic or inorganic acids and bases.
[00241 Compounds of the invention that contain one or more basic functional
groups, e.g., amino or alkylamino,
are capable of forming pharmaceutically acceptable salts with pharmaceutically
acceptable organic and
inorganic acids. These salts can be prepared in situ during the final
isolation and purification of the
compounds of the invention, or by separately reacting a purified compound of
the invention in its free base
form with a suitable organic or inorganic acid, and isolating the salt thus
formed. Examples of suitable
acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric,
fumaric, maleic, phosphoric, glycolic,
gluconic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic,
citric, methanesulfonic, formic,
benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, 1,2 ethanesulfonic
acid (edisylate), galactosyl-
d-gluconic acid, and the like. Other acids, such as oxalic acid, while not
themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds
of this invention and their pharmaceutically acceptable acid addition salts.
See, e.g., Berge et al.
"Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 (1977).
[00251 Cornpounds of the present invention that contain one or more acidic
functional groups are capable of
forming pharmaceutically-acceptable'salts with pharmaceutically-acceptable
bases. The tenm
"pharmaceutically-acceptable salts" in these instances refers to the
relatively non-toxic, inorganic and
organic base addition salts of compounds of the present invention. These salts
can likewise be prepared in
situ during the fmal isolation and purification of the compounds, or by
separately reacting the purified
compound in its free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic
primary, secondary or tertiary amine. Representative alkali or alkaline earth
salts include the lithium,
sodium, potassium, calcium, magnesium, and aluminum salts and the like.
Illustrative examples of some of
the bases that can be used include sodium hydroxide, potassium hydroxide,
choline hydroxide, sodium
carbonate, and the like. Representative organic amines useful for the
formation of base addition salts
include ethylamine, diethylanmine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like.
See, for example, Berge et al., supra.
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0026] "Prodrugs" are derivative compounds derivatized by the addition of a
group that endows greater solubility
to the compound desired to be delivered. Once in the body, the prodrug is
typically acted upon by an
enzyme, e.g., an esterase, amidase, or phosphatase, to generate the active
compound. Suitable positions for
derivatization of the conrpounds of the invention to create "prodrugs" include
but are not limited to the Y
group, the phenyl ring of the purines, and the Q group. Those of ordinary
skill in the art have the
knowledge and means to accomplish this without undue experimentation. Examples
of prodrugs of
contenplated by the present application, without lin-utation, include:
Alcohols prodrugs
Drug-OH
Drug-OX, X = prodrug moiety
16
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
0
X = I I R R = alkyl, aryl, or heteroaryl
O
X = ~CH2N-Me2
I
O H
X = 11. CH2CH2COO'
O
X=
N"'H
O
~ 11-~O-
X -P\ O-
O
X = I I CH2S03
O
XC(R')(R")NH2 R', R" are independently selected from
hydrogen, alkyl, aryl, or heteroaryl.
0
XO-R R= alkyl, aryl, or heteroaryl
0
11 H
X N-R R = alkyl, aryl, or heteroaryl
0
X=I I S-R R= alkyl, aryl, or heteroaryl
O
X ~ ~
N
Me
Amine prodrugs
Drug-NHX
17
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
0
X = I I R R alkyl, aryl, or heteroaryl
0
X= CHN+H3
I R hydrogen, alkyl, aryl, or heteroaryl
R
0
X=-1J-O-R R alkyl, aryl, or heteroaryl
X= CH2NHC(O)R R = aryl, or heteroaryl
X = CHR R = aryl, or heteroaryl
X= NR R = aryl, or heteroaryl
Carboxylic prodrugs
Drug-COOX
X = alkyl, aryl or heteroaryl
[0027) "Tautomers" are compounds whose structures differ in arrangements of
atoms, but which exist in
equilibrium. By way of example, the structure shown below and designated T is
in equilibrium with a second
tautomeric form designated T'.
OH O
Nx ~ I ~
Z \
I,NI \ Q HN
I Z N i 0
y y
T T'
[0028) The predominance of one tautomer versus another is controlled by
factors which include but are not limited
to the nature of the solvent, temperature, pressure, the presence or absence
of other molecules, and the nature of
substituents on the molecule having tautomeric forms.
100291 The term "alkyl," alone or in combination, refers to an optionally
substituted straight-chain, optionally
substituted branched-chain, or optionally substituted cyclic alkyl radical
having from I to about 30 carbons, more
preferably 1 to 12 carbons. Examples of alkyl radicals include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
The term "cycloalkyl" embraces cyclic
configurations, is subsumed within the defmition of alkyl and specifically
refers to a monocyclic, bicyclic, tricyclic,
and higher multicyclic alkyl radicals wherein each cyclic moiety has from 3 to
about 8 carbon atorns. Examples of
cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and the like. A "lower alkyl" is a
shorter alkyl, e.g., one containing from 1 to about 6 carbon atoms.
18
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0030] The term "alkenyl," alone or in combination, refers to an optionally
substituted straight-cbain, optionally
substituted branched-chain, or optionally substituted cyclic alkenyl
hydrocarbon radical having one or more carbon-
carbon double-bonds and havi.ng from 2 to about 30 carbon atoms, more
preferably 2 to about 18 carbons.
Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-
butadienyl and the like. The term can also
embrace cyclic alkenyl structures. A "lower akenyl" refers to an alkenyl
having from 2 to about 6 carbons.
[0031] The term "alkynyl," alone or in combination, refers to an optionally
substituted straight-chain, optionally
substituted branched-chain, or cyclic alkynyl hydrocarbon radical having one
or more carbon-carbon triple-bonds
and having from 2 to about 30 carbon atoms, more preferably 2 to about 12
carbon atoms. The term also includes
optionally substituted straight-chain or optionally substituted branched-chain
hydrocarbon radicals having one or
more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as
well as those having from 2 to about
4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl,
butynyl and the like.
[0032] The terms heteroalkyl, heteroalkenyl and heteroalkynyl include
optionally substituted alkyl, alkenyl and
alkynyl structures, as described above, and which have one or more skeletal
chain atoms selected from an atom
other that carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations
thereof.
[0033] The term "carbon chain" may embrace any alkyl, alkenyl, alkynyl, or
heteroalkyl, heteroalkenyl, or
heteroalkynyl group, and may be linear, cyclic, or any combination thereof. If
part of a tinker and that linker
comprises one or more rings as part of the core backbone, for purposes of
calculating chain length, the "chain" only
includes those carbon atoms that compose the bottom or top of a given ring and
not both, and where the top and
bottom of the ring(s) are not equivalent in length, the shorter distance shall
be used in determining chain length. If
the chain contains heteroatoms as part of the backbone, those atoms are not
calculated as part of the carbon chain
length.
[0034] The term "alkoxy," alone or in combination, refers to an alkyl ether
radical, alkyl-O-, wherein the term
alkyl is defined as above. Examples of alkoxy radicals include methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy and the like.
[0035] The term "aryloxy," alone or in combination, refers to an aryl ether
radical wherein the term aryl is defined
as below. Exatnples of aryloxy radicals include phenoxy, benzyloxy and the
like.
[0036] The term "alkylthio," alone or in combination, refers to an alkyl thio
radical, alkyl-S-, wherein the term
alkyl is defined as above.
[0037] The term "arylthio," alone or in combination, refers to an aryl thio
radical, aryl-S-, wherein the term aryl is
defined as below.
[0038] The term "oxo" refers to =0.
[0039] The term "aryl," alone or in combination, refers to an optionally
substituted aromatic ring system. The
term aryl includes monocyclic aromatic rings, polyaromatic rings and
polycyclic aromatic ring systems containing
from six to about twenty carbon atoms. The term aryl also includes monocyclic
aromatic rings, polyaromatic rings
and polycyclic ring systems containing from 6 to about 12 carbon atoms, as
well as those containing from 6 to about
10 carbon atoms. The polyaromatic and polycyclic aromatic rings systems may
contain from two to four rings.
Exarnples of aryl groups include, without limitation, phenyl, biphenyl,
naphthyl and anthryl ring systems.
100401 The term "heteroaryl" refers to optionally substituted aromatic ring
systems containing from about five to
about 20 skeletal ring atoms and having one or more heteroatoms such as, for
example, oxygen, nitrogen, sulfur, and
phosphorus. The term heteroaryl also includes optionally substituted aromatic
ring systems having from 5 to about
12 skeletal ring atoms, as well as those having from 5 to about 10 skeletal
ring atoms. The term heteroaryl may
include five- or six-membered heterocyclic rings, polycyclic heteroaromatic
ring systems and polyheteroaromatic
19
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
ring systems where the ring system has two, three or four rings. The terms
heterocyclic, polycyclic heteroaromatic
and polyheteroaromatic include ring systems containing optionally substituted
heteroaromatic rings having more
than one heteroatom as described above (e.g., a six membered ring with two
nitrogens), including polyheterocyclic
ring systems of from two to four rings. The term heteroaryl includes ring
systems such as, for example, furanyl,
benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N=alkyl
pyrrolyl, pyridyl-N-oxide, pyrimidoyl,
pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl,
indolizinyl, thienyl and the like.
The term "heteroarylalkyl" refers to a Cl-C4 alkyl group containing a
heteroaryl group, each of which may
be optionally substituted.
[0041] The term "heteroarylthio" refers to the group -S-heteroaryl.
(0042] The term "acyloxy" refers to the ester group -OC(O)-R, where R is H,
alkyl, alkenyl, alkynyl, aryl, or
arylalkyl, wherein the alkyl, alkenyl, alkynyl and arylalkyl groups may be
optionally substituted.
(0043] The term "carboxy esters" refers to -C(O)OR where R is alkyl, aryl or
arylalkyl, wherein the alkyl, aryl and
arylalkyl groups may be optionally substituted.
[0044] The term "carboxamido" refers to
O
R-C-N-
R'
where each of R and R' are independently selected from the group consisting of
H, alkyl, aryl and arylalkyl,
wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
[0045] The term "arylalkyl," alone or in combination, refers to an alkyl
radical as defined above in which one H
atom is replaced by an aryl radical as defuied above, such as, for example,
benzyl, 2-phenylethyl and the like.
[0046] The term "alkylaryl," alone or in combination, refers to an aryl
radical as defmed above in which one H
atom is replaced by an alkyl radical as defined above, such as, for example,
tolyl, xylyl and the like.
[0047] The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include
alkyl, alkenyl, alkynyl and alkoxy
structures, as described above, that are substituted with one or more
fluorines, chlorines, bromines or iodines, or
with combinations thereof.
[0048] The temis cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl,
alkenyl, haloalkyl and heteroalkyl include
optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl,
alkynyl, alkenyl, haloalkyl and heteroalkyl
groups.
[0049] The term "carbocycle" includes optionally substituted, saturated or
unsaturated, three- to eight-membered
cyclic structures in which all of the skeletal atoms are carbon.
[0050] The term "heterocycle" includes optionally substituted, saturated or
unsaturated, three- to eight-membered
cyclic structures in which one or more skeletal atoms is oxygen, nitrogen,
sulfur, phosphorus or combinations
thereof. Illustrative exan=iples include pyridine, pyran, thiophan, pyrrole,
furan, thiophen, pentatomic and hexatomic
lactam rings, and the like.
[0051] The terrn "membered ring" can embrace any cyclic structure, including
carbocycles and heterocycles as
described above. The term "membered" is meant to denote the number of skeletal
atoms that constitute the ring.
Thus, for example, pyridine, pyran, and thiophan are 6 membered rings and
pyrrole, furan, and thiophen are 5
membered rings.
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0052] The term "acyl" includes alkyl, aryl, heteroaryl, arylalkyl or
heteroarylalkyl substituents attached to a
compound via a carbonyl functionality (e.g., -CO-alkyl, -CO-aryl, -CO-
arylalkyl or -CO-heteroarylalkyl, etc.).
[00531 "Optionally substituted" groups may be substituted or unsubstituted.
The substituents of an "optionally
substituted" group may include, without limitation, one or more substituents
independently selected from the
following groups or designated subsets thereof: alkyl, alkenyl, alkynyl,
heteroalkyl, haloalkyl, haloalkenyl,
haloalkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy,
aryloxy, haloalkoxy, amino, alkylamino,
dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, carboxyesters
(C(O)OR''), carboxamido (C(O)NRy2), acyloxy,
H; halo, CN, NOZ, N3, OH, C(O)RY, pyridinyl, thiophenyl, furanyl, indolyl,
indazolyl, phosphonates (-P(O)(OR'')2),
phosphates (-O-P(O)(OR'')Z), phosphoramides (-NR"-P(O)(ORS')2), sulfonates (-
S(O)2-0-), sulfates (-O-S(O)2-O-R''),
sulfonaniides (-NR-S(O)Z-O-Ry), carbamates (-NH-C(O)-O-R3'), ureayl,
thioureyl, thioamidyl, thioalkyl. An
optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully
substituted (e.g., -CF2CFs),
monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between
fully substituted and
monosubstututed (e.g., -CH2CF3).
[0054] The term "halogen" includes F, Cl, Br and I.
[0055] The term sulfide refers to a sulfur atom covalently linked to two
atoms; the formal oxidation state of said
sulfur is (11). The term "thioether" may used interchangebly with the term
"sulfide".
[0056] The term "sulfoxide" refers to a sulfur atom covalently linked to three
atoms, at least one of which is an
oxygen atom; the formal oxidation state of said sulfur atom is (IV).
[0057] The term "sulfone' refers to a sulfur atom covalently linked to four
atoms, at least two of which are oxygen
atoms; the formal oxidation state of said sulfur atom is (VI).
[0058] Some of the compounds of the present invention may contain one or more
chiral centers and therefore may
exist in enantiomeric and diastereomeric forms. The scope of the present
invention is intended to cover all isomers
per se, as well as mixtures of cis and trans isomers, mixtures of
diastereomers and racemic mixtures of enantiomers
(optical isomers) as well. Further, it is possible using well known techniques
to separate the various forms, and
some embodiments of the invention may feature purified or enriched species of
a given enantiomer or diasteriomer.
[0059] A"pharniacological composition" refers to a mixture of one or more of
the compounds described herein,
or pharmaceutically acceptable salts thereof, with other chemical components,
such as pharmaceutically acceptable
carriers and/or excipients. The purpose of a pharmacological composition is to
facilitate adniinistration of a
compound to an organism.
[0060] The phrase "pharmaceutically acceptable carrier" as used herein means a
phazmaceutically-acceptable
material, composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material,
involved in carrying or transporting the subject agent from one organ, or
portion of the body, to another organ, or
portion of the body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of
the formulation and not injurious to the patient. Some examples of materials
which can serve as pharmaceutically-
acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose;
(2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and
cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower
oil, sesame oil, olive oil, corn oil and
soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and
polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13)
agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-
free water; (17) isotonic saline; (18)
Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and
(21) other non-toxic compatible
21
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
substances employed in pharmaceutical formulations. A physiologically
acceptable carrier should not cause
significant irritation to an organism and does not abrogate the biological
activity and properties of the administered
compound.
[0061] An "excipient" refers to an inert substance added to a pharmacological
composition to further facilitate
adrninistration of a compound. Examples of excipients include but are not
limited to calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose derivatives, gelatin,
vegetable oils and polyethylene glycols.
[00621 Assays to Determine HSP90 Binding and Downstream Effect
A variety of in vitro and in vivo assays are available to test the effect of
the compounds of the invention on
HSP90. HSP90 competitive binding assays and functional assays can be performed
as known in the art substituting
in the compounds of the invention. Chiosis et al., Chemistry & Biology 8:289-
299 (2001), describe some of the
known ways in which this can be done. For example, competition binding assays
using, e.g., geldanamycin or 17-
AAG as a competitive binding inhibitor of HSP90 can be used to detemune
relative HSP90 affinity of the
compounds of the invention by immobilizing the compound of interest or other
competitive inhibitor on a gel or
solid matrix, preincubating HSP90 with the other inhibitor, passing the
preincubated mix over the gel or matrix, and
then measuring the amount of HSP90 that sticks or does not stick to the gel or
matrix.
Downstream effects can also be evaluated based on the known effect of HSP90
inhibition on function and
stability of various steroid receptors and signaling proteins including, e.g.,
Rafl and Her2. Compounds of the
present invention induce dose-dependent degradation of these molecules, which
can be measured using standard
techniques. Inhibition of HSP90 also results in up-regulation of HSP90 and
related chaperone proteins that can
similarly be measured. Antiproliferative activity on various cancer cell lines
can also be measured, as can
morphological and functional differentiation related to HSP90 inhibition. For
example, the
Many different types of methods are known in the art for determining protein
concentrations and measuring
or predicting the level of prpteins within cells and in fluid samples.
Indirect techniques include nucleic acid
hybridization and amplification using, e.g., polymerase chain reaction (PCR).
These techniques are known to the
person of skill and are discussed, e.g., in Sambrook, Fritsch & Maniatis,
Molecular Cloning: A Laboratory Manual,
Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor,
N.Y., Ausubel, et al., Current
Protocols in Molecular Biology, John Wiley & Sons, NY, 1994, and, as
specifically applied to the quantification,
detection, and relative activity of Her-2/neu in patient samples, e.g., in
U.S. Patents 4,699,877, 4,918,162,
4,968,603, and 5,846,749. A brief discussion of two generic techniques that
can be used follows.
The determination of whether cells overexpress or contain elevated levels of
HER-2 can be determined
using well known antibody techniques such as immunoblotting,
radioimmunoassays, western blotting,
immunoprecipitation, enzyme-linked immunosorbant assays (ELISA), and
derivative techniques that make use of
antibodies directed against HER-2. As an example, HER-2 expression in breast
cancer cells can be determined with
the use of an immunohistochemical assay, such as the Dako HercepTM test (Dako
Corp., Carpinteria, CA). The
HercepTM test is an antibody staining assay designed to detect HER-2
overexpression in tumor tissue specimens.
This particular assay grades HER-2 expression into four levels: 0, 1, 2, and
3, with level 3 representing the highest
level of HER-2 expression. Accurate quantitation can be enhanced by employing
an Automated Cellular Imaging
System (ACIS) as described, e.g., by Press, M, et al, (2000), Modern Pathology
13:225A.
22
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Antibodies, polyclonal or monoclonal, can be purchased from a variety of
commercial suppliers, or may be
manufactured using well-known methods, e.g., as described in Harlow et al.,
Antibodies: A Laboratory Manual, 2nd
Ed; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).
HER-2 overexpression can also be determined at the nucleic acid level since
there is a reported high
correlation between overexpression of the HER-2 protein and amplification of
the gene that codes for it. One way to
test this is by using RT-PCR. The genomic and cDNA sequences for HER-2 are
known. Specific DNA primers can
be generated using standard, well-known techniques, and can then be used to
amplify template already present in the
cell. An example of this is described in Kurokawa, H et al, Cancer Res. 60:
5887-5894 (2000). PCR can be
standardized such that quantitative differences are observed as between normal
and abnormal cells, e.g., cancerous
and noncancerous cells. Well known methods eniploying, e.g., densitometry, can
be used to quantitate and/or
compare nucleic acid levels amplified using PCR.
Similarly, fluorescent in situ hybridization (FISH) assays and other assays
can be used, e.g., Northem
and/or Southern blotting. These rely on nucleic acid hybridization between the
HER-2 gene or mRNA and a
corresponding nucleic acid probe that can be designed in the same or a similar
way as for PCR primers, above. See,
e.g., Mitchell MS, and Press MF., 1999, Semin. Oncol., Suppl. 12:108-16. For
FISH, this nucleic acid probe can be
conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that
preferably does not interfere with
hybridization, and which fluorescence can later be measured following
hybridization. See, e.g., Kurokawa, H et al,
Cancer Res. 60: 5887-5894 (2000) (describing a specific nucleic acid probe
having sequence 5'-FAM-NucleicAcid-
TAMRA-p-3' sequence). ACIS-based approaches as described above cari be
employed to make the assay more
quantitative (de la Torre-Bueno, J, et al, 2000, Modern Pathology 13:221A).
[0063] Imnmuno and nucleic acid detection can also be directed against
proteins other than HSP90 and Her-2,
which proteins are nevertheless affected in response to HSP90 inhibition.
[0064] Synthesis of the Compounds of the Invention
The following synthetic schemes are applicable to various of the compounds,
compositions, methods, and
formulations of the invention:
A A A
\ NH2 -_' N \ NE ~ \ N IE N Q
G N NN2 G/\ N N G N N ZN N
7 5 H 2 Y y
A A A
\ NHZ N NHZ N\
>--L
G fV d G~N NH GN N %
y Y
6 4 3
23
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Synthetic scheme A
[00651 Synthesis of compounds of formula 1[X = C]
Synthesis of compounds of formula 1(when X= C) in synthetic scheme A may
include some or all of the
following general steps. The 8-substituted purine analogs of formula 5 or 2
can be prepared from 4,5-
diarninopyrimidines and the carboxylates or their derivatives, such as amides,
esters, nitriles, orthoesters, imidates
etc (see, e.g.,Townsend Chemistry of Nucleosides and Nucleotides, Vol. 1;
Plenum Press, New York and London,
page 148-158; Tetrahedron Lett. 36, 4249, 1995). Substituted 4,5-
diaminopyrimidines can be obtained
commercially or from substituted 2-chloro-3-amino pyriniidine or 2-chloro-3-
nitropyrimidines as known in the art.
See, e.g., Tetrahedron, 40, 1433 (1984); J. Am. Chem. Soc., 118, 135 (1975);
Synthesis 135 (1975); J. Med. Chem.
39, 4099 (1996).
Compounds of -formula 5 can be converted to compounds of formula 2 by simple
alkylation with
alkylhalides, alkyltosylates, mesolates or triflates in polar solvents like
THF, DMF or DMSO using bases like NaI-I,
Cs2CO3 or KZCO3i or by the well-known Mitsunobu alkylation method.
Compounds of formula 2 can be further modified to give compounds of formula- 1
or the intermediates to
prepare compounds of formula 1, e.g., substitution of 6-chloropurine by
ammonia or alkylamines. C-2 substitution
of purines, e.g., halogenation with F, Cl or Br can be introduced via 2-
aminopurines as described by Eaton et al., J.
Org. Chem. 34(3), 747-8 (1969) or by nucleophilic substitution as described,
e.g., in. J. Med. Chem. 36, 2938 (1993)
and Heterocycles, 30, 435, (1990). These C-2 substitutions also can be
introduced via metalation as described, e.g.,
in J. Org. Chem. 62(20), 6833 (1997), followed by addition of desired
electrophile. General purine substitution can
be accomplished as described in J. Med. Chem. 42, 2064 (1999).
Alternatively, intermediates of formula 2 can be prepared from
chloroaminopyrimidines such as formula 6
by the following two steps: (1) treatment of the compounds of formula 6 with
corresponding amine (Y-NH2), e.g.,
butylamine, in presence of base such as triethyl amine or N,N-diisopropyl
amine in polar solvents such as n-BuOH
to give the substituted diamine compounds of formula 4; (2) treatment of the
compounds of formula 4 using the
same methods as described earlier going from formula 7 to formula 5. Similar
methods as described earlier can be
used to introduce the C-2 substitution (point at which Z or G moiety
attaches).
Compounds of formula 1 where A is other than NH2, e.g., halogen, methoxy,
alkyl, or trifluoro alkyl, can
be prepared starting with the corresponding substituent in place (if it can
withstand the transformations), or, for
halogen or substituted anunes, these can be prepared from the 6-amine.
The compounds of forrnula I can also be prepared from formula 3, where L is
halogen, using Negishi-type
couplings (e.g., as described in J. Org. Chem. 2001, 66, 7522; J. Org. Chem.
1991, 56, 1445).
[0066} Synthesis of compounds of formula 1[X = heteroatom e.g. S, 0, N)
Compounds of formula 1 wherein X is a heteroatom such as S, 0 or N can be
prepared by scheme B. In
general, these compounds are linked via their C-8 to one of the heteroatoms X
= S, O, or N and can be prepared
from the corresponding 8-halo (e.g., bromo, iodo or chloro) conipounds such as
formula 10 using nucleophiles such
as sulfides, a11cyI or arylthiols, amines, azides, and alcohols.
24
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
A A A A
N> N>--N~ II N~ M -~ II ~ ~--XE
GN N GN N GJ~ N G/IN N
H H Y
8 9 10 11
J J A A
N NHa ~ ~ NHZ ---~- ~ ~ N-L
J N J J N NH J N N Z N Y
Y Y
14 15 16 1
I J = halogen
J J .
N NO2 E N '
J N JN J
13 12
Synthetic scheme B
With reference to scheme B, substituted adenines or purines of formula 8 can
be treated with halogenating
agents such as bromine or iodine, followed by alkylation at N-9 to give
compounds of formula 10, wherein M is
halogen such as bronzine or iodine (Dang et.al. PCT, WO 98/39344). Compounds
of formula 16 can be prepared
from trihalopyrimidines such as those of formula 12 by nitration to give
compounds of formula 13. Subsequent
displacement of the halogen with amine (YNH2) and reduction of the nitrogroup
gives the diamines of formula 15.
Alternatively, reduction of the nitrogroup may precede halogen displacement.
Diamines of formula 15 can be
readily cyclized to the imidazole ring of the compounds of formula 16, wherein
L is H, SH, OH or NHZ (Org. Syn.
Collective Vol. 2, 65; Org. Syn. Collective Vol. 4, 569). The compounds of
formula 1 can also be synthesized from
the compounds of formula 16, wherein L is SH, OH, or NH2, by reacting with
aromatic halides, boronic acids,
triflates, or their equivalents in presence of a catalyst such as palladium or
copper (Buchwald, S. L. et. al. J. Am.
Chem. Soc., 1998, 120, 213-214; Buchwald, S. L. et. al. Acc. Chem. Res. 1998,
31, 805; Buchwald, S. L. et. al Org.
Lett., 2002, 4, 3517-3520).
Alternately, compounds of formulae 1 and 11 (wherein X= S or 0) can be
synthesized by coupling of the
diazonium salts of the compounds of formulae 10 or 16 (wherein M or L is
N2.BF4, N:Z.HCI, Na.H2SO4 etc.) with
HXE or HXQ (wherein X=S or 0) in the presence of base such as t-BuOK, NaH,
etc. in solvents such as DMF,
MeOH, etc.
Z-groups of formula 1 can be introduced by modifying existing 2-substituents
such as G. For example, 2-
halopurines of formula 1 can be prepared from 2-aminopurines (G = NH2) via
chemistry well described in the
literature. Other substitutions such as S-alkyl or aryl, 0-alkyl can be made
from nucleophilic substitution reactions;
metal-catalysed reactions, etc. (see, e.g., Aerschot et. ai., J. Med. Chem.
36:2938 (1993); Buchwald, S. L. et. al.,
Heterocycles, 30: 435 (1990).
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
The E component (aromatic or heteroaromatic or alkyl) of the compounds of
formula 11 can be further
modified as needed using well known procedures including, e.g., nucleophilic
additions, electrophilic additions,
halogenations, etc. to give Q (see, e.g., Advanced Organic Chemistry, March.
J. Wiley Interscience).
Compounds of formula 1, wherein X is S(O) or S(O)2 can be prepared by the
oxidation of the compounds
of formula 1, wherein X=S, using reagents such as MCPBA, H202, Na104, Oxone,
etc. in solvents such as CHC13,
CH2CI2 etc. Also, these sulfone compounds can be made by coupling of sulfonyl
salts such as Li, Na, K (ArS(O)
2Li) and compounds of formulae 10 or 16 (wherein M or L is halogen such as Br
or I) in polar solvents such as
DMF. (Chem. Abstr. 1952, 4549). With controlled reduction of these sulfones,
one can make compounds of formula
1 where X is S(O) and S(O)2.
[0067] Synthesis of 8-(sulfanyl)adenines from 8-haloadenines
8-Haloadenines can be coupled to thiophenols under basic conditions. A wide
array of bases is available, as
for instance, LiOH, NaOH, t-BuONa, K2C03a KOH, t-BuOK, Cs2CO3i or CsOH. The
thiophenol can already carry
all the substituents necessary for biological activity or can be modified
after coupling (Scheme C).
Preparation of thiophenol, then coupling
NH2
+NZ Leuckart synthesis ~g \ N Y
I i~
oll, NH2
Coupling, then functionalization '--
N N
NH2 NH2 Y O
~ N~X ~ I N>S~ +
N N N N
Y Y O
X = halide or other leaving group
Y = substitued alkyl
Synthetic scheme C: Preparation of (Arylsulfanyl)adenines from 8-haIoadenines
Following the first route, the thiophenol is first prepared using one of the
many known methods. These
methods have been extensively reviewed (Wardell, J.L. Preparation of Thiols.
In The Chemistry of the Thio Group,
Part 1. Patai S. Ed. John Wiley & Sons. London, 1974, pp 163-263.). The most
popular of them is perhaps the
Leuckart synthesis, in which an aryl diazonium salt is treated with a sulfur
nucleophile, typically EtOCS2K, to give
a xanthate which is hydrolyzed with a base. For instance, the 2-iodo-5-
(methoxy)benzenethiophenol indicated
scheme C was prepared in this manner. (Ma, C. J. Org. Chem. 2001, 66, 4525.
Flynn, B. L. Org. Lett. 2001, 3, 651).
The thiophenol is then deprotonated (e.g. K2C03) and coupled to a 8-
haloadenine. The coupling can be catalyzed by
transition metals, e.g. Ni(acac)Z.
The second route of scheme C entails coupling of 8-haloadenine to a
thiophenol, and subsequent treatment
with an electrophilic species (Cl', Br , I, NO+ etc.) using standard reagents
for electrophilic aromatic substitutions.
26
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[00681 Synthesis of 8-(sulfanyl)adenines from 8-mercaptoadenines
8-(Arylsulfanyl)adenines can be prepared from 8-mercaptoadenines with
electrophilic species, as illustrated
in scheme D. The mercaptoadenine is reacted with a diazonium salt, in a polar
solvent such as DMF or DMSO, in
the presence or absence of base (Biamonte, M. A., J. Org. Chem., 2005, 70,
717), or a radical cation is generated
with Phl(OCOCF3)2 and is trapped with a 8-mercaptoadenine (Kita, Y., J. Org.
Chem., 1995, 60, 7144).
Coupling of a 8-mercaptoadenine with a diazonium salt
NHZ H *Nz NHz t
1\ N>=5 O\ N~S
N N
y -a- Y ~O
Coupling of a 8-morcaptoadenine with a radical cation
NHz H
>= S O-O NHz O
O~O Phl(OCOCF3)3 O~O N N, NHZ N N
. -' ~N + L J ~. ~ S/~
N N
+ Y Y
Synthetic scheme D: Preparation of (Arylsulfanyl)adenines from 8-
mercaptoadenines
[0069) Synthesis of Benzothi(ox)azolopurines or Pyridothiazolopurines
These conmpounds can be prepared from the intermediate 10, in scheme B.
Compounds of formula 3,
wherein L is halogen, Y is H or a substituent that can be modified if
necessary (for example -(CHZ)õO(CO)CH3, n=
2-4) G is H or halogen, A is NH2 can be treated with substituted
benzothi(ox)azole-2-thiol or pyridothi(ox)azole-2-
thiol in presence of base for example t-BuOK, NaH, or KaC03 in polar solvents
such as DMF, THF or DMSO to
give the formula 17, wherein T is '0' or 'S', V is 'C' or 'N', R is a
substituent such as halogen, alkyl, aryl, alkoxy,
CN etc., scheme E.
R
A A -t-~~ =
N L --~ ~/ N S~ N
GN ~ G N
Y Y
3 17
Synthetic scheme E: Preparation of (heteroarylsulfanyl)purines
Substituted benzothiazole-2-thiols and benzoxazole-2-thiols were prepared from
the condensation O-
ethylxanthic acid, potassium salt or any suitable salts and 2-haloanilines or
2-hydroxyanilines respectively, scheme
F. These compounds can also be prepared from 2-aminobenzothiazoles (ref.
Kasibhatla et. al. US Patent 6,489,476
B1) by diazotization followed by displacement with SH using thiourea or O-
ethylxanthic acid, potassium salt (see
ref. The Chemistry of the Thio Group, Part 1, Patai S. Ed. John Wiley & Sons.
London, 1974, pp 163-263-and Ma,
C. J. Org. Chem. 2001, 66, 4525. ).
27
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NHZ S
N
SK _ HS~ ~ R
x T
7
X halogen T= O or S
X = OH
Synthetic scheme F: Preparation of benzothi(ox)azole-2-thiols
Similarly, condensation of 2-amino-3-halopyridines or 4-amino-3-halopyridines
or 3-amino-2-
halopyridines with O-ethylxanthic acid, potassium salt can give the other
pyridylthiazole-2-thiols isomers, scheme
G. These can also be prepared from 2-aniino pyridothiazoles.
4
NHz S N - - N 5
R SK ~- HS-{~ \ ~6
+
7
X = halogen
Synthetic scheme G: Preparation of pyridothiazole-2-thiols
100701 Synthesis of 8-benzyladenines
The 8-benzyladenines were synthesized by either of the two methods illustrated
in Scheme H. The first
method followed a sequence closely related to the one described by Drysdale et
al., and started from con--mercial
4,6-dichloro-5-aminopyrimidine, which was treated with butylamine, acylated
with the appropriate phenacyl
chloride, and cyclized to afford the desired 9-butyl-8-(2,5-dimethoxybenzyl)-
9H-purin-6-ylarnine. The second
method was similar to the one of Chiosis et al. and started with 4,5,6-
triaminopyrimidine, which was acylated and
cyclized to give 8-(3-methoxy-benzyl)-9H-purin-6-ylamine. The final alkylation
gave predominantly the desired
N(9)-alkyl isomer, together with a minor regioisomer which was removed by
chromatography (regioselectivity = 5:1
by 'H NMR analysis of the crude product). The anisole was halogenated using
standard reagents (SO2C12i Br2,
NIS/AcOH). One improvement in the synthetic sequence pertained to the
acylation step. The published method
involves acylation of 4,5,6-triaminopyrimidine hemisulfate in aqueous solution
(4,5,6-trianiinopyrimidine is soluble
only in water at pH ~ 7), and required, in our hands, several equivalents of
the appropriate acyl fluoride to
conipensate for the accompanying hydrolysis of the reagent. We found that the
free base of 4,5,6-
triaminopyrimidine was readily isolated as needles by neutralizing and cooling
to 0-5 C an aqueous solution of the
commercial heniisulfate. The free base proved to be soluble in N-methyl-2-
pyrrolidone (NMP), and could be
efficiently acylated in this solvent with a single equivalent of acyl chloride
to give the amide. The use of DMF as a
solvent was less satisfactory, since it gave rise to a competitive formylation
of the 5-NH2 group via a Vilsmeier-
Haack type of reaction. Bases such as Et3N were best avoided, to prevent over-
acylation, and the desired amide
precipitated as its HCI salt. The symmetry of the 'H-NMR spectrum of the
acyated product indicated that the
acylation had occurred selectively at the 5-position. Finally, the cyclization
of arnide to the desired purine was
carried out with MeONa in refluxing n-BuOH, a minor deviation from the
original MeOH, but which provided more
forceful and generally applicable conditions.
28
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Method A
CI CI CI H OMe NH2
N NHZ a N~ NHZ b N N c N1~N
OMe
N
N CI N NH N N1-O
I N
OMe
MeO
Method B
NH2
NH2 NH2 H
N NH2 NHZ e N ~ OMe f
O
N NH2 N NH2 N NH
NH2 NH2 NH2
N' N g N N
tl ~ -~- '~ _~ I'~ ~ I, Br, I
N HN N N N N
MeO MeO MeO
Synthetic scheme H: Preparation of 8-benzyladenines.
Reagents and conditions: (a) BuNH2, Et3N, n-BuOH, 90 C, 16 h(83 l0);
(b) 2,5-dimethoxyphenylacetic acid, TsCI, Et3N, DCE, 40 C, 16 h(71%);
5 (c) NH3, MeOH, 120 C, 3 d(80%); (d) NaOH, H20, 0-5 C (67%);
(e) 3-methoxyphenylacetyl chloride, NMP, 40-50 C (98%);
(f) MeONa, n-BuOH, reflux, 2 h(75%); (g), BuI, CsZCO3, DMF, rt, 16 h (54%);
(h) S02C12, Br2, or NIS (31-57%).
10 [0071] Synthesis of 8-arylsulfanyladenines
A different approach was necessary to investigate the effect of the linker
between the purine and the
benzene ring. The compounds with a sulfur atom as a linker were prepared
according to the example shown in
Scheme I. 8-Bromoadenine was alkylated to give a 2:1 mixture of the N(9)- and
N(3)-alkylated isomers, from which
the desired N(9)-butyl isomer could be isolated by chromatography.
Displacement of the bromine atom with the
desired thiophenolate gave the desired 8-sulfanyladenine.
NH2 NH2 NH2
x:\Br b {I ~-Br -~ ~ ~}-S OMe
N H 'N N N N
MeO
Synthetic scheme I: Preparation of 8-(arylsulfanyl)adenine
29
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Reagents and conditions: (a) Bul, CsZCO3, DMF, rt, 16 h (62%);
(b) 2,5-dimethoxybenzenethiol, 150 C, 4 h (69%).
[00721 Synthesis of 8-(Iodo-substituted-phenylsulfanyl)-adenines
A sinular approach was used to generate 8-(benzenesulfanyl)-adenines carrying
an iodo substituent on the
benzene ring via the convergent synthesis shown in Scheme J. The methoxy-
nitroaniline was converted in three
known steps (1. NaNO2, KI. 2. HaN-NHZ/Fe. 3. NaNO2i HBF4) to the diazonium
salt, which gave after a two-step
Leuckart synthesis, (4. EtOCS2K, 5. KOH) the potassium salt of 2-iodo-5-
methoxy-benzenethiophenol. Purification
of this compound proved to be challenging. Dissolution in MeOH and
precipitation with EtOAc gave a low recovery
(<20%) of the desired thiophenolate, while neutralization and chromatography
was complicated by the odor of the
thiophenol and its tendency to oxidize to the corresponding disulfide. In the
event, the highest overall yield for the
conversion to phenylsulfanyl adenine was achieved by hydrolyzing the
intermediate xanthate with 2 equivalents of
KOH in MeOH, concentrating the reaction mixture, and using it without removing
the excess of potassium salts.
Alkylation of 8-bromoadenine with homoprenyl bromide gave a 2:1 mixture of the
desired N(9)- vs. N(3)-alkylated
products, and the desired isomer was isolated by chromatography. Coupling the
thiophenolate with 8-bromoadenine
gave the desired 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine. Similarly, 8-
bromoadenine could be alkylated with 5-chloro-l-pentyne to give 8-Bromo-9-pent-
4-ynyl-9H-purin-6-ylamine, and
coupled to the thiophenolate to provide the pentyne analog 8-(2-Iodo-5-methoxy-
phenylsulfanyl)-9-pent-4-ynyl-9H-
purin-6-ylamine.
2-Fluoro-8-(2-iodo-5-methoxy-phenylsulfanyi)-9-pent-4-ynyl-9H-purin-6-ylamine
was prepared by a conceptually
similar route starting from 2,6-diamino-8-bromopurine, using a Balz-Schiemann
reaction (iso-AmONO/FBF4) to
replace the 2-NH2 group with a fluorine.
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 3 steps +N
O2N ref.18 2 a KS
BF4' A
OMe OMe OMe
NH2 NH2
b ~ ~ ~Br ---- ~i ~ N---S
N N N N
NH2
O
\
Nj N
H
NH2 NHZ
~ N N e
--Br N~ -S 1
N N N J
NH2 NH2
II \> Br , ) ~-Br -"-
N
H2N~N ~ H2N N N
NH2 NHZ
(il ~ N~-S I _ h ~~ N S I
HzNN N ~ ~ F N
0 O\
Synthetic scheme J: Preparation of 8-(iodo-substituted phenylsulfanyl)adenines
Reagents and conditions: (a) EtOCS2K, -40 C to rt, 30 min, then KOH, MeOH, 40
C, 2h;
(b) 5-bromo-2-methyl-pent-2-ene, CsZCO3, DMF, rt, 3h (38%);
(c) 21, DMF, 100 C, 16h (15%); (d) 5-chloro-l-pentyne, CsZCO3, DMF, 70 C, 3h
(25%);
(e) 21, DMF, 70 C, 16h (71%); (f) 5-chloro-l-pentyne, Cs2CO3, DMF, 85 C, 16h
(66%);
(g) 21, DMF, 100 C, 16h (43%); (h) i-AmONO, HBF4, THF, -20 C - +40 C, 10 min
(13%).
However, these routes suffered from two drawbacks. First, the alkylation was
not regioselective and
required a tedious chromatographic separation. Second, the thiophenolate was
malodorous, difficult to purify, and if
used without chromatographic purification gave results which were very
sensitive to its purity. One improvement
(Scheme K, route A) consisted of starting from pure adenine, which underwent
alkylation solely at N(9). Br-(CH2)2-
OAc or Cl-(CHZ)3-OAc were selected as as alkylating agents, in which the
masked hydroxyl group provided a
31
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
handle for further functionalization. Unlike the unsubstituted adenine, the
alkylated product was easily brominated
at C(8). The bromine atom was then displaced with the potassium thiophenolate,
and the acetyl protecting group
cleaved in situ to give the 8-sulfanyladenine. The hydroxy group was
rriesylated and displaced with amines to give
the corresponding N-alkylamines of generic structure A (Scheme K).
This route, however, still required the disagreeable preparation of the
thiophenolate. We therefore
investigated the direct treatment of the diazonium salt with the anion of 8-
thionoadenine, which already contained
the desired sulfur atom (Scheme K, route B), thus avoiding the preparation of
the thiophenolate. Condensation of
4,5,6-triaminopyrimidine with thiourea, followed by treatment with the
diazonium salt gave the desired 8-(2-Iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-ylamine. The yield (un-optimized) was
low'and the subsequent alkylation with
Br-(CHZ)3-CI still gave a 2:1 mixture of N(9)- and N(3)-regioisomers. In spite
of these problems, the route was
effective in generating small amounts of amines of formula A. However, an
improved route was needed to prepare
gram amounts of A. A third route was selected (Scheme K, route C) which
eliminated the use of the thiophenolate
and gave only one regioisomer. The alkylated bromoadenine from route A, scheme
K. was converted with thiourea to
the 8-thionoadenine, which was coupled directly with the diazonium salt to
give the desired, known adduct. Finally,
the same standard manipulations of the side-chain (deacetylation, mesylation,
amination) gave the desired amines of
generic formula A. Routes A and C gave similar overall yields and were used
interchangeably, but the latter was
consistently reproducible, and avoided the use of the thiophenylate.
Route A
NH2 iVH2 NH2 I ~\ O/
N
a KS b
S
II / N _~ II N N ~Br + I ~ c
~N
N
H (CH2)n 0 - 1 N HO CH2)n
OAo
Route B
NH2 H +NZ 1~ NHz p NH2 I p
N 20oM NHz I ~\ O e N~ N~ f N~ N~
N S N N >S ~S
N H d }-S N N N
N N (CH2)n
CI A NHR
Route C
NHz NH2 BF4 NH2 I 0
h +N2
N Br C~S + I \ -~- N
N N
~ N N r N c
(CH2)~ (CHa)3 (CH2)3
OAc OAc Rp
R=Ac
R=H
Synthetic scheme K: Preparation of water-soluble 8-sulfanyladenines of generic
structure A
Reagents and conditions: (a) AcO-(CHa)Z-Br, Cs2CO3, DMF, 45 C, 5h (67%) or
AcO-(CH2)3-Cl, CS2CO3i DMF, 70 C, 12h (88%), then Br2, AcOH, THF, H20 (34-
81%);
(b) DMF, 50 C, 16 h; then K.ZCOs, MeOH (37%);
(c) MsCI, Et3N, dioxane, rt, 30 min; then amine, 55 C, 16 h (45-75%);
32
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
(d) DMF, -60 to rt, 2h (26%); (e) Br-(CH2)3-Cl, CsZCO3a DMF, 50 C, 2
h(21%);
(f) anvne, 90-110 C, 16 h, (67-73%); (g) thiourea, n-BuOH, reflux, 3 h(88%)
(h) DMSO, rt, 24 h(51%); (i) K2C03, MeOH (37%).
100731 Synthesis of 7'-substituted benzolothio and pyridothiazole purines
Hsp90 inhibitor analogs could also be prepared using the three-step general
procedure outlined in Scheme
L. Adenine alkylation with the appropriate alkyl halide in the presence of
CsaCO3 in DMF gave predominantly the
N-9 substituted isomers. Bromination of the purines followed by coupling with
substituted benzothiazole-2-thiols in
the presence of t-BuOK in DMF at elevated temperature provided the final
products.
NH2 NH2 NH2 NH2
N a N b N c N
N I \~ -- I \~ -~ ' I Br
H ' ~N N N 4' N N
Rl R, N 5' R, S
S~J6, ~
~Y
7'RZ R
z
Synthetic scheme L
Reagents and conditions: (a) RIX, CsZCO3i DMF, rt, -70 C;
(b) Br2, Buffer; (c) t-BuOK, DMF, 80-150 C
Adenine alkylation to give the N-9 regiosisomer was unambiguously assigned by
preparing a representative
compound via a different synthetic route (Scheme M). Following the described
synthesis (Howson et al. J.Med.
Cherre. 1988, 23, 433-439), 5-amino-4,6-dichloropyrimidine was treated with
aminopropylalcohol to give the
diaminosubstituted pyrimidine. Cyclization with triethylorthoformate in acetic
anhydride gave the 6-chloropurine
derivative which was further reacted with ammonia in MeOH to give, without
purification, the 9-substituted
adenine. Acylation with acetic anhydride in the presence of DMAP and pyridine
afforded the protected alcohol
whose NMR spectrum was identical to the compound obtained via the scheme
outlined above. This unequivocally
established that the alkylation of the purine in this step occurred
predominantly at the 9-position.
CI CI Ci NH2 NH2
N NHz a N NH2 b I N~ c~ ( N
CI d N 1 ~
/
~
N NH N N N N N 0
N NHOH ~"~OH " OH Ll-~OH
. Synthetic scheme M
Reagents and conditions: (a) EtOH, reflux, lh; (b) HC(OEt)3, (CH3CO)20,
reflux, 3h;
(c) NH3.MeOH, 120 C; (d) Pyridine, DMAP, (CH3CO)20, DCM
[0074] Synthesis of 7'-substituted benzolothio-2-thiols
Benzothiazole-2-thiols were obtained by four different synthetic approaches as
depicted in Schemes N, 0,
P, Q. The key reaction in all four routes involved the condensation of 2-
haloanilines with the potassium salt of
ethylxanthic acid to give benzothiazole-2-thiols. The substituted 2-
haloanilines were prepared via three different
33
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
routes: 1) Reduction of 2-nitrobromobenzene with Fe in EtOH to give the
substituted 2-haloaniline, 2) bromination
of 2-nitroaniline through Sandmeyer reaction followed by reduction with Fe in
EtOH (Scheme 0) and, 3) nitrolation
of 1,2-dibromobenzene with HNO3 in HZSO4 (Scheme P) to give a mixture of the 3-
and 4- NOZ regioisomers,
followed by reduction of the desired 3-NO2 regioisomer with Fe in EtOH to give
2,3-dibromoaniline. The
compounds obtained by these methods were subjected to condensation with the
potassium salt of ethylxanthic acid
in DMF at 160 C for 4 h to give substituted benzothiazole-2-thioles in good
yield. The 6-Cl-, 5-Cl-, 4-Cl- and 7-H-
benzothiazole isomers were purchased from Acros.
4'
N02 a / I NH2 b HS--<N
Br Br 7( 5'
6'
Synthetic scheme N
Reagents and conditions: (a) Fe, EtOH, H+; (b) EtOCSSK, DMF, 160 C, 4h
4'
~ N02 a cx: b, HS--, ~ ~ s
NH2 S 7~
OH R2 R2
Synthetic scheme 0
Reagents and conditions: (a) R21, KZC03, DMF;
(b) EtOCSSK, DMF, 160 C, 4h; (c) [X = NH2 - Br) NaNO2a Hi', CuBr, (d) [Y = NO2
- NH2] Fe, EtOH, H*
&Br NH~ N
cc:: Br b c HS-a Br Br
Syntheic scheme P
Reagents and conditions: (a) HNO3/H2SO4=, (b) Fe, EtOH, HCI; (c) EtOCSSK, DMF,
160 C, 4h
[0075] Synthesis of thiazo[e [4,5-c] pyridine-2-thiols
Halogenation (Nantka-Namirski et. ai. Acta Poloniae Pharmaceutica; 1961; 18,
391-399) of 3-nitro-
pyridin-4-ol (Scheme Q) introduced the 5-Cl or 5-Br groups. Subsequently, the
4-OH group was converted to the 4-
Cl by treating with POC13 (Molecules: EN; 7; 1; 2002; 7-17) and the nitro
group was reduced to amino group
(Chaudhun et.al. Synth. Commun. 26, 20; 1996; 3783-3790) with SnC12. Finally,
cyclization with the potassium salt
of ethylxanthic acid gave the target thiazole [4,5-c] pyridine-2-thiols.
34
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
OH OH CI CI N r N
NO2 a X \ NO2 b X ~ NO, c X I\ NH2 d HS--~S
CN ( ~ N N N X
X = Br or CI
Synthetic scheme Q
Reagents and conditions: (a) Br2 or C12 gas, 50% acetic acid;
(b) POC13i DMF, 120 C, 0.5h; (c) SnCI2.H20, HCI, rt, 4h; (d) EtOCSSK, DMF, 160
C, 4h
Further modification of the 9-alky-side chains is shown in Scheme R. The 9-
alkyl esters were hydrolized by
treatment with NH3 in MeOH to form the 9-hydroxy substituted purines, which
were treated with MsCl in DMF and
the resulting crude mesylates reacted with appropriate amines to give the fmal
compounds.
Ci ci ci , CI
NH2 S NHZ S~ L NHz S NHZ S
-s g N c N S N
NI\ N~--S N a N I N N
N N N N -- ~N N N
)n )n )n )n
O OH OMs R2
n=1,2,3
Scheme R
Reagents and conditions: (a) NH3.MeOH, rt, overnight; (b) MsC1, Et3N, DMF, 0 C
to rt; (c) amine, rt, overnight
[00761 The following examples are offered by way of illustration only and are
not intended to be limiting of the
fall scope and spirit of the invention.
The chemical reagents used below are all available commercially, e.g., from
Aldrich Chemical Co.,
Milwaukee, WI, USA, and/or their facile preparation known to one of ordinary
skill in the art, or otherwise
described or referenced herein. Unless otherwise stated, all reactions were
carried out under a nitrogen atmosphere.
The organic solvents were purchased from Fisher Scientic. Thin layer
chromatography (TLC) was performed with
Whatman K6F silica Gel 60A plates; 1H-NMR spectra were determined on Bruker
400 MHz'instruments. HPLC
method used for these compounds: Agilent Zorbax 300 SB C18, 4.6 X 150 mm, 5
m; Colunui Ternperature:
Ambient; Flow Rate: 1.0 nil/min, Gradient: 5% acetonitrile (0.05% TFA) in
water (0.1% TFA) to 100% acetonitrile
(0.05% TFA) in 7 minutes, hold at 100 % for 2 minutes) (method: 5-100-7), or
Gradient: 5% acetonitrile (0.05%
TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 15 minutes, hold
at 100 % for 2 minutes) (method:
5-100-15).
[0077) Synthesis of compounds
Example 1 Synthesis of 8-(2,5-dimethoxybenzyl)-N9-butyladenine (1)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
CI C1 CI ' H OMe NH2
N NHZ a ~ NH2 b N I-~ ~' N
OMe
~ i N
N CI N NH N NH N
OMe
MeO
Step 1. A solution of 5-anuno-4,6-dichloropyrimidine (1 nunol) in n-BuOH was
treated with Et3N (1.2
mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed
under reduced pressure. The residue
was dissolved in EtOAc, the organic layer washed with water and then dried
(MgSO4). Filtration and removal of
solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid. Rf = 0.5 in
1:1 EtOAc:hexane. 'H NMR
(CDC13) S 8.07 (s, 111), 4.88 (br s, iH), 3.49 (m, 2H), 3.35 (br s, 2H), 1.6
(m, 2H), 1.44 (m, 2H), 0.95 (t, 3H).
Step 2: To a solution of 2,5-dimethoxyphenylacetic acid (1 mmol) and Et3N (1
mmol) in CHaC12 was
added p-toluenesulfonyl chloride (1 mmol) at rt. After 1 h, the mixture was
treated with a solution of the product of
step 1, 6-chloro-5-amino-4-butyl pyrimidine (1 nunol in CHaC1Z), followed by
addition of Et3N (2 nunol). The
resultant niixture was refluxed for 20 h. Solvent was removed and the residue
dissolved into EtOAc, the organic
layer washed with water and dried. The crude compound was taken into acetone,
and precipitated product filtered
out and washed with a small amount of acetone to give N-(4-butylamino-6-chloro-
pyrimidin-5-yl)-2-(2,5-
dimethoxyphenyl) acetamide. Rf= 0.45 in 1:1 EtOAc:hexane. 'H NMR (DMSO-d6) S
9.37 (s, 1H), 8.17 (s, 1H),
7.11 (t, 1H), 6.9 (d, 1H),.6.88 (d, 1H), 6.78(dd, 1H), 3.73 (s, 3H), 3.69 (s,
3H), 3.63 (s, 3H), 3.35 (m, 2H), 1.48 (m,
2H), 1.29 (m, 2H), 0.88 (t, 3H).
Step 3: A mixture of N-(4-butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-
dimethoxyphenyl) acetamide (1
nunol) and p-TSA (0.5 mmol) in toluene was refluxed for 72 h. Solvent was
removed, diluted with EtOAc and
washed with water, bicarbonate and dried. Purification on a silica gel column
(200-400 mesh, Fisher Scientific,
Tustin, CA, USA) gave 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine. Rf =
0.65 in 1:1 EtOAc:hexane. 'H
NMR (DMSO-d6) S 8.7 (s, 1H), 6.96 (d, 1H), 6.84 (m, 1H), 6.8(dd, 1H), 4.28 (s,
2H), 4.23 (t, 2H), 3.69 (s, 3H), 3.67
(s, 3H), 1.62 (m, 2H), 1.25 (m, 2H), 0.88 (t, 3H).
Step 4: To a solution of 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine (1
nunol) in dioxane was
added 28 % NH4OH (50 mmol) and the mixture was then heated at 100 C in a seal
tube for 48 h. Solvent was
removed by azeotrope distillation with toluene. Purification on a silica gel
column (see above) gave pure 8-(2,5-
diinethoxybenzyl)-9-butyl adenine, 1.1. Rf = 0.35 in 5 % MeOH in EtOAc. 'H NMR
(DMSO-d6) S 8.08 (s, 1H),
7.04 (br s, 2H), 6.94 (d, IH), 6.80 (dd, 1H), 6.66(d, 1H), 4.14 (s, 2H), 4.04
(t, 2H), 3.72 (s, 3H), 3.63 (s, 3H), 1.52
(m, 2H), 1.22 (in, 2H), 0.82 (t, 3H).
Alternatively, 8-(2,5-dimethoxybenzyl)-9-butyl adenine can also be prepared
from N-(4-butylamino-6-chloro-
pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl) acetamide according to the following
procedure: A solution of N-(4-
butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl) acetamide (1 mmol)
is taken into 7M NH3 in MeOH
(70 mmol) and the mixture heated at 120 C in a steel bomb for 72 h. Solvent is
removed by azeotrope distillation
with toluene. Purification on the silica gel column gave pure 8-(2,5-
dimethoxybenzyl)-9-butyl adenine.
Example 2 Synthesis of 8-(2,5-dimethoxybenzyl)-N9- pentynyl -2-fluoro adenine
(2)
36
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NHz
NN
OMe
FN N
OMe
Step 1: 2-(2,5-Dimethoxy-phenyl)-N-(2,5,6-triamino-pyrimidin-4-yl)-acetarnide,
HC1
A solution of 2,4,5,6-tetraaminopyrimidine (52.8 g, 378 mmol) in NMP (750 ml)
was treated at 70 C with 2,5-
dimethoxyphenyl acetyl chloride (90 g, 419 mmol). After cooling to r.t., the
precipitate was collected by filtration
and washed with EtOAc to give the title compounds as a pale yellow powder (127
g, 95%). 1H NMR (DMSO-d6) S
9.12 (s, 1H), 7.80-7.40 (m, 3H), 6.22 (s, 2H), 6.04 (s, 4H), 4.41 (s, 3H),
4.29 (s, 3H), 4.25 (s, 2H); MS 319 (M+1).
Step 2: 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine
Sodium metal (2.3 g, 100 mmol) was dissolved in n-BuOH (50 ml) at 70 C. To
this was added the acetarnide of
step 1, above (5.0 g, 14.1 mmol), and the mixture was heated to reflux for 1.5
h. Neutralization with 6N HCI to pH
8-9, extraction with EtOAc, drying, and evaporation gave the title compound as
a pale yellow powder (3.2 g, 76%).
Ri = 0.45 in 1:3 MeOH:EtOAc. 1H NMR (DMSO-d6) S 12.3-11.7 (br. s, 1H), 6.92
(d, J = 10.0 Hz, IH), 6.82 (dd, J
= 10.0 & 3.0 Hz, IH), 6.73 (s, IH), 6.70-6.50 (br. s, 2H), 5.85-5.70 (br. s,
2H), 3.95 (s, 2H), 3.74 (s, 311), 3.67 (s,
3H); MS 301 (M+1).
Step 3: 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purine-2,6-diamine
A mixture of the purine 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine (19.0
g, 63 mmol), 5-chloro-pent-1-yne
(12.3 ml, 116 mmol), and Cs2CO3 (37.8 g, 116 mmol) in DMF (180 g) was heated
to 50 C for 16h. Filtration and
washing (2 x 200 ml H20) afforded some desired product (5.8 g, 25%). The
mother liquor was concentrated, diluted
with EtOAc, and heated to reflux for lh to yield additional product (6.0 g,
26%). After cooling to room temperature,
addition of 1 volume hexane to the EtOAc mother liquor gave additional product
(2.6 g, l 1%). Final work-up
(CH2C12:MeOH 4:1 - water) yielded additional product (5.3 g, containing 1
equivalent penty-4-yn-1-o1, 18%). Rf =
0.65 in 1:10 MeOH:EtOAc. IH NMR (DMSO-d6) 6 6.92 (d, J= 8.9 Hz, IH), 6.98 (dd,
J= 8.9 & 3.0 Hz, IH), 6.59
(s, J= 2.9 Hz, IH), 6.58-6.53 (br. s, 2H), 5.72-5.68 (br. s, 211), 4.02 (s,
2H), 3.92 (t, J= 7.4 Hz, 2H), 3.73 (s, 3H),
3.62 (s, 311), 2.84 (t, J= 2.5 Hz, IH), 2.13 (td, J = 7.0 & 1.7 Hz, 2H), 1.74
(quint., J = 7.3 Hz, 2H); MS 367 (M+1).
Step 4: 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine
A solution of the above purine-2,6-diamine (11.8 g, 32.2 mrnol) in 48% aq.
HBF4 (250 ml) was treated at -10 C
with iso-amyl nitrite (5.20 ml, 38.8 mmol), and warmed to r.t over 2.5 h. The
reaction mixture was diluted with
MeOH (400 ml) and CH2CI2 (1500 ml), and carefully neutralized with a solution
of K2C03 (125 g) in water (500
ml). Caution: vigorous gas evolution. The aqueous layer was re-extracted with
MeOH:CH2C12 (500 ml, 1:5).
J Concentration of the organic phase and two flash chromatography
purifications (CHZC1a:EtOAc:hexane:MeOH:Et3N
1500:750:750:50:10 - 1500:750:750:150:10) yielded 8-(2,5-Dimethoxy-benzyl)-2-
fluoro-9-pent-4-ynyl-9H-purin-
6-ylamine (4.5 g, 38%), 2.1 as a colorless powder. Rf = 0.45 in 1:1
EtOAc:hexane. 'H NMR (DMSO-d6) S 6.82 (d, J
= 8.9 Hz, IH), 6.75 (dd, J = 8.9 & 3.0 Hz, 1H), 6.68 (d, J = 2.9 Hz, 1H), 6.25-
6.10 (br. s, 2H), 4.20 (s, 2H), 4.13 (t, J
= 7.4 Hz, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.16 (td, J= 7.0 & 2.6 Hz, 2H),
1.97 (t, J = 2.6 Hz, 11-1), 1.95 (quint., J
7.3 Hz, 2H); MS 370 (M+1).
37
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
The following corripounds 3-5, were prepared using essentially the same
procedures described for Example 2, except
that in step 3 the electrophiles 1-bromo-4-methyl-pent-3-ene, 1-chloro-pent-4-
ene, and 1,5-bromopentane were used
in place of 5-chloro-pent-1-yne:
Example 3 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-(4-methyl-pent-3-enyl)-9H-purin-
6-ylamine (3)
NHZ
N N
OMe
F N N
OMe
isolated as solid, retention time = 7.70.
Example 4 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-enyl-9H-purin-6-ylamine
(4)
isolated as solid, retention time = 7.61.
Example 5 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-(5-bromo-pentyl)-9H-purin-6-
ylamine (5)
NH2
N ~ N
It ~ ,
OMe
F J\= N N ~/ ~
OMe
Br
isolated as solid, retention time = 7.86.
Example 6 8-(2,5-Dimethoxy-benzyl)-2-chloro-9-pent-4-ynyl-9H-purin-6-ylamine
(6)
This compound was prepared analogously to the method described in example 5,
step 4 using HCl and CuC1 in place
of HBF4. Rt=8.02 'H NMR (CDC13) b 6.83 (d, J= 8.9 Hz, 1H), 6.77 (dd, J = 8.9 &
3.0 Hz, IH), 6.68 (d, J = 3.0 Hz,
IH), 6.18-6.00 (s, 2H), 4.20 (s, 2H), 4.18 (t, J= 7.4 Hz, 2H), 3.78 (s, 3H),
4.93 (s, 3H), 2.20 (td, J= 7.0 & 2.4 Hz,
2H), 2.63 (t, 2.4 Hz, IH), 1.97 (quint., J = 7.3 Hz, 2H).
HPLC method: Agilent Zorbax 300 SB C18, 4.6 X 150 mm, 5 m; Column
Temperature: Ambient; Flow Rate: 1.0
nil/min, Gradient: 10% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100%
acetonitrile (0.05% TFA) in 10
minutes, hold at 100 % for 1 minutes); Retention times are measured in
minutes.
The above procedures can similarly be applied to produce compounds wherein the
2 position is unsubstituted (i.e. is
H) by starting with 4,5,6, triarninopyrimidine sulfate and using the
appropriate electrophile.
Example 7 9-(4-Chloro-butyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-ylamine (7)
isolated as solid; rt = 6.34.
Example 8 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine (8)
38
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N
N ~Me
OMe
isolated as solid rt= 5.88 min.
Example 9 8-(2,5-Dimethoxy-benzyl)-9-(2-[1,3]dioxolan-2-yl-ethyl)-9H-purin-6-
ylamine (9)
isolated as solid, rt = 5.36.
Example 10 8-(2,5-Dimethoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-
ylamine (10)
NH2
N
N
: ~ OMe
N N
OMe
isolated as solid., rt = 6.60.
Example 11 9-(5-Bromo-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-ylamine (11)
isolated as solid, rt = 6.94.
Example 12 9-(5-Bromo-3-methyl-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-
ylamine (12)
isolated as solid, rt = 7.32.
Example 13 9-(5-Chloro-pentyl)-8-(2,5-dimethoxy-benzyl)-9H-purin-6-ylamine
(13)
isolated as solid, rt = 6.34.
Example 14 8-(2,5-Dimethoxy-benzyl)-9-(4-ethylanvno-butyl)-9H-purin-6-ylamine
(14)
isolated as solid, rt = 3.9.
Example 15 6-[6-Amino-8-(2,5-dimethoxy-benzyl)-purin-9-yl]-hexan-l-ol (15)
The alkylation was done with 1-bromo-4-chlorobutane followed by treatment with
ethylarnine to give the 4-
ethylaminobutyl isolated as solid.
Example 16 8-(2,5-Dimethoxy-benzyl)-9-[2-(dimethyl-bicyclo[3.1.1]hept-2-en-2-
yl)-ethyl]-9H-purin-6-
ylaniine (16)
isolated as solid.
Example 17 Acetic acid 5-[6-amino-8-(2,5-dimethoxy-benzyl)-purin-9-y1]-pentyl
ester (17)
isolated as solid; rt =6.06.
Example 18 8-(2,5-Dimethoxy-benzyl)-9-(3,3,3-trifluoro-propyl)-9H-purin-6-
ylamine (19)
isolated as solid
39
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 19 8-(2,5-Dimethoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine (20)
isolated as solid; rt = 5.88.
Example 20 9-Butyl-8-(2-iodo-5-methoxy-benzyl)-9H-purin-6-ylamine (20)
To a solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (1.24 g, 4
mmol) in AcOH (6 ml) was added N-
iodo-succinamide (NIS) (1.8 g, 8 nunol). After 3h at r.t., additional NIS (1.8
g, 8 nunol) was added, and the mixture
was stirred for another 24 h. The reaction mixture was diluted with CH2C12
(500 ml), and carefnlly neutralized with
a solution of sat. aq. K2C03 (2 x 100 ml), then washed with 0.1 N NaaSZO3 (3 x
100 ml), brine (3 x 100 ml), dried
(Na2SO4), evaporated, and purified by flash chromatography (CH2CI2:
MeOH=100:5) to give the 9-Butyl-8-(2-iodo-
5-methoxy-benzyl)-9H-purin-6-ylamine (20), as a colorless powder (0.53 g,
30%); rt = 7.7 min.; 'H NMR (CDC13-
d) S 8.36 (s, 1H), 7.77 (d, J= 7.9 Hz, 1H), 6.68 (s, IH), 6.61 (d, J= 7.9 Hz,
1H), 5.62 (s, 2H), 4.33 (s, 211), 4.06 (t, J
= 7.7 Hz, 2H), 3.72 (s, 3H), 1.67 (quint., J= 7.7 Hz, 2H), 1.36 (sext., J= 7.5
Hz, 2H), 0.92 (t, J= 7.4 Hz, 3H).
Bromo and chloro derivatives were made using the same procedure, substituting
NBS and NCS for NIS as
appropriate. The following compounds were also synthesized according to
essentially the same procedure, using as
appropriate NIS, NCS or NBS:
Example 21 9-Butyl-8-(5-iodo-2-methoxy-benzyl)-9H-purin-6-ylamine (21)
was made from 9-Butyl-8-(2-methoxy-benzyl)-9H-purin-6-ylamine as starting
material in 48 % yield 'H NIVIR.
(CDC13) 6 8.32 (s, 1H), 7.55 (dd, J= 8.7, 2.2 Hz, 111), 7.37 (d, J= 2.2 Hz,
IH), 6.68 (d, J= 8.7 Hz, 1H), 6.05-5.85
(br. s, 2H), 4.17 (s, 2H), 4.07 (t, J= 7.6 Hz, 2H), 3.82 (s, 3H), 1.62
(quint., J= 7.5 Hz, 2H), 1.30 (sext., J= 7.5 Hz,
2H),0.89 (t, J= 7.4 Hz, 3H).
Example 22 9-Butyl-8-(5-ethyl-2-methoxy-benzyl)-9H-purin-6-ylamine (22)
Rt = 7.59; 'HNMR (CDC13-d) S 8.35 (s, IH), 7.34 (d, J = 8.8 Hz, 1H), 6.79 (dd,
J= 8.7, 2.8 Hz, 11-1), 6.69 (d, J= 2.7
Hz, 1H), 5,64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J= 7.7 Hz, 2H), 3.73 (s, 3H),
1.64 (quint, J= 7.7 Hz, 2H), 1.32 (sext., J
= 7.5 Hz, 2H), 0.90 (t, J = 7.4 Hz, 311).
Example 23 8-(2-Bromo-5-methoxy-benzyl)-9-butyl-9H-purin-6-ylamine (23)
Rt = 7.66; 'HNMR (CDC13-d) S 8.36 (s, IH), 7.52 (d, J= 8.7 Hz, 1H), 6.74 (dd,
J= 8.7, 3.0 Hz, 1H), 6.89 (d, J= 3.0
Hz, 1H), 5,64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J= 7.7 Hz, 2H), 3.72 (s, 3H),
1.64 (quint., J= 7.6 Hz, 2H), 1.34 (sext., J
= 7.5 Hz, 2H), 0.90 (t, J= 7.4 Hz, 3H).
9-Butyl-8-(2-methoxy-benzyl)-9H-purin-6-ylamine and 9-butyl-8-(3-methoxy-
benzyl)-9H-purin-6-ylarnine were
prepared from 4,5,6-triarninopyrimidine sulfate and, respectively 2-
methoxyphenyl acetyl chloride or 3-
methoxyphenyl acetic acid, by procedures analogous to the one described above.
2-Fluoro purine analogs were aIso
prepared from 2,4,5,6-tetraaminopyrimidine, by procedures analogous to those
described above. See Example 2,
step 4.
For compounds 24-29, in which the N9 substituent is sensitive to halogenation,
addition of the N9 substituent was
done as a fmal step:
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 24 8-(2-Bromo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-
ylamane (24)
Rt = 8.22; 'HNMR (CDC13-d) S 8.37 (s, IH), 7.51 (d, J= 8.7 Hz, IH), 6.73 (dd,
J= 8.7 Hz, 3.0 Hz, 1H), 6.65 (d, J=
3.0 Hz, 1H), 5.53 (s, 2H), 5.12 (t, J= 7.1 Hz, 2H), 4.35 (s, 2H), 4.07 (t, J=
7.1 Hz, 2H), 3.72 (s, 3H), 2.43 (quart., J
= 7.1 Hz, 2H), 1.65 (s, 3H), 1.40 (s, 3H).
Example 25 8-(2-Bromo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-ylamine (25)
Rt = 8.17;'H1VMR (CDC13-d) 6 8.35 (s, 1H), 7.52 (d, J= 8.8 Hz, 1H), 6.74 (dd,
J= 8.8 Hz, 2.9 Hz, IH), 6.66 (d, J
2.9 Hz, IH), 5.61 (s, 2H), 4.39 (s, 2H), 4.21 (t, J= 7.4 Hz, 2H), 3.73 (s,
3H), 2.24 (td, J= 6.8 Hz, 2.5 Hz, 2H), 2.03
(t, J= 2.5 Hz, 1H), 1.99 (quint., J= 7.2 Hz, 2H).
Example 26 8-(2-Iodo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-}ilamine (26)
NH2
N
N ' ~ \ (
N N
OMe
~~
Rt = 7.35; 'HNMR (CDC13-d) S 8.36 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 6.64-6.60
(in, 2H), 5.56 (s, 2H), 4.35 (s, 2H),
4.20 (t, J= 7.4 Hz, 2H), 3.73 (s, 3H), 2.26 (td, J= 6.9 Hz, 2.7 Hz, 2H), 2.03
(t, J= 2.7 Hz, 1H), 2.02 (quint., J= 7.0
Hz, 2H).
Example 27 8-(2-Iodo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-
ylamine (27)
NH2
N N
'N N
Me
Rt = 8.17; 'HNMR (CDC13-d) S 8.58 (s, 1H), 8.33 (d, J= 8.6 Hz, 1H), 6.60 (d,
J= 2.9 Hz, 1H), 6.57 (dd, J 8.6, 2.9
Hz, 1H), 6.15 (s, 2H), 5.12 (t, J= 7.4 Hz, 2H), 4.29 (s, 2H), 4.04 (t, J= 7.3
Hz, 2H), 3.67 (s, 3H), 2.42 (quart., J=
7.2 Hz, 2H), 1.65 (s, 3H), 1.39 (s, 3H).
Example 28 2-Fluoro-8-(2-iodo-5-methoxy-benzyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine (28)
NH2
N N
F N N
OMe
Rt = 10.04; 1HNMR (CDC13-d) S 7_76 (d, J= 8.6 Hz, IH), 6.65 (d, J= 2.5 Hz,
1H), 6.60 (dd, J= 8.6, 2.5 Hz, 1H),
6.14 (s, 2H), 5.13 (t, J= 6.9 Hz, 1H), 4.26 (s, 2H), 4.01 (t, J= 7.0 Hz, 2H),
3.72 (s, 3H), 2.43 (quint., J= 7.0 Hz,
2H), 1.68 (s, 3H), 1.42 (s, 3H).
Example 29 2-Fluoro-8-(2-iodo-5-methoxy-benzyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (29)
41
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N N
F N N
OMe
Rt = 8.75; 'HNMR (CDC13-d) S 7.77 (d, J= 8.7 Hz, 1H), 6.67 (d, J= 2.7 Hz, 1H),
6.62 (dd, J= 8.7, 2.7 Hz, 1H),
5.99 (s, 2H), 4.32 (s, 2H), 4.16 (t, J= 7.2 Hz, 2H), 3.74 (s, 3H), 2.26 (td,
J= 6.7, 2.6 Hz, 2H), 2.02 (t, J= 2.4 Hz,
1H), 1.99 (quint., J = 6.9 Hz, 2H); MP: 172-177 C.
General procedure for palladium-mediated couplings
A mixture of 9-Butyl-8-(5-iodo-2-methoxy-benzyl)-9H-purin-6-ylamine (50 mg,
0.1 nunol) and Pd(PPh3)4 (12 mg,
0.01 mmol) was treated under N2 at r.t. with a 1M solution of the
organometallic coupling partner (0.5 ml, 0.5
mmol). Reactions were performed typically in THF at r:t. for 10 min with
organornagnesium compounds in THF at
r.t. for 16 h with organozinc conipounds, or in DMF at 80 C for 3h with
organostannanes. After work-up, the
product was purified by chromatography on preparative plates (1000 uM, SiO2),
eluting with
CH2C1Z:EtOAc:hexane: MeOH: Et3N 1500:750:750:50:10.
Compounds 30, 31, 32 were prepared using the corresponding commercially
available organozinc compound; the
skilled artisan will recognize that equivalent organnostannane, and
organoboron, and organomagnesium coupling
partners may be used in place of organozinc compounds. A general review of
appropriate methodologies may be
found in "Palladium Reagents in Organic Synthesis" Richard F. Heck, Academic
Press, 1990.
Example 30 9-Butyl-8-(5-ethyl-2-methoxy-benzyl)-9H-purin-6-ylamine (30)
Rt = 8.23; 'H NMR (CDC13) S 8.30 (s, 1H), 7.07 (dd, J 8.4 & 2.0 Hz, 1H), 6.91
(d, J= 2.0 Hz, 1H), 6.83 (d, J
8.4 Hz, IH), 5.65-5.55 (s, 2H), 4.23 (s, 2H), 4.04 (t, J= 7.6 Hz, 2H), 3.83
(s, 3H), 2.51 (q, J= 7.6 Hz, 2H) 1.65-
1.55 (m, 2H), 1.30-1.25 (m, 2H), 1.41 (t, J= 7.6 Hz, 3H), 0.86 (t, J = 7.3 Hz,
3H).
Example 31 9-Butyl-8-(5-butyl-2-methoxy-benzyl)-9H-purin-6-ylamine (31)
Rt = 9.24; 'H NMR (CDC13) S 8.33 (s, 1H), 7.05 (dd, J= 8.4 & 1.9 Hz, 1H), 6.88
(d, J= 1.8 Hz, 1H), 6.82 (d, J=
8.3 Hz, 1H), 5.58-5.48 (s, 2H), 4.23 (s, 2H), 4.04 (t, J= 7.6 Hz, 2H), 3.83
(s, 3H), 2.47 (q, J = 7.6 Hz, 2H), 1.57
(quint., J = 7.5 Hz, 211), 1.48 (quint., J= 7.6 Hz, 2H), 1.32-1.22 (m, 4H),
0.87 (t, J= 7.3 Hz, 3H), 0.86 (t, J= 7.3
Hz, 3H).
Example 32 9-Butyl-8-(2-methoxy-5-vinyl-benzyl)-9H-purin-6-ylamine (32)
Rt = 7.91; 'H NMR (CDC13) S 8.31 (s, IH), 7.31 (dd, J= 8.5 & 2.3 Hz, 1H), 7.16
(d, J = 2.2 Hz, 1H), 6.87 (d, J =
8.5 Hz, IH), 6.59 (dd, J= 17.6 & 10.9 Hz, 1H), 5.82-5.72 (s, 2H), 5.53 (dd, J
= 17.6 & 0.7 Hz, IH), 5.09 (dd, J=
10.9 & 0.7 Hz, 1H), 4.22 (s, 2H), 4.06 (t, J= 7.6 Hz, 2H), 3.85 (s, 3H), 1.62
(quint., J=7.7 Hz, 2H), 1.30 (sext., J =
7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).
General procedure for the nitration of benzene ring and derivatizations
A solution of the purine anlog in H2SO4 or in HZSO4:AcOH 1:4 was treated at 0
C with I equiv HNO3. The mixture
was diluted with EtOAc, neutralized with NaHCO3 and purified by chromatography
on Si02 preparative plates
(1000 uM) with CHZCIZ: EtOAc:hexane: MeOH: Et3N 1500:750:750:50:10.
42
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Nitro derivatives (20 mg) can be reduced with 10 ooPd/C (Aldrich) (20 mg)
under HZ atmosphere in THF at r.t. over
16h. The resulting aniline can be further monoalkylated (Acetylchloride;
CH2C12) or reductively alkylated (RCHO,
NaBH(OAc)3, 1,2-dichloroethane, r.t.)
Compounds 33 - 38 were prepared by this method:
Example 33 8-(2,5-Dimethoxy-4-nitro-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-
ylamine (33)
Rt = 8.05; 'H NMR (CDC13) 6 7.94 (s, 1H), 6.85 (s, IH), 6.37-6.27 (s, 2H),
4.06 (s, 2H), 4.01 (t, J = 7.3 Hz, 2H),
3.69 (s, 3H), 3.66 (s, 3H), 2.13 (td, J = 7.0 & 2.6 Hz, 2H), 1.87 (t, J= 2.6
Hz, IH), 1.82 (quint., J= 7.3 Hz, 2H).
Example 34 9-Butyl-8-(3,5-dimethoxy-2-nitro-benzyl)-9H-purin-6-ylamine;
sulfuric acid salt (34)
Rt = 7.33; 'H NMR (DMSO-d6) S 8.27 (s, IH), 8.15-7.90 (br. s, 2H), 6.78 (d, J=
2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz,
1H), 4.32 (s, 211), 4.12 (t, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.58
(quint., J =7.5 Hz, 2H), 1.21 (sext., J= 7.5
Hz, 2H), 0.84 (t, J= 7.4 Hz, 3H).
Example 35 8-(4-Amino-3,5-dimethoxy-benzyl)-9-buty1-9H-purin-6-ylamine (35)
Rt = 805; 'H NMR (CDCI3) 6 8.31 (s, 1H), 7.31 (dd, J= 8.5 & 2.3 Hz, 1H), 7.16
(d, J= 2.2 Hz, IH), 6.87 (d, J=
8.5 Hz, 1H), 6.59 (dd, J= 17.6 & 10.9 Hz, 1H), 5.82-5.72 (s, 2H), 5.53 (dd, J=
17.6 & 0.7 Hz, 1H), 5.09 (dd, J=
10.9 & 0.7 Hz, IH), 4.22 (s, 2H), 4.06 (t, J= 7.6 Hz, 2H), 3.85 (s, 3H), 1.62
(quint., J=7.7 Hz, 2H), 1.30 (sext., J =
7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).
Example 36 8-(4-Ami.no-2,5-dimethoxy-benzyl)-9-butyl-9H-purin-6-ylamine (36)
Rt = 6.95; 1H NMR (CDC13) S 8.33 (s, 1H), 6.57 (s, 1H), 6.33 (s, 1H), 6.37-
6.27 (s, 2H), 4.20 (s, 2H), 4.01 (t, J=
7.3 Hz, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 1.59 (quint., J =7.5 Hz, 2H), 1.32
(sext., J= 7.5 Hz, 2H), 0.86 (t, J = 7.4 Hz,
3H).
Example 37 8-(2-Anuno-3,5-dimethoxy-benzyl)-9-buty1-9H-purin-6-ylamine (37)
'H NMR (CDC13) S 8.28 (s, 113), 6.40 (d, J = 2.5 Hz, 1H), 6.30 (d, J = 2.5 Hz,
1H), 5.85-5.75 (s, 2H), 4.14 (s, 2H),
4.13 (t, J = 7.6 Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 1.62 (quint., J=7.5 Hz,
2H), 1.48 (sext., J= 7.5 Hz, 2H), 0.91 (t, J
= 7.4 Hz, 3H).
Example 38 2-(6-Anuno-9-butyl-9H-purin-8-ylmethyl)-4-methoxy-benzaldehyde-O-
methyl-oxime (38)
NF{=
N
N -- \
I N
\ N
Rt = 7.69; 'H NMR (CDC13) S 8.88 (s, 1H), 8.31 (s, IH), 7.72 (d, J= 7.9 Hz,
1H), ), 6.80 (d, J 8.0 Hz, 1H), 6.74
(s, IH), 5.80-5.76 (s, 2H), 4.24 (s, 2H), 4.00 (t, J= 7.7 Hz, 211), 3.94 (s,
3H),3.76 (s, 3H), 1.58 (quint., J= 7.7 Hz,
2H), 1.28 (sext., J = 7.5 Hz, 214), 0.86 (t, J= 7.3 Hz, 3H).
43
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Formylation of benzene ring and derivatization
A solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (100 rrig, 0.32
mmol), 1,1-dichlorodirnethyl ether
(40 mg, 0.35 mmol) and TiCl4 (133 mg, 0.70 mmol) in CH2C12 (10 ml) was
prepared at 0 C and stirred at r.t.
overnight. Dilution with CH2C12, washing (NazSO4, NH4CI), drying, and
preparative thin layer chromatography gave
the title aldehyde as a yellow glass (47 mg, 43%).
Standard procedures can give the corresponding alcohol (NaBH4, MeOH, r.t.),
tosyl hydrazone (TsNHNHZ, EtOH,
reflux), oximes (RONHa=HCl, DMF, 60 C), amines (RIR2NH, NaBH(OAc)3i Cl-(CHZ)2-
Cl r.t.), homoallylic alcohol
(A11SiMe3a TiCl4), CHZCIZ, -78 C), or alkenes.
Example 39 2-(6-Amino-9-butyl-9H-purin-8-ylmethyl)-4-methoxy-benzaldehyde (39)
NHZ
-O
--- N
~ I \ r
N
Rt = 6.52; 'HNMR (CDC13-d) S 10.39 (s, IH), 8.32 (s, 1H), 7.76 (d, J 7.8 Hz,
1H), 6.87 (m, 2H), 6.22 (s, 2H),
4.28 (s, 2H), 4.03 (t, J = 7.6 Hz, 2H), 3.85 (s, 3H), 1.61 (quint., J = 7.3
Hz, 2H), 1.29 (sext., J= 7.4 Hz, 2H), 0.86 (t,
J=72Hz,3H).
Negishi couplings
A mixture of 3,4-dichlorobenzyl bromide (0.47 g, 1.96 mmol) and Rieke Zinc
(3.0 nil, 5g/100 ml THF, 2.35 mrnol)
was stirred overnight at r.t. in a flame-dried Schlenk tube and decanted to
provide a 0.65M stock solution of 3,4-
dichlorobenzyl zinc bromide. A solution of 8-bromo-9-butyl-9H-purin-6-ylarnine
(42.7 mg, 0.158 mol), Pd(dppf)Clz
(16.8 mg, 0.020 mmol), and 3,4-dichlorobenzyl zinc bromide (0.61 ml, 0.65M in
THF) was stirred in a flame-dried
Schlenk tube at 66 C overnight, quenched with sat. aq. NH4CI and sat. aq.
EDTA., extracted into EtOAc, dried and
concentrated. Preparative TLC purification (EtOAc/CHzC12/MeOH 14:14:2)
provided the title compound as a
colorless oil (approx. 15 mg, 20%).
Example 40 9-Butyl-8-(3,4-dichloro-benzyl)-9H-purin-6-ylamine (40)
compound isolated as solid, Rt = 7.98.
Example 41 3-(6-Amino-9-butyl-9H-purin-8-ylsulfanyl)-phenol (41)
N
i N
~
N
HO
H2
Step 1: Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHC13 before
adding bromine (180 ml, 3.5
mole) in one portion. The suspension was left stirring at room temperature for
72 hours in a closed system that was
vented by a 20G needle. The reaction was worked up by adding shaved ice into
the suspension before slowly
44
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the
desired product with acetic acid.
The crude product was dried under reduced pressure for 2 days to give 8-
Bromoadenine as a light brown powder (45
g, 60% yield). 'H NMR (DMSO-d6) S 8.12 (s, 1H), 7.22 (s, 2H). Rf(75%
EtOAc/Hex) = 0.4.
Step 2: 8-Bromopurine (2.2g, 10nunole) was dissolved in 50 ml of DMF before
adding 1-bromo-butane
(2.2 nil, 20 mmol) and cesium carbonate (6.7g, 20 mmol) into the solution. The
reaction mixture was left stirring at
room temperature for 16 hours before quenching with water and extracting with
EtOAc. The organic layer was
washed with water and dried with MgSO4 before removing solvent under reduced
pressure. A white powder (0.9g,
33%) of 8-Bromo-9-butyl-9H-purin-6-ylamine was isolated using silica gel
column chromatography (50%
EtOAc/Hexanes). 'H NMR (CDCl3) 6 8.32, (s, 1 H), 5.81 (s, 2H), 4.20 (t, 2H),
1.82 (rn, 2H), 1.40 (m, 214), 0.96 (t,
3H). Rf (75% EtOAc/Hex) = 0.6.
Step 3: To a mixture of sodium hydride (96 mg, 4 mmol) in DMF (4ml) was added
3-methoxy-
benzenethiol (1.12 g, 8 mmol). After 30 min, a solution of 8-bromo-9-butyl-9H-
purin-6-ylamine (0.54 g, 2 mmol) in
DMF (6 ml) was added and stirred for 12 h at 70 C. The reaction mixture was
quenched by addition of MeOH
(4m1), diluted with EtOAc (400 ml), washed with Na2CO3 (3 x 100 ml), brine (3
x 100 ml), dried (NaZSO4),
evaporated, purified with flash chromatography (CHZC12:MeOH = 100:5) to give 3-
(6-Amino-9-butyl-9H-purin-8-
ylsulfanyl)-phenol as a colorless powder (0.59 g, 89%). Rt = 6.75 min 'HNMR
(DMSO-d6): S 9.69 (s, IH), 8.17 (s,
1H), 7.45 (s, 2H), 7.17 (t, J=7.9Hz, 111), 6.76(d, J=7.4Hz, 1H), 6.68 (d,
J=8.2Hz, 1H), 6.62 (s, 1H), 4.11 (t, J=7.OHz,
2H), 1.57 (quint., J=7.3Hz, 2H), 1.19 (sext., J=6.8Hz, 2H), 0.81 (t, J=7.4Hz,
3H).
HPLC method used for these compounds: Agilent Zorbax 300 SB C18, 4.6 X 150 mm,
5 pm; Column Temperature:
Ambient; Flow Rate: 1.0 ml/min, Gradient: 5% acetonitrile (0.05% TFA) in water
(0.1% TFA) to 100% acetonitrile
(0.05% TFA) in 15 minutes, hold at 100 % for 2 niinutes).
The following compounds were prepared as for example 41, using the
corresponding thiol in place of the 3-
methoxybenzene thiol used in step 3:
Example 42 9-Butyl-8-(3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (42)
Rt= 8.6 nzin; 'H NMR (DMSO-d6) S 0.80 (t, J = 7.4 Hz, 3H, CH3), 1.20 (m, 2H,
CH2), 1.61 (m, 2H, CHz), 3.60 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 4.13 (t, J = 7.4 Hz, 2H, CHa), 6.46(s, 1H, Ar-
H), 6.85 (d, J= 8.9 Hz, 1H, Ar-H),
7.02 (d, J = 8.9 Hz, 1H, Ar-H), 7.41(bs, 2H, NH2), 8.15 (s, 1H, purine-H).
Example 43 9-Butyl-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine) (43)
Rt= 7.62 min; 'HNMR (CDC13-d6): S 8.30 (s, 1H), 7.18 (t, J=8.2Hz, 1H), 6.90
(m, 2H), 6.77 (m, 3H), 4.17 (t,
J=7.6Hz, 2H), 3.70 (s, 3H), 1.67 (quint., J=7.5Hz, 2H), 1.28 (sext., J=7.5Hz,
2H), 0.86 (t, J=7.4Hz, 3H).
Example 44 9-Butyl-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (44)
and
NH2
N N
N N
OMe
Example 45 9-Butyl-8-(4-iodo-3-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (45)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N N
\>--S
N N ~ ~
OMe I
As for example 42, followed by:
Step 4: To a solution of 9-butyl-8-(3-rnethoxy-phenylsulfanyl)-9H-purin-6-
ylami.ne (0.26g, 0.73mmol) in
AcOH ( 4m1) was added NIS (0.53g, 2.19mmol) in portions. The mixture was
stirred for 24 h at r.t. The reaction
mixture was diluted with EtOAc (200 rnl), and carefully neutralized with a
solution of K2C03 (2 x 50 ml), them
washed with NaZS2O3 (3 x 50 rrd), brine (3 x 50 ml), dried (Na2SO4),
evaporated, purified by preparative TLC
chromatography (CH2Cla: MeOH = 100:5) to give
the 2-iodo isomer (60 mg), and
Rt= 8.45 min;'HNMR (CDC13-d): 8 8.38 (s, 1H), 7.73 (d, J=8.7Hz, IH), 6.71 (d,
J=2.7Hz, 1H), 6.58 (dd, J=8.7,
2.7Hz, 1H), 5.91 (s, 211), 4.22 (t, J=7.4Hz, 2H), 3.68 (s, 3H), 1.75 (quint.,
J=7.7Hz, 2H), 1.34 (sext., J=7.5FIz, 2H),
0.93 (t, J=7.4Hz, 3H).
the 4-iodo isomer (65 mg).
Rt= 8.63 min; 'HNMR (CDC13-d): S 8.38 (s, 1H), 7.72 (d, J=8.lHz, IH), 6.92 (d,
J=1.8Hz, 1H), 6.58 (dd, J=8.1,
1.8Hz, 1H), 5.82 (s, 2H), 4.22 (t, J=7.4Hz, 2H), 3.85 (s, 3H), 1.75 (quint.,
J=7.7Hz, 2H), 1.37 (sext., J=7.5Hz, 2H),
0.93 (t, J=7.4Hz, 3H).
For compounds in which the N9 substituent is sensitive to halogenation
conditions, these may be prepared using
iodide already present in the benzenethiol moiety:
To a suspension of sodium hydride (96 mg, 4 mmol) in DMF (3 ml) was added 2-
iodo-5-methoxy-benzenethiol
(1.06 g, 4 mrnol; J Org. Chem, 2001, 66(13), 4525-4542). After 30 min, a
solution of 8-bromo-9-(4-methyl-pent-3-
enyl)-9H-purin-6-ylamine (296 mg, 1 nunol) in DMF (3 ml) was added, and the
mixture was stirred for 12 h at 70
C. The reaction was quenched by addition of MeOH (2 ml), diluted with EtOAc
(200 ml),washed with Na2CO3 (3 x
50 ml), brine (3 x 50 ml), dried (Na2SO4), evaporated, and purified by flash
chromatography (CHZC12: MeOH=
100:5) to give 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine as a colorless
powder (280 mg, 58%).
The following compounds were prepared by this method using, respectively, the
electrophiles 1-bromo-4-methyl-
pent-3-ene and 1-chloro-pent-4-yn:
Example 46 8-(2-Iodo-5-methoxy-phenylsuifanyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine (46)
NH2
ac>-s / \ =
OMe
46
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Rt= 9.14 mdn; 'HNMR (CDC13-d): 5 8.39 (s, 1H), 7.72 (d, J=8.7Hz, 1H), 6.72 (d,
J=2.7Hz, IH), 6.58 (dd, J=8.7,
2.7Hz, 1H), 5.81 (s, 2H), 5.15 (t, J=7.3Hz, IH), 4.25 (t, J=7.4Hz, 2H), 3.69
(s, 3I-I), 2.50 (quint., J=7.3Hz, 2H), 1.66
(s, 3H), 1.44 (s, 3H); MP: 167-167.5 C.
Example 47 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (47)
NH2
' N
N ~~--S
OMe
ei
Rt= 7.93 min; 'HNMR (CDC13-d): 5 8.38 (s, 1H), 7.75 (d, J=8.7Hz, IH), 6.74 (d,
J=2.7Hz, 1H), 6.60 (dd, J=8.7,
2.7Hz, 1 H), 5.72 (s, 2H), 4.32 (t, J=7.3Hz, 2H), 3.70 (s, 3H), 2.28 (td,
J=6.8, 2.6Hz, 2H), 2.06 (quint., J=7.3Hz, 2H),
2.00 (t, J=2.4Hz, IH); MP: 168-169 C.
The following compounds were prepared using the corresponding thiol in place
of the 3-methoxybenzene thiol and
base t-BuOK in place of NaH used in step 3:
Example 48 8-(Benzothiazole-2-ylsulfanyl)-9-butyl-9H-purin-6-ylamine (48)
Rt=6.53 min; 'H NMR (CDC13) 8 8.41 (s, 1H), 7.94 (d, 1H), 7.74 (d, 1H), 7.47
(t, 1H), 7.38 (t, IH), 6.01 (s, 2H),
4.32 (t, 2H), 1.79 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
Example 49 9-Butyl-8-(5-chloro-benzothiazole-2-ylsulfanyl)-9H-purin-6-ylarnine
(49)
Mass (M+1) = 391-8 et (M+3) = 393.8; 'H NMR (CDC13) 5 8.43 (s, IH), 7.92 (s,
IH), 7.65 (d, 1H), 7.35 (d, 1H),
6.01 (s, 2H), 4.32 (t, 2H), 1.79 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
Example 50 9-Butyl-8-(5-methoxy-benzothiazole-2-ylsulfanyl)-9H-purin-6-ylamine
(50)
'H NMR (CDC13) 8 8.42 (s, IH), 7.60 (d, IH), 7.43 (s, IH), 7.02 (d, 1H), 5.82
(s, 2H), 4.33 (t, 2H), 3.99 (s, 3H),
1.80 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H).
Example 51 9-Butyl-8-(2,5-dichloro-phenylylsulfanyl)-9H-purin-6-ylamine (51)
'H NMR (CDC13) S 8.37 (s, IH), 7.35 (d, 1H), 7.20 (dd, 1H), 7.14 (d, 1H), 5.72
(s, 2H), 4.24 (t, 2H), 1.79 (m, 2H),
1.35 (m, 2H), 0.89 (t, 3H).
Example 52 9 Butyl-8-(2,4,5-trichloro-phenylylsulfanyl)-9H-purin-6-ylamine
(52)
Rt=7.8 min; 'H NMR (CDCl3) S 8.37 (s, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 5.98
(s, 2H), 4.27 (t, 2H), 1.80 (m, 2H),
1.36 (m, 2H), 0.92 (t, 3H).
General Procedure
8-(2,5-dimethoxy-phenylsulfanyl)-2-fluoro-9(4-methyl-pent-3-enyl)-9H-purin-6-
ylamine and 8-(2,5-dimethoxy-
phenylsulfanyl)-2-amino-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine were
prepared from 2,6-diaminopurine by
procedures analogous to the one described above. The final conversion of amino
to fluoro was done by a method
siniilar to that reported in Example 2, step 4.
47
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 53 8-(2,5-dimethoxy-phenylsulfanyl)-2-amino-9(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine (53)
'H NMR (DMSO-d6) S 1.28 (s, 3H, CH3), 1.58 (s, 3H, CH3), 2.35 (m, 2H, CHZ),
3.60 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 4.12 (t, J= 7.0 Hz, 2H, CHa), 5.05 (t, J = 7 Hz, 1H, CH=), 6.50(s, 1H,
Ar-H), 6.91 (d, J 8.9 Hz, IH, Ar-H),
7.05 (d, J = 8.9 Hz, 1H, Ar-H).
Example 54 8-(2,5-dimethoxy-phenylsulfanyl)-2-fluoro-9(4-methyl-pent-3-enyl)-
9H-purin-6-ylatnine (54)
'H NMR (DMSO-d6) S 1.30 (s, 3H, CH3), 1.55 (s, 3H, CH3), 2.35 (m, 2H, CHZ),
3.60 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 4.10 (t, J = 7.0 Hz, 2H, CH2), 5.05 (t, J= 7 Hz, 1H, CH=), 6.47(s, 1H,
Ar-H), 6.86 (d, J= 8.9 Hz, 1H, Ar-H),
7.02 (d, J = 8.9 Hz, 1 H, Ar-H); MS (m/z) 426 (M+Na).
The following 12 compounds were prepared analogously to the method described
above in Example 41 using
various electrophiles to generate a library of N9 substituted compounds. N9
alkylation was done as a fmal step after
the broniine displacement of 8-bromopurine with 2,5-dimethoxy thiophenol.
Example 55 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine (55)
'H NMR (DMSO-d6) S 3.62 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.61(s, 1H, Ar-H),
6.85 (d, J = 8.9 Hz, IH, Ar-H),
7.02 (d, J = 8.9 Hz, 1H, Ar-H), 7.24 (bs, 2H, NH2), 8.13 (s, IH, purine-H)
13.33 (s, 1H, purine-NH); electrophile:
No substitution on N9.
Example 56 8-(2,5-dimethoxy-phenylsulfanyl)-9-pentyl-9H-purin-6-ylamine (56)
'H NMR (DMSO-d6) S 0.80 (t, J = 7.4 Hz, 3H, CH3), 1.20 (m, 4H, 2CH2), 1.61 (m,
2H, CHZ), 3.60 (s, 3H, OCH3),
3.76 (s, 3H, OCH3), 4.13 (t, J = 7.4 Hz, 2H, CH2), 6.46(s, 1H, Ar-H), 6.85 (d,
J= 8.9 Hz, 1H, Ar-H), 7.02 (d, J = 8.9
Hz, 1H, Ar-H), 7.41(bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-
bromopentyl.
Example 57 8-(2,5-dimethoxy-phenylsulfanyl)-9-pent-4-yny1-9H-purin-6-ylamine
(57)
NH2
N N
~}-S OMe
N N
OMe -
'H NMR (DMSO-d6) S 1.89(m, 2H, CH2), 2.20(t, J=8.OHz, 2H, CH2), 2.78(s, IH,
CH=), 3.62 (s, 3H, OCH3), 3.76 (s,
3H, OCH3), 4.23 (t, J= 7.4 Hz, 2H, CHZ), 6.46(s, 1H, Ar-H), 6.85 (d, J= 8.9
Hz, 1H, Ar-H), 7.02 (d, J= 8.9 Hz, 1H,
Ar-H), 7.41(bs, 2H, NH2), 8.15 (s, 1H, purine-H); electrophile: 1-chloro-pent-
4-yne.
Example 58 8-(2,5-dimethoxy-phenylsulfanyl)-9(3,3,3-trifluoromethylpropyl)-9H-
purin-6-ylamine (58)
'H NMR (DMSO-d6) S 2.54(t, J=8.OHz, 2H, CH2), 3.62 (s, 3H, OCH3), 3.74 (s, 3H,
OCH3), 4.46 (t, J= 8.0 Hz, 2H,
CH2), 6.46(s, 1H, Ar-H), 6.85 (d, J = 8.9 Hz, 1H, Ar-H), 7.02 (d, J = 8.9 Hz,
IH, Ar-H), 7.41(bs, 2H, NHz), 8.30 (s,
1H, purine-H); electrophile: 1-bromo-3,3,3-trifluoro-propane.
Example 59 8-(2,5-dimethoxy-phenylsulfanyl)-9(4-chlorobutyl)-9H-purin-6-
ylamine (59)
'H NMR (DMSO-d6) S 1.82(m, 2H, CH2), 1.98(m, 2H, CHZ), 3.56(t, J=6.4Hz, 2H,
CHZ), 3.75 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 4.23 (t, J= 7.4 Hz,.2H, CH2), 6.46(s, 1H, Ar-H), 6.85 (d, J=
8.9 Hz, 1H, Ar-H), 7.02 (d, J= 8.9 Hz,
1H, Ar-H), 7.41(bs, 2H, NHz), 8.15 (s, 1H, purine-H); electrophile: 1-bromo-4-
chlorobutane.
48
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 60 8-(2,5-dimethoxy-phenylsulfanyl)-9(4-acetyloxybutyl)-9H-purin-
6;ylamine (60)
'H NMR (DMSO-d6) 8 1.70(nz, 2H, CHa), 1.90(m, 2H, CHZ), 2.02(s, 3H, CH3), 3.75
(s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 4.10 (t, J=6.4Hz, 2H, CH2), 4.30 (t, J= 7.4 Hz, 2H, CHZ), 6.46(s, 1H,
Ar-H), 6.85 (d, J= 8.9 Hz, 1H, Ar-H),
7.02 (d, J = 8.9 Hz, 1H, Ar-H), 7.41(bs, 2H, NHa), 8.15 (s, 1H, purine-H);
electrophile: 1-bromo-4-acetyloxybutane.
Example 61 8-(2,5-dimethoxy-phenylsulfanyl)-9(5-bromopentyl)-9H-purin-6-
ylamine (61)
'H NMR (DMSO-d6) S 1.46 (m, 2H, CHZ), 1.85(ni, 4H, 2CH2), 3.36(t, J=6.7Hz, 2H,
CH2), 3.72 (s, 3H, OCH3), 3.80
(s, 3H, OCH3), 4.30 (t, J= 7.4 Hz, 2H, CHa), 6.46(s, 1H, Ar-H), 6.85 (d, J=
8.9 Hz, 1H, Ar-H), 7.02 (d, J= 8.9 Hz,
111, Ar-H), 7.41(bs, 2H, NH2), 8.15 (s, IH, purine-H); electrophile: 1,5-
dibromopentane.
Example 62 8-(2,5-dimethoxy-phenylsulfanyl)-9(2-[1,3]dioxolan-2-yl-ethyl)-9H-
purin-6-ylamine (62)
'H NMR (DMSO-d6) 52.26 (m, 2H, CH2), 3.75 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
3.85(t, J=7.OHz, 2H, CHZ),
3.98(t, J=7.0Hz, 2H, CHZ), 4.46 (t, J= 7.4 Hz, 2H, CHZ), 4.96(t, J=4.IHz, 1H,
CH), 6.46(s, 1H, Ar-H), 6.85 (d, J=
8.9 Hz, 1H, Ar-H), 7.02 (d, J= 8.9 Hz, 1H, Ar-H), 7.41(bs, 2H, NH2), 8.15 (s,
1H, purine-H); electrophile: 2-(2-
Chloro-ethyl)-[1,3]dioxolane.
Example 63 8-(2,5-dimethoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-
6-ylamine (63)
NH2
N N
>-S OMe =
N N / \
OMe
'H NMR (DMSO-d6) S 1.28 (s, 3H, CH3), 1.54 (s, 3H, CH3), 2.35 (m, 2H, CHZ),
3.60 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 4.15 (t, J= 7.0 Hz, 2H, CH2), 5.05 (t, J = 7 Hz, 1H, CH=), 6.46(s, 1H,
Ar-H), 6.86 (d, J= 8.9 Hz, IH, Ar-H),
7.02 (d, J= 8.9 Hz, 1H, Ar-H), 7.42(bs, 2H, NH2), 8.17 (s, IH, purine-H);
electrophile: 1-bromo-4-methyl-pent-3-
ene; MP: 148-150 C.
Example 64 8-(2,5-dimethoxy-phenylsulfanyl)-9-(pent-4-enyl)-9H-purin-6-ylamine
(64)
'H NMR (DMSO-d6) S 1.89(m, 2H, CH2), 2.19(t, J=8.OHz, 2H, CH2), 3.62 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 4.23
(t, J= 7.4 Hz, 2H, CH2), 5.05(m, 2H, CHZ=), 5.82(m, 1H, CH=), 6.46(s, 1H, Ar-
H), 6.85 (d, J= 8.9 Hz, IH, Ar-H),
7.02 (d, J= 8.9 Hz, IH, Ar-H), 7.41(bs, 2H, NHZ), 8.15 (s, IH, purine-H);
electrophile: 1-chloro-pent-4-yne.
Example 65 8-(2,5-dimethoxy-phenylsulfanyl)-9-(3-hydroxypropyl)-9H-purin-6-
ylamine (65)
'H NMR (DMSO-d6) S 1.82(m, 2H, CHZ), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
4.12(m, 2H, CH2), 4.21 (t, J
7.0 Hz, 2H, CHZ), 6.47(s, 1H, Ar-H), 6.86 (d, J= 8.9 Hz, 1H, Ar-H), 7.02 (d,
J= 8.9 Hz, IH, Ar-H); 8.15 (s, 1H,
purine-H); electrophile: 1-bromo-3-hydroxypropane.
Example 66 4-[6-Amino-8(2,5-dirnethoxysulfanyl)-purin-9-yl]-butyronitrile (66)
'H NMR (DMSO-d6) S 1.89(m, 2H, CHz), 2.20(t, J=8.0Hz, 2H, CHZ), 3.62 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 4.23
(t, J= 7.4 Hz, 2H, CHa), 6.46(s, 1H, Ar-H), 6.85 (d, J= 8.9 Hz, 1H, Ar-H),
7.02 (d, J= 8.9 Hz, IH, Ar-H), 7.41(bs,
2H, NH2), 8.15 (s, IH, purine-H); electrophile: 1-bromobutyronitrile.
Example 67 9-Butyl-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (67)
This compound was prepared using diazonium salts and thiols as coupling
partners.
49
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 1: A suspension of 8-bromo-9-butyl-9H-purin-6-ylarnine (0.50 g, 1.85
mmol) and thiourea (1.49 g,
19.6 mmol) in n-butanol (10 ml) was heated to reflux for 14 h. Dilution with
CHZC12 (70 ml), washing with water
and concentration afforded 6-amino-9-butyl-7,9-dihydro-purine-8-thione as a
white powder (0.42 g, 1.87 nunol, 100
%). 'H NMR (DMSO-d6) 6 12.35-12.25 (br. s, IH), 8.13 (s, 1H), 6.92-6.72 (br.
s., 2H), 4.09 (t, J= 7.6 Hz, 2H), 1.71
(quint., J = 7.5 Hz, 2H), 1.29 (sext., J= 7.5 Hz, 2H),0.87 (t, J= 7.4 Hz, 3H).
Step 2: A solution of the above thione (30.8 mg, 0.138 nunol) and t-BuOK (15.5
mg, 0.138 nunol) in
MeOH (0.55 ml) was treated portion-wise with crude 2-iodo-5-methoxy-
benzenediazonium tetrafluoroborate (48
mg, 0.138 mmol). The vigorous N2 evolution ceased after 2 mi.n. Work-up and
preparative TLC (MeOH:CH2C12
5:95) yielded the title sulfide.Example 68 2-Fluoro-8-(2-iodo-5-rnethoxy-
phenylsulfanyl)-9-pent-4-ynyl-9H-
purin-6-ylamine (68)
Step 1 8-Bromo-9-pent-4-ynyl-9H-purine-2,6-diamine
A mixture of 8-bromo-9H-purine-2,6-diamine (600 mg; Bearnan et al, J. Org.
Chem., 1962, 27, 986), CsaCO3 (1.94
g), 5-chloro-pent-l-yne (0.56 mL), and DMF (5 mL) was heated to 85 C
overnight. Work-up and evaporation gave
the title compound as a crude solid. 'H NMR (CDC13) S 6.80 (s, 2H), 5.95 (s,
2H), 3.98 (t, 2H), 2.81 (t, 1H), 2.22 (t,
2H), 1.96 (quint., 2H).
Step 2 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purine-2,6-diamine
A mixture of 8-bromo-9-pent-4-ynyl-9H-purine-2,6-diamine (500 mg), 2-iodo-5-
methoxy-benzenethiol (1.34 g), t-
BuOK (475 mg) and DMF (7 mL) was heated to 100 C overnight. Extraction and
chromatography gave the title
conipound. Rt= 7.85 niin.'H NMR (CDC13) S 7.72 (d, IH), 6.98 (s, 211), 6.63
(d, 1H), 6.22 (dd, 1H), 6.01 (s, 2H),
4.01 (t, 2H), 3.60 (s, 3H), 2.67 (t, 1H), 2.12 (dt, 2H), 1.78 (quint., 2H),
1.97 (t, 1H).
Step 3 2-Fluoro-8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine
A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purine-2,6-
diamine (79 mg) and 48% aq.
HBF4 (0.5 mL) in THF (0.5 mL) was treated at -20 C with iso-amyl nitrite (22
uL). The reaction mixture was
allowerd to reach rt and was further heated to 40 C for 10 min. Work-up
(DCMlaq. K2C03) and chromatography
(EtOAc/Hexane 1:4) gave the title compound as a solid. Rt= 9.43 min. 'H NMR
(CDC13) S 7.72 (d, 1H), 6.70 (d,
IH), 6.59 (dd, 1H), 4.25 (t, 2H), 3.69 (s, 3H), 2.25 (dt, 2H), 2.02 (quint.,
2H), 1.97 (t, 1H).
Example 69 9-(tert-Butyl-dimethyl-silanyloxymethyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine (69)
A solution of 9-(tert-Butyl-dimethyl-silanyloxymethyl)-8-iodo-9H-purin-6-
ylamine (817 mg; Lang, J. Org. Chem.
2000, 65, 7825) and of potassium 2-iodo-5-methoxy-benzenethiolate (920 mg;
Flynn, Org. Lett. 2001, 3, 651) in
DMF (10 mL) was heated to 60 C for lh and to 100 C for another lh. Work-up
and flash chromatogrpahy
(CH2CI2:EtOAc 67:33 - 0:100) gave the title compound as a white solid. Rt=
10.47 min.'H NMR (CDC13) S 8.37
(s, 1H), 7.70, (d, 1H), 6.83 (d, 1H), 6.56 (dd, IH), 5.83 (s, 2H), 5.75 (s,
2H), 3.67 (s, 3H), 0.83 (s, 9H), 0.09 (s, 6H).
Example 70 9-(2-Chloro-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (70)
Step 1 6-Amino-7,9-dihydro-purine-8-thione
3,4,5-Triaminopyrimidine (50 g) and thiourea (60 g, 2 equiv.) were ground
together in a mortar, and heated until
molten (T ; t = 150 C), whereupon an endothermic reaction took place. The
reaction mixture was stirred at that
temperature until solidification occurred (2 h), cooled to room temperature,
finely ground, and stirred in water
overnight to remove the excess thiourea. The desired material was obtained by
filtration (88-94% yield, 100%
purity). Rt= 1.99 min. 'H-NMR (DMSO-d6) 6 13.04 (s, IH), 12.05 (s, 1H), 8.07
(s, 1H), 6.75 (s, 2H). 13C-NMR
(DMSO-d6) S 167.0, 153.1, 150.33, 147.8, 108.5.
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 2 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9h-purin-6-ylamine
A suspension of the finely ground 6-amino-7,9-dihydro-purine-8-thione (46 g)
in DMF (700 ml) was cooled to -60
C, and treated with 2-iodo-5-methoxybenzenediazonium tetrafluoroborate (100 g,
1.1 equiv; (a) Ma, J. Org. Chem.
2001, 66,4525 (b) Flynn, Org. Lett, 2001, 3, 651). The mixture was allowed to
warm up gradually. When it reached
- 10 C, a gas evolution was observed, as well as the formation of a deep red
color due to a minor but highly colored
by-product. The reaction mixture was allowed to reach room temperature, before
being neutralized with NaHCO3
(38 g, 1.7 equiv.) concentrated, suspended in chloroform, filtered until no
more red dye could be washed off, and
fiuther washed with water to afford the crude title material (64 g, "61%").
This material could be used without
further purification. Alternatively, a work-up (extraction into NaOH 1M, EtOAc
washing, acidification with HCI,
EtOAc washing, neutralization, extraction into EtOAc) is feasible. Rt = 6.08
min (5-100-12). 'HNMR (DMSO) S
(hr. s, IH), 8.13 (s, 1H), 7.79 (d, 1H), 7.38 (br., s, 2H), 6.71 (d, 1H), 6.62
(s, 2H), 3.65 (s, 3H).
Step 3 9-(2-Chloro-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine
8-(2-lodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (7.3 g) was treated
with 1-bromo-2-chloroethane (3.7 ml,
2.5 equiv.) and K2C03 (7.6 g, 3 equiv.) in DMF at 40 C for 16 h. The reaction
mixture was concentrated, dissolved
in MeOH: CH2C12 10:90 and washed with water. Chromatography (EtOAcCH3CN:MeOH
800:200:2) gave 1.7 g
(21%) of the desired material. Combining the impure fractions and
crystallization (70 ml EtOH) gave an additional
0.9 g (11%). Rt = 7.61 min (5-100-12). 'HNMR (CDC13) S(s, 1H), 7.73 (d, J =
8.4Hz, 1H), 6.77 (s, 1H), 6.60 (d,
1H), 5.93(br., s, 2H), 4.61 (t, J= 4.4Hz, 2H), 3.90 (t, J= 4.4Hz, 2H), 3.70
(s, 3H).
Example 71 9-(3-chloro-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (71)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with 1-
bromo-3-chloro-propane as in Example 15 Step 1. Rt = 7.93 min (5-100-12). 'H
NMR (CDC13) S 8.36 (s, 1H), 7.73
(d, IH), 6.72 (d, 1H), 6.59 (dd, 1H), 6_07 (br.s, 2H), 4.38 (t, 2H), 3.68 (s,
3H), 3.55(t, 2H), 2.27 (quint. 211).
Example 72 9-(4-Chloro-butyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (72)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with 1-
bromo-4-chloro-butane as in Example 15 Step 1. Rt = 8.27 min (5-100-12). 'H
NMR (CDC13) S 8.36 (s, IH), 7.72
(d, 1H), 6.73 (s, 1H), 6.58 (d, 1H), 6.30 (br.s, 2H), 4.40 (m, 211), 3.68 (s,
311), 3.53 (m, 2H), 1.93 (m, 2H), 1.79 (m,
2H).
General procedure A
A mixture of the alkyl chloride and the appropriate amine (5-30 eq in DMF or
neat) was heated to 40-120 C in a
sealed tube overnight. Evaporation, work-up (CH2CI2/sat. aq. NaHCO3) and
preparative TLC gave the desired
amine.
Compounds 73-82, 84-120 were prepared in this manner.
Example 73 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-[3-(4-methyl-piperazin-l-yl)-
propyl]-9H-purin-6-ylamine
(73)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with N-methylpiperazine according to the general procedure A. Rt= 5.24
min. 'H NMR (CDC13) 6 8.37 (s,
1H), 7.70, (d, 1H), 6.62 (d, 111), 6.52 (dd, 1H), 5.78 (s, 2H), 4.30 (t, 2H),
3.62 (t, 3H), 2.30 (m, 10 H), 2.22 (s, 311),
1.95 (quint., 2H).
Example 74 9-(3-Dimethylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H
purin-6-ylamine (74)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with dimethylamine (generated from dimethylamine hydrochloride and t-
BuOK in DMF) according to the
51
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
general procedure A. Rt= 5.37 min. 'H NMR (CDC13) 6 8.34 (s, 1H), 7.71, (d,
IH), 6.71 (d, 1H), 6.56 (dd, iH), 5.83
(s, 2H), 4.31 (t, 2H), 3.68 (s, 3H), 2.29 (t, 3H), 2.37 (s, 6H), 2.11 (quint,
211).
Example 75 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-piperidin-l-yl-propyl)-9h-
purin-6-ylamine (75)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with piperidine according to the general procedure A. Rt= 5.78 rnin.
'H NMR (CDCl3/CD3OD 10:1) S 8.17
(s, 1H), 7.71 (d, IH), 6.80 (d, 1H), 6.57 (dd, IH), 4.20 (t, 2H), 3.66 (s,
3H), 2.30 (m, 4H), 1.94 (quint., 2H), 1.46
(quint., 4H), 1.21 (m, 2H).
Example 76 9-(3-Cyclopropylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine (76,)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylaniine with cycloprpylamine according to the general procedure A. Rt= 5.58
min. 'H NMR (CDC13) S 8.34 (s, 1H),
7.72 (d, 1H), 6.79 (d, IH), 6.57 (dd, iH), 5.80 (s, 2H), 4.28 (t, 2H), 3.66
(s, 3H), 2.67 (t, 2H), 2.05 (m, 1H), 1.99
(quint., 2H), 0.42 (m, 4H).
Example 77 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-morpholin-4-yl-propyl)-9H-
purin-6-ylamine (77)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with morpholine according to the general procedure A. Rt= 5.34 min. 'H
NMR (CDC13/CD3OD 10:1) 6
8.21 (s, 1H), 7.72 (d, 1H), 6.79 (d, 1H), 6.57 (dd, 1H), 4.26 (t, 2H), 3.67
(s, 3H), 3.61 (t, 4H), 2.36 (m, 6H), 1:96
(quint., 2H).
Example 78 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-methylamino-propyl)-9H-
purin-6-ylamine (78)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 40% aq. methylamine in DMF according to the general procedure A.
Rt= 5.34 min. 'H NMR (CDC13)
S 8.35 (s, IH), 7.71 (d, 1H), 6.68 (d, 1H), 6.56 (dd, 1H), 5.82 (s, 2H), 4.29
(t, 2H), 3.66 (s, 3H), 2.53 (t, 2H), 2.87 (s,
3H), 2.73 (quint., 2H).
Example 79 9-(3-Ethylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (79)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 70% aq. ethylamine in DMF according to the general procedure A.
Rt= 5.53 min. 'H NMR (CDC13) S
8.35 (s, 1H), 7.72 (d, iH), 6.69 (d, 1H), 6.57 (dd, 1H), 5.78 (s, 2H), 4.31
(t, 2H), 3.67 (s, 3H), 2.56 (m, 4H), 1.96
(quint., 2H), 1.08 (t, 3H).
Example 80 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-[2-(4-methyl-piperazin-l-yl)-
ethyl]-9H-purin-6-ylanune
(80)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylarnine with N-methyl piperazine according to the general procedure A. Rt=
5.56 min. 'H NMR (CDC13) S 8.34 (s,
IH), 7.69 (d, 1H), 6.67 (d, 1H), 6.54 (dd, 1H), 5.73 (s,'21-1), 4.34 (t, 2H),
3.66 (s, 3H), 2.69 (t, 2H), 2.50 (m, 4H),
2.30 (m, 4H), 2.24 (s, 3H).
Example 81 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(2-piperidin-1-yl-ethyl)-9H-
purin-6-ylamine (81)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with piperidine according to the general procedure A. Rt= 5.80 min. 1H
NMR (CDC13) S 8.34 (s, IH), 7.69
(d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 5.68 (s, 2H), 4.33 (t, 2H), 3.66 (s,
3H), 2.63 (t, 2H), 2.41 (m, 4H), 1.51 (m, 4H),
1.30 (m, 2H).
Example 82 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(2-propylamino-ethyl)-9H-
purin-6-ylamine (82)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with propylamine according to the general procedure A. Rt= 5.69 min.
'H NMR (CDC13) S 8.34 (s, 1H),
52
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
7.69 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 11-1), 5.85 (s, 2H), 4.33 (t, 2H), 3.65
(s, 3H), 2.97 (t, 2H), 2.53 (t, 2H), 1.39
(sext., 2H), 0.85 (t, 3H).
Example 83 8-(2,5-Dimethoxy-phenylsulfanyl)-9-(3-dimethylamino-propyl)-9H-
purin-6-ylamine (83)
A suspension of 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine (127 mg),
Me2N-(CH2)3-CI.HCI (236 mg),
CsZCO3 (680 mg) in DMF (2 mL) was heated to 90 C for 2 h. Work-up and
preparive TLC (MeOH:DCM 1:10)
gave the title compound. Rt= 4.83 min. 'H NMR (CDC13) S 8.33 (s, 1H), 6.85 (d,
IH), 6.81 (d, 1H), 6.75 (d, 1H),
5.68 (s, 2H), 4.42 (t, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.35 (t, 2H), 2.22 (s,
6H), 1.99 (quint., 2H).
Example 84 8-(2-lodo-5-methoxy-phenylsulfanyl)-9-(2-isopropylamino-ethyl)-9H-
purin-6-ylamine (84)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with iso-propylamine according to the general procedure A. Rt= 5.61
min. 'H NMR (CDC13) S 8.34 (s, IH),
7.69 (d, IH), 6.69 (d, IH), 6.52 (dd, 1H), 5.68 (s, 2H), 4.33 (t, 2H), 3.66
(s, 3H), 3.02 (t, 2H), 3.85 (sept., 1H), 0.95
(d, 6H).
Example 85 9-(2-Butylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-
6-ylamine (85)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylanune with butylamine according to the general procedure A. Rt= 6.10 min. 'H
NMR (CDC13) S 8.34 (s, 1H), 7.70
(d, 1H), 6.72 (d, 1H), 6.55 (dd, IH), 5.78 (s, 2H), 4.32 (t, 2H), 3.67 (s,
3H), 3.00 (t, 2H), 2.60 (t, 2H), 1.40 (sext.,
2H), 1.28 (quint., 2H), 0.87 (t, 3H).
Example 86 9-(2-sec-Butylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (86)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfany])-9H-purin-6-
ylamine with see-butylanvne according to the general procedure A. Rt= 5.91
min. 'H NMR (CDCI3) S 8.35 (s, 1H),
7.70 (d, 1H), 6.72 (d, 111), 6.55 (dd, IH), 5.67 (s, 2H), 4.35 (t, 2H), 3.68
(s, 3H), 3.03 (m, 1H), 2.95 (m, 1H), 2.54
(sext., 1H), 1.38 (sext., 1H), 1.24 (m, 1H), 0.96 (d, 3H), 0.82 (t, 3H).
Example 87 9-[2-(I-Ethyl-propylamino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine (87)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 1-ethyl-propylamine according to the general procedure A. Rt=
6.34 min. 'H NMR (CDC13) S 8.33 (s,
IH), 7.69 (d, 111), 6.71 (d, IH), 6.54 (dd, IH), 6.07 (s, 2H), 4.33 (t, 2H),
3.65 (s, 3H), 2.96 (t, 2H), 2.34 (quint., 1H),
1.31 (m, 4H), 0.77 (t, 6H).
Example 88 9-(2-Cyclopropylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylaniine (88)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclopropylaniine according to the general procedure A. Rt= 5.51
min. 'H NMR (CDC13) S 8.36 (s,
1H), 7.69 (d, 1H), 6.71 (d, 1H), 6.54 (dd, IH), 5.71 (s, 2H), 4.33 (t, 2H),
3.66 (s, 3H), 3.07 (t, 2H), 2.11 (sept., 1H),
0.34 (m, 2H), 0.23 (m, 2H).
Example 89 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-isobutylamino-ethyl)-9H-
purin-6-ylamine (89)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylarnine with iso-butylamine according to the general procedure A. Rt= 6.10
min (5-100-12). 'H NMR (DMSO-d6) S
8.16 (s, 1H), 7.74 (d, 1H), 6.45 (br. s, 1H), 6.67 (dd, 111), 6.46 (d, 1H),
4.19 (t, 2H), 3.60 (s, 3H), 2.77 (t, 2H), 2.22
(d, 2H), 1.41 (m, 1H), 0.75 (d, 611).
Example 90 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-[2-(3-methyl-butylamino)-
ethyl]-9H-purin-6-ylamine (90)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with iso-amylamine according to the general procedure A. Rt= 6.53 min
(5-100-12). 'H NMR (CDCl3) 8
8.34 (s, 1H), 7.98 (d, 1H), 6.71 (d, IH), 6.65 (dd, IH), 5.70 (br. s, 2H),
4.33 (t, 2H), 3.68 (s, 314), 3.25 (q, 2H), 2.97
(t, 2H), 2.70 (t, 2H), 1.95 (m, IH), 0.91 (d, 6H).
53
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 91 9-[2-(3,3-Dimethyl-butylamino)-ethyl]-8-(2-iodo-5-methoxy-
phenyisulfanyl)-9H-purin-6-ylamine
(91)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 3,3-dimethyl-butylamine according to the general procedure A. Rt=
6.87 niin (5-100-12).
Example 92 {2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethylamino}-acetonitrile (92)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with amino-acetonitrile according to the general piocedure A. Rt= 6.31
min (5-100-12). 'H NMR (CDC13) S
8.37 (s, 1H), 7.74 (d, 1H), 6.73 (d, IH), 6.60 (dd, 1H), 5.63 (br. s, 2H),
4.38 (t, 211), 3.67 (s, 3H), 2.58 (m, 2H), 3.10
(m, 2H).
Example 93 2-{2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethylamino}-ethanol (93)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with ethanolamine according to the general procedure A. Rt= 5.14 niin
(5-100-12). 'H NMR (CDC13) 6 8.37
(s, IH), 7.70 (d, 1H), 6.76 (d, IH), 6.56 (dd, IH), 5.71 (br. s, 2H), 4.33 (t,
211), 3.68 (s, 311), 3.56 (t, 2H), 3.01 (t,
2H), 2.97 (3, 2H).
Example 94 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-[2-(2-methoxy-ethylamino)-
ethyl]-9H-purin-6-ylamine
(94)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with MeO-(CHZ)a-NHZ according to the general procedure A. Rt= 5.52 min
(5-100-12). 'H NMR (CDC13) a
8.32 (s, IH), 7.68 (d, 1H), 6.72 (d, IH), 6.56 (dd, 1H), 5.68 (br. s, 2H),
4.32 (t, 213), 3.68 (s, 3H), 3.42 (t, 2H), 3.32
(s, 3H), 3.03 (t, 2H), 2.81 (3, 2H).
Example 95 9-(3-tert-Butylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (95)
Step 1 Methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-
purin-9-y1]-propyl ester
was reacted with tert-butylamine according to the general procedure A. The
crude reaction product was extracted
into aq. HCI, and the aqueous solution was washed ten times with CHC13.
Neutralization (NaHCO3) and back-
extraction into CHC13 gave the title compound as a crude oil. The free base
(4.34 g) was dissolved in MeOH (100
mL), treated with conc. HCI (2.7 mL) and the solution was evaporated to
dryness. The hydrochloride salt was re-
dissolved in refluxing MeOH and precipitated with acetone. Filtration gave
pure hydrochloride salt. The salt was =
dissolved in water, neutralized with sat. aq. NaHCO3, and extracted with
CHC13. Drying and concentration gave the
pure title compound in its free base form. Rt = 5.87 niin (5-100-12). 'H NMR
(CDC13) & 8.33 (s, IH), 7.70 (d, 1H),
6.69 (d, 1H), 6.55 (dd, 1H), 5.90 (br. s, 211), 4.30 (t, 2H), 3.66 (s, 3H),
2.50 (t, 2H), 1.96 (quint, 2H), 1.05 (s, 9H).
Step 2 9-(3-tert-Butylamino-propyl)-8-(2-iodo-5-xnethoxy-phenylsulfanyl)-9H-
purin-6-ylamine,
phosphoric acid salt.
9-(3-tert-Butylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (7.29 g) was dissolved in
refluxing EtOH, and treated with a solution of H3PO4 (0.84M in EtOH, 17.0 mL)
whereupon a precipitate
immediately appeared. This was collected by filtration, washed (EtOH), and
dried to give the phosphate salt. Rt =
4.77 niin (5-100-7). S 8.04 (br. s, 1H), 7.72 (br. d, 1H), 6.89 (br. s; 1H),
6.65 (br. d, 1H), 4.21 (br. t, 2H), 3.61 (br. s,
3H), 2.86 (br. t, 2H), 2.04 (br. quint., 2H), 1.15 (s, 9H).
Example 96 9-(2-Cyclopentylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (96)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclopentylamine according to the general procedure A. Rt= 6.05
min (5-100-12). 'H NMR (CDCI3) S
54
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
8.34 (s, 1H), 7.70 (d, 1H), 6.71 (d, 1H), 6.58 (dd, IH), 5.85 (br. s, 2H),
4.38 (t, 2H), 3.65 (s, 3H), 3.03 (quint., 2H),
2.98 (t, 2H), 1.80 (m, 4H), 1.60 (m, 4H).
Example 97 9-(2-Cyclohexylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (97)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy_phenylsulfanyl)-9H-purin-6-
ylamine with cyclohexylamine according to the general procedure A. Rt= 6.40
niin (5-100-12). '14 NMR (CDC13) S
8.34 (s, 1H), 7.70 (d, IH), 6.75 (d, 1H), 6.62 (dd, 1H), 5.80 (br. s, 2H),
4.25 (t, 2H), 3.65 (s, 3H), 3.03 (m,-1H), 2.98
(t, 2H), 1.301.10 (m, 10H).
Example 98 9-(2-Cycloheptylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (98)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cycloheptylamine according to the general procedure A. Rt= 6.80
nun (5-100-12). 'H NMR (CDC13) S
8.34 (s, 1H), 7.68 (d, 1H), 6.75 (d, 1H), 6.32 (dd, IH), 5.80 (br. s, 2H),
4.30 (t, 2H), 3.65 (s, 3H), 2.98 (t, 2H), 2.80
(m, IH), 1.73 (m, 4H), 1.55 (m, 4H), 1.42 (m, 4H).
Example 99 9-(2-Cyclooctylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (99)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclooctylamine according to the general procedure A. Rt= 7.10
min (5-100-12). 'H NMR (CDC13) 6
8.34 (s, 1H), 7.68 (d, 1H), 6.82 (d, 1H), 6.66 (dd, IH), 5.72 (br. s, 2H),
4.40 (t, 2H), 3.65 (s, 3H), 3.00 (t, 2H), 2.72
(m, 1H), 1.60-1.10 (m, 14H).
Example 100 9-[2-(Cyclopropylmethyl-amino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine (100)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylaniine with C-cyciopropyl-metyl-amine according to the general procedure A.
Rt= 5.82 min (5-100-12): 'H NMR
(CDC13/CD3OD 3:1) S 8.13 (s, 1H), 7.67 (d, 1H), 6.82 (d, 1H), 6.59 (dd, IH),
4.24 (t, 2H), 3.63 (s, 3H), 2.91 (t, 2H),
2.37 (d, 2H), 0.78 (m, 1H), 036 (m, 2H), 0.00 (m, 2H).
Example 101 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-[2-(2-methyl-allylamino)-
ethyl]-9H-purin-6-ylamine
(101)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 2-methyl-allylamine according to the general procedure A. 'H NMR
(CDC13/CD3OD 10:1) S 8.16 (s,
IH), 7.69 (d, 1H), 6.84 (d, IH), 6.58 (dd, 1H), 4.76 (s, 2H), 4.32 (t, 2H),
3.66 (s, 3H), 3.12 (br. s, 2H), 2.94 (t, 2H),
1.61 (s, 3H).
Example 102 9-(2-tert-Butylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (102)
The title compound was obtained by reacting toluene-4-sulfonic acid 2-[6-amino-
8-(2-iodo-5-methoxy-
phenylsulfanyl)-purin-9-ylj-ethyl ester with tert-butylamine according to the
general procedure A. Solid, Rt= 4.73
min (5-100-7).
Example 103 9-(3-Amino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylanvnen (103)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with NH3 (7M in MeOH) according to the general procedure A. Rt = 5.45
min (5-100-12). 'HNMR
(CD3OD) S 8.21 (s, 1H), 7.86 (d, IH), 7.00 (s, 1H), 6.79 (d, IH), 4.31 (t,
2H), 3.76 (s, 3H), 2.74 (t, 2H), 1.88 (quint.,
2H), 1.57 (quint., 2H).
Example 104 9-(2-Cyclopropylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine (104)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclopropylamine according to the general procedure A. Rt = 5.48
min. 'H NMR (CD3OD) S 8.21 (s,
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
IH), 7.83 (d, 1H), 6.94 (d, IH), 6.57 (dd, 1H), 4.40 (t, 2H), 3.72 (s, 3H),
3.06 (t, 2H), 2.05 (ni, IH), 0.69 (m, 2H),
0.44 (m, 2H).
Example 105 9-(2-Allylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (105)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with allylamine according to the general procedure A. Rt = 5.62min. 'H
NMR (CD3OD ) 6 8.21 (s, 1H),
7.85 (d, IH), 6.96 (d, 1H), 6.48 (dd, 1H), 5.90 (in, 1H), 5.20 (m, 211), 4.41
(m, 2H), 3.74 (s, 3H), 3.24 (m, 2H), 3.06
(t, 2H), 2.05 (rn, 1H), 0.69 (m, 2H), 0.44 (m, 2H).
Example 106 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-morpholin-4-yl-ethyl)-9H-
purin-6-ylamine (106)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with morpholine according to the general procedure A. Rt = 5.33 min.
'H NMR (CDCl3) S 8.36 (s, 1H),
7.69 (d, 1H), 6.70 (d, 1H), 6.53 (dd, 1H), 5.76 (s, 2H), 4.36 (t, 2H), 3.68
(s, 3H), 2.70 (t, 2H), 2.49 (m, 4H), 1.82 (m,
4H).
Example 107 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-propylamino-propyl)-9H-
purin-6-ylamine (107)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with n-propylamine according to the general procedure A. Rt = 5.78 nun
(5-100-12M). 'H NMR (MeOH) S
8.21 (s, 1H), 7.85 (d, IH), 6.97 (d, 1H), 6.77(dd, 1H), 4.34 (t, 2H), 3.75 (s,
3H), 2.57 (t; 2H), 2.47 (t, 2H), 2.03
(quint., 2H), 1.51 (q, 2H), 0.94 (t, 3H).
Example 108 9-[3-(1-Ethyl-propylamino)-propyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylarnine
(108)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 1-ethyl-propylamine according to the general procedure A. Rt =
6.28 min (5-100-12). 'H NMR
(MeOH) fi 8.20 (s, 1H), 7.82 (d, 1H), 6.96 (d, 1H), 6.75(dd, IH), 4.35 (t,
2H), 3.73 (s, 3H), 2.74 (t, 2H), 2.55 (quint.,
1H), 2.08 (s, quint., 2H), 1.52 (m, 4H), 0.91 (t, 6H).
Example 109 9-(3-sec-Butylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine
(racemate) (109)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with sec-butylamine according to the general procedure A. The same
procedure was also used with
enantiomerically pure (S- or R)-sec-butylamine to give the corresponding
enantiomer. Rt = 5.93 min (5-100-12). IH
NMR (MeOH) S 8.21 (s, 1H), 7.85 (d, 1H), 6.96 (d, 1H), 6.76(dd, 1H), 4.35 (t,
2H), 3.73 (s, 3H), 2.70-2.64 (m, 3H),
2.07 (quint., 2H), 1.58 (m, 1H), 1.34 (m, 1H), 1.08 (d, 3H), 0.92 (s, 3H).
Example 110 9-(3-Heptylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (110)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with n-heptylamine according to the general procedure A. Rt = 7.50 min
(5-100-12). 'H NMR (MeOH) S
8.21 (s, 1H), 7.85 (d, 1H), 6.99 (d, 1H), 6.79(dd, 1H), 4.39 (t, 2H), 3.75 (s,
3H), 2.99 (t, 2H), 2.89 (t, 2H), 2.19
(quint., 2H), 1.65 (m, 2H), 1.34 (m, 8H), 0.90(t, 3H).
Example 111 9-(3-Cyclopentylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine (111)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclopentylamine according to the general procedure A. Rt = 6.12
min (5-100-12). 'H NMR (CDC13) S
8.30 (s, 1H), 7.69 (d, 1H), 6.68 (d, 1H), 6.55(dd, 1H), 6.06 (br.s., 2H), 4.29
(t, 2H), 3.65 (s, 3H), 2.98 (quint., 1H),
2.56 (t, 2H), 1.99 (quint., 2H), 1.64-1.40 (m, 8H).
56
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 112 9-(3-Cyclooctylamino-propyl)-8-(2-iodo-5-rnethoxy-phenylsulfanyl)-
9H-purin-6-ylamine (112)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyciooctylamine according to the general procedure A. Rt = 7.07
min (5-100-12). 'H NMR (CDC13) 8
8.31 (s, 1H), 7.70 (d, 1H), 6.68 (d, 1H), 6.55 (dd, 1H), 6.00 (br.s., 2H),
4.30 (t, 2H), 3.65 (s, 3H), 2.70 (quint., 1H),
2.59 (t, 2H), 1.53-1.40 (m, 14H).
Example 113 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-isobutylamino-propyl)-9H-
purin-6-ylamine (113)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with isobutyIamine according to the general procedure A. Rt = 6.00 min
(5-100-12). 1H NMR (CDC13) 8
8.32 (s, 1H), 7.70 (d, IH), 6.67 (d, IH), 6.56 (dd, 1H), 5.97 (br.s., 2H),
4.30 (t, 2H), 3.65 (s, 3H), 2.56( t, 2H), 2.33
(d, 211), 1.79 (quint., 2H), 1.72(m, 1H), 0.90(d, 14H).
Example 114 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-[3-(1,2,2-trimethyl-
propylamino)-propyl]-9H-purin-6-
ylamine (114)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 1,2,2-trimethyl-propylamine according to the general procedure A.
Rt = 6.56 min (5-100-12). 1H NMR
(CDC13) S 8.35 (s, 1H), 7.72 (d, 1H), 6.70 (d, 1H), 6.59 (dd, 1H), 5.95
(br.s., 2H), 4.33 (t, 2H), 3.67 (s, 3H), 2.79 (m,
IH), 2.50 (m, IH), 2.21 (rn, 1H), 1.99 (m, 2H), 0.90 (s, 9H).
Example 115 4-{3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-y1]-
propylamino}-piperidine-l-
carboxylic acid tert-butyl ester (115)
The title compound was obtained by reacting 9-(3-chloro-propyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylarnine with 4-amino-piperidine-l-carboxylic acid tert-butyl ester according
to the general procedure A. Rt = 6.14
min (5-100-12). 'H NMR (CDCI3) 6 8.29 (s, 1H), 7.69 (d, IH), 6.66 (d, 1H),
6.55 (dd, IH), 6.29 (br.s., 2H), 4.29 (t,
2H), 3.64 (s, 3H), 3.15 (quint., IH), 2.79 (t, 2H), 2.57 (m, 4H), 1.96 (m,
2H), 1.80 (m, 2H), 1.23 (s, 9H).
Example 116 9-(2-Benzylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (116)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with benzylamine according to the general procedure A. Rt = 6.31 min.
'H NMR (CDC13) S 8.35 (s, 111),
7.71 (d, 1H), 7.36-7.22 (m, 5H), 6.75 (d, IH), 6.57 (dd, 1H), 5.84 (br.s, 2H),
4.39 (t, 2H), 3.79 (s, 2H), 3.67 (s, 3H),
3.04 (t, 2H).
Example 117 (R)-9-(3-sec-Butylamino-propyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine
(117)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with R-(-)-2-aminobutane according to the general procedure A. Rt =
5.915min. 'H NMR (CDC13) S 8.27
(s, 1H), 7.63 (d, 1H), 6.74 (br.s., 2H), 6.61(d, 1H), 6.48 (dd, IH), 4.26 (t,
2H), 3.58 (s, 3H), 2.57-2.14 (m,3H), 1.92
(quint., 211), 1.43 (7, IH), 1.28 (7, 1H), 1.02 (t, 2H), 0.94 (d, 3H), 0.81
(t, 3H).
Example 118 (S)-9-(3-sec-Butylamino-propyl)-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine
(118)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with S-(-)-2-aminobutane according to the general procedure A. Rt =
5.941min. 'H NMR (CDC13) S 8.32
(s, IH), 7.68 (d, 1H), 6.65(d, 111), 6.54 (dd, 1H), 6.39 (br. s., 2H), 4.29
(t, 2H), 3.63 (s, 3H), 2.59-2.44 (m,3H), 1.95
(quint., 2H), 1.45 (7, 1H), 1.28 (7, 111), 1.05 (t, 2H), 0.97 (d, 3H), 0.84
(t, 3H).
57
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 119 9-[3-(1,1-Dimethyl-propylamino)-propyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine (119)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with 1,1-dimethyl-propylamine according to the general procedure A. Rt
= 6.218 min. 'H NMR (CDC13) S
8.35 (s, IH), 7.71 (d, IH), 6.68(d, 1H), 6.56 (dd, IH), 6.12 (br. s., 211),
4.31 (t, 211), 3.66 (s, 3H), 2.50 (t,3H), 1.95
(quint., 2H), 1.07 (q, 2H), 0.99 (s, 6H), 0.80,(t, 3H).
Example 120 9-(3-Cyclobutylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-
9H-purin-6-ylamine (120)
The title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-
methoxy-phenylsulfanyl)-9H-purin-6-
ylamine with cyclobutylamine according to the general procedure A. Rt =
5.785min. 'H NMR (CDC13) S 8.37 (s,
1H), 7.72 (d, 1H), 6.67(d, 1H), 6.56 (dd, 1H), 6.02 (br. s., 211), 4.30 (t,
2H), 3.67 (s, 3H), 3.17 (quint., 1H), 2.50 (t,
3H), 2.16 (d, 2H), 1.94 (quint., 2H), 1.64 (m, 4H).
Example 121 9-(3-Amino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (121)
Step 1{3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl}-
carbamic acid tert-butyl ester
A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (260 mg),
BocNH-(CHZ)3-Cl, and CsaCO3
(1.29 g) in DMF (3mL) was heated to 50 C for 16 h. Work-up and flash
chormatography (1% MeOH in DCM, then
EtOAc, then 5% MeOH in EtOAc) gave the desired product. Rt= 8.23 nun. 'H NMR
(CDC13) S 8.34 (s, 1H), 7.70
(d, 1H), 6.70 (d, IH), 6.55 (dd, 1H), 6.15 (s, 2H), 5.59 (t, 1H), 4.28 (t,
2H), 3.65 (t, 3H), 3.01 (q, 211), 1.90 (quint.,
2H), 1.44 (s, 9H).
Step 2 9-(3-Amino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine
A solution of {3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
propyl}-carbamic acid tert-butyl ester
(54 mg) in DCM (3 mL) was treated with TFA (0.5 mL) for 30 min and evaporated.
Reverse-phase MPLC (ClBi
gradient Ha0/CH3CN, 1%TFA) gave the title compound as a TFA salt which was
diluted in DCM, washed with
NaHCO3 and concentrated to give the title compound as a free base. Rt= 5.21
min. 'H NMR (CDC13/CD3OD) 6 8.18
(s, 1H), 7.77 (d, 1H), 7.12 (d, 1H), 6.68 (dd, 1H), 4.30 (t, 211), 3.74 (s,
3H), 2.89 (t, 2H), 2.16 (quint., 2H).
Example 122 {2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl}-
carbamic acid tert-butyl
ester (122)
Step 1 (2-Chloro-ethyl)-carbamic acid tert-butyl ester
A suspension ofCl-(CHZ)Z-NHa.HCI in DCM (10 mL) was treated at 0 C with Et3N
(1.39 mL) and (tBoc)ZO (2.18
g). The reaction was then stirred at rt overnight, concentrated, and worked-up
(EtOAc/'12 sat. brine) to give the title
compound.
Step 2 {2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl}-
carbamic acid tert-butyl
ester
A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (0.15 g),
(2-Chloro-ethyl)-carbamic acid
tert-butyl ester (0.10 g) and CsaCO3 (0.45 g) in DMF (I mL) was heated to 80
C for 2 h, and to 100 C for another
1.5 h. Flash chromatography (EtOAc/Hexane 1:1 -> 1:0) gave the title compound.
Rt= 7.85 min. 'H NMR (CDCI3)
6 8.30 (s, 1H), 7.80 (d, 1H), 6.80 (d, 1H), 6.65 (dd, 1H), 6.02 (s, 2H), 4.40
(t, 2H), 3.66 (s, 3H), 3.53 (q, 2H), 1.23 (s,
9H).
Example 123 9-(2-Amino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (123)
{2-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl}-carbamic
acid tert-butyl ester (6.4 mg) was
treated with TFA/DCM 1:10 for I h at rt, washed with aq NaHCO3, and
evaporated. Rt= 5.16 min. 'H NMR
(CDC13) S 8.24 (s, 1H), 7.82 (d, 1H), 7.20 (d, 111), 6.72 (dd, 1H), 4.61 (t,
2H), 3.77 (s, 3H), 3.42 (t, 21-1).
58
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 124 2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
acetamide (124)
A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (80 mg), 2-
bromoacetamide (55 mg) and
Cs2CO3 (316 mg) in DMF (1 mL) was stirred at rt overnight. Preparative TLC
gave the title compound. Rt= 5.70
min. 'H NMR (DMSO-ds) S 8.26 (s, 1H), 8.08 (s, IH), 7.67 (d, 1H), 7.50 (s,
IH), 6.96 (d, 1H), 6.51 (dd, 1H), 4.93
(s, 2H), 3.59 (s, 2H), 3.31 (s, 3H).
Example 125 1-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propan-
2-one (125)
A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (80 mg),
chloroacetone (32 uL) and CsZCO3
(350 mg) in DMF (1 mL) was stirred at 75 C overnight. Work-up and preparative
TLC (5% MeOH in DCM) gave
the title compound. Rt= 6.74 min.'H NMR (CDC13) S 8.32 (s, 111), 7.68 (d, 1H),
6.74 (d, IH), 6.55 (dd, IH), 5.67
(s, 2H), 5.05 (s, 211), 3.67 (s, 3H), 2.23 (s, 3H).
EXample 126 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-isopropylamino-propyl)-9H-
purin-6-ylamine H3PO4
salt (126)
Step 1 3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propan-l-ol
A solution of acetic acid 3-[6-amino-8-(2-iodo-5-rnethoxy-phenylsulfanyl)-
purin-9-yl]-propyl ester (831 mg;
Biamonte, J. Org. Chem., 2005, 70, 717) in MeOH (10 mL) was treated with K2C03
(88 mg) at rt for 2 h and
concentrated. The solid was stirred in a mixture of water (4mL) and Et20 (15
mL) at rt for Ih. Filtration afforded the
deisred product. Rt = 5.04 mut (5-100-7). 'H NMR (DMSO-d6) S 8.18 (s, 1H),
7.78 (d, 1H), 7.48 (s, 2H), 6.71 (dd,
1H), 6.47 (d, iH), 4.66 (t, 1H), 4.21 (t, 2H), 3.61 (s, 3H), 3.40 (q, 2H),
1.82 (quint, 211).
Step 2 Methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-
purin-9-yl]-propyl ester.
3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-y1]-propan-l-ol was
dissolved in anhydrous 1,4-dioxane
at 80 C. Triethylantine (3 equiv.) were added, and the mixture was cooled to
40 C before adding MsCI (1.5 equiv.).
After 15 niin, the solvent and triethylamine were evaporated in vacuo, to give
the title compound as a crude oil
which was used immediately in the next step, without additional purification.
Step 3 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-isopropylamino-propyl)-9H-
purin-6-ylamine
Methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-
yl]-propyl ester was reacted with
isopropylaniine according to the general procedure A. The crude reaction
product was extracted into aq. HCI, and
the aqueous solution was washed ten times with CHC13. Neutralization (NaHCO3)
and back-extraction into CHC13
gave the title compound as a crude oil. The free base was dissolved
isopropanol. Addition of HBr 48% induced
crystallization, and the crystals were washed with acetone. The crystals were
dissolved in a mixture of CH2C12 and
sat. aq. NaHCO3. The organic layer was dried (Na2SO4) and concentrated to
afford the pure title compound as the
free base. Rt = 5.61 min (5-100-12). 'H NMR (CD3OD) S 8.24 (s, 1H), 7.86 (d,
1H), 6.87 (d, lH), 6.64 (dd, 1H),
4.42 (t, 2H), 3.77 (s, 3H), 3.37-3.33 (m, 311), 3.08 (t, 2H), 2.24 (quint.,
2H), 1.34 (d, 6H).
Step 4 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(3-isopropylamino-propyl)-9H-
purin-6-ylamine, H3PO4
salt.
A solution of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-(3-isopropylamino-propyl)-
9H-purin-6-ylamine (1.03 g) in
refluxing EtOH (30 mL) was treated with a 0.84 M solution of H3PO4 in EtOH
(2.1 rnL). The phosphate salt
precipitated imrnediately, and was collected by filtration, and washed with
EtOH. Rt = 4.46 min (5_100 7). 'H
NMR (DZO) & 8.04 (br. s, 1H), 7.71 (br. d, 1H), 6.87 (br. s, 1H), 6.64 (br. d,
1H),.4.18 (br. t, -2H), 3.62 (br. s, 3H),
3.13 ( sept., 1H), 2.88 (br. t., 2H), 2.03 (br. quint., 2H), 1.13 (d, 6H).
Example 127 N-{2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9_yl]-
ethyl}-acetamide (127)
59
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 P O
N
N S
N
HN--~
O
A solution of 9-(2-amino-ethyl)-8-(2-iodo-5-rnethoxy-phenylsulfanyl)-9H-purin-
6-ylamine (123; 12 mg) in 1,2-
dichloroethane (200 uL) was treated with Ac20 (40 uL) at rt overnight.
Concentration and preparative TLC
(EtOAC/DCM/MeOH 7:7:1) gave the title compound. Rt= 5.97 min (5-100-12). 'H
NMR (CDC13/CD3OD 5:1) S
8.32 (s, 1H), 7.68 (d, 1H), 7.30 (t, 1H), 6.88 (d, 1H), 6.60 (dd, 1H), 4.28
(t, 2H), 3.65 (s, 3H), 3.48 (q, 2H), 1.80 (s,
3H).
Example 128 N-{2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethyl}-methanesuIfonamide
(128)
NH2 Q O
N
\$
N N
\-~ O
HN-S
O
A solution of 9-(2-amino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-
ylamine (123) and triethylamine
(3 equiv.) in 1,2-dichloroethane was treated with MsC1(1.5 equiv) at rt
overn.ight. Concentration ad preparative TLC
(EtOAClDCM/MeOH 7:7:1) gave the title compound. Rt= 6.20 min (5-100-12). 'H
NMR (CDC13/CD3OD 5:1) S
8.33 (s, 1H), 7.70 (d, 1H), 6.90 (t, 111), 6.50 (d, 1H), 4.27 (dd, 1H), 3.65
(s, 3H), 3.38 (y, 2H), 2.74 (s, 3H).
Example 129 N-{2-[6-Amin.o-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethyl}-N-isobutyl-acetamide
(129)
NH2 p
N
N N
O
~N~
A solution of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-(2-isobutylamino-ethyl)-9H-
purin-6-ylamine (15 mg) in 1,2-
dichloroethane (500 uL) was treated with Ac20 (60 uL) at rt for 45 min.
Concentration ad preparative TLC
(EtOAC/DCM/MeOH 70:70:4) gave the title compound. Rt= 7.70 min (5-100-12). 'H
NMR (CDC13) 3:1 mixture of
s-trans and s-cis rotamers. Major rotamer: S 8.32 (s, 1H), 7.72 (d, IH), 6.80
(d, IH), 6.58 (dd, 1.H), 5.78 (br. s, 2H),
4.42 (t, 2H), 3.68 (t, 2H), 3.65 (s, 3H), 2.75 (d, 2H), 1.72 (m, 1H), 0.80 (d,
6H).
Example 130 N-{2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethyl}-N-isobutyi-
methanesulfonamide (130)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 1- p p
~
N N
N_S_
O
A solution of 9-(2-ami.no-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-
6-ylamine (123; 34 mg) and
triethylamine (35 uL) in 1,2-dichloroethane (0.5 niL) was treated with MsC1(10
uL) at rt for 10 nun. Concentration
and preparative TLC (EtOAC/DCM/IvIeOH 70:70:4) gave the title compound. Rt=
8.03 min (5-100-12). 'H NMR
(CDC13/CD3OD 5:1) S 8.20 (s, 1H), 7.70 (d, 1H), 6.83 (d, 1H), 6.59 (dd, IH),
4.39 (t, 2H), 3.66 (s, 3H), 3.49 (t, 211),
2.95 (d, 2H), 1.78 (m, 1 H), 0.84 (d, 6H).
Example 131 2-Chloro-8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-
purin-6-ylamine(131)
NH2 p
N
N
~ N N
CI
. A suspension of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purine-
2,6-diamine (55 mg; see example
15) in DCM (2 mL) was treated with TMSCI (205 uL) and Et3N (30 uL) at rt for
10 min. A solution of BnEt3N+
NOz (83 mg; Francom, J. Org. Chem. 2003, 68, 666) in DCM (1.5 mL) was added,
and the reaction mixture was
stirred for 30 niin at rt. Work-up and flash chromatography (EtOAc/Hexane I:1-
3 1:0) gave the title compound. Rt=
9.73 min (5-100-12). 'H NMR (CDC13) S 7.74 (d, 1H), 6.75 (d, 1H), 6.60 (dd,
lH), 4.27 (t, 2H), 3.70 (s, 3H), 2.26
(dt, 2H), 2.04 (quint., 2H), 1.96 (t, 1H).
Example 132 9-[2-(2,2-Dimethyl-propylamino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine (132)
Step 1 Acetic acid 2-(6-amino-purin-9-yl)-ethyl ester
A mixture of adenine (60.0 g), CsZCO3 (223 g), AcO-CH2-CH2-Br (75.8 ml) and
DMF (187 g) was stirred at 45 C
for 5 h. The DMF was evaporated and the residue was added to a mixture of AcOH
(50 ml, 2 equiv.) water (100 ml)
and ice (100 g). The solid was filtered, washed with 100 rnl ice-cold water,
and dried under high vacuum on a rotary
evaporator to give the title compound as a white powder (62.4 g, 67%). Rt =
3.05 min (5-100-12). 'H NMR (DMSO)
S 8.13 (s, IH), 8.12 (s, IH), 4.37 (s, 4H), 191 (s, 3H).
Step 2 Acetic acid 2-(6-arnino-8-bromo-purin-9-yl)-ethyl ester
Acetic acid 2-(6-amino-purin-9-yl)-ethyl ester (16.6 g) was dissolved in a
mixture of AcOH buffer (100 mi, note 1),
MeOH (30 ml), and THF (30 ml) using magnetic stirring at rt. Bromine (7.0 ml)
was added over 1 min, and the
stirring was stopped, whereupon the desired product gently crystallized out of
solution. After 1 h the crystals were
collected by filtration, washed (1120) and air-dried to give the title
compound (11.6 g, 51%) as purple prisms. Rt =
4.01 min (5-100-12). 'H NMR (DMSO) S 8.18 8.32 (s, 1H), 5.69 (s, 2H), 4.47 (m,
4H), 2.00 (s, 3H).
61
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 3 2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethanol
A solution of acetic acid 2-(6-arnino-8-bromo-purin-9-yl)-ethyl ester (16.5 g)
and potassium 2-iodo-5-methoxy-
benzenethiolate (33 g; (a) Ma, J. Org. Chem. 2001, 66, 4525 (b) Flynn, Org.
Lett, 2001, 3, 651) in DMF (600 ml)
was heated to 50 C overnight. The reaction mixture was concentrated,
dissolved in MeOH, and treated with a
catalytic amount of K2C03 for 3h at 50 C to cleave the acetyl group in situ.
The mixture was concentrated again,
add stirred in a mixture of water and EtzO overnight. The desired alcohol,
which was soluble neither in EtZO nor in
water, was recovered by filtration. Washing with ether and drying gave the
title compound as an orange-brown
powder (9 g, 37%). Rt = 6.13 min (5-100-12). 'H NMR (DMSO) S 8.18 (s, 1H),
7.76 (d, 1H), 7.35 (s, 2H), 6.68 (dd,
IH), 6.55 (d, 1H), 5.03 (s, IH), 4.26 (t, 2H), 3.70 (t, 2H), 3.69 (s, 3H).
Step 4 9-[2-(2,2-Dimethyl-propylamino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine
A suspension of 2-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
ethanol (6.0 g) in dioxane (400 ml)
was heated to 80 C until fully dissolved. The solution was cooled to 40 C,
treated with Et3N (3 equiv.) and MsCl
(1.5 equiv.). The reaction was cooled to r.t., filtered to remove the
Et3N.HC1, and evaporated to give the crude
mesylate which was immediately taken in dioxane (75 mL) and neopentylamine (25
ml) and heated to 70 C in a
pressure vessel for 4 h. Concentration gave the desired crude amine which was
diluted with water, acidified with aq
T4C1 to pH 1, and washed with 1% MeOH in CHC13 10 times. The aqueous layer was
neutralized with solid NaHCO3
and the amine was extracted in 1% MeOH in CHC13 to give the title compound as
a pale brown oil (approx. yield:
50%). Recrystallization from MeOH gave the title compound as fine off-white
needles. Rt = 5.13 min (5-100-12).
'H NMR (CDC13/CD3OD 3:1) S 8.03 (s, 1H), 7.65 (d, 1H), 6.80 (d, 1H), 6.59 (dd,
IH), 4.48 (br. t, 2H), 3.62 (s, 3H),
3.20 (br. t, 2H), 2.76 (s, 2H), 0.88 (s, 9H).
Step 5 9-[2-(2,2-Dimethyl-propylamino)-ethyl]-8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-
ylamine, H3P04 salt.
The purified amine (1.0 g) was dissolved in refluxing EtOH (30 ml) and with
very vigorous agitation a H3PO4
solution (0.84M in EtOH, 2.3 mL, 1 equiv) was added in one shot. The
crystallization was immediate. After cooling,
filtration gave the desired phosphate as off-white fme needles (1.0 g, 83%).
Rt = 5.08 min (5-100-12). 'H NMR
(D20) S 8.09 (s, iH), 7.75 (d, 1H), 6.89 (d, 1H), 6.68 (dd, 1H), 4.51 (br. t,
2H), 3.63 (s, 3H), 3.36 (br. t, 2H), 2.83 (s,
2H), 0.95 (s, 9H).
General procedure C
A suspension of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (1
equiv.), alkyl halide (RCI, RBr, or RI;
1.1-3 equiv.) and CsZCO3i (3-5 equiv.) in DMF was heated to 40-80 C for 2-16
h to give, typically, a 2:1 mixture
of the N(9)- and N(3)-alkylated isomer. The reaction mixture was diluted with
EtOAc, and washed water and and
brine. Drying (Na2SO4), evaporation, and preparative TLC or flash
chromatography (e.g. AcOEtlHexane/Et3N
80:20:3) gave the desired compound.
Example 133 9-(2-Dimethylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (133)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with (2-
chloro-ethyl)-dimethyl-anvne according to the general procedure C. Rt = 5.18
min. 'H NMR (CDCl3) S 8.33 (s, 1H),
7.67 (d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 6.11 (s, 2H), 4.31 (t, 2H), 3.67
(s, 3H), 2.67(t, 2H), 2.63 (s, 6H).
Example 134 9-(2-Diethylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-
purin-6-ylamine (134)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with(2-
chloro-ethyl)-diethyl-amine according to the general procedure C. Rt = 5.60
min. 'H NMR (CDC13) 6 8.38 (s, IH),
62
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
7.68 (d, IH), 6.72 (d, IH), 6.54 (dd, IH), 5.86 (s, 2H), 4.30 (t, 2H), 3.67
(s, 311), 2.74 (t, 2H), 2.53(q, 4H), 1.07 (t,
6H).
Example 135 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-pyn-olidin-1-yl-ethyl)-9H-
purin-6-ylamine (135)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine, with the
hydrochloride salt of 1-(2-chloro-ethyl)-pyrrolidine according to the general
procedure C. Rt = 5.55 rnin.'H NMR
(CDC13) S 8.35 (s, 1H), 7.68 (d, IH), 6.68 (d, 1H), 6.53 (dd, 1H), 6.14 (s,
211), 4.38 (t, 2H), 3.65 (s, 3H), 2.83 (t,
214), 2.55(m, 4H), 1.74 (m, 4H).
Example 136 8-(2-Iodo-S-methoxy-phenylsulfanyl)-9-(2-vinyloxy-ethyl)-9H-purin-
6-ylamine (136)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with (2-
chloro-ethoxy)-ethene according to the general procedure C.
Rt = 9.91nun. 'H NMR (CDC13 ) S 7.97 (s, 1H), 7.69 (d, 1H), 7.20 (s, 1H), 6.54-
6.35 (m, 4H), 4.78 (t, 211), 4.05(t,
2H), 3.74 (s, 3H).
Example 137 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-isopropoxy-ethyl)-9H-
purin-6-ylamine (137)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with 2-(2-
chloro-ethoxy)-propane according to the general procedure C.
Rt = 8.20min. 'H NMR (CDC13 ) 6 8.37 (s, 1H), 8.08 (d, 1H), 7.12 (d, J = 2.6
Hz 1H), 6.84 (dd, 1H), 5.80 (s, 2H),
4.48 (m, 2H), 3.85-3.80(m, 3H), 3.74 (s, 3H), 1.18( d, 6H).
Example 138 {3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-
propyl}-methyl-carbamic acid
tert-butyl ester (138)
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine reacting
with (3-chloro-propyl)-carbamic acid tert-butyl ester (see previous example,
step 1) according to the general
procedure C. Rt = 8.18 min (5-100-12). 'H NMR (CDC13) S 8.28 (s, 1H), 7.73 (d,
1H), 6.74 (d, 1H), 6.59 (dd,
1H),6.01 (br.s., 2H), 4.29 (t, 2H), 3.,68 (s, 3H), 2.96(t, 2H), 1.99 (quint.,
2H), 1.45 (s, 9H).
Example 139. 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-pyn-ol-1-yl-propyl)-9H-
purin-6-ylamine (139)
The title compound was obtained by reacting 8-(2-iodo-5-rnethoxy-
phenylsulfanyl)-9H-purin-6-ylamine with 1-(3-
bromo-propyl)-IH-pyrrole according to the general procedure C. Rt = 8.27 min
(5-100-12). 'H NMR (CDC13) S 8.38
(s, IH), 7.74 (d, IH), 6.70 (d, 1H), 6.65 (s, 2H), 6.59 (dd, 1H), 6.15 (s,
2H), 6.00 (br.s., 2H), 4.25 (t,3H), 3.95 (t, =
3H), 3.69 (s, 3H), 2.26 (quint., 2H).
Example 140 {3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-y1]-
propyl}-carbamic acid tert-butyl
ester (140)
Stepl (3-Chloro-propyl)-carbamic acid tert-butyl ester
Di-tert-butyldicarbonate 21.8g (0.1 mol) was added to a nuxture of
triethylamine (12.6 g, 0.12 mol) and 3-
chloropropylamine hydrochloride (14.0g, 0.11 mol) in THF. The mixture was
stirred at 0 C for 20 min, then
warmed to rt for 18h, diluted with aq. NaHCO3, and extracted with ether (2x80
mL). The extract was washed with
brine, dried, and evaporated to give the title compound. 'H NMR (DMSO) 6 6.84
(br.s., 1H), 3.59 (t, 2H), 3.02 (t,
3H), 1.81 (quint., 2H), 1.36 (s, (H).
Step2 (3-Chloro-propyl)-methyl-carbamic acid tert-butyl ester
NaH (0.24 g, 10 mmol) was added to a solution of (3-chloro-propyl)-carbamic
acid tert-butyl ester (1.0 3g, 5 mmol)
and CH3I (1.07 g, 7.5 mmol) in THF (5 mL) under N2. The reaction mixture was
stirred at rt overnight, and
quenched with water (3 mL). Extraction (3 x 100mL, EtOAc), evaporation, and
chromatography gave the title
compound. 'HNMR (DMSO) 6 3.60 (t, 2H), 3.28 (t, 3H), 2.78 (s, 2H), 1.91
(quint., 2H), 1.39 (s, (H).
63
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 3 {3-[6-Amino-8-(3-methoxy-l-methyl-buta-1,3-dienylsulfanyl)-purin-9-yl]-
propyl}-methyl-
carbamic acid tert-butyl ester
The title compound was obtained by reacting 8-(2-iodo-5-methoxy-
phenylsulfanyl)-9H-purin-6-ylamine with (3-
chloro-propyl)-methyl-carbamic acid tert-butyl ester according to the general
procedure C. Rt = 8.51 min (5-100-
12). 'H NMR (CDC13) S 8.24 (s, 1H), 7.58 (d, 1H), 6.96 (br.s., 2H), 6.45 (d,
1H), 6.36 (dd, 1H), 4.14 (s, 2H), 3.53 (t,
314), 2.72 (s, 311), 2.51(t, 211), 2.22 (s, 6H), 1.99 (quint., 2H), 1.32 (s,
9H).
Example 141 8-(2-Iodo-5-trifluoromethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-
purin-6-ylamine (141)
Step 1 1-Iodo-2-nitro-4-trifluoromethoxy-benzene
A vigorously stirred solution of 2-nitro-4-trifluoromethoxy-phenylamine (4.4
g) in conc. HCI (19 mL) and water (19
mL)'was cooled with ice (33 g), and sodium nitrite (1.5 g) was added in one
portion. The reaction mixture was
poured into a cold solution of KI (4.9 g) and to give a solid which was
collected by filtration. The solid was washed
with 6N HCl and water to afford the crude product, which was crystallized from
hexane to give the pure title
compound (5.6 g). Rt = 7.26 (5-100-7). 'H NMR (CDC13) S 8.1 1(d, 111), 7.77
(d, 1H), 7.20 (dd, 111).
Step 2 2-Iodo-5-trifluoromethoxy-phenylamine
To a solution of 1-iodo-2-nitro-4-trifluoromethoxy-benzene (5.58 g) in
methanol (100 mL) were added FeC13.6HZ0
(70 rng) and active carbon (35 mg). The mixture was heated to reflux,
hydrazine monohydrate (1.6 g) was added
slowly and the reaction progress was monitored by TLC. The catalyst was
removed by filtration, and the methanol
was evaporated in vacuo. The residue was dissolved in DCM and washed with
water and brine, and the organic layer
was concentrated to afford the title product (4.5 g). Rt = 7.10 min (5-100-7).
'H NMR (CDCl3) S 7.61 (d, 1H), 6.59
(s, 1H), 6.37 (d, 1H), 4.32 (br.s., 2H).
Step 3 2-Iodo-5-trifluoromethoxy- benzenediazonium tetrafluoroborate
A slurry of 2-iodo-5-trifluoromethoxy-phenylamine (4.5 g) in water (2 mL) and
48% aq. HBF4 (10.3 mL) was
cooled to -10 C and treated dropwise with a solution of NaNOa (1.1 g) in
water (1 mL). The solid diazonium salt
was collected by filtration, washed with diethyl ether, and air-dried to give
the title compound 2.9 g, which was used
without further purification.
Step 4 8-(2-Iodo-5-trifluoromethoxy-phenylsulfanyl)-9H-purin-6-ylamine
A suspension of 6-amino-7,9-dihydro-purine-8-thione (0.99g) in DMF (10 mL) was
cooled to -35 C and treated
with 2-iodo-5-trifluoromethoxy-benzenediazonium tetrafluoroborate (2.86 g).
The mixture was allowed to reach rt,
and was neutralized with solid NaHCO3 (465 mg). The mixture was evaporated,
triturated in CHC13, filtered, and the
solid was washed sequentially with CHC13, H20, Et20, and DCM to give the title
compound (0.72 g).
Step 5 8-(2-Iodo-S-trifluoromethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine
A mixture of 8-(2-iodo-5-trifluoromethoxy-phenylsulfanyl)-9H-purin-6-ylamine
(0.45 g), CS2CO3 (0.65g), 4-chloro-
but-l-yne (0 :12 g) in DMF (2 mL) was stirred at 80 C. The reaction progress
was monitored by TLC. The DMF
was evaporated and the residue was purified by chromatography to give the
title compound. 'H NMR (CDC13) S
8.40 (s, 1H), 7.89 (d, 1H), 7.03 (d, 1H), 6.90(dd, 1H), 5.80 (br.s., 2H), 4.37
(t, 2H), 2.28 (td, 2H), 2.06 (quint., 2H),
2.00 (t, 1H).
Example 142 8-(2-Iodo-S-trifluoromethyl-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-
6-ylamine (142)
Step 1 1-Iodo-2-nitro4-trifluoromethyl-benzene
A vigorously stirred solution of 2-nitro-4-trifluoromethyl-aniline (4.7 g) in
cone. HCl (19 mL) and water (19 niL)
was cooled by addition of ice (33 g), and sodium nitrite (1.7 g) was added in
one portion. The reaction mixture was
poured into a cold solution of KI (5.6 g) and to give a solid which was
collected by filtration. The solid was washed
64
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
with 6N HCl and water to afford the crude product, which was crystallized from
hexane to give pure the iodide (4.9
g). Rt = 7.10 (5-100-7). 'H NMR (CDC13) S 8.24 (d, 1H), 8.13(d, 1H), 7.54 (dd,
1H).
Step 2 2-Iodo-5-trifluoromethyl-aniline
To a solution of I-iodo-2-nitro-4-trifluoromethyl-benzene (4.9 g) in methanol
(100 mL) were added FeC13.6Hz0 (65
mg) and active carbon (33 mg). The mixture was heated to reflux, hydrazine
monohydrate (1.5 g) was added slowly
and the reaction progress was monitored by TLC. The catalysts were removed by
filtration, and the methanol was
removed in vacuo. The solid residue was dissolved in DCM and washed with water
and brine, and the organic layer
was concentrated to afford the title compound (3.8 g). Rt = 6.95 min (5-100-
7). 'H NMR (CDC13) S 7.74 (d, 1H),
6.95 (s, 1H), 6.70 (d, 1H), 4.35 (br.s., 2H).
Step 3 2-Iodo-5-trifluoromethyl- benzenediazonium tetrafluoroborate
A slurry of 2-iodo-5-trifluoromethyl-aniline (3.8 g) in water (2 mL) and 48%
aq. HBF4 (9.2 mL) was cooled to -10
C and treated dropwise with a solution ofNaNO2 (1.0 g) in water (1 mL). The
solid diazonium salt was collected by
filtration, washed with diethyl ether, and air-dried to give the title
compound (2.8 g), which was used without further
purification.
Step 4 8-(2-Iodo-5-trifluoromethyl-phenylsulfanyl)-9H-purin-6-ylamine
A suspension of 6-amino-7,9-dihydro-purine-8-thione (1.02g) in DMF (10 mL) was
cooled to -35 C and treated
with 2-iodo-5-trifluoromethyl-benzenediazonium tetrafluoroborate (2.8 g). The
mixture was allowed to reach rt, and
was neutralized with solid NaHCO3 (460 mg). The mixture was evaporated,
triturated in CHC13i filtered, and the
solid was washed sequentially with CHC13, H20, Et20, and DCM to give the title
compound (1.02 g).
Step 5 8-(2-lodo-5-trifluoromethyl-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylarnine
A mixture of 8-(2-iodo-5-trifluoromethyl-phenylsulfanyl)-9H-purin-6-ylarnine
(0.44 g), CS2CO3 (0.65 g), 4-chloro-
but-l-yne (0.12 g), and DMF (2 mL) was stirred at 80 - C. The reaction
progress was monitored by TLC. The DMF
was evaporated and the residue was purified by chromatography to give the
desired product. 'H NMR (CDC13) 6
8.39 (s, 1H), 8.04 (d, 1H), 7.52 (d, 1H), 7.25 (dd, 1H), 5.76 (br.s., 2H),
4.38 (t, 2H), 2.29 (dt, 2H), 2.08 (quint., 2H),
1.99 (t, 1H).
Example 143 8-(2,4-Diiodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (143)
Step I 2-Iodo-5-methoxy-aniline and 2,4-Diiodo-5-methoxy-aniline
To a solution of I-iodo-4-methoxy-2-nitro-benzene (100g) in methanol (1000
nrnL) were added FeC13.6H20 (1.5g)
and active carbon (0.76g). The mixture was heated to reflux, hydrazine
monohydrate (35mL) was added slowly and
the reaction progress was monitored by TLC. The catalyst was removed by
filtration and methanol was removed
under vacuo. The residue was dissolved in DCM, washed with water and brine,
and the organic layer was
concentrated to afford the crude product (83g), which was purified by flash
chromatography to give 2-iodo-5-
methoxy-aniline (80g) and 2,4-diiodo-5-methoxy-aniline (lg).
Step 2 2,4-diiodo-5-methoxy- benzenediazonium tetrafluoroborate
A slurry of 2,4-diiodo-5-methoxy-aniline (0.84 g) in water (3 mL) and 48% aq.
HBF4 (1.5 mL) was cooled to -10 C
and treated dropwise with a solution of NaNOZ (0.17g) in water (1 mL). The
solid diazonium salt was collected by
filtration, washed with diethyl ether, and air-dried to give the title
compound (0.77g), which was used without
further purification.
Step 3 8-(2,4-diiodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine
A suspension of 6-arnino-7,9-dihydro-purine-8-thione (0.27g) in DMF (5 mL) was
cooled to -35 C and treated with
2,4-diiodo-5-methoxy- benzenediazonium tetrafluoroborate (0.77g). The mixture
was allowed to reach rt, and was
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
neutralized with solid NaHCO3 (465 mg). The mixture was evaporated, triturated
in CHC13i filtered, and the solid
was washed sequentially with CHC13, H20, Et20, and DCM to give the title
compound (0.14 g).
Step 4 8-(2,4-diiodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine
A mixture of 8-(2,4-diiodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (0.14
g), CsZCO3 (0.173 g), 4-chloro-
but-l-yne (0.3 mL), and DMF (3 mL) was stirred at 80 C for 3h. The DMF was
evaporated and the residue was
purified by chromatography to give the desired product. Rt = 8.84 min. 'H NMR
(DMSO) S 8.21 (s, 1H), 8.18 (s,
IH), 7.44 (s, 3H), 4.25 (t, 2H), 3.62 (s, 3H), 2.79 (d, 1H), 2.22 (td, 2H),
1.90 (quint.,,2H).
Example 144 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (144)
Step 1 2,5-Dimethoxy-3-nitro-biphenyl
A mixture of 1-bromo-2,5-dimethoxy-3-nitro-benzene (1.35 g), PhB(OH)2 (1.00
g), K3PO4 (2.3 g), Pd(PPh3)4 (0.33
g) and toluene (20 mL) was heated to 108 C for 24 h. The organic layer was
diluted with toluene, washed with
NaOH 1M, and water, and concentrated to afford the title product. 'H NMR
(CDC13) 57.67 (dd, IH), 7.55 (dd, 2H),
7.44 (dd, 2H), 7.24 (d, 1H), 7.10 (d, 1H), 3.85 (s, 3H), 3.46 (s, 3H).
Step 2 2,5-Dimethoxy-biphenyl-3-ylamine
A mixture of 2,5-dimethoxy-3-nitro-biphenyl (1.88 g), 10% Pd/C (0.55 g) in
EtOAc (40 mL) was shaken in a Parr
hydrogenator under H2 (4.8 atm) for 2 h. Filtration and chromatography gave
the title compound. 'H NMR (CDC13)
57.59 (d, 2H), 7.57 (t, 2H), 7.40 (d, 1H), 6.32 (d, IH), 6.27 (d, IH), 3.76
(s, 3H), 3.34 (s, 3H).
Step 3 2;5-Dimethoxy-3-phenyl-benzenediazonium tetrafluoroborate
A slurry of 3,5-dimethoxy-biphenyl-3-ylamine (970 mg) in water (2 mL) and 48%
aq. HBF4 (2 mL) was cooled to -
10 C and treated dropwise with a solution of NaNO2 (380 mg) in water (1 mL)
for 30 min. The solid diazonium salt
was collected by filtration, washed with diethyl ether, and air-dried to give
the title compound. 'H NMR (DMSO-d6)
57.98 (d, 1H), 7.76 (d, IH), 7.56 (m, 5H), 3.96 (s, 3H), 3.70 (s, 3H).
Step 4 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9H-purin-6-ylamine
A suspension of 6-amino-7,9-dihydro-purine-8-thione (346 mg; Biamonte, J. Org.
Chem. 2005, 70, 717) in DMF (2
mL) was cooled to -40 C and treated with 2,5-dimethoxy-3-phenyl-
benzenediazonium tetrafluoroborate (1.0 g).
The mixture was allowed to reach rt, and was neutralized with solid NaHCO3
(529 mg). The mixture was
evaporated, tritutrated in CHC13, filtered, and the solid was washed
sequentially with CHCI3i H20, Et20, and DCM.
The solid was redissolved in DMF, diluted with EtOAc, washed with NaOH 1M, and
concentrated to give the
desired product, free of unreacted starting material. 'H NMR (CDC13) 58.01 (s,
1H), 7.42 (d, 2H), 7.26 (m, SH), 6.59
(s, 2H), 3.55 (s, 3Fi), 3.29 (s, 3H).
Step 5 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine
A suspension of 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9H-purin-6-ylamine (39
mg), 5-chloro-pent-1-yne (130
uL) and KZC03 (167 mg) in DMF (2 mL) was heated to 70 C overnight. Work-up
and reverse-phase
chromatography (C18; gradient water/CH3CN) afforded the title compound. Rt=
8.80 min (5-100-12). 'H NMR
(CDC13/CD30D 10:1) 58.23 (s, 1H), 7.52 (d, 2H), 7.53 (m, 3H), 6.94 (d, 2H),
6.92 (d, 1H), 4.36 (t, 2H), 3.79 (s,
3H), 3.34 (s, 3H), 2.32 (dt, 2H), 2.11 (quint., 2H), 1.96 (t, 1H).
Example 145 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (145)
66
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Br
NH2 O O
N
\~-S
N N
ee
A suspension of crude 8-(3-bromo-2,5-dirnethoxy-phenylsulfanyl)-9H-purin-6-
ylamine (640 mg), 5-chloro-pent-l-
yne (420 uL) and K2C03 (550 mg) in DMF (2 mL) was heated to 75 C overnight.
Work-up and reverse-phase
chromatography (C18; gradient water/CH3CN) afforded the title compound. Rt=
7.84 min (5-100-12). 'H NMR
(CDC13/CD3OD 10:1) ~8.25 (s, 1H), 7.06 (d, IH), 6.74 (d, 1H), 4.36 (t, 2H),
3.85 (s, 3H), 3.71 (s, 3H), 2.28 (dt, 2H),
2.05 (quint., 2H), 1.97 (t, 1H).
General procedure B
NH2 NH2
N
eN~' ~--Br ~ SH, base N~S
N -~ ~ N N/ Ar
R R/
A solution of of Ar-SH (1-4 equiv.) in DMF was treated with one equivalent of
base (NaH or t-BuOK, 1-4 equiv.)
for 10 min at rt. The 8-bromoadenine (1 equiv.) was added, and the mi.cture
was stirred at 50-140 C for 2-16 h. The
reaction mixture was diluted with EtOAc, washed with NaOH 1M, water, and
brine_ Drying Na2SO4, evporation,
and prepartive TLC or flash cromatography (e.g. AcOEtlHexane/Et3N 80:20:3)
gave the desired compound. The
following compounds were prepared in this manner.
Example 146 8-(Benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine
(146)
NH=
N
I I S
N ~--
N ~--
l\e N
S
~ I
~
The title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine with
benzothiazole-2-thiol according to the general procedure B. Rt = 7.098 min (5-
100-7). 'H NMR (CDC13) S 8.41 (s,
1H), 7.92 (d, IH), 7.73 (d, 1H), 7.46 (t, 1HO, 7.35 (t, 1H), 6.42 (br. s. 2H),
4.45 (t, 2H), 2.25 (d, 2H), 2.13 (quint,
2H), 1.94 (s, 1H).
Example 147 9-Pent-4-yny1-8-(quinolin-2-ylsulfanyl)-9H-purin-6-ylamine (147)
67
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
M,N
~N ~ =
\ / \
The title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine with
quinoline-2-thiol according to the general procedure B. Rt = 7.064 min (5-100-
7).'H NMR (CDC13) S 8.40 (s, I H),
8.00 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.64 (t, IH), 7.48 (t, 1H), 7.21 (d,
1H), 6.50 (br. s. 2H), 4.39 (t, 2H), 2.20 (d,
2H), 2.10 (quint, 2H), 1.84 (s, 1H).
Example 148 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine (148)
Step 1 1 -Bromo-2,5-dirnethoxy-3-nitro-benzene
A solution of 2-bromo-4-methoxy-6-nitro-phenol (17.3 g; Guay, J. Heterocycl.
Chem. 1987, 24, 1649) in acetone
(173 mL) was treated with CszCO3 (55 g) and Me2SO4 (16 mL) at reflux for I h.
The mixture was filtered through a
silica- gel pad, concentrated, and chromatographed (toluene/hexane 1:1) to
give the title compound as a pale yellow
solid. 'H NMR (CDC13) 57.55 (s, 2H), 4.01 (s, 3H), 3.90 (s, 3H).
Step 2 3-Bromo-2,5-dimethoxy-phenylamine
A suspension of 1-bromo-2,5-dimethoxy-3-nitro-benzene (1.82 g), AcOH (250 uL)
and Fe powder (325 mesh; 2.7 g)
in water ( 8 mL) was heated to reflux for 2 h. The organic materials were
extracted with DCM, washed (NaHCO3)
and evaporated to give the title compound. 'H NMR (CDCI3) 56.46 (d, 1 H), 6.24
(d, 1 H), 3.91 9s, 211), 3.78 (s, 3H),
3.71 (s, 3H).
Step 3 3-Bromo-2,5-dimethoxy-benzenediazonium tetrafluoroborate
A slurry of 3-bromo-2,5-dimethoxy-phenylamine (1.2 g) in water (2 mL) and 48%
aq. HBF4 (2 mL) was cooled to -
10 C and treated dropwise with a solution of NaNOa (411 mg) in water (1 mL).
The solid diazonium salt was
collected by filtration, washed with diethyl ether, and air-dried to give the
title compound, which was used without
further purification.
Step 4 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine
A suspension of 6-amino-7,9-dihydro-purine-8-thione (458 mg; Biamonte, J. Org.
Chem. 2005, 70, 717) in DMF (3
mL) was cooled to -35 C and treated with 3-bromo-2,5-dimethoxy-
benzenediazonium tetrafluoroborate (1.0 g). The
mixture was allowed to reach rt, and was neutralized with solid NaHCO3 (465
mg). The mixture was evaporated,
tritutrated in CHC13i filtered, and the solid was washed sequentially with
CHC13, H20, Et20, and DCM to give a 1:1
mixture of unreacted starting material and desired product.
Step 5 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine
A suspension of crude 8-(3-bromo-2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-
ylamine (183 mg), 5-bromo-2-
methyl-pent-2-ene (172 uL) and CsZCO3 (422 mg) in DMF (2 mL) was heated to 50
C for I h. Work-up and
chromatography (EtOAc/MeOH/Et3N 100:3:3) afforded the title compound. Rt= 9.01
min (5-100-12). 'H NMR
(CDC13/CD3OD 10:1) S 8.38 (s, 1H), 7.00 (d, IH), 6.51 (d, 1H), 5.10 (t, IH),
4.25 (t, 2H), 3.88 (s, 3H), 3.67 (s, 3H),
2.48 (q, 2H), 1.39 (s, 3H), 1.25 (s, 3H).
Example 149 9-(4-Methyl-pent-3-enyl)-8-(thiazol-2-ylsulfanyl)-9H-purin-6-
ylamine (149)
68
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NHz NH2
~
NII~ ~ Br N N N
N N ~S
N N
The title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine with 2-
mercaptothiazole according to the generalprocedure B.
Rt= 6.80 min (5-100-12). 'H NMR (CDC13) S 8.35 (s, 1H), 7.73 (d, IH), 7.34 (d,
IH), 6.24 (s, 2H), 5.10 (t, IH), 4.30
(t, 2H), 2.48 (q, 2H), 1.63 (s, 3H), 1.34 (s, 3H).
Example 150 8-(Benzothiazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-
ylamine (150)
/ ~
\
NH2 g
N }=N
N N
/
The title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine with 2-
mercaptobenzothiazole according to the general procedure B.
Rt= 8.25 min (5-100-12). 'H NMR (CDCI3) S 8.39 (s, IH), 7.91 (d, 1H), 7.70 (d,
1H), 7.42 (t, 2H), 7.33 (t, 2H), 6.19
(s, 211), 5.09 (t, 1H), 4.32 (t, 2H), 2.51 (q, 2H), 1.58 (s, 311), 1.28 (s,
3H).
Example 151 8-(1H-Benzoimidazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine (151)
/ ~
NH2 N \
N ~NH
~ ~--S
N N
B
The title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine with 2-
mercaptobenzimidazole according to the general procedure B.
Rt= 5.18 min (5-100-7). 'H NMR (CDC13) S 12.80 (s, 1H), 8.12 (s, 1H), 7.70
(br. s, 1H), 7.40 (br. s, 1H), 7.12 m
(2H), (d, IH), 6.72 (s, 2H), 5.10 (t, 1H), 4.12 (t, 2H), 2.39 (q, 2H), 1.52
(s, 3H), 1.25 (s, 3H).
Example 152 8-(1-Allyl-IH-benzoimidazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-
9H-purin-6-ylamine (152)
69
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 N
P
N N
N
\>-S
N N
8-(1H-Benzoimidazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine
(151; 72 mg) was treated with
allyl bromide (35 uL) and Cs2CO3 (237 mg) in DMF (4 mL) at 65 C for 15 nun.
Work-up and flash
chromatography (0-8% MeOH in DCM) gave the title compound. Rt= 5.90 min (5-100-
7). 'H NMR (CDC13) S 8.28
(s, 1H), 7.70 (d, 1H), 7.26 (rn, 3H), 6.20 (s, 2H), 5.88 (m, 1H), 5.15 (m,
2H), 4.96 (m, 3H), 4.33 (t, 2H), 2.51 (q,
2H), 1.62 (s, 3H), 1.36 (s, 3H).
Example 153 8-(1-Methyl-lH-benzoinlidazol-2-ylsulfanyl)-9-(4-methyl-pent-3-
enyl)-9H-purin-6-ylamine (153)
NH2 NJ
p
, N N
N '>-S
N N
/
8-(1H-Benzoimidazol-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylaniine
(151; 62 mg) was treated with
Me2SO4 (35 uL) and CsZCO3 (238 mg) in DMF (4 mL) at 65 C for 15 min. Work-up
and flash chromatography (0-
8% MeOH in DCM) gave the title compound. Rt= 5.43 niin (5-100-7). 'H NMR
(CDC13) S 8.29 (s, 1H), 7.71 (d,
1H), 7.31 (m, 3H), 5.84 (s, 2H), 5.11 (t, 1H), 4.35 (t, 2H), 3.88 (s, 3H),
2.54 (q, 2H), 1.64 (s, 3H), 1.39 (s, 3H).
Example 154 2-[6-Amino-8-(naphthalen-2-ylsulfanyl)-purin-9-yl]-ethanol(154)
N H2
~ N
\/\- S
N N
~ - ~
OH
A solution of acetic acid 2-[6-amino-8-(naphthalen-2-ylsulfanyl)-purin-9-yl]-
ethyl ester (157; 20 mg) in refluxing
EtOH (1 mL) was treated with one drop NaOH IM and let cool to rt, whereupon
the desired compound crystallized.
Filtration and washing (EtOH) gave the title compound. Rt= 4.94 min (5-100-7).
'H NMR (CDC13/CD3OD 10:1)
8.15 (s, 1H), 7.97 (s, 1H), 7.80 (m, 3H), 7.49 (m, 2H), 7.42 (m, 3H), 4.32 (t,
2H), 3.84 (t, 2H).
Example 155 - 2-[6-Amino-8-(naphthalen-1-ylsulfanyl)-purin-9-yl]-ethanol (155)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N N
N N
~
OH
A solution of acetic acid 2-[6-amino-8-(naphthalen-1-ylsulfanyl)-purin-9-yl]-
ethyl ester (158; 20 mg) in refluxing
EtOH (i mL) was treated with one drop NaOH 1M and let cool to rt, whereupon
the desired compound crystallized.
Filtration and washing (EtOH) gave the title compound. Rt= 4.81 min (5-100-7).
'H NMR (CDC13/CD3OD 10:1) S
.8.25 (s, 1H), 8.13 (s, IH), 7.95 (d, 1 H), 7.89 (ni, I H), 7.78 (dd, IHO,
7.53 (m, 2H), 7.47 (dd, 1 H), 4.31 (t, 2H), 3.90
(t, 2H).
Example 156 2-[6-Amino-8-(quinolin-8-ylsulfanyl)-purin-9-yl]-ethanol (156)
N H2
N N
~~--S
N N
OH
A solution of acetic acid 2-[6-amino-8-(quinolin-8-ylsulfanyl)-purin-9-y1]-
ethyl ester (159; 32 mg) in refluxing
EtOH (4.5 mL) was treated with one drop NaOH 1M and let cool to rt, whereupon
the desired compound
crystallized. Filtration and washing (EtOH)''gave the title compound. Rt =
3.93 min (5-100-7). 'H NMR
(CDCI3/CD3OD 10:1) S 8.85 (dd, 1H), 8.20 (d, IH), 8.18 (s, IH), 7.78 (d, 1H),
7.43 (m, 3H), 2.14 (t, 2H0, 3.87 (t,
2H).
Example 157 Acetic acid 2-[6-amino-8-(naphthalen-2-ylsulfanyl)-purin-9-yl]-
ethyl ester (157)
NH2 NH2
N' N>--Br N N~--S
N N N N>
~O \O
O O
The title compound was obtained by reacting acetic acid 2-(6-amino-8-bromo-
purin-9-yl)-ethyl ester with 2-
naphtalenethiol according to the general procedure B. Rt= 5.65 min (5-100-7).
'H NMR (DMSO-d6) S 8.17 (s, 1 H),
8.02 (s, 1H), 7.91 (m, 3H), 7.55 (m, 2H), 7.42 (m, 3H), 4.46 (t, 2H), 4.35 (t,
2H), 1.83 (s, 3H).
Example 158 Acetic acid 2-[6-amino-8-(naphthalen-1-ylsulfanyl)-purin-9-yl]-
ethyl ester (158)
NH2
N N
~ "--S
N N
O
71
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
The title compound was obtained by reacting acetic acid 2-(6-amino-8-bromo-
purin-9-yl)-ethyl ester with 1-
naphtalenethiol according to the general procedure B. Rt= 5.51 min (5-100-7).
'H NMR (CDC13) S 8.28 (s, 1H), 8.15
(s, 1H), 8.02 (m, 2H), 7.66 (dt, 1H), 7.63 (dt, 1H), 7.60 (dd, IH), 7.51 (t,
1H), 7.31 (s, 2H), 4.47 (t, 2H), 4.33 (t, 2H),
1.87 (s, 3H).
Example 159 Acetic acid 2-[6-amino-8-(quinolin-8-ylsulfanyl)-purin-9-yl]-ethyl
ester (159)
NH2
N N
~-S~
N N
O
The title compound was obtained by acetic acid 2-(6-amino-8-bromo-purin-9-yl)-
ethyl ester with 8-quinolinethiol
hydrochloride according to the general procedure B. Rt= 4.60 min (5-100-7). 'H
NMR (DMSO-d6) S 8.98 (dd, IH),
8.45 (dd, IH), 7.83 (dd, IH), 7.67 (dd, 1H), 7.52 (s, 2H), 7.48 (t, 1H), 7.08
(dd, IH), 4.47 (t, 2H), 4.35 (t, 2H), 1.77
(s, 3H).
Example 160 Acetic acid 2-[6-amino-8-(1H-indol-2-ylsulfanyl)-purin-9-yl]-ethyl
ester (160)
NH2 NH2
N N~Br -~-- N N/
N N N N
H
O Ozz~ O
The title compound was obtained by reacting acetic acid 2-(6-amino-8-bromo-
purin-9-yl)-ethyl ester with 1,3-
dihydro-indole-2-thione (Takada, Chem. Phar. Bull. 1984, 32, 877) according to
the general procedure B. Rt= 5.30
min (5-100-7). 'H NMR (DMSO-d6) S 8.13 (s, 1H), 7.53 (d, 1H), 7,34 (dd, 1H),
7,28 (s, 2H), 7.15 (ddd, 1H), 6.81
(dd, 1H), 4.48 (t, 2H), 4.35 (t, 2H), 1.92 (s, 311).
Example 161 Acetic acid 2-[6-amino-8-(2,5-dimethoxy-phenylsulfanyl)-purin-9-
yl]-ethyl ester (161)
NH2
N N
\>--5 O-
N N
-O
0
The title compound was obtained by reacting acetic acid 2-(6-amino-8-bromo-
purin-9-yl)-ethyl ester with 2,5-
dimethoxybenzenethiol according to the general procedure B. Rt= 5.94 min (5-
100-7). 'H NMR (CDC13) S 8.32 (s,
1H), 8.21 (d, 1H), 8.04 (d, IH), 7.58 (m, 1H), 7.51 (m, 1H), 5.82 (s, 211),
4.55 (t, 2H), 4.43 (t, 2H), 3.98 (s, 311),
3.85 (s, 3H), 1.97 (s, 3H).
Example 162 Acetic acid 2-[6-arnino-8-(benzo[b]thiophen-2-ylsulfanyl)-purin-9-
yl]-ethyl ester (162)
72
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N
N S
N
O
The title compound was obtained by reacting acetic acid 2-(6-amino-8-bromo-
purin-9-yl)-ethyl ester with
benzo[b]thiophene-2-thiol (Mitra, J. Sci. Indust. Res., 1957, 16B, 348)
according to the general procedure B. Rt=
5.58 min (5-100-7). 'H NMR (CDC13) 6 8.21 (s, IH), 7.71 (m, 2H), 7.58 (s, IH),
7.32 (m, 2H), 6.04 (s, 2H), 4.55 (t,
2H), 4.44 (t, 2H), 2.00 (s, 311).
Example 163 Acetic acid 2-[6-amino-8-(3-chloro-lH-indol-2-ylsulfanyl)-purin-9-
y1]-ethyl ester (163)
NH2 ci
~ ~S ~ ~
Nj N N
H
O
A solution of acetic acid 2-[6-amino-8-(1H-indol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester (160; 49 mg) in THF (2 mL)
was treated with NCS (21 mg) at 60 C for 1 h. Work-up (EtOAc/NaHCO3) and
prepartive TLC (EtOAc/Et3N
100/3) gave the title compound. Rt= 5.68 min (5-100-7). 'H NMR (CDC13) S 8.23
(s, 1H), 7.53 (d, IH), 7,23 (d,
1H), 7.15 (t, 1H), 7.10 (t, 1H), 6.16 (s, 214), 4.45 (t, 2H), 4.38 (t, 2H),
1.98 (s, 311).
Example 164 Acetic acid 2-[6-amino-8-(3-bromo-lH-indol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester (164)
NH2 Br
N\/11-S I \
N N N
O e H
~
A solution of acetic acid 2-[6-amino-8-(1H-indol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester (160; 49 mg) in DCM (2 mL)
and MeOH (0.5 mL) was treated with NBS (40 mg) at rt for 15 min. Work-up
(EtOAc/NaHCO3) and preparative
TLC (EtOAc/Et3N 100/3) gave the title compound. Rt= 5.77 min (5-100-7). 'H
NMR. (CDC13) 6 9.90 (s, 1H), 8.39
(s, 1H), 7.64 (m, 1H), 7.28 (m, 314), 6.30 (s, 2H), 4.53 (t, 2H), 4.48 (s,
3H), 1.97 (s, 3H).
Example 165 Acetic acid 2-[6-amino-8-(3-iodo-lH-indol-2-ylsulfanyl)-purin-9-
y1]-ethyl ester (165)
73
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 ~
[ ~1 N S N I /
N H
O
A solution of acetic acid 2-[6-amino-8-(1H-indol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester (160; 46 mg) in THF (2 mL)
was treated with NIS (36 mg) at 60 C for 1 h. Work-up (EtOAc/NaHCO3) and
prepartive TLC (EtOAc/Et3N 100/3)
gave the title conipound.
Rt= 5.81 min (5-100-7). 'H NMR (CDC13) S 8.30 (s, IH), 7.38 (d, 1H), 7.26 (in,
2H), 7.18 (t, 1H), 5.73 (s, 2H), 4.45
(t, 2H), 4.57 (t, 2H), 4.45 (s, 311), 2.00 (s, 3H).
Example 166 Acetic acid 2-[6-amino-8-(1-propyl-lH-indol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester (166)
NH2
N N
\>-~ ( \
nj N N ~
~
O
A solution of acetic acid 2-[6-amino-8-(1H-indol-2-ylsulfanyl)-purin-9-y1]-
ethyl ester (160; 49 mg) in DMF (2 mL)
was treated with 95% NaH (36 mg) and 1-iodopropane (370 uL) at rt for 1 h.
Work-up (EtOAc/NaHCO3) and
prepartive TLC (EtOAc) gave the title compound. Rt= 6.04 min (5-100-7). 'H NMR
(CDC13) S 8.26 (s, 1H), 7.60 (d,
1H), 7.34 (d, 1H), 7.26 (t, IH), 7.11 (t, 1H), 6.95 (s, 1H), 5.80 (s, 211),
4.55 (t, 2H), 4.44 (t, 2H), 4.25 (t, 2H), 2.03
(s, 3H), 1.71 (sext., 2H), 0.89 (t, 3H).
Example 167 Acetic acid 2-[6-aniino-8-(3-iodo-l-propyl-lH-indol-2-ylsulfanyl)-
purin-9-y1]-ethyl ester (167)
N H2
N\/\- S I \
nj N N ~
O
A solution of acetic acid 2-[6-amino-8-(1-propyl-lH-indol-2-ylsulfanyl)-purin-
9-yl]-ethyl ester (166; 163 mg) in
THF (2 mL) was treated with NIS (131 mg) at rt for lh. Preparative TLC (EtOAc)
gave the title compound. Rt=
6.48 min (5-100-7). 'H NMR (CDC13) S 8.24 (s, 1H), 7.44 (m, 2H), 7.15 (m, 1H),
2.04 (s, 2H), 4.63 (t, 2H), 4.44 (t,
2H), 4.36 (t, 211), 2.03 (s, 3H), 1.75 (sext., 2H), 0.89 (t, 3H).
Example 168 Acetic acid 2-[6-amino-8-(1,4-dimethoxy-naphthalen-2-ylsulfanyl)-
purin-9-yl]-ethyl ester (168)
74
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2 H NH2
nIj N n N
\>-'S O-
~S ---a-
N N N N
oi
-o
0 o
A solution of acetic acid 2-(6-amino-8-thioxo-7,8-dihydro-purin-9-yl)-ethyl
ester (40 mg) and 1,4-
dimethoxynaphthalene (30 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (400 uL) was
degassed by bubbling N2 through
the solution. Bis(trifluoroacetoxy)iodo]benzene (PIFA, 70 mg) was added at rt,
whereupon the reaction turned from
purple to deep green (radical cation) and then brown. After lh, the reaction
mixture was evaporated, diluted with
EtOAc, washed (diluted K2C03, Na2SZO3, brine). Preparative TLC (EtOAc)
afforded the title compound. Rt= 5.08
min (5-100-7). 'H NMR (CDCI3) 6 8.34 (s, 1H), 6.81 (m, 3H), 5.53 (s, 2H), 4.55
(t, 2H), 4.41 (t, 2H), 3.78 (s, 311),
3.71 (s, 3H), 1.98 (s, 3H).
Example 169 3-[6-Amino-8-(benzo[1,3]dioxol-5-ylsulfanyl)-purin-9-yl]-propan-l-
ol (169)
O~O
O~O
NH2 H NH2 NH2
N N~S N N 2 N
N">- S
N N N N N N
0 . O HO
~O
Step 1 Acetic acid 3-[6-amino-8-(benzo[l,3]dioxol-5-ylsulfanyl)-purin-9-yl]-
propyl ester
A solution of acetic acid 3-(6-amino-8-thioxo-7,8-dihydro-purin-9-yl)-propyl
ester (174 mg) and 1,3-benzodioxole
(75 uL) in 1, 1, 1,3,3,3-hexafluoro-2-propanol (0.8 mL) was treated with
bis(trifluoroacetoxy)iodo]benzene (PIFA,
280 mg) for 30 min at rt. Work-up and preparative TLC (EtOAc/DCM/MeOH 50:50:3)
gave the title compound. 'H
NMR (CDC13) S 8.27 (s, 1H), 7.00 (dd, 111), 6.95 (d, 1H), 6.75 (d, 1H), 6.18
(s 2H), 5.94 (s, 2H), 4.29 (t, 2H), 4_07
(t, 2H), 2.10 (quint., 2H), 2.02 (s, 311).
Step 2 3-[6-Amino-8-(benzo[1,3]dioxol-5-ylsulfanyl)-purin-9-yl]-propan-l-o1
A solution of acetic acid 3-[6-anvno-8-(benzo[1,3]dioxol-5-ylsulfanyl)-purin-9-
yl]-propyl ester (33 mg) in THF
(0.5 mL) and MeOH (3 mL) was treated with K2C03 (100 mg) at rt for 30 min to
give, after work-up, the title
compound. Rt=4.47 min (5-100-7). 'H NMR (CDC13/CD3OD 5:1) S 8.12 (s, 1H), 7.05
(dd, 1H), 6.95 (d, 1H), 6.80
(d, 1H), 5.98 (s 211), 4.25 (t, 2H), 3.45 (t, 2H), 1.85 (quint., 2H).
Example 170 3-[6-Amino-8-(2,3-dihydro-benzo[1,4]dioxin-6-ylsulfanyl)-purin-9-
yl]-propan-l-ol (170)
Step 1 Acetic acid 3-[6-amino-8-(2,3-dihydro-benzo[ 1,4]dioxin-6-ylsulfanyl)-
purin-9-yl]-propyl ester
A solution of acetic acid 3-(6-amino-8-thioxo-7,8-dihydro-purin-9-yl)-propyl
ester (337 mg) and 1,4-benzodioxane
(225 uL) in 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL) was degassed by bubbling
N2 through the solution.
Bis(trifluoroacetoxy)iodo]benzene (PIFA, 814 mg) was added at rt, whereupon
the reaction turned deep blue
(radical cation). After 30 min, the reaction mixture was evaporated, diluted
with EtOAc, and washed (diluted
K2C03, Na2SZO3, brine). Flash chromatography (0-15% MeOH in EtOAc) afforded
the title compound. Rt= 5.22
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
rrrnin (5-100-7). 'H NMR (CDC13) 8 8.24 (s, 1H), 6.99 (dd, 1H), 6.92 (d, 1H),
6.80 (d, 11-1), 6.28 (s 2H), 4.30 (t, 2H),
4.20 (s, 4H), 4.05 (t, 2H), 2.12 (quint., 2H), 2.01 (s, 3H).
Step 2 3-[6-Amino-8-(2,3-dihydro-benzo[1,4]dioxin-6-ylsulfanyl)-purin-9-yl]-
propan-l=ol
A solution of acetic acid 3-[6-amino-8-(2,3-dihydro-benzo[ 1,4]dioxin-6-
ylsulfanyl)-purin-9-yl]-propyl ester (54 mg)
in MeOH (5 m.l.) was treated with KZC03 (113 mg) at rt for 30 min. Work-up and
reverse-phase chromatography
(CI8; gradient water/CH3CN) afforded the title compound. Rt= 4.56 min (5-100-
7). 'H NMR (CDC13) 6 8.27 (s,
1H), 7.04 (d, 1H), 6.97 (dd, 1H), 6.86 (d, 1H), 5.87 (s, 211), 4.38 (t, 2H),
4.25 (m, 4H), 3.40 (t, 2H), 1.82 (quint.,
2H).
Example 171 8-(7-Bromo-benzothiazol-2-ylsulfanyt)-9-butyl-9H-purine-6-ylamine
(171)
NH2
I \ S
N N N
S
Br
Step 1 7-Bromo-benzothiazole-2-thiol
To a mixture of HNO3 (90rn1) and H2SO4 (45m1) cooled to 0 C was added 1,2-
dibromo-benzene (148.3mmo1, 35g).
The mixture was stirred at 0 C for 30 min and then poured into 1.4 L of ice
water. A solid precipitated and filtered.
The solid was washed with water and dried over vacuum pump to give a mixture
of 2,3-dibromonitrobenzene and
3,4-dibromonitrobenzene in 1:4 ratio (95% yield). The mixture of both
regioisomers (142mmol, 40g) were treated
with Fe (427nnnol, 23.9g) in a solution comprised of 50% BtOH/HaO (270m1) and
HCl (15m1). The mixture was
heated to 85 C for 2 hours. Then the mixture was cooled to room temperature
and solvent was removed. The crude
material was extracted with EtOAC. The combined extracts were washed with
water and brine, dried over MgSO4,
and concentrated to give a mixture of 2,3-dibromoaniline and 3,4-
dibromoaniline in 1:4 ratio (95% yield). The
mixture (34.86mmo1, 8.75g) was added to a solution of O-ethylxanthic acid,
potassium salt (52.3mrnol, 33.47g) in
DMF (150m1) and heated to 160 C for 4 hours. The work-up was the same as that
described in 7-chloro-
benzothiazole-2-thiol. 7-Bromo-benzothiazole-2-thiol was isolated from the
unreacted 3,4-dibromoaniline as white
solid with 94% yield. 'H NMR (CD3OD) S 7.21 (t, J=6.34Hz, 1H), 7.29 (d,
J=6.30Hz, 1H), 7.34 (d, J=7.34 Hz, 1H).
Step 2 8-(7-Bromo-benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine
8-(7-Bromo-benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine was prepared
by the same method described in
example 232 except that 7-bromo-benzothiazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol. 'H
N1VIR (CDC13) fi 0.92 (t, J= 7.45Hz, 3H), 1.38(m, 2H), 1.83(m, 2H), 4.34 (t,
J=7.45 Hz, 2H), 5.83 (s, 2H, NH2), 7.36
(d, 8.12Hz, 1H), 7.50(t, J=8.12Hz, 1H), 7.87 (d, J=8.12 Hz, IH), 8.44 (s, 1H).
HPLC: RT=6.51min (method:5-100-
7).
Example 172 9-Butyl-8-(7-methyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ytamine
(172)
NH=
>-S
'I \
N~-
S
76
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 1 7-Methyl-benzothiazole-2-thiol
To a solution of2-bromo-3-nitrotoluene (2.5g, 11.57 mmol) in EtOH (18zn1) was
added Fe (1.94g, 34.7mmol) and
con. HCI (1 ml) at room temperature. The reaction mixture was heated to reflux
for 1.5 hr and then cooled to room
temperature. The solvent was removed. The residue was diluted with NH4C1(sat.)
and extracted with EtOAC. The
combined extracts were washed with water and brine, dried over MgSO4,
concentrated to give crude material2-
bromo-3-methylaniline with 90% yield. The compound 2-bromo-3-methylaniline was
reacted with O-ethylxanthic
acid, potassium salt to form 7-methyl-benzothiazole-2-thiol in 89% yield. 'H
NMR (CD3OD) S 7.10 (m, 2H),
7.29(t, J=8.08Hz, IH).
Step 2 9-Butyl-8-(7-methyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
9-Butyl-8-(7-methyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described
in example 49.1 except that 7-methyl-benzothiazole-2-thiol was used instead of
7-chloro-benzothiazole-2-thiol. IH
NMR (CDC13) S 0.88 (t, J= 7.45Hz, 3H), 1.34(m, 2H), 1.80(m, 2H), 2.47 (s, 3H),
4.33 (t, J=7.45 Hz, 2H), 6.10(s,
2H, NHa), 7.16 (d, 7.34Hz, IH), 7.39(t, J=7.34Hz, 1H), 7.78 (d, J=7.34 Hz,
1H), 8.42 (s, 1H). HPLC: RT=6.27min
(method:5-100-7).
Example 173 9-Butyl-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine (173)
NHz
N N
\ S
N
s
O
I
Step 1 7-Methoxy-benzothiazole-2-thiol
To a solution of 2-anuno-3-nitrophenol (lOg, 64.9mmol) in DMF at room
temperature was added K2CO3 (9.86g,
71.4mmo1) and iodomethane (10.13g, 71.4mmol). The reaction mixture was stirred
overnight, and the solvent
removed under reduced pressure. The residue was diluted with NH4C1(sat.) and
extracted with EtOAC. The
combined extracts were washed with water and brine, dried over MgSO4,
concentrated and recrystalized from
EtOAC and hexane to give 2-amino-3-nitroanisole. The 2-amino-3-nitroanisole
was converted to 2-bromo-3-
nitroanisole using the usual NaNOa, aq. HaSO4 and CuBr, aq. HBr method.
Reduction of 2-bromo-3-nitroanisole
was achieved by treatment with iron in EtOH/HCi to give 2-bromo-3-aminoanisole
which upon reaction with 0-
ethylxanthic acid, potassium salt gave 7-methoxy-benzothiazole-2-thiol in 89%
yield. 'H NMR (CD3OD) S 3.95 (s,
3H), 6.74 (d, J=8.2OHz, 1H), 6.95 (d, J=8.08Hz, 1H), 7.34 (t, J=8.15 Hz, 1H).
Step 2 9-Butyl-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
9-Butyl-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described
in example 232 except that 7-methoxy-benzothiazole-2-thiol was used instead of
7-chloro-benzothiazole-2-thiol. 'H
=30 NMR (CDC13) S 0.91 (t, J= 7.45Hz, 3H), I.35(m, 2H), 1.82(m, 2H), 3.96(s,
3H), 4.33 (t, J=7.45 Hz, 2H), 5.68(s, 2H,
NH2), 6.83 (d, J=8.00Hz, 1H), 7.43(t, J=8.OOHz, 1H), 7.58 (d, J=8.00 Hz, 1H),
8.44(s, IH). HPLC: RT=6.14min
(method:5-100-7).
Example 174 9-Butyl-8-(7-ethoxy-benzothiazol-2-ylsulfanyl)-9N-purine-6-ylamine
(174)
77
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH=
N
>-s
N~-- N
S/ I .
O
J
Step 1 7-Ethoxy-benzothiazole-2-thiol
7-Ethoxy-benzothiazole-2-thiol was prepared by the method described for 7-
methoxy-benzothiazole-2-thiol
(exaniple 173, step 1) except that iodoethane was used instead of iodomethane.
7-Ethoxy-benzothiazole-2-thiol was
obtained as a white powder. 'H NMR (CD3OD) S 1.44 (t, J=7Hz, 3H), 4.21 (m,
2H), 6.84 (d, J=8.09Hz, 1H), 6.91
(d, J=8.08Hz, 1H), 7.34 (t, J=8.15 Hz, 1H).
Step 2 9-Butyl-8-(7-ethoxy-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
9-Buty1-8-(7-ethoxy-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described
example 232 except that 7-ethoxy-benzothiazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol. 'H
NMR (CDC13) S 0.90 (t, J= 7.45Hz, 3H), 1.35(m, 2H), 1.45 (t, J= 7.45Hz, 3H),
1.82(m, 2H), 4.21(t, J= 7.45Hz, 2H),
4.33 (t, J=7.45 Hz, 2H), 5,76(s, 2H, NHZ), 6.80 (d, J=8.OOHz, 1H), 7.41(t,
J=8.OOHz, 11-1), 7.56 (d, J=8.00 Hz, 1H),
8.44(s, 1H). HI'LC: RT=6.lOmin (method 5-100-7)
Example 175 9-Butyl-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(175)
NH2
N
rlL+\ S
-
N
/\
s
Step 1 7-Fluoro-benzothiazole-2-thiol
7-Fluoro-benzothiazole-2-thiol was prepared by the same method described in 7-
chloro-benzothiazole-2-thiol
(example 232, step 3) except that 2,3-difluoro-phenylamine was used instead of
2,3-dichloro-phenylamine. 7-fluoro-
benzotbiazole-2-thiol was obtained as a white powder (92% yield). 'H NMR
(CDC13) 6 7.0 (t, J=8.3Hz, IH), 7.10 (d,
J= 8.13Hz, =1H), 7.38(m, 1H).
Step 2 9-Butyl-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
9-Butyl-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described
example 232 except that 7-fluoro-benzothiazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol.'H
NMR (CDCI3) 6 0.90 (t, J= 7.45Hz, 3H), 1.35(m, 2H), 1.82(m, 2H), 4.33 (t,
J=7.45 Hz, 2H), 5.71(s, 2H, NH2), 7.1
(t, J=8.30Hz, 1H), 7.44(m, 1H), 7.75 (d, J=8.30Hz, IH), 8.44(s, 1H). HPLC:
RT=6.14min. (method:5-100-7).
Example 176 9-Butyl-8-(7-trifluoromethyl-benzothiazol-2-ylsulfanyl)-9H-purine-
6-ylamine (176)
78
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH;
N
I S
\ \
N N N
8
F
Step 1 7-Trifluoromethyl-benzothiazole-2-thiol
7-Trifluoromethyl-benzothiazole-2-thiol was prepared by the same method
described in 7-chloro-benzothiazole-2-
thiole (example 232, step 3) except that 2-fluoro-3-trifluoromethyl-
phenylamine was used instead of 2,3-dichloro-
phenylamine. 7-trifluoromethyl-benzothiazole-2-thiol was obtained as a white
powder (85% yield). 'H NMR
(CDC13) S 7.50 (m, 2H), 7.57 (d, J= 6.6 Hz, 1H).
Step 2 9-Butyl-8-(7-trifluoromethyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine
9-Butyl-8-(7-trifluoromethyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
was prepared by the same method
described example 232 except that 7-trifluoromethyl-benzothiazole-2-thiol was
used instead of 7-chloro-
benzothiazole-2-thiol. 'H NMR (CDC13) S 0.90 (t, J= 7.45Hz, 3H), 1.30 (m, 2H),
1.84 (m, 2H), 4.36 (t, J=7.45 Hz,
2H), 5.78 (s, 2H, NHZ), 7.60 (t, J=8.12Hz, IH), 7.68 (d, J=8.lOHz, IH), 8.11
(d, J=8.lOHz, 1H), 8.45 (s, IH). HPLC:
RT=6.57min (method:5-100-7).
Example 177 9-Butyl-8-(7-chloro-thiazole[4,5-c]pyridin-2-ylsulfanyl)-9l-I-
purin-6-ylamine (177)
9-Butyl-8-(7-chloro-thiazole[4,5-c]pyridin-2-ylsulfanyl)-9H-purin-6-ylamine
was prepared by the same method
described in example 232 except that 7-chloro-thiazole [4,5-c] pyridine-2-
thiol (see 206, step 1) was used instead of
7-chloro-benzothiazole-2-thiol. 'H NMR (CDC13) S 0.94 (t, J= 7.45Hz, 3H), 1.38
(m, 2H), 1.86 (m, 2H), 4.35 (t,
J=7.45 Hz, 2H), 5.74 (s, 2H, NHZ), 8.46 (s 1H), 8.49 (s, IH), 9.10 (s, 1H).
HPLC: RT=5.74 niin (5-100-7).
Example 178 8-(Benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine (178)
NHz
I ~ N
N N ~N
8-(Benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine was prepared by the
same method described in example
232 except that benzotbiazole-2-thiol (purchased from Acros) was used instead
of 7-chloro-benzothiazole-2-thiol.
'H NMR (CDCl3) S 0.87 (t, 311), 1.32 (m, 211), 1.79 (m, 2H), 4.33 (t, 2H),
6.62 (s, 2H, NH2), 7.33 (in, 1H), 7.44(m,
1H), 7.70 (d, IH), 7.90 (d, 1H), 8.40 (s, IH). HPLC: RT= 8.63min (method:5-100-
15min).
Example 179 9-Butyl-8-(6-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(179)
9-Butyl-8-(6-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232 except that 6-chloro-benzothiazole-2-thiol (purchased from Acros)
was used instead of 7-chloro-
benzothiazole-2-thiol. 'H NMR (CDC13) 6 0.92 (t, 3H), 1.27 (m, 2H), 1.84 (m,
2H), 4.33 (t, 2H), 5.82 (s, 2H, NH2),
7.42 (d, 1H), 7.74(s, IH), 7.85 (d, 1H), 8.43 (s, 1H). MS: 391 (M+1), HPLC:
RT= 9.743ri-in (method:5-100-
15min).
79
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 180 9-Butyl-B-(5-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(180)
9-Butyl-8-(5-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232 except that 5-chloro-benzothiazole-2-thiol (purchased from Acros)
was used instead of 7-chloro-
benzothiazole-2-thiol. 'H NMR (CDC13) 6 0.91 (t, 3H), 1.33 (m, 2H), 1.83 (m,
211), 4.33 (t, 2H), 6.01 (s, 2H, NH2),
7.34 (dd, IH), 7.65(d, 1H), 7.92 (d, IH), 8.43 (s, 1H). MS: 391.8 (M+1),
383.83 (M+3).
Example 181 9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9N-purine-6-ylamine
(181)
Step 1 4-Chloro-benzothiazole-2-thiol
4-Chloro-benzothiazole-2-thiol was prepared by the same method described for 7-
chloro-benzothiazole-2-thiole
(exanzple 232, step 3) except that 2,6-dichloro-phenylamine was used instead
of 2,3-dichloro-phenylamine. 6-
Chloro-benzothiazole-2-thiol was obtained as a white powder (94% yield). 'H
NMR (CDC13) S 7.21 (t, J=8.OHz,
1H), 7.36 (m, 2H). HPLC
Step 2 9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232 except that 4-chloro-benzothiazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol.'H
NMR (CDC13) S 0.90 (t, 3H), 1.35 (m, 2H), 1.83 (m, 214), 4.35 (t, 2H), 5.98
(s, 2H, NHZ), 7.29 (t, 1H), 7.51 (d, 1H),
7.65 (d, IH), 8.43 (s, IH). HPLC: RT=9.43 min (method:5-100-15).
Example 182 9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(182)
9-Butyl-8-(4-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232. 'H NMR (CDC13) S 1.33 (s, 3H), 1.73 (s, 3H), 2.54 (m, 211), 4.35
(t, 2H), 5.13 (m, 1H), 5.86 (s, 2H,
NHa), 7.34 (d, 1H), 7.42(m, IH), 7.84 (d, 1H), 8.45 (s, IH). HPLC: RT=6.71 min
(method:5-100-7).
Example 183 9-Butyl-B-(thiazolo[5,4-b]pyridin-2-ylsulfanyl)-9H-purine-6-
ylamine (183)
9-Butyl-8-(thiazolo[5,4-b]pyridin-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232. 'H NMR (CDC13) S 0.92 (t, 3H), 1.34 (m, 2H), 1.85 (m, 2H), 4.36
(t, 2H), 5.74 (s, 2H), 7.44 (dd, 1H),
8.15(d, 1H), 8.45 (s, IH), 8.54(d, 1H). HPLC: RT=: 5.33 niin (method:5-100-7).
Example 184 8-(4-Bromo-6,7-difluoro-benzothiazol-2-ylsulfanyl)-9-butyl-9H-
purine-6-ylamine (184)
8-(4-Bromo-6,7-difluoro-benzothiazol-2-ylsulfanyl)-9-butyl-9H-purine-6-
ylarnine was prepared by the same method
described in example 232. 'H NMR (CDC13) 6 0.94 (t, 3H), 1.38 (m, 2H), 1.83
(m, 2H), 4.35 (t, 2H), 5.90 (s, 214),
7.56 (dd, 1H), 8.70 (s, 1H). HPLC: RT=6.83 nun (method:5-100-7).
Example 185 9-Butyl-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylarnine (185)
9-Butyl-8-(6,7-dichloro-benzothiazol-2-ylsulfanyi)-9H-purine-6-ylaminc was
prepared by the same method
described in example 232. 'H NMR (CDC13) & 0.89 (t, 3H), 1.35 (m, 2H), 1.83
(m, 2H), 4.35 (t, 2H), 6.14(s, 2H), 7.
58(d, 1H), 7.75 (d, 1H), 8.40 (s, 1H). HPLC: RT=6.92 min (method:5-100-7).
Example 186 9-Butyl-8-(6,7-difluoro-benzothiazoI-2-ylsulfanyl)-9H-purine-6-
ylamine (186)
9-Butyl-B-(6,7-difluoro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method
described in example 232. 'H NMR (CDC13) S 0.92 (t, 3H), 1.35 (m, 2H), 1.83
(rn, 2H), 4.35 (t, 2H), 6.26(s, 2H), 7.
34(dd, 1H), 7.67 (dd, IH), 8.43 (s, 1H). HPLC: RT= 6.32mi.n (method:5-100-7).
Example 187 9-Butyl-B-(7-methoxymethoxymethyl-benzothiazol-2-ylsulfanyl)-9H-
purine-6-ylamine (187)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N
INl\
N N N
S
06
~o I
9-Butyl-8-(7-methoxymethoxymethyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine was prepared by the same
method described in example 232. 'H NMR (CDC13) S 0.89 (t, 3H), 1.35 (rn, 2H),
1.83 (m, 2H), 3.40 (s, 3H), 4.35 (t,
2H), 4.68 (s,2H), 4.77(s,2H), 5.65 (s, 2H), 7.31(d, IH), 7.55 (t, 1H),
7.90(d,IH), 8.45 (s, 1H). HPLC: RT=6.06min
Example 188 Acetic acid 4-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-butyl ester (188)
/
N~ ~ ~
s
N }~-N
Il'\ 5
N N
0
Acetic acid 4-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-
butyl ester was prepared by the same
method described in example 232. 'H NMR (CDC13) 5 1.69(m, 2H), 1.95(m, 2H),
1.98 (s, 3H), 4.06(t, 2H), 4.39
(t,2H), 5.69(s, 2H), 7.29 (t, IH), 7.44(dd, l H), 7.74(d, IH), 8.44 (s,1 H);
HPLC: RT=5.66min(5-100-7).
Example 189 Acetic acid 3-[6-amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-propyl ester (189)
Acetic acid 3-[6-amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-
propyl ester was prepared by the
same'method described in exanrple 232. 'H NMR (CDC13) S 1.99 (s, 3H), 2.22 (m,
2H), 4.07 (t, 2H), 4.46 (t, 2H),
5.70 (s, 2H), 7.54 (d, 1H), 7.73 (d, 1H), 7.82 (d, IH), 8.41(s, IH). HPLC:
RT=6.19min. (method: 5-100-7).
Example 190 8-(6,7-Dichloro-benzothiazol-2-ylsulfanyl)-9-pent-4-yny1-9H-purin-
6-ylamine (190)
NH2
'I >-S
\I
N ~--N
S
G
a
8-(6,7-Dichloro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine
was prepared by the same method
described in example 232. 'H NMR (CDC13) S 1.90(s, 1H), 2.14 (rn, 2H), 2.28(m,
2H), 4.43 (t, 2H), 5.74 (s, 211),
7.53 (d, 1H), 7. 73(d, IH), 8.43 (s, 1H). HPLC: RT=6.48min (method: 5-100-7).
Example 191 -(7-Methoxy-benzothiazol-2-y1sulfanyl)-9-pent-4-yny1-9N-purin-6-
ylamine (191)
8-(7-1vlethoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 232. 'H NMR (CDC13) S 1.95(s, 1 H), 2.15 (nz, 2H),
2.28(m, 2H), 4.47 (t, 2H), 5.66 (s, 2H),
6.82 (d, 1H), 7.40(t, IH), 7.58 (d, 1H), 8.43 (s, IH). HPLC: RT=6.78min
(method: 5-100-7).
81
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 192 8-(7-Methyl-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (192)
8-(7-Methyl-benzothiazol-2-y1sulfanyl)-9-pent-4-ynyl-9H-purin-6-ylanurie was
prepared by the same method
described in example 232 except that 7-methyl-benzothiazole-2-thiol was used
instead of 7-chloro-benzothiazole-2-
thiol. 'H NMR (CDC13) S 1.94(s, 1H), 2.13 (m, 2H), 2.28(m, 2H), 2.48 (s, 3H),
4.47 (t, 2H), 5.98 (s, 2H), 7.16 (d,
IH), 7.40(t, 1H), 7.78 (d, 1H), 8.43 (s, 1H). HPLC: RT= 5.90min (method: 5-100-
7).
Example 193 8-(4-Amino-7-fluorol-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-
purin-6-ylamine (193)
8-(4-Amino-7-fluorol-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine was prepared by the same
method described in example 232. 'H NMR (CDC13) S 2.04 (t, 1H), 2.16 (m, 2H),
2.36(m, 2H), 4.43 (t, 2H), 5.58 (s,
2H), 7.03 (m, 2H), 8.41 (s, 1H). HPLC: RT=5.19min (method: 5-100-7).
Example 194 8-(7-Ethoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (194)
8-(7-Ethoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 232 except that 7-ethoxy-benzothiazole-2-thiol was used
instead of 7-chloro-benzothiazole-2-
thiol. 'H NMR (CDC13) S 1.43 (t, 3H), 1.95(s, 1H), 2.15 (m, 2H), 2.28(m, 2H),
4.19(m, 2H), 4.47 (t, 2H), 6.14 (s,
2H), 6.78 (d, 1H), 7.40(t, 1H), 7.55 (d, 1H), 8.42 (s, 1H). HPLC: RT=6.08min
(method: 5-100-7).
Example 195 Acetic acid 2-[6-amino-8-(7-methoxy-benzothiazoI-2-ylsulfanyl)-
purin-9-yl]-ethyl ester (195)
Acetic acid 2-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester was prepared by the same
method described in example 232. 'H NMR (CDC13) & 1.93 (s, 3H), 3.94(s, 3H),
4.45 (t, 2H), 4.62(t, 2H), 5.72 (bs,
2H), 6.81 (d, 1H), 7.41 (t, 1H), 7.55 (d, 1H), 8.41 (s, 1H). HPLC: RT=5.36min
(5-100-7).
Example 196 Acetic acid 3-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-propyl ester (196)
Acetic acid 3-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]
propyl ester was prepared by the same
method described in example 232. 'H NMR (CDC13) & 2.06(s, 3H), 2.25 (m, 2H),
3.95(s, 3H), 4.13 (t, 2H), 4.47 (t,
2H), 5.90 (s, 2H), 6.81 (d, 1H), 7.42(t, 1H), 7.58 (d, 1H), 8.50 (s, 1H).
HPLC: RT=5.47min (method: 5-100-7).
Example 197 Acetic acid 3-[6-amino-8-(7-methyl-benzothiazol-2-ylsulfanyi)-
purin-9-yl]-propyl ester (197)
Acetic acid 3-[6-amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propyl ester was prepared by the same
method described in example 232. 'H NMR (CDC1,3) S 1.99 (s, 3H), 2.22 (m, 2H),
2.48 (s, 3H), 4.00 (t, 2H), 4.48 (t,
2H), 6.07 (s, 211), 7.16 (d, IH), 7.42(t, 1H), 7.78 (d, 1H), 8.42 (s, 1H).
HPLC: RT= 5.59min (method: 5-100-7).
Example 198 8-(7-Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-2-chloro-9-methyl-
9H-purin-6-ylamine(198)
8-(7-Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-2-chloro-9-methyl-9H-purin-6-
ylamine was prepared by the same
method described as in 232. 'H NMR (MeOD) 8 3.96 (s, 3H), 8.31 (s, 2H), 8.56
(s 1H), 9.15 (s, 1H). HPLC:
RT=5.S6niin (5-100-7).
Example 199 Acetic acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-
ylsulfanyl)-purin-9-yl]-ethyl ester
(199)
NHa
N
~
I'\ ~--5
N/ N
s//
/ I .
Bf
\' O \ N
O
Acetic acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-
yl]-ethyl ester was prepared by the
same method described as in 232. 'H NMR (CDC13) S 1.98(s, 3H), 4.53 (t, 2H),
4.64 (t, 2H), 5.73 (s, 2H), 8.43 (s,
IH), 8.72(s, 1H), 9.2 (s, IH). HPLC: RT=4.98min (method:5-100-7).
82
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 200 Acetic acid 3-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-
ylsulfanyl)-plu-in-9-y1]-propyl ester
(200)
NHx
N
NS N N
N
er
Acetic acid 3-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-
yl]-propyl ester was prepared by
the same method described in 232. 'H NMR (CDC13) S 1.98 (s, 3H), 2.22 (m, 2H),
4.53 (t, 2H), 4.64 (t, 2H), 6.14 (s,
2H), 8.40 (s, IH), 8.57(s, IH), 9.1 (s, IH). HPLC: RT=5.lOmin (method:5-100-
7).
Example 201 8-(7-Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-9-(4-methyl-pent-3-
enyl)-9H-purin-6-ylamine
(201)
NHg
i N
~-S
N N >-- N
S
/ I .
N
Br
8-(7-Bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-
purin-6-ylamine was prepared by the
same method described in 232. 'H NMR (CDC13) S 9.12(s, 1H), 8.58 (s, 1H), 8.47
(s, IH), 5.80 (bs, 2H, NH2),
5.14(t, J=1.37Hz, 11-I, CH), 4.37(t, J=6.87Hz, 2H, CHz), 2.56(m, 2H, CHZ),
1.38(s, 6H, 2CH3). HPLC: RT=6.116 (5-
100-7).
Example 202 {2-[6-ami.no-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-
9-yl]ethyl}-phosphonic acid
diethyl ester (202)
NHZ
\ S
I
~N N -~N
D~P'O N
Br
{2-[6-Amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]ethyl}-
phosphonic acid diethyl ester was
prepared by the same method described in 232. 'H NMR (CDC13) & 9.25(s, 1H),
8.58 (s, IH), 8.46 (s, IH), 5.71(bs,
2H, NHZ), 4.65(m, 2H, CH2), 4.07(m, 4H, 2CH2), 2.52(m, 2H, CHa), 1.28(t,
J=7.1Hz, 6H, 2CH3). HPLC: RT=5.013
(5-100-7)_
Example 203 {3-[6-Amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-y1sulfanyl)-purin-
9-y1]propyl}-phosphonic acid
diethyl ester (203)
83
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
{3-[6-Amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-y1]propyl}-
phosphonic acid diethyl ester was
prepared by the same method described as in 232. 'H NMR (CDC13) S 9.12(s, 1H),
8.58 (s, 1H), 8.44 (s, 1H),
5.83(bs, 2H, NHZ), 4.45(t, J=7.23Hz, 2H, CH2), 4.04(m, 4H, 2CHa), 2.21(m, 2H,
CHZ), 1.35(m, 2H, CHZ), 1.26(t,
J=7.06Hz, 6H, 2CH3). HPLC: RT=4.925 (Method: 5-100-7).
Example 204 Acetic acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-
ylsulfanyl)-purin-9-y1]-ethyl ester
(204)
Acetic acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-
yl]-ethyl ester was prepared by the
same method described as in 232. 'H NMR (CDC13) 6 2.02 (s, 3H), 4.47 (t, 2H),
4.64 (t, 2H), 5.71 (s, 2H), 8.45 (s,
1H), 8.50(s, 1H), 9.1 (s, 1H). HPLC: RT=4.90min (method:5-100-7).
Example 205 Acetic acid 3-[6-amino-8-(7-chloro-thiazolo[4,5-c]pyridin-2-
ylsulfanyl)-purin-9-yl]-propyl ester
(205)
NH2
N
S
N )-
N/ N
G
Acetic///acid 3-[6-amino-8-(7-chloro-thiazolo[4,5-c]pyridin-2-ylsulfanyl)-
purin-9-y1]-propyl ester was prepared by
the same method described in 177. NMR (CDC13) 6 2.02 (s, 3H), 2.26 (m, 2H),
4.09 (t, J=5.9Hz, 2H), 4.47 (t,
J=7.OHz, 2H), 5.75 (s, 2H, NH2), 8.45 (s, 1H), 8.50 (s, 1H), 9.09 (s, IH).
HPLC: RT=5.06min (5-100-7).
Example 206 {2-[6-Amino-8-(7-chloro-thiazolo[4,5-c]pyridinl-2-ylsulfanyl)-
purin-9-yl]-ethyl}-phosphonic acid
diethyl ester (206)
NHZ
N N
)'-s
N N ~-- N
s
\O'~O \ IN
O--\
Step 1 7-Chloro-thiazole [4,5-c] pyridine-2-thiol
To a solution of 3-nitro-pyridin-4-ol (15g, 107mrno1) in 50% of Acetic acid
(200m1) was bubbled with C12 gas for
20niin at room temperature. The precipitate was filtered off and washed with
water. Pure 3-nitro-4-chloro-pyridine
was obtained after recrystallized from EtOH with 95% yield. To a solution of 3-
nitro-4-chloro-pyridine (14g,
79.8mmol) in DMF (30m1) at room temperatare was added POC13 (7.42mi,
79.8mmo1). The mixture was heated to
120 C for 30niin and then cooled to room temperature. The reaction mixture was
neutralized with NaHCO3 (sat.)
and then extracted with EtOAC. The combined extracts were washed with water
and brine, dried over MgSO4,
concentrated to give 3-nitro-4,5-dichloro-pyridine with 94% yield. To a
solutionof 3-nitro-4,5-dichloro-pyridine
(14g, 72.16mmol) in HCI (160m1) and ether (80m1) at room temperature was added
SnC1Z (162.8g, 721.6mmo1) to
give 3-amino-4,5-dichloro-pyridine with 85% yield, which was further reacted
with O-ethyixanthic acid, potassium
84
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
salt to form chloro-thiazole [4,5-c] pyridine-2-thiol with 89% yield, (see
scheme Q). 'H NMR (DMSO) 6 8.09(s,
1H), 8.35(s, 1H).
Step 2 {2-[6-Amino-8-(7-chloro-thiazolo[4,5-c]pyridinl-2-ylsulfanyl)-purin-9-
yl]-ethyl}-phosphonic acid
diethyl ester
12-[6-Amino-8-(7-chloro-thiazolo[4,5-c]pyridinl-2-ylsulfanyl)-purin-9-yl]-
ethyl}-phosphonic acid diethyl ester was
prepared by the same method described in example 232 eucept that chloro-
thiazole [4,5-c] pyridine-2-thiol was used
instead of 7-chloro-benzothiazole-2-thiol. 'H NMR (CDC13) S 9.08(s, 1H), 8.25
(s, 1H), 8.46(s, 1H), 5.76 (bs, 2H,
NHZ), 4.65(m, 2H, CHz), 4.07(m, 2H, CHZ), 2.52(m, 2H, CHa), 1.28(t, J=7.1Hz,
3H, CH3). HPLC: RT=4.969min (5-
100-7).
Example 207 8-(7-Bromo-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-9-butyl-9H-purine-
6-ylamine (207)
NH=
N
!ItJ\ \~-S
N N/
S
N
6r
8-(7-Bromo-thiazolo[5,4-bJpyridin-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine
was prepared by the same method
described as in example 232. 'H NMR (CDC13) 6 0.92 (t, 3H), 1.34 (in, 2H),
1.85 (m, 2H), 4.36 (t, 2H), 5.74 (s, 2H),
8.50 (s, 1H), 8.70(s, IH), 9.20 (s, IH). HPLC: RT=5.79min (method: 5-100-7).
Example 208 8-(7-Bromo-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-9-butyl-9H-purine-
6-ylamine (208)
NHZ
N ~ N
~S
N N N
s
N
Br
8-(7-Bromo-thiazolo[5,4-bJpyridin-2-ylsulfanyl)-9-butyl-9H-purine-6-ylamine
was prepared by the same method
described in example 232. 'H NMR (CDCl3) S 0.92 (t, 3H), 1.34 (m, 2H), 1.85
(m, 2H), 4.36 (t, 2H), 5.74 (s, 2H),
8.50 (s, 1H), 8.70(s, 1H), 9.20 (s, 1H). HPLC: RT=5.79min (method:5-100-7).
Example 209 8-(7-Bromo-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-2-chloro-9-methyl-
9H-purine-6-ylamine (209)
NH2
N
}--s
Cl~ N N/ ~N
N
Br
8-(7-Bromo-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-2-chloro-9-rnethyl-9H-purine-6-
ylamine was prepared by the same
method described in example 232. 'H NMR (MeOD) S 3.97 (s, 3H), 8.31 (s, 2H),
8.59 (s, 1H), 9.15 (s, 1H).
HPLC:RT=:5.86min (method:5-100-7).
Example 210 9-Butyl-8-(7-chloro-benzooxazol-2-ylsulfanyl)-9H-purine-6-ylamine
(210)
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
a
NH=
N ~N
N N
9-Butyl-8-(7-chloro-benzooxazol-2-ylsulfanyl)-9H-purine-6-ylamine was prepared
by the same method described in
example 232 except that 7-chloro-benzooxazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol. 'H
NMR (CDCl3) S 0.92 (t, 3H), 1.37 (m, 2H), 1.88 (m, 211), 4.37 (t, 2H), 5.78
(s, 2H), 7.42 (d, 1H), 7.27(t, 1H), 7.32
5 (d, 1H), 7.53 (d, IH), 8.45(s, 1H). HPLC: RT=6.155min (method:5-100-15min).
Example 211 Acetic acid 2-[6-amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-
9-yl]-ethyl ester (211)
NH~ ~
fl\N/ N
~ /BO
Acetic acid 2-[6-amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-9-yl]-ethyl
ester was prepared by the same
method described in example 232 except that 7-chloro-benzooxazole-2-thiol was
used instead of 7-chloro-
benzothiazole-2-thiol. 'H NMR (CDC13) S 2.00 (s, 3H), 4.52 (t, 2H), 4.67 (t,
2H), 5.78 (s, 211), 7.29 (t, 1H), 7.35 (d,
1H), 7.52 (d, 111), 8.44(s, 1H). HPLC: RT=5.376min (method:5-100-7).
Example 212 Acetic acid 3-[6-amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-
9-yl]-propyl ester (212)
a
O ~ I
&H,
N ~_N N
O
Acetic acid 3-[6-amino-8-(7-chloro-benzooxazol-2-ylsulfanyl)-purin-9-yl]-
propyl ester was prepared by the same
method described in example 232 except that 7-chloro-benzooxazole-2-thiol was
used instead of 7-chloro-
benzothiazole-2-thiol. 'H NMR (CDC13) S= 1.97 (s, 3H), 2.31 (m, 2H), 4.11 (t,
2H), 4.49 (t, 2H), 5.78 (s, 211), 7.29
(t, 1H), 7.32 (d, IH), 7.52 (d, 1H), 8.44(s, IH). HPLC: RT = 5.478min (method:
5-100-7).
Example 213 Acetic acid 3-[6-amino-8-(7-bromo-benzothiazol-2-ylsulfanyl)-purin-
9-yl]-propyl ester (213)
86
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH,
N
~ S
N~--
~N N
Br \
O
Acetic acid 3-[6-amino-8-(7-bromo-benzothiazol-2-ylsulfanyl)-purin-9-y1]-
propyl ester was prepared by the same
method described in 241. 'H NMR (CDC13) S= 2.00 (s, 3H), 2.22 (m, 2H), 4.07
(t, 211), 4.46 (t, 2H), 5.70 (s, 2H),
7.54 (t, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.41(s,.1H). HPLC: RT=5.81min
(method: 5-100-7).
Example 214 3-[6-Amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-l-ol (214)
NHz
~-S
I N~
~N N >-- N
s
HO G
q
3-[6-Amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-propan-l-ol
was prepared by the same method
described in example 244. 'H NMR (CDC13) S= 2.06(m, 2H), 3.48(zn, 2H), 4.53
(t, 2H), 4.47 (t, 2H), 5.80 (s, 2H),
7.55 (d, 1H), 7.76 (d, 1H), 8.43 (s, 1H). HPLC: RT=5.56min (method:5-100-7).
Example 215 3-[6-Amino-8- (7-bromo-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-ol (215)
NHZ
N
i
>-S
~N N
HO Br
3-[6-Amino-8- (7-bromo-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-ol was
prepared by the same method
described in example 244. 'H NMR (CDC13) 6 1.95(ni, 2H), 3.47(t, 2H), 4.54 (t,
2H), 5.92 (bs, 2H), 7.13 (t, 1H),
7.44 (dd, 1H), 7.74 (d, 1H), 8.44 (s, 11-1); HPLC: RT=5.19min (method5-100-7).
Example 216 3-[6-Amino-8- (7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-ol (216)
3-[6-Amino-8- (7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-pzopan-ol was
prepared by the same method
described in example 244. 'H NMR (CDC13) 6 1.91(m, 2H), 3.45(t, 2H), 3.90 (s,
3H), 4.54 (t, 2H), 5.88 (bs, 2H),
6.82 (d, 1H), 7.45 (t,IH), 7.57 (d, 1H), 8.41 (s,1H); HPLC: RT=4.86min (method
5-100-7).
Example 217 2-[6-Amino-8-(7-methoxy-benzothiazol-2-y1sulfanyl)-purin-9-yl]-
ethanol(217)
2-[6-Amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethanol was
prepared by the same method
described in example 244. 'H NMR (CDC13) S 8.35 (s, 1H), 7_52(d, J=1.08Hz,
1H), 7.41(t, J=8.4Hz, 1H), 6.81(d,
J=1.08Hz, IH), 4.48(t, J=5.09, 2H, CH2), 3.94(m, 5H, CH2+CH3), 3.40(s, 1H;
OH). HPLC: RT= 4.803 (Method:
5-100-7).
87
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 218 2-[6-amino-8-(7-bromo-thiazolo[4,5-c]pyzidin-2-ylsulfanyl)-purin-9-
yl]-ethanol (218)
2-[6-amino-8-(7-bromo-thiazolo[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-ethanol
was prepared by the same method
described in 244. 'H NMR (DMSO) S 3.79 (m, 211), 4.29 (t, 211), 7.63 (s 2H),
8.25 (s, 1H), 8.66 (s, IH), 9.17 (s,
1H), 8.24 (s, 114). HPLC: RT=4.42min (5-100-7).
Example 219 2-[6-Amino-8-(7-chloro-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-purin-
9-yl]-ethanol (219)
2-[6-Amino-8-(7-chloro-thiazolo[5,4-b]pyridin-2-ylsulfanyl)-purin-9-yl]-
ethanol was prepared by the same method
described in 244. 'H NMR (MeOD) 8 3.91 (t, 2H), 4.52 (t, 2H), 8.14 (s, 1H),
8.49 (s, IH), 9.04 (s, 1H). HPLC:
RT=4.36min (method:5-100-7).
Example 220 8-(7-Fluoro-benzothiazol-2-ylsulfanyl)-9-(2-vinyloxy-ethyl)-9H-
purin-6-ylamine (220)
8-(7-Fluoro-benzothiazol-2-ylsulfanyl)-9-(2-vinyloxy-ethyl)-9H-purin-6-ylamine
was prepared by the same method
described in example 271. 'H NMR (CDC13) S 3.98 (dd, 1H), 4.09 (t, 2H), 4.13
(dd, 1H), 4.68 (t, 2H), 5.79 (s, 211),
6.23(dd, 1H), 7.10 (t, 1H), 7. 44 (dd, IH), 7.76 (d, 1H), 8.44 (s, IH). HPLC:
RT=5.748min (method: 5-100-7).
Example 221 8-(7-Fluoro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (221)
8-(7-Fluoro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 271. 'H NMR (CDC13) 8 1.96(s, IH), 2.18 (m, 211), 2.26
(m, 2.H), 4.47 (t, 2H), 5.79 (s, 2H),
6.23(dd, 1H), 7.10 (t, 1H), 7. 44 (dd, 1H), 7.76 (d, 1H), 8.45(s, 1H). HPLC:
RT=5.779min (method: 5-100-7).
Example 222 2-[6-Amino-8-(7-fuloro-benzothiazol-2-ylsulfanyl)-puri.n-9-y1]-
ethanol (222)
NH2
N
N )----5
N N~~ N
S
OH
F
2-[6-Amino-8-(7-fuloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethanol was
prepared by the same method described
in example 244. 'H NMR (DMSO) S 3.67 (m, 2H), 4.32 (t, 2H), 5.07 (t, IH), 7.31
(m, 1H), 7.55 (m, 1H), 7.73 (bs,
2H), 7.78 (m, 111), 8.24 (s, iH). HPLC: RT=4.75min (5-100-7).
Example 223 4-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
butan-l-ol (223)
F
Nry2
S
N y~-N
Il'\ S
N N
OH
4-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butan-l-ol was
prepared by the same method
described in example 244. 'H NMR (CDC13) S 1.69(m, 2H), 1.95 (m, 2H), 3.79(t,
21-1), 4.39 (t, 2H), 5.32 (bs, 2H),
7.29 (t,1H), 7.44 (dd,1H), 7.74 (d, 1H), 8.43 (s,1H); HPLC: RT=4.969min (5-100-
7).
Example 224 3-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-ol
88
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
ry N~s
3-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-ol was
prepared by the same method
described in example 244. 'H NMR (CDC13) 5 1.95(m, 2H), 3.47(t, 2H), 4.54 (t,
2H), 5.92 (bs, 2H), 7.13 (t,1H),
7.44 (dd,1H), 7.74 (d, IH), 8.44 (s,IH); HPLC: RT=4.863min (5-100-7).
Example 225 9-Butyl-8-(7-fluoro-benzooxazol-2-ylsulfanyl)-9H-purine-6-ylamine
(225)
F
NV1a 0 ~
N ~N
N~ N
9-Butyl-8-(7-fluoro-benzooxazol-2-ylsulfanyl)-9.Fl-purine-6-ylamine was
prepared by the same method described in
example 232 except that 7-fluoro-benzooxazole-2-thiol was used instead of 7-
chloro-benzothiazole-2-thiol. 'H NMR
(CDC13) S 0.92 (t, 3H), 1.37 (m, 2H), 1.88 (m, 2H), 4.37 (t, 2H), 5.80 (s,
2H), 7.12 (t, 1H), 7.29(d, 1H), 7.43 (d, IH),
8.45(s, 1H). HPLC: RT= 5.900min (method:5-100-15min).
Example 226 Acetic acid 2-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester (226)
NH=
i N
N N
~O \
Acetic acid 2-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester was prepared by the same
method described in example 241. 'H NMR (CDC13) S 4.13 (t, 2H), 4.64 (t, 2H),
5.73 (s, 2H), 7.09 (t, 1H), 7.42(m,
1H), 7.74 (d, 1H), 8.43 (s, 1H). HPLC: RT= 5.31niin (method:5-100-7).
Example 227 Acetic acid 3-[6-amino-8-(7-fluoro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-propyl ester (227)
F
NH2 N N
N N
Acetic acid 3-[6-amino-8-(7-#luoro-benzothiazol-2-ylsulfanyl)-purin-9-yl)-
propyl ester was prepared by the same
method described in example 241. (CDC13) S 2.00 (s, 3H), 2.25(m, 211), 4.09(t,
2H), 4.47 (t, 2H), 5.92(s, 2H), 7.13
(t, 1H), 7.44(dd,IH), 7.74(d, 1H), 8.43 (s, 1H); HPLC: RT=5.448min (5-100-7).
89
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 228 2-Chloro-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-methyl-9H-purine-
6-ylamine (228)
NH,
~ N
\ S
CI N \ -N
s
CI
2-Chloro-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-methyl-9H-purine-6-ylamine
was prepared by the same method
described in example 232. 'H NMR (CDC13) S 3.81 (s, 3H), 5.83 (s, 2H, NH2),
7.37 (d, IH), 7.44(t, 1H), 7.83 (d,
1H). HPLC: RT= 6.99min (method:5-100-7).
Example 229 9-ethyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(229)
9-Ethyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described in
example 232. 'H NMR (CDC13) S 1.46 (t, 3H), 4.43 (q, 2H), 5.88 (bs, 2H), 7.38
(d, 1H), 7.43 (t, IH), 7.83 (d, 1H),
8.43 (s, 1H). HPLC: RT= 5_84min (5-100-7)
Example 230 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-ethyl-9H-purine-6-ylamine
(230)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-ethyl-9H-purine-6-ylamine was
prepared by the same method described in
example 232. 'H NMR (CDC13) S 0.95 (t, J= 7.45Hz, 3H), 4.32 (t, J=7.45 Hz,
2H), 5.83 (s, 2H, NH2), 7.35 (d,
8.06Hz, 1H), 7.43(t, J=8.06Hz, 1H), 7.83 (d, J=7.84Hz, 1H), 8.44 (s, 1H).
HPLC: RT=5.844min (method:5-100-7).
Example 231 9-Propyl-8-(7-chloro-benzotbiazol-2-ylsulfanyl)-9Fl-purine-6-
ylamine (231)
NHZ
N
N N N
CI b
9-Propyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine (CF1905)
was prepared by the same method
described in exarnple 232. 'H NMR (CDC1-,) 6 0.95 (t, J= 7.45Hz, 3H), 1.91 (m,
2H), 4.32 (t, J=7.45 Hz, 2H), 5.83
(s, 2H, NH2), 7.35 (d, 8.06Hz, 1H), 7.43(t, J=8.06Hz, 1H), 7.83 (d, J=7.84Hz,
1H), 8.44 (s, 1H). HPLC: RT=
6.09min (method:5-100-7).
Example 232 9-Butyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(232)
NH=
N
~
j---S
N N/
~ I
G \
Step 1 9-Butyl-9H-purin-6-ylamine
To a mixture of Adenine (lOg, 74rnmol) and cesium carbonate (28.93g, 88.8mmol)
in DMF (100m1) was added 1-
iodobutane (10.15m1, 88.8mmol) at room temperature. The reaction mixture was
left stirring at room temperature for
16 hours before quenching with water (200m1). The precipitate was filtered off
and dried under vacuum pump to
give title compound with 95% yield (13.5g, 70mmo1). 'H NMR (DMSO) S 0.89 (t,
J= 7.36Hz, 3H), 1.20 (m, 2H),
1.77 (m, 2H), 4.13 (t, J=7.34 Hz, 2H), 7.17 (s, 1H), 8.14 (s, 1H).
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 2 8-Bromo-9-butyl-9H-purin-6-ylamine
9-Butyl-9H-purin-6-ylamine (lOg, 52.35mmo1) was suspended in HOAC/NaOAC buffer
(6m1), THF (6m1) and
MeOH (6m1) before adding Br2 (16.75g, 104.7mmol) slowly at room temperature.
After added Br2, the reaction
mixture became clear and continued to stir at rt for 0.5h. Then the reaction
mixture was concentrated to 1/3 of
original volume followed by extracted with EtOAc, wash with water, brine,
dried over MgSO4 and concentrated to
give crude material. Pure material (11g, 40.6mmo1) was obtained by
recrystalization from MeOH with 77.6% yield.
'H NMR (MeOH) S 0.98 (t, J= 7.36Hz, 3H), 1.40 (m, 2H), 1.80 (m, 2H), 4.24 (t,
J=7.34 Hz, 2H), 8.28 (s, 1H).
Step 3 7-Chloro-benzothiazole-2-thiol
To a solution of 2,3-dichloro-phenylamine (2g, 12.34n-mol) in DMF ( l Omi) at
room temperature was added 0-
ethylxanthic acid, potassium salt (1.98g, 12.34mmol). The reaction mixture was
then heated to 150 C for 4 hours.
The reaction mixture was cooled to room temperature and the solvent was
removed in vacue. The crude material
was diluted with NH4C1(sat.) and a solid precipitate. The solid was filtered
off, washed with water (50rn1 x2) and
dried under vacuum to give 7-chloro-benzothiazole-2-thiol with 89% yield
(2.2g, 10.94mmo1). 'H NMR (CDC13) S
7.16 (d, J=7.8Hz, 1H), 7.38 (m, 2H), 10.0(s, 1H).
Step 4 9-Butyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
To 7-Chloro-benzothiazole-2-thiol (222mg, 1.1mmo1) in DMF (5m1) was added
potassium t-butoxide (124mg,
1.lmmol) at room temperature. After 15min., a solution of 8-bromo-9-Butyl-9H-
purin-6-ylamine (100mg,
0.37mmol) in DMF (lnil) was added and stirred for 6h at 130 C. The reaction
mixttue was cooled to room
temperature, diluted with water. Extract with EtOAC (200m1), washed with brine
(50m1), dried over MgSO4,
concentrated, and purified from fresh chromatography (silica gel) (5%
MeOH/CH2CI2) to give the final product
(110mg, 0.28nimol) as a white powder with 75.7% yield. 'H NMR (CDC13) 50.91
(t, J= 7.36Hz, 3H), 1.37 (m, 2H),
1.83 (m, 2H), 4.33 (t, J=7.34 Hz, 2H), 6.03 (s, 2H, NH2), 7.36 (dd, J=1.OHz,
7.84Hz, 1H), 7.42(t, J=7.89Hz, 1H),
7.83 (dd, J=1.OHz, 7.84Hz, 1H), 8.43 (s, 1H). HPLC: RT=9.73min (method: 5-100-
15)
Example 233 9-Pentyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine (233)
NH=
I N
I' j--S
\N N// ~--N
5
cl
9-Pentyl-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method described
in example 232. 'H NMR (CDC13) S 0.81 (t, J= 7.45Hz, 3H), 0.94 (m, 2H),
1.31(rn, 2H), 1.86(m, 2H), 4.35 (t,
J=7.45 Hz, 2H), 5.97 (s, 2H, NH2), 7.35 (d, 8.06Hz, IH), 7.43(t, J=8.06Hz,
1H), 7.83 (d, J=7.84Hz, 1H), 8.44 (s,
1H). HPLC: RT=6.80min, (method:5-100-7)
Example 234 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (234)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 232. 'H NMR (CDC13) & 1.96 (t, 1H), 2.14 (m, 2H), 2.31(m,
211), 4.47 (t, 2H), 5.75 (s, 2H),
7.36 (d, IH), 7. 43(t, IH), 7.82 (d, 1H), 8.44 (s, 1H). HPLC: RT=6.Olmin
(method: 5-100-7).
Example 235 8-(7-Chloro-bcnzothiazol-2-ylsulfanyl)-9-pent-4-yny1-9H-purin-6-
ylamine (235)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 232, except that 7-bromo-benzothiazole-2-thiol was used
instead of 7-chloro-benzothiazole-2-
91
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
thiol. 'H NMR (CDC13) S 1.96(s, 1H), 2.29 (m, 2H), 2.58(m, 2H), 4.49 (t, 2H),
5.88 (s, 2H), 7.35 (t, 1H), 7. 60(d,
IH), 7.90 (d, 1H), 8.45 (s, IH). HPLC: RT=6.10min (method: 5-100-7).
Example 236 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methoxy-ethyl)-9H-
purin-6-ylarnine (236)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methoxy-ethyl)-9H-purin-6-ylamine
was prepared by the same method
described in example 232. 'H NMR (CDC13) 6 3.23(s, 3H), 3.75 (t, 2H), 4.56(t,
2H), 5.88 (s, 2H), 7.35 (d, 1H), 7.
43(t, IH), 7.84 (d, 1H), 8.43 (s, 1H). HPLC: RT= 5.61min (method: 5-100-7).
Example 237 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-vinyloxy-ethyl)-9H-
purin-6-ylamine (237)
8-(7-Chloro-benzothiazol-2-ylsulfanyi)-9-(2-vinyloxy-ethyl)-9H-purin-6-ylamine
was prepared by the same method
described in example 232. 'H NMR (CDC13) S 3.96 (m, 1H), 4.09 (m, 3H), 4.69
(t, 2H), 5.77 (s, 2H), 6.25(m, 1H),
7.35 (d, IH), 7. 43(t, 1H), 7.84 (d, 1H), 8.44 (s, 1H). HPLC: RT=6.01min
(method: 5-100-7).
Example 238 {2-[6-anvno-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ethyl}-phosphonic acid diethyl
ester (238)
{2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethyl}-
phosphonic acid diethyl ester was prepared
by the same method described in example 232. 1H NIVIR (CDC13) S 1.28 (t, 6H),
2.52 (m 2H), 4.07(m, 4H), 4.65 (m,
2H), 5.67 (bs, 2H), 7.38 (d, 1H), 7.43 (t, 1H), 7.83 (d, 1H), 8.53 (s, 1H).
HPLC: RT=5.66min (5-100-7).
Example 239 . {2-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ethyl}-phosphonic acid diethyl
ester (239)
NN,
N
i
J -S
N~ N\s ~3
J N p
C /F
{2-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethyl}-
phosphonic acid diethyl ester was prepared
by the same method described in example 232. 'H NMR (CDC13) S 8.53 (s, IH),
7.83(d, J=7.OHz, 1H), 7.43(t,
J=7.9Hz, IH), 7.38(d, J=7.0Hz, 1H), 5.67(bs, 2H, NH2), 4.65(m, 2H, CH2),
4.07(m, 4H, 2CH2), 2.52(m, 2H, CH2),
1.28(t, J=7.1Hz, 6H, 2CH3). HPLC: RT=5.667rnin(5-100-7).
Example 240 {2-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purine-9-yl]-
ethyl}-phosphoramidic acid
diethyl ester (240)
{2-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purine-9-yl]-ethyl}-
phosphoramidic acid diethyl ester was
prepared by the same method described in example 271. 'H NMR (CDC13) S 1.19(t,
6H), 3.50 (m 2H), 3.80 (m, 1H),
3.90 (m 4H), 4.47 (t, 2H), 6.00 (bs, 2H), 7.36 (d, 1H), 7.41 (t, 1H), 7.83 (d,
1H), 8.38 (s, 1H). HPLC: RT=5.49min
(5-100-7).
Example 241 Acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester (241)
NHz
N
>-S G
92
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Step 1 Acetic acid 2-(6-amino-purin-9-yl)-ethyl ester
Acetic acid 2-(6-amino-purin-9-yl)-ethyl ester was prepared by the same
rimethod described in example 232, step 1
except that 2-bromo-ethanol acetate was used instead of 1-iodobutane. Acetic
acid 2-(6-amino-purin-9-yl)-ethyl
ester was obtained in 95% yield as white powder. 'H NIvIR (CDC13) 6 2.06 (s,
3H), 4.47 (m, 4H), 5.62 (s, 2H, NHz),
7.85 (s IH), 8.39 (s, 1H).
Step 2 Acetic acid 3-(6-amino-8-bromo-purin-9-yl)-ethryl ester
Acetic acid 3-(6-amino-8-bromo-purin-9-yl)-ethyl ester was prepared by the
same method described in example 49,
step 2 and was obtained in 90% yield. 'H NMR (CDC13) 6 2.06 (s, 3H), 4.51 (rn,
4H), 582(s, 2H, NHZ), 8.34 (s, 1H).
Step 3 Acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-
yl]-ethyl ester
Acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ethyl ester was prepared by the same
method described in example 232, step 3 using acetic acid 3-(6-amino-8-bromo-
purin-9-yl)-ethyl ester. Title
compound was obtained as a white powder (85% yield). 'H NMR (CDC13) 6 1.96 (s,
3H), 4.48 (t, J=5.OHz, 211),
4.64 (t, J=5.OHz, 2H), 5.87 (s, 2H, NHa), 7.37 (d, J=7.79Hz, 1H), 7.44 (t,
J=7.8OHz, IH), 7.83 (d, J=7.80Hz, 1H),
8.43 (s, 1H). HPLC: RT=5.57min (method: 5-100-7).
Example 242 Acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-propyl ester (242)
NH2
S
N
Nll \ ~ .
N N N
s
G
O
~--O
Acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propyl ester was prepared by the same
method described in example 241. 'H NMR (CDC13) 6 2.00 (s, 3H), 2.26 (m, 2H),
4.08 (t, J=5.9Hz, 2H), 4.47 (t,
J=7.OHz, 2H), 6.06 (s, 2H, NH2), 7.36 (d, J=7.79Hz, 1H), 7.42 (t, J=7.80Hz,
1H), 7.82 (d, J=7.80Hz, 1H), 8.42 (s,
1H). HPLC: RT=5.76min (method:5-100-7).
Example 243 Acetic acid 4-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-butyl ester (243)
N N ~N
Acetic acid 4-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-
butyl ester was prepared by the same
method described in example 241. 'H NMR (CDCI3) S 1.66 (m, 2H), 1.95 (m, 2H),
1.96 (s, 3H), 4.11 (t, 211), 4.39(t,
2H), 6.31 (s, 2H), 7.33 (d, 1H), 7.42 (t, 1H), 7.82 (d, 1H), 8.40(s, 1H).
HPLC: RT=5.89min (method:5-100-7).
Example 244 2-[6-Amino-8-(7-chloro-benzothiazol-2-y1sulfanyl)-purin-9-yl]-
ethanol (244)
93
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N
>-5
N N ~--N
S
OH ~
A solution of acetic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester, (241; 200mg,
0.476mmo1) in I Ond of 7N NH3 in methanol was stirred at room temperature for
4h. The solvent was evaporated and
the residue was purified with flash chromatography (5% MeOH/CH2C12) to yield 2-
[6-amino-8-(7-chloro-
benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethanol, as a white powder (172mg,
0.455mmo1) with 94% yield. 'H NMR
(DMSO) S 3.58 (m, 2H), 4.33 (t, J=5.9Hz, 2H), 5.04 (t, J= 5.0Hz, 1H, OH),
7.55(rn, 2H), 7.64 (s, 2H, NH2), 7.93 d,
J= 5.0Hz, 111), 8.26 (s, 1H). HPLC:RT= 5.01min (method:5-100-7).
Example 245 2-[6-Anzino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propan-l-ol (245)
NHz
NI \ N
\ S
N N --_._N
S
06
HO
2-[6-Amino-S-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-l-ol was
prepared by the same method
described in example 244, and was obtained as a white powder (94% yield). 'H
NMR (CDC13) 6 1.93 (m, 2H), 3.47
(m, 2H), 4.52 (t, J=7.OHz, 2H), 5.78 (s, 211, NHZ), 7.39 (d, J=7.79Hz, 1H),
7.42 (t, J=7.80Hz, 1H), 7.82 (d,
J=7.80Hz, 1H), 8.43 (s, 1H). HPLC: RT=5.134min (5-100-7).
Example 246 4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
butan-l-ol (246)
4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-y1]-butan-l-ol was
prepared by the same method
described in example 244. 'H NMR (CDC13) S 1.59(ni,2H), 2.02(m,2H), 3.72 (t,
2H), 4.47 (t, 2H), 5.83 (s, 2H), 7.36
(d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H). HPLC: RT= 5.21min (method:5-
100-7).
Example 247 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(2,2-dimethyl-
propylamino)-ethyl]-9H- purin-6-yl
amine (247)
Step 1 Methanesulfonic acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester
To a solution of 2-[6-Amino-8-(7-chloro-benzothiazol-2-y1sulfanyl)-purin-9-yl]-
ethanol(244; 100mg, 0.29mmo1) in
5m1 of DMF at 0 C was slowly added methanesulfonyl chloride (33.7ul,
0.45nunol) and triethyl amine (48.6u1,
0.35mmo1). The reaction mixture was stirred for 10 min at 0 C. Most of solvent
was then removed. The product was
obtained after quenching the crude with water followed by filtration, to yield
the title compound as a white powder
(94% yield). 'H NMR (CDC13) S 2.9 (s, 3H), 4.68 (t, J= 4.87Hz, 2H), 4.75 (t,
J=4.90Hz, 2H), 5.88 (s, 2H, NHZ),
7.37 (d, J=7.79Hz, IH), 7.45 (t, J=7.80Hz, 1H), 7.82 (d, J=7.8OHz, 1H), 8.44
(s, 1H).
Step 2 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(2,2-diinethyl-propylamino)-
ethyl]-9H- purin-6-yl
amine
To Methanesulfonic acid 2-[6-am.ino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ethyl ester (100mg,
0.22mmo1) was added lml of 2,2-Dimethyl-propylamine. The reaction mixture was
stirred overnight at room
temperature. The excess amine was removed. The residue was purified by flash
chromatography (silica gel) (5%
MeOH/CHZClZ) to give 8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-[2-(2,2-dimethyl-
propylamino)-ethyl]-9H- purin-6-
94
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
yl amine (30mg, 0.067mmol) as a white powder with 30.5% yield. 'H NMR (CDCl3)
6 0.82 (s, 3H), 2.31 (s, 2H),
3.05 (t, J= 4.87Hz, 2H), 4.47 (t, J=4.90Hz, 2H), 5.74 (s, 2H, NH2), 7.35 (d,
J=7.79Hz, 1H), 7.43 (t, J=7.8OHz, 1H),
7.84 (d, J=7.80Hz, 1H), 8.44 (s, IH). HPLC: RT= 5.38min (method:5-100-7).
Example 248 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-isopropylamino)-ethyl)-
9H- purin-6-yl amine (248)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-isopropylamino)-ethyl)-9H- purin-6-
yl amine was prepared by the same
method described in example 247. 'H NMR (CDCI3) 6 0.92 (d, 6H), 2.85 (m, 1H),
3.05 (t, 2H), 4.47 (t, 2H), 5.76 (s,
2H), 7.35 (d, 1H), 7.41 (t, 1H), 7.81 (d, 1H), 8.43(s, 1H). HPLC: RT=4.81min
(method:5-100-7).
Example 249 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-isobutylamino)-ethyl)-
9H- purin-6-yl amine (249)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-isobutylanuno)-ethyl)-9H- purin-6-
yl amine was prepared by the same
method described in example 247. 'H NMR (CDC13) 6 0.82 (d, 6H), 1.65 (m, 1H),
2.39 (d, 2H), 3.05 (t, 2H), 4.46(t,
2H), 5.72 (s, 2H), 7.33 (d, IH), 7.41 (t, 1H), 7.81 (d, 1H), 8.43(s, 1H).
HPLC: RT=5.l0min (method:5-100-7).
Example 250 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(1-ethyl-propylamino)-
ethyl)-9H- purin-6-yl amine
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(1-ethyl-propylamino)-ethyl)-9H-
purin-6-yl amine was prepared by
the same method described in example 247. 'H NMR (CDC13) 6 0.73 (d, 6H), 1.24
(m, 4H), 2.27 (t, 1H), 3.01 (t,
2H), 4.44(t, 2H), 5.75 (s, 2H), 7.34 (d, 1H), 7.44 (t, 1H), 7.82 (d, 1H),
8.43(s, 1H). HPLC: RT=5.19min (method:5-
100-7).
Example 251 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-propylamino)-ethyl)-9H-
purin-6-yl amine (251)
8-(7-ChIoro-benzothiazol-2-ylsulfanyl)-9-(2-propylamino)-ethyl)-9H- purin-6-yl
amine was prepared by the same
method described in example 247. 'H NMR (CDC13) 6 0.83 (t, 3H), 1.40 (m, 2H),
2.57 (t, 2H), 3.05 (t, 2H), 4.48(t,
2H), 5.78(s, 2H), 7.33 (d, IH), 7.42 (t, 1H), 7.82 (d, IH), 8.43(s, 1H). HPLC:
RT=4.88nzin (method:5-100-7).
Example 252 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(1-ethyl-propylamino)-
propyl]-9Ff- purin-6-yl aniine
(252)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(1-ethyl-propylamino)-propyl]-9H-
purin-6-yl anune was prepared by
the same method described in example 247. 'H NMR (CDC13) 6 0.95 (t, 6H), 1.58
(m, 4H), 2.20 (m, 2H), 2.79 (m,
1H), 2.95 (t, 2H), 4.50(t, 2H), 5.67 (s, 2H), 7.47 (d, 1H), 7.54 (t, 1H), 7.86
(d, 1H), 8.32(s, 1H). HPLC:
RT=5.158min (method:5-100-7).
Example 253 9-(3-tert-Butylamino-propyl)-8-(7-chloro-benzothiazol-2-
ylsulfanyl)- 9H- purin-6-yl amine (253)
9-(3-tert-Butylamino-propyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)- 9H- purin-
6-yl anzine was prepared by the
same method described in example 247. 'H NMR (CDC13) S 1.32 (s, 9H), 2.22 (m,
2H), 3.02 (t, 2H), 4.53 (t, 2H),
5.67 (s; 2H), 7.47 (d, IH), 7.54 (t, 1H), 7.86 (d, 1H), 8.34(s, 1H). HPLC:
RT=5.005min (method:5-100-7).
Example 254 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-isobutylamino-propyl)-
9H- purin-6-yl amine (254)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-isobutylamino-propyl)- 9H- purin-6-
yl amine was prepared by the same
method described in example 247. 'H NMR (DMSO) S 8.28
(s, IH), 7.93(t, J=8.4Hz, IH), 7.76(bs, 2H, NHZ), 7.57(d, J=1.08Hz, 2H),
4.36(t, J=7.35Hz, 2H), 2.90(t, J=7.35Hz,
2H), 2.38(d, J=6.89, 2H, CH2), 2.25(m, 2H, CH2), 1.64(m, 1H, CH), 0.83(s, 6H,
2CH3). HPLC: RT=5.035 (5-100-7).
Example 255 9-(3-sec-Butylamino-propyl)-S-(7-Chloro-benzothiazol-2-ylsulfanyl)-
9H- purin-6-yl amine (255)
9-(3-sec-Butylamino-propyl)-8-(7-Chloro-benzothiazol-2-ylsulfanyl)- 9H- purin-
6-yl amine was prepared by the
same method described in example 247. 'H NMR (DMSO) S 8.28(s, IH), 7.93(t,
J=8.4Hz, 1H), 7.76(bs, 2H, NH2),
7.57(d, J=1.08Hz, 2H), 4.36(t, J=7.35Hz, 2H), 3.17(m, 1H, CH), 2.90(t,
J=7.35Hz, 2H), 2.70(m, IH, CH), 2.25(m,
2H, CH2), 1.51(m, 2H, CH2), 1.10(nrn, 6H, 2CH3). HPLC: RT=5.034 (5-100-7).
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 256 9-[2-(2,2-Dimethyl-propylamino)-ethyl]-8-(7-Chloro-benzothiazol-2-
ylsulfanyl)-9H- purin-6-yl
amine (256)
9-[2-(2;2-Dimethyl-propylamino)-ethyl]-8-(7-Chloro-benzothiazot-2-ylsulfanyl)-
9H- purin-6-yl amine was prepared
by the same method described in example 247. 'H NMR (CD3OD) & 8.29 (s, IH),
7.50(d, J=1.08Hz, 1H), 7.48(t,
J=8.4Hz, IH), 6.99(d, J=1.08Hz, 1H), 4.48(t, J=5.09, 2H, CH2), 3.97(s, 3H,
CH3), 2.97(t, J=5.09, 2H, CH2), 2.25(s,
2H, CH2), 0.80(s, 9H, 3CH3). HPLC: RT= 5.110 (Method: 5-100-7).
Example 257 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(2,2-dimethyl-
propylamino)-propyl]-9H- purin-6-yl
amine (257)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(2,2-dimethyl-propylamino)-propyl]-
9H- purin-6-yl amine was
prepared by the same method described in example 247. 'H NMR (CDC13) S 0.88(s,
9H), 2.02 (m, 2H), 2.24 (s, 2H),
2.62 (t, 2H), 4.47 (t, 2H), 5.73 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d,
IH), 8.43(s, 1H). HPLC: RT=5.21min
(method:5-100-7).
Example 258 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(cycloprpylmethyl-
amino)-ethyl]-9H- purin-6-yl
amine (258)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(cycloprpylmethyl-amino)-ethyl]-9H-
purin-6-yl amine was prepared
by the same method described in example 247. 'H NMR (CDC13) 8 0.09(m, 2H),
0.41(m 2H), 0.85(m, 1H), 2.46 (d,
2H), 3.07 (t, 2H), 4.47 (t, 2H), 5.82 (s, 2H), 7.35 (d, 1H), 7.43 (t, IH),
7.84 (d, 1H), 8.43(s, 1H). HPLC:
RT=4.97min (method: 5-100-7).
Example 259 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-prop-2-ynylamino-
ethyl)-9H=purin-6-yl amine (259)
8-(7-Chloro-benzothiazol-2-yisulfanyl)-9-(2-prop-2-ynylarnino-ethyl)-9H-purin-
6-yl amine was prepared by the
same method described in example 247. 'H NMR (CDCl3) S 2.10 (t, IH), 3.16 (m,
2H), 3.51 (s, 2H), 4.49 (t, 2H),
5.83 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, IH). HPLC:
RT=4.74min (method:5-100-7).
Example 260 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-cyclopentylamino-
ethyl)-9H-purin-6-y1 amine (260)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-cyclopentylarimino-ethyl)-9H-purin-
6-yl amine was prepared by the
same method described in example 247. 'H NMR (CDC13) 6 8.42(s, 1H), 7.83(d,
J=7.OHz, 1H), 7.43(t, J=7.9Hz,
iH), 7.38(d, J=7.0Hz, 1H), 5.70(bs, 2H, NHa), 4.48(t, J=5.95Hz, 2H, CHa),
3.08(t, J=5.95Hz, 2H, CHZ), 1.75(m, 1H,
CH), 1.61(m, 4H, 2CH2), 1.48(m, 4H, 2CH2). HPLC: RT=5.090 (Method: 5-100-7
Example 261 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(3-methyl-butylamino)-
ethyl]-9H-purin-6-yl amine
(261)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(3-methyl-butylamino)-ethyl]-9H-
purin-6-yl amine was prepared by the
same method described in example 247. 'H NMR (CDC13) 6 8.44(s, 1H), 7.83(d,
J=7.OHz, 1H), 7.43(t, J=7.9Hz,
1H), 7.38(d, J=7.OHz, 1H), 5.79(bs, 2H, NH2), 4.49(t, J=5.95Hz, 2H, CH2),
3.06(t, J=5.95Hz, 2H, CHZ), 2.61(t,
J=8.19Hz, 2H, CHa), 1.55(m4 3H, CH+CH2), 0.85(d, J=6.62, 6H, 2CH3). HPLC:
RT=5.323 (Method: 5-100-7).
Example 262 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(1,1-dimethyl-
propylamino)-ethyl]-9H-purin-6-yl
amine (262)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(1,1-dimethyl-propylamino)-ethyl]-
9H-purin-6-y1 amine was prepared
by the same method described in example 247. 'H NMR (CDC13) S 8.44(s, 1H),
7.81(d, J=7.OHz, IH), 7.43(t,
J=7.9Hz, 1H), 7.35(d, J=7.OHz, 1H), 5.74(bs, 2H, NHZ), 4.43(t, J=5.95Hz, 2H,
CH2), 2.95(t, J=5.95Hz, 2H, CHa),
1.30(m, 2H, CH2), 0.92(s, 6H, 2CH3), 0.74(t, J=6.12Hz, 3H, CH3). HPLC:
RT=5.145 (Method: 5-100-7).
96
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 263 9-(2-Allylamino-ethyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-
purin-6-ylamine (263)
9-(2-Allylarnino-ethyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purin-
6=ylamine was prepared by the same
method described in example 247. 'H NMR (CDCI3) S 3.03(t, 2H), 3.223(d 211),
4.47 (t, 2H), 5.00(m, 2H), 5.71(m,
IH), 5.80 (s, 2H), 7.35 (d, IH), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H).
HPLC: RT=:4.82 min (method:5-100-7).
Example 264 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino)-
ethyl)-9H- purin-6-yl amine
(264)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino)-ethyl)-9H- purin-
6-yl amine was prepared by the
same method described in example 247 except that cyclopropylamine was used
instead of 2,2-dimethyl-
propylamine. 'H NMR (CDC13) S 0.16 (m, 2H), 0.36 (m, 2H), 2.15 (m, 1H), 3.15
(t, J= 4.87Hz, 2H), 4.46 (t,
J=4.90Hz, 2H), 5.70 (s, 2H, NH2), 7.35 (d, J=7.79Hz, 1H), 7.43 (t, J=7.80Hz,
1H), 7.84 (d, J=7.80Hz, 1H), 8.44 (s,
IH). HPLC: RT=4.95min (method 5-100-7).
Example 265 9-(2-tert-Butylamino-ethyl)-8-(7-chloro-benzothiazole-2-
ylsulfanyl)-9H- purin-6-yl amine (265)
9-(2-tert-Butylamino-ethyl)-8-(7-chloro-benzothiazole-2-ylsulfanyl)-9H- purin-
6-yl amine was prepared by the
same method described in example 247 except that tert-butylamine was used
instead of 2,2-dimethyl-propylamine.
'H NMR (CDC13) S 0.96 (s, 9H), 3.00 (t, J= 4.87Hz, 2H), 4.46 (t, J=4.90Hz,
2H), 5.77 (s, 2H, NHz), 7.35 (d,
J=7.79Hz, 1H), 7.43 (t, J=7.80Hz, 1H), 7.84 (d, J=7.80Hz, IH), 8.43 (s, 1H).
HPLC: RT=5.04min (method 5-100-
7).
Example 266 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-isopropylamino-propyl)
9H- purin-6-yl amine (266)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-isopropylamino-propyl) 9H- purin-6-
yl amine was prepared by the
same method described in example 247 except that isopropyl amine was used
instead of 2,2-dimethyl-propylamine.
'H NMR (DMSO) S 1.09 (s, 3H), 1.10 (s, 3H), 2.10 (m, 2H), 2.90 (in, 2H), 3.17
(m, IH), 4.36(t, 2H), 7.57 (d, 2H),
7.76 (bs, 211), 7.93 (t, 1H), 8.28(s, 1H). HPLC: RT=4.811min (method:5-100-7).
Example 267 8-(7-Chlorol-benzothiazol-2-ylsulfanyl)-9-(3-pyrrol-1-yl-propyl)-
9H-purine-6-ylamine (267)
8-(7-Chlorol-benzothiazol-2-ylsulfanyl)-9-(3-pyrrol-1-yl-propyl)-9H-purine-6-
ylamine was prepared by the same
method described in example 247. 'H NMR (CDC13) S 2.40 (nz, 211), 3.97 (t,
2H), 4.35 (t, 2H), 5.82 (bs, 2H), 6.11
(d, 2H), 6.66 (d, 2H), 7.37(d, IH), 7.44 (t, IH), 7.83(d,1H), 8.45 (s, 1H).
HPLC: RT=6.372min (method:5-100-7).
Example 268 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(3,3-dimethyl-
butylamino)-ethyl]-9H- purin-6-yl
amine (268)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(3,3-dimethyl-butylamino)-ethyl]-
9H- purin-6-yl amine was prepared
by the same method described in example 247. 'H NMR (CDC13) & 8.44 (s, 1H),
7.83(d, J=7.0Hz, 1H), 7.43(t,
J=7.9Hz, 1H), 7.38(d, J=7.0Hz, IH), 5.70(bs, 2H, NH2), 4.47(t, J=5.95Hz, 2H,
CHZ), 3.06(t, J=5.95Hz, 2H,.CH2),
2.55(t, J=8.19Hz, 2H, CHZ), 1.22(t, J=8.19Hz, 2H, CH2), 0.83(s, 9H, 3CH3).
HPLC: RT=5.558(Method: 5-100-7).
Example 269 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-morpholin-4-yl-propyl)-
9H-purin-6-ylamine (269)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-morpholin-4-yl-propyl)-9H-purin-6-
ylamine was prepared by the same
method described in example 247. 'H NMR (CDC13) 6 1.30 (m, 2H), 2.22 (m, 411),
2.40 (m, 2H), 3.62(m, 4H), 4.48
(t,2H), 5.70 (s, 2H), 7.37 (d, 1H), 7.44(t, 1H), 7.83 (d, 1H), 8.44 (s, 1H).
HPLC: RT= 4.77min (method: 5-100-7).
Example 270 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-morpholin-4-yl-ethyl)-
9H-purin-6-ylamine (270)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-morpholin-4-yI-ethyl)-9Fl-purin-6-
ylamine was prepared by the same
method described in example 247. 'H NMR (CDC13) S 2.50 (t, 4H), 2.76 (t, 2H),
3.64(t, 4H), 4.46 (t, 2H), 5.85 (s,
2H), 7.35 (d, 1H), 7.44(t, IH), 7.83 (d, 1H), 8.42 (s, 1H). HPLC: RT=4.71niin
(method: 5-100-7).
97
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 271 9-(2-Bromo-ethyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-
6-ylamine (271)
Step 1 8-Bromoadenine was prepared as reported, see Collect. Czech. Chem.
Commun. 2000, 65, 1126-
1144.
Step 2 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
Followed the same procedure given in example 232, step 4. 'H NMR (DMSO) S
8.23(s, 1H), 8.10(t, 1H), 7.90(d,
1H), 7.82(bs, 2H), 7.59 (d, 1H).
Step 3 9-(2-Bromo-ethyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-
ylamine
To a mixture of 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine
(200mg, 0.599mmo1) and cesium
carbonate (292.6mg, 0.898mmo1) in DMF (lOml) was added 1,2-dibromo-ethane
(168.7mg, 0.898mmo1) at room
temperature. The reaction mixture was stirred at room temperature for 16 hours
before quenched with water (20m1).
The precipitate was filtered off and dried under vacuum. The crude material
was purified by flash chromatography
with 35% yield. 'H NMR (CDC13) S 3.82 (t, 2H), 4.78 (t, 2H), 5.71 (s, 2H),
7.36 (d, 1H), 7. 42(t, 1H), 7.84 (d, 1H),
8.45 (s, 1H). HPLC: RT=6.05min (method:5-100-7).
Example 272 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-chloro-ethyl)-9H-
purine-6-ylamine (272)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-chloro-ethyl)-9H-purine-6-ylamine
was prepared by the same method
described in example 271. 'H NMR (CDC13) 5 3.92 (t, 2H), 4.72 (t, 2H), 5.86
(s, 2H), 7.36 (d, 1H), 7. 43(t, 1H),
7.83(d, 1H), 8.45 (s, 1H). HPLC: RT= 5.93min (method:5-100-7).
Example 273 9-(3-Bromo-propyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)- 9FI-
purine-6-ylamine (273)
9-(3-Bromo-propyl)-8-(7-chloro-benzothiazol-2-ylsulfanyl)- 9H-purine-6-ylamine
was prepared by the same method
described in example 271. 'H NMR (CDC13) S 2.49 (m, 2H), 3.89 (t, 2H), 4.51
(t, 2H), 5.67 (s, 2H), 7.37 (d, 1H), 7.
44(t, 1H), 7.83(d, IH), 8.43(s, 1H). HPLC: RT=6.261min (method:5-100-7).
Example 274 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2,(2,5-dimethoxy-phenyl)-
ethyl]- 9H-purine-6-ylamine
(274)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2,(2,5-dimethoxy-phenyl)-ethyl]- 9H-
purine-6-ylamine was prepared by
the same method described in example 271. 'H NMR (CDCl3) 8 3.15 (t, 2H),
3.61(s, 3H), 3.62 (s, 3H), 4.60(t, 2H),
5.7 (bs, 2H), 6.37 (s, 1H), 6.56(d, 1H), 6.61(d, IH), 7.31(d, 1H), 7.39
(t,1H), 7.77(d,1H), 8.46(s,IH); HPLC:
RT=6.515min (method 5-100-7).
Example 275 9-But-2-ynyl-8-(7-chloro-benzothiazol-2-yisulfanyl)-9Fl-purine-6-
ylamine (275)
9-But-2-ynyl-8-(7-chloro-benzothiazoi-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method
described in example 271.'H NMR (CDC13) S 1.54(s, 3H), 5.09(t, 2H), 6.00(bs,
2H), 7.36(d,1H), 7.44(t,1H),
7.86(d,1H), 8.47(s,1H); HPLC: RT=5.964min (method 5-100-7).
Example 276 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3,4,4-trifluoro-but-3-
enyl)-9H-purin-6-ylamine (276)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3,4,4-trifluoro-but-3-enyl)-9H-purin-
6-ylamine was prepared by the same
method described in example 271. 'H NMR (CDC13) S 2.92 (m, 2H), 4.59 (t, 2H),
5.90 (bs, 2H), 7.35 (d, 1H), 7.44(t,
1H), 7.84 (d, 1H), 8.45 (s, 1H). HPLC: RT=6.29min (method: 5-100-7).
Example 277 6-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
hexanenitrile (277)
6-[6-Amino-8-(7-chloro-benzothiazol-2-y1sulfanyl)-purin-9-yl]-hexanenitrile
was prepared by the same method
described in example 271. 'H NMR (CDC13) S 1.52 (m, 2H), 1.72 (m, 2H), 1.94
(m, 2I1), 2.33 (t, 2H), 4.41 (t, 2H),
7.42 (d, 1H), 7.47(t, 1H), 7.86(d, IH), 8.40 (s, 1H). HPLC: RT=5.879min
(method: 5-100-7).
98
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 278 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-rnethyl-but-3-enyl)-9H-
purin-6-ylamine (278)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(3-methyl-but-3-enyl)-9H-purin>6-
ylamine was prepared by the same
method described in example 271. 'H NMR (CDC13) 6 1.55 (s, 3H), 1.81 (s, 3H),
4.94 (d, 2H), 5.25 (t, 1H), 5.81 (bs,
2H), 7.35 (d, 1H), 7.44(t, 1H), 7.84 (d, 1H), 8.45 (s, 1H). HPLC: RT=6.524min
(method: 5-100-7).
Example 279 4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
butyronitrile (279)
4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butyronitrile
was prepared by the same method
described in example 271. 'H NMR (CDC13) 6 2.31 (rn, 2H), 2.46(t, 2H), 4.50
(t, 2H), 5.74 (bs, 2H), 7.36 (d, 1H),
7.43(t, IH), 7.83(d, IH), 8.44 (s, IH). HPLC: RT=5.516min (method: 5-100-7).
Example 280 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-hex-5-ynyl.-9Fl-purin-6-
ylamine (280)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-hex-5-ynyl-9H-purin-6-ylamine was
prepared by the same method
described in example 271. 'H NMR (CDC13) S 1.57 (m, 2H), 1.84 (t, 2H),
2.18(rn, 2H), 2.22 (m, 2H), 4.39 (t, 2H),
5.71 (s, 2H), 7.36 (d, IH), 7.44(t, IH), 7.84 (d, 1H), 8.45 (s, IH). HPLC:
RT=6.276min (method: 5-100-7).
Example 281 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(tetrahydro-furan-2-
yl)-propyl]-9H-purin-6-ylamine
(281)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[3-(tetrahydro-furan-2-yl)-propyl]-9H-
purin-6-ylamine was prepared by
the same method described in example 271. 'H NMR (CDC13) 8 1.48 (m, 4H), 2.21
(rn, 2H), 3.42(m, 2H), 3.81 (m,
2H), 4.52 (m, 3H), 5.92 (s, 2H), 7.37 (d, 1H), 7.44(t, IH), 7.83 (d, 1H), 8.44
(s, IH). HPLC: RT=6.395min
(method: 5-100-7).
Example 282 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(tetrahydro-furan-2-
ylmethyl)-9H-purin-6-ylamine
(282)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(tetrahydro-furan-2-ylmethyl)-9H-
purin-6-ylamine was prepared by the
same method described in example 271. 'H NMR (CDC13) S 1.68 (rn, 4H), 3.21 (t,
IH), 3.68(m, IH), 3.78 (d, 1H),
4.37(d, 2H), 5.78 (s, 2H), 7.37 (d, IH), 7.44(t, IH), 7.83 (d, 1H), 8.44 (s,
1H). HPLC: RT=6.404min (method: 5-
100-7).
Example 283 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(2-ethoxy-ethoxy)-
ethyl]-9H-purin-6-ylamine (283)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-[2-(2-ethoxy-ethoxy)-ethyl]-9H-purin-
6-ylamine was prepared by the
same method described in example 271. 'H NMR (CDC13) S 1.15 (t, 3H), 3.46 (m,
614), 3.88(t, 2H), 4.58 (t, 2H),
5.84(s, 2H), 7.37 (d, 1H), 7.44(t, IH), 7.83 (d, 1H), 8.44 (s, 1H). HPLC:
RT=5.925min (method: 5-100-7).
Example 284 5-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
pentanenitrile (284)
5-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-pentanenitrile
was prepared by the same method
described in example 271. 1H NMR (CDC13) S 1.71 (m, 2H)2.05(m, 2H), 2.42(t,
2H), 4.41 (t, 2H), 5.88 (bs, 2H),
7.36 (d, IH), 7.43(t, IH), 7.83(d, 1H), 8.44 (s, 1H). HPLC: RT=5.694min
(method: 5-100-7).
Example 285 8-(7-Chlorol-benzothiazol-2-ylsulfanyl)-9-(4-methoxy-3,5-dimethyl-
pyridin-2-ylmethyl)-9H-
purine-6-ylamine (285)
8-(7-Chlorol-benzothiazol-2-ylsulfanyl)-9-(4-methoxy-3,5-dimethyl-pyridin-2-
ylmethyl)-9H-purine-6-ylami.ne was
prepared by the same method described in example 271. 'H NMR (CDC13) S 2.08(s,
3H), 2.35 (s, 3H), 3.71 (s, 3H),
5.60 (s, 2H), 5.82 (bs, 2H), 731(d, IH), 7.39 (t, 1H), 7.77(d,1H), 8.45 (s,
1H). HPLC: RT=5.570m.in (method:5-
100-7).
Example 286 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-prop-2-ynyl-9H-purine-6-
ylamine (286)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-prop-2-ynyl-9H-purine-6-ylamine was
prepared by the same method
described in example 271. 'H NMR (CDC13) S 8.49(s, 1H), 7.84(d, J=1.08Hz, 1H),
7.46(t, J=8.4Hz, 1H), 7.36(d,
J=1.08Hz, 1H), 5.83(bs, 2H, NH2), 5.15(s, 2H, CH.z), 2.25(s, IH, CH). HPLC:
RT=5.700 (Method: 5-100-7).
99
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 287 8-(7-Chloro-benzothiazol-2-yisulfanyl)-9-(2-piperidin-1-yl-ethyl]-
9H- purin-6-yl amine (287)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-piperidin-1-yl-ethyl]-9H- purin-6-
yl amine was prepared by the same
method described in example 271. 'H NMR (CDC13) 6 8.44(s, 1H), 7.83(d,
J=7.OHz, IH), 7.43(t, J=7.9Hz, 1H),
7.38(d, J=7.OHz, lH), 5.70(bs, 2H, NH2), 4.44(t, J=5.95Hz, 2H, CH2), 2.68(t,
J=5.95Hz, 2H, CHZ), 2.42(t, J=8.19Hz,
4H, 2CHa), 1.57(t, J=8.19Hz, 4H, 2CH2), 1.40(m, 2H, CH2). HPLC:
RT=4.923(Method: 5-100-7).
Example 288 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methylsulfanyl-ethyl)-
9H-purin-6-ylamine (288)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methylsulfanyl-ethyl)-9H-purin-6-
ylamine was prepared by the same
method described in example 271. 'H NMR (CDCl3) 6 2.15(s, 3H), 2.99 (t, 2H),
4.57 (t, 2H), 5.72 (s, 2H), 7.35 (d,
1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H). HPLC: RT=6.04min (method:5-100-
7).
Example 289 {3-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-y1]-propyl}-
phosphonic acid diethyl ester
(289)
{3-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-yl]-propyl}-phosphonic
acid diethyl ester was prepared by
the same method described in example 271. 'H NMR (CDC13) 6 8.43(s, 1H),
7.83(d, J=7.OHz, 1H), 7.43(t, J=7.9Hz,
1H), 7.38(d, J=7.OHz, IH), 5.80(bs, 2H, NH2), 4.45(t, J=7.23Hz, 2H, CHZ),
4.04(m, 4H, 2CH2), 2.21(m, 2H, CH2),
1.35(m, 2H, CH2), 1.26(t, J=7.06Hz, 611, 2CH3). HPLC: RT=5.696 (Method: 5-100-
7).
Example 290 8-(7-Chloro-benzothiazol-2-y1sulfanyI)-9-(2-ethylsulfanyl-ethyl)-
9H-purin-6-ylamine (290)
8-(7-Chioro-benzothiazol-2-ylsulfanyl)-9-(2-ethylsulfanyl-ethyl)-9H-purin-6-
ylamine was prepared by the same
method described in example 271. 'H NMR (CDC13) S 1.21 (t, 3H), 2.58 (m, 2H),
3.00 (t, 2H), 4.57 (t, 2H), 5.72 (s,
2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H). HPLC: RT=6.34min
(method:5-100-7).
Example 291 Phosphoric acid 3-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
9-yl]-propyl ester diethyl ester
(291)
Phosphoric acid 3-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfapyl)-9-yl]-propyl
ester diethyl ester was prepared by
the same method described in example 271. 'H NMR (CDC13) 6 8.43(s, 1H),
7.83(d, J=7.OHz, 1H), 7.43(t, J=7.9Hz,
1H), 7.38(d, J=7.OHz, 1H), 5.80(bs, 2H, NHZ), 4.50(t, J=7.23Hz, 2H, CHa),
4.12(m4 6H, 3CH2), 2.30(m, 2H, CHa),
1.32(t, J=7.06Hz, 6H, 2CH3). HPLC: RT=5.834 (Method: 5-100-7).
Example 292 Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
purin-9-yl]-ester bis-(2-
chloro-ethyl ester (292)
Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
ester bis-(2-chloro-ethyl ester was
prepared by the same method described in example 271. 'H NMR (CDCl3) S 8.43(s,
1H), 7.83(d, J=7.OHz, 1H),
7.43(t, J=7.9Hz, 1H), 7.38(d, J=7.OHz, 1H), 5.80(bs, 2H, NH2), 4.70(t,
J=7.23Hz, 2H, CH2), 4.54(t, J=7.23Hz, 2H,
CH2), 4.19(m, 411, 2CH2), 3.62(t, J=7.06Hz, 4H 2CH2). HPLC: RT=5.909 (Method:
5-100-7).
Example 293 {3-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
propenyl}-phosphonic acid
diethyl ester (293)
{3-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propenyl}-
phosphonic acid diethyl ester was
prepared by the same method described in example 271. 'H NMR (CDC13) S 8.43(s,
1H), 7.83(d, J=7.OHz, 1H),
7.43(t, J=7.9Hz, 1H), 7.38(d, J=7.OHz, IH), 6.85(t, J=8.OHz, 1H, CH), 5.86(bs,
2H, NHZ), 5.56(t, J=8.OHz, 1H, CH),
5.13(t, J=7.23Hz, 2H, CH2), 3.99(m, 4H, 2CH2), 1.26(t, J=7.06Hz, 6H, 2CH3).
HPLC: RT=5.622 (Method: 5-100-7).
Example 294 Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-
9-yl]-ethyl ester diethyl ester
(294)
Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-9-y1]-ethyl
ester diethyl ester was prepared by
the same method described in example 271. 'H NMR (CDC13) S 8.43(s, 1H),
7.83(d, J=7.OHz, 1H), 7.43(t, J=7.9Hz,
100
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
1H), 7.38(d, J=7.OHz, 1H), 5.80(bs, 2H, NHZ), 4.66(t, J=7.23Hz, 2H, CHZ),
4.48(m, 2H, CHa), 3.99(rn, 4H, 2CH2),
1.22(t, J=7.06Hz, 6H, 2CH3). HPLC: RT=5.713 (Method: 5-100-7).
Example 295 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-methyl-9H-purine-6-
ylamine (295)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-methyl-9H-purine-6-ylamine was
prepared by the same method described
in example 271. 'H NMR (CDC13) S 3.91 (s, 3H), 5.76 (s, 2H, NHa), 7.36 (d,
IH), 7.45(t, IH), 7.83 (d, 1H), 8.46(s,
1H). HPLC: RT= 5.51min (method:5-100-7).
Example 296 4-[6-Amino-8-(7-chloro-benzotluazol-2-ylsulfanyl)-purin-9-yl]-
butan-2-one (296)
4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butan-2-one was
prepared by the same method
described in example 271. 'H NMR (CDC13) 6 2.1 (s, 3H), 3.10 (xn, 2H), 4.61
(rn, 2H), 5.84 (s, 2H), 7.35 (d, 1H),
7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H). HPLC: RT=5.60min (method:5-100-7).
Example 297 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethylsulfinyl-ethyl)-
9Fl-purin-6-ylamine (297)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethylsulfinyl-ethyl)-9H-purin-6-
ylamin.e was prepared from 8-(7-
Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethylsulfanyl-ethyl)-9H-purin-6-ylamine
(see example 290) by treating it
with H202 in HOAC at rt. 'H NMR (CDC13) 6 1.29 (t, 3H), 2.75 (m, 2H), 3.20(m,
1H), 3.33 (m, 1H), 4.80 (ni, 1H),
4.88(m, IH), 6.11 (s, 2H), 7.35 (d, IH), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s,
1H). HPLC: RT=5.05min (method:5-100-
7).
Example 298 4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-
butan-2-thione (298)
4-[6-Amino-8-(7-chloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butan-2-thione
was prepared by the same method
described in example 297. 'H NMR (CDC13) 6 2.6 (s, 3H), 3.22 (m, 1H), 3.43 (m,
1H), 4.81 (m, 1H), 4.92 (m, 1H),
5.77 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.63(s,1H). HPLC:
RT=4.87min (method:5-100-7).
Example 299 8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethanesulfonyl-ethyl)-
9H-purin-6-ylamine (299)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethanesulfonyl-ethyl)-9H-purin-6-
ylamine was prepared from 8-(7-
Chloro-benzothiazol-2-ylsulfanyl)-9-(2-ethylsulfanyl-ethyl)-9H-purin-6-ylamine
(see example 290) by treating it
with mCPBA in CH2C12 at rt. 'H NMR (CDC13) 6 1.37 (t, 3H), 3.00 (m, 2H),
3.28(t, 2H), 4.86(t, 2H), 5.76 (s, 2H),
7.35 (d, IH), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H). HPLC: RT=5.39min
(method:5-100-7). *
Example 300 8-(7-Chloro-benzothiazol-2-yisulfanyl)-9-(2-methanesulfonyl-ethyl)-
9H-purin-6-ylamine (300)
8-(7-Chloro-benzothiazol-2-ylsulfanyl)-9-(2-methanesulfonyl-ethyl)-9H-purin-6-
ylamine was prepared by the same
method described in example 299. 'H NMR (CDC13) 6 2.96 (s, 3H), 3.76(t, 2H),
4.87(t, 2H), 5.76 (s, 2H), 7.37 (d,
1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43(s, 1H). HPLC: RT=5.30min (method:5-100-
7)
Example 301 [2-(6-Amino-9-butyl-9H-purin-8-ylsulfanyl)-benzothiazol-7-yl]-
methanol (301)
OH
MHz S /
N
N >-.1 !!!
l\N N
[2-(6-Amino-9-butyl-9H-purin-8-ylsulfanyl)-benzothiazol-7-yl]-methanol was
prepared from 9-Butyl-8-(7-
methoxymethoxymethyl-benzothiazol-2-ylsulfanyl)-9H-purine-6-ylamine (187) by
treating it with HCI in MeOH at
65 C for 15min. 'H NMR (CDC13) 6 0.90 (t, 3H), 1.33 (m, 2H), 1.84 (m, 2H),
4.33 (t, 2H), 4.89 (s, 2H), 6.19 (bs,
2H), 7.29(d, IH), 7.43 (t, 1H), 7.87 (d, 1H), 8.42 (s, IH). HPLC: RT=5.36min
(method:5-100-7).
101
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example 302 9-[2-Isopropylamino-ethyl]-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-
9H-purin-6-yl amine (302)
9-[2-Isopropylamino-ethyl]-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purin-6-
yl amine was prepared by the
same method described in Example 247. 'H NMR (CD3OD) & 8.29(s, 1 H), 7.50(d,
J=l .08Hz, 1 H), 7.48(t, J=8.4Hz,
IH), 6.99(d, J=1.O8Hz, 1H), 4.50(t, J=5.09, 2H, CHz), 3.97(s, 3H, CH3),
3.07(t, J=5.09, 2H, CHZ), 2.87(rn, 1H, CH),
1.00(d, J=6.32, 6H, 2CH3). HPLC: RT=4.575 (Method: 5-100-7).
Example 303 9-[2-tert-Butylamino-ethyl]-8-(7-methoxy-benzothiazol-2-
ylsulfanyl)-9H-purin-6-yl anune (303)
9-[2-tert-Butylamino-ethyl]-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purin-6-
yl amine was prepared by the
same method described in Example 247. 'H NMR (CD3OD) 6 8.29(s, 1H), 7.50(d,
J=1.08Hz, 1H), 7.48(t, J=8.4Hz,
1H), 6.99(d, J=1.08Hz, 1H), 4.47(t, J=5.09, 2H, CHa), 3.97(s, 3H, CH3),
3.07(t, J=5.09, 2H, CHZ), 2.87(nz, 1H, CH),
1.02(s, 9H, 3CH3). HPLC: RT=4.727 (Method: 5-100-7).
Example 304 9-(2-Isobutylamino-ethyl)-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-
9H-purin-6-yl amine (304)
9-(2-Isobutylamino-ethyl)-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-9H-purin-6-
yl amine was prepared by the same
method described in Example 247. 'H NMR (CD3OD) S 8.29(s, 1H), 7.50(d,
J=1.08Hz, IH), 7.48(t, J=8.4Hz, 1H),
6.99(d, J=1.08Hz, 1H), 4.507(t, J=5.09, 2H, CH2), 3.97(s, 3H, CH3), 3.02(t,
J=5.09, 2H, CHZ), 2.38(d, J=6.89, 2H,
CHZ), 1.64(m, 1H, CH), 0.83(s, 6H, 2CH3). HPLC: RT=4.869 (Method: 5-100-7).
Example 305 6-Amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)-purin-9-y1]-propan-
ol (305)
3-[6-Amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propan-ol was
prepared by the same method
described in 244. IH NMR (CDC13) 6 1.91(m, 2H), 2.50(s, 3H), 3.45(t, 2H), 4.54
(t, 2H), 5.78 (bs, 2H), 7.02 (d, 1H),
7.40 (t,1H), 7.79 (d, 1H), 8.42(s,1H); HPLC:RT=4.96niin (method 5-100-7).
Example 306 9-But-3-enyl-8-(7-chloro-benzothoazol-2-ylsulfanyl)-9H-purine-6-
ylamine (306)
9-But-3-enyl-8-(7-chloro-benzothoazol-2-ylsulfanyl)-9H-purine-6-ylamine was
prepared by the same method
described in exaniple 232. 'H NMR (CDC13) 52.14 (m, 2H), 4.36 (t, 2H), 5.04
(m, 2H), 5.74(m, 1H), 5.90(bs, 2H),
7.35(d, 1H), 7.44 (t, IH), 7.84(d,1H), 8.45(s, 1H); HPLC: RT= 6.185min
(method:5-100-7).
Example 307 8-(7-Chloro-benzothoazol-2-ylsulfanyl)-9-pent-4-enyl-9H-purine-6-
ylamine (307)
8-(7-Chloro-benzothoazol-2-ylsulfanyl)-9-pent-4-enyl-9H-purine-6-ylamine was
prepared by the same method
described in example 271. 'H NMR (CDC13) 51.97 (m, 2H), 2.14(m, 2H), 4.36
(t,2H), 5.04(m,2H), 5.74 (m,1H),
5.90(bs,2H), 7.35(d,1H), 7.44 (t,1H), 7.84(d,1H), 8.45(s,1H); HPLC:RT=6.488min
(method(5-100-7).
Example 308 8-(7-Chloro-benzothoazol-2-ylsulfanyl)-9-hex-5-enyl-9H-purine-6-
ylamine (308)
8-(7-Chloro-benzothoazol-2-ylsulfanyl)-9-hex-5-enyl-9H-purine-6-ylamine was
prepared by the same method
described in example 271. 'H NMR (CDC13) 51.41 (m, 2H), 1.83(m, 2H), 2.02 (m,
2H), 4.33 (t, 2H), 4.92 (m 2H),
5.64(m, IH), 5.75(bs,2H), 7.33(d,IH), 7.42 (t,IH), 7.82(d,1H), 8.42(s,1H);
HPLC: RT=6.761min (method 5-100-7).
Example 309 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-
ylamine (309)
The preparation of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-
6-ylamine has been descroibed
elsewhere (see Kasibhatla et. al. WO 3037860, 2003 and Llauger et. al. J.1Vled
Chern. 2005, 48, 2892-2905).
Example 310 9-Butyl-8-(3-methoxy-benzyl)- 9hl-purin-6-ylamine (310)
Step 1 N-(5,6-diamino-pyrimidin4-yl)-2-(3-methoxy-phenyl)-acetamide
hydrochloride
4,5,6-Triaminopyrimidine (6.25 g, 50 mmol) was dissolved in N-methyl-2-
pyrrolidone (NMP, 70 mL) at 70 C. The
solution was cooled to rt, and treated with 3-methoxyphenylacetyl chloride
(9.2 g, 50 mmo1;.1.0 equiv.) for 3 h at 50
C, whereupon the desired compound precipitated as its HCl salt. The
precipitate was collected, washed with EtOAc
and acetone, and dried to give the product as a white solid (15.2 g, 98%).
HPLC Purity: 97.4%. tR = 4.13 min
(Conditions I). mp = 286-288 C. 'H NMR (DMSO-d6) b 9.22 (s, IH), 8.20 (s,
1H), 6.75-7.58 (br. s, 4H), 7.21 (t, J
102
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
= 7.9 Hz, 1H), 6.95 (d, J = 1.3 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.80 (dd,
J= 7.6 & 1.3 Hz, 1H), 3.74 (s, 211), 3.73
(s, 3H). 13C NMR (DMSO-d6) S 170.9, 159.4, 156.4 (2C), 147.9, 137.7, 129.3,
122.8, 116.2, 112.2, 93.9, 55.4, 41.8
Step 2 8-(3-Methoxy-benzyl)-9H-purin-6-ylamine
A solution of crude N-(5,6-diamino-pyrimidin-4-yl)-2-(3-methoxy-phenyl)-
acetamide hydrochloride (17.6 g, 57
mmol) and MeONa (12.3 g, 227 mmol, 4.0 equiv.) in n-BuOH (150 mL) was heated
to reflux for 2 h, cooled to rt,
and neutralized with HC12M. Brine was added, which gave a bi-phasic mixture.
Concentration of the organic layer
afforded the title compound as a solid (10.7 g, 75%). tR = 4.70 min
(Conditions II). mp = 252-254 C 'H NMR
(DMSO-d6) S 8.06 (s, IH), 7.43 (br. s, IH), 7.21 (t, J= 7.9 Hz, 1 H), 7.05 (s,
2H), 6.93 (s, I H), 6.87 (d, J= 7.6 Hz,
IH), 6.79 (dd, J= 8.1 & 2.3 Hz, IH ), 4.09 (s, 2H), 3.73 (s, 3H).'3C NMR (DMSO-
d6) 6 159.8, 155.5, 152.3, 151.6,
150.8, 139.3, 130.0, 121.4, 119Ø 115.0, 112.4, 55.5, 35.5.
Step 3 A mixture of 8-(3-methoxy-benzyl)-9H-purin-6-ylamine (0.50 g, 2.2
nzunol), BuI (0.30 mL, 2.65
mmol, 1.2 equiv.), CsaCO3 (1.43 g, 4.4 mmol, 2.0 equiv.), and DMF (2.5 mL) was
stirred at rt for 16 h. Flash
chromatography (MeOH:CH2CI2 5:95) gave the title compound as a white solid
(370 mg, 54%). HPLC Purity:
91.0%. tR = 6.92 niin (Conditions II). mp = 163-165 C. 'H NMR (CDC13:CD3OD
5:1) S 8.13 (s, 1H), 7.16 (t, J=
7.9 Hz, IH), 6.73-6.67 (m, 3H), 4.13 (s, 2H), 3.95 (t, J= 7.7 Hz, 2H), 3.68
(s, 3H), 1.48 (quint., J= 7.7 Hz, 2H),
1.20 (sext., J= 7.5 Hz, 2H), 0.78 (t, J=7.4 Hz, 3H). 13C NMR (CDCI3:CD3OD 5:1)
S 159.9, 154.7, 152.0, 150.9,
150.7, 136.6, 129.9, 120.8, 117.8, 114.5, 112.3, 55.07, 42.9, 34.2, 31.5,
19.8, 13.4. HRMS: calcd for C17H22N50
(MH)+ m/z 312.1819, found 312.1817.
Example 311 9-Butyl-8-(2-chloro-5-methoxy-benzyl)-9H-purin-6-ylamine (311)
A solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (310) (100 mg,
0.32 mmol) in THF (4 mL) was
treated with SO2CIZ (78 NcL, 0.96 mmol, 3.0 equiv.) at rt for 2 h. Work-up and
preparative TLC (MeOH:CHzCIz
10:90) gave the title compound (60.2 mg, 54%). mp = 138-139 C. HPLC Purity:
92.4%. tR = 7.77 min (Conditions
II). 'H NMR (CDCI3) 6 8.31 (s, 1H), 7.30 (d, J= 8.8 Hz, IH), 6.75 (dd, J= 8.8
& 3.0 Hz, 1H), 6.67 (d, J=3.0 Hz,
IH), 6.26 (s, 2H), 4.32 (s, 2H), 4.04 (t, J= 7.7 Hz, 2H), 3.67 (s, 3H), 1.62
(quint., J= 7.7 Hz, 2H), 1.30 (sext., J=
7.5 Hz, 2H), 0.87 (t, J= 7.4 Hz, 3H). 13C NMR (CDC13) 8 157.1, 153.6, 150.9,
149.8, 148.4, 133.1, 128.8, 123.4,
117.3, 114_7, 112.5, 54.0, 41.5, 30.4, 30.2,18.6, 12.2. HRMS: calcd for
C17H21N5C1O (MH)+ m/z 346.1429, found
346.1426
[0078] Biological testing of compounds
[0079] Example 312 Fluorescence-based Conipetitive Binding Assay for
Biotinylated-Geldanamycin to
Purified Hsp90
This assay directly measures the binding of biotinylated-geldanamycin (biotin-
GM) to purified Hsp90 and thus tests
the ability of compounds to compete for binding to Hsp90.
Purified native Hsp90 protein (mixture of alpha and beta) from HeLa cells
(Stressgen Biotechnologies Corp., San
Diego, CA, USA) was coated onto 96-well plates by incubating for Ihr at 37 C.
Uncoated Hsp90 was removed and
the wells washed twice in lx PBS (phosphate-buffered saline) buffer. Biotin-GM
was then added to the wells, and
the reaction was further incubated for lhr 37 C. The wells were washed twice
with lx PBS, before the addition of
20ug/mi streptavidin-phycoerythrin, and incubated for lhr at 37 C. The wells
were again washed twice with lx
PBS. The fluorescence was then measured in a Gemini spectrofluorometer
(Molecular Devices) using an excitation
of 485nrn and emission of 580nm.
103
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0080J Example 313 Screening of compounds of the invention for HSP90 binding
ability
The compounds in the table below were prepared as described above and
evaluated for HSP90 binding ability based
on the above assay (example 312).
Example # Compound # IC50
_ M
1.1 1 10
2.1 2 2
2.2 3 1.1
2.4 5 2.0
3.2 8 6
3.4 10 2.8
4.7 26 1.1
4.8 27 0.9
4.9 28 2.3
4.10 29 0.9
9.4 44 1.5
9.5 45' 1.8
9.6 46 0.9
9.7 47 0.8
11.3 57 4.0
11.10 63 1.3
[0081] Example 314 HER2 Inhibition Assay
MCF-7 cells are seeded in 24 well plates at a density of approximately 30,000
cells/well and allowed to grow for 16
hours in DMEM supplemented with 10% FBS. Drug is then added at a concentration
range of 100 uM to .01 uM.
Cells are incubated for an additiona124. Drug treated cells and untreated
control cells are trypsinized, and incubated
at room temperature for 15 minutes with anti Her-2 neu Ab conjugated with
phycoerythrin (Becton Dickinson, San
Jose CA; Cat no. 340552) at a concentration of 0.25 ug/ml, or non-specific
control IgGl conjugated with
phycoerytbrin (Becton Dickinson, San Jose CA; Cat no. 340761). Samples were
analyzed using a FACS Calibur
flow cytometer (Becton Dickinson) equipped with Argon-ion laser that which
emits 15 mW of 488 nm light for
excitation of the phycoerythrin fluorochrome. 10,000 events were collected per
sample. A fluorescence histogram
was generated and the mean fluorescence intensity (mfi) of each sample was
determined using Cellquest software.
The background was defined as the mfi generated from cells incubated with
control IgG, and was subtracted from
each sample stained with the HER-2/neu Ab. Percent degradation of Her-2 was
calculated as follows:
%Her-2 degradation =(mfi HER-2 sample)/(mfi HER-2 untreated cells) x 100
[0082] Example 315 Screening of=compounds of the invention for Her-2
degradation ability
The compounds in the table below were prepared as described above and
evaluated for Her-2 degradation ability
based on the above assay (example 314).
Inhibitory Concentration 50 (IC5o) for this assay is the concentration
necessary to degrade 50 % of Her 2 expression
(protein).
104
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Example # Cn-tpound # IC50
M
1.1 1 6.0
2.1 2 0.6
2.2 3 0.5
2.4 5 1.0
3.2 8 1.5
3.4 10 1.5
4.7 26 1.5
4.8 27 0.8
4.9 28 1.0
4.10 29 0.8
9.4 44 1.5
9.5 45 2.0
9.6 46 0.3
9.7 47 0.3
11.3 57 1.4
11.10 63 0.7
Optiniization of Compound Activity
[0083] One of the strategies for improving the activity of purine-based Hsp90
inhibitors was to independently
optimize the substituents on the benzene ring of 8-benzyladenines and the
nature of the linker spanning
between the benzene and the purine rings. The preferred structural elements
emerging from both
optimizations could then be combined and compounds selected for acceptable
pharmaceutical properties.
This plan allowed us to take full advantage of the known methods for the
preparation of 8-benzylpurines,
although in some cases refinements proved to be necessary.
[00841 Example 316 HER-2 degradation assay
The potency of the compounds was assessed using a HER-2 degradation assay,
which has been described elsewhere,
(Le Brazidec et. al. .1. tLled. Chem. 2004, 47, 3865-3 873). Briefly,
compounds were incubated for 16 h with MCF-7
cells, a breast cancer cell line expressing on its surface medium levels of
the HER-2 receptor, which is a Hsp90
client. Inhibition of Hsp9O induces the degradation of HER-2, which was
monitored with a combination of
phycoerythrin-labeled antibody and flow cytometiy. This assay is highly
reproducible, with 17-AAG consistently
giving an HER-2 ICso of 12.9 :L 0.3 nM, wherein the error refers to the
standard error of the mean (SEM).
[0085] Example 317 Examination of the effect of substituents on the benzene
ring.
The 2,5-dimethoxy substitution pattern emerged as more potent than the
prototypic 3,4,5-trimethoxy pattern.
Replacing the 2-MeO group by Cl marginally decreased the activity, but
replacing it with Br or I led to an increase
in activity. The effect of the linker was investigated. The compounds with a
NH or 0 as linker are inactive, and it
was assumed that only the CH2 linker could be tolerated. However, upon
introduction of an S linker it was observed
that the sulfur atom was superior to the original CHZ linker.
105
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
x
NH2 2 / I \ 5
N N
N N
Cmpd # ID L X HER-2 IC50 [ M]
PU3 3a CH2 3,4,5-triMeO 40
1 8 CH2 2,5-diMeO 12
311 12b CH2 2-Cl, 5-MeO 20
23 12c CH2 2-Br, 5-MeO 8.0
20 12d CH2 2-I, 5-MeO 5.0
43 18 S 2,5-diMeO 3.5
All values represent the average of at least three independent observations.
The standard errors of the mean (SEM) are 6-11 % of the mean value.
100861 Example 318 Examination of the effect of N(9) side-chain.
The N(9) side-chain was next optimized, and over 100 analogues of the 2,5-
dimethoxybenzyl adduct were screened.
The homoprenyl side-chain emerged as an equipotent alternative to the already
disclosed pent-4-ynyl side-chain,
both analogs having an HER-2 IC50 = 1.5 M. Thus, having separately optimized
the benzene ring substituents (2-
iodo-5-methoxy), the linker (-S-), and the side-chain (homoprenyl or pent-4-
ynyl), we examined the combination of
these preferred structural features. The homoprenyl analog and the pent-4-ynyl
analog had similar potencies (HER-2
IC50 =0.3 M). However, the addition of a 2-F substituent on the adenine ring,
an operation known to be favorable
in the 8-benzyladenine series, did not bring additional activity to the 8-
sulfanyl series.
NH2 OMe Pent-4-ynyl = Homoprenyl =
N -
N
Xli-1, N N~S
R
Entry II) X R HER-2 IC5o [ M]
309 4 H Pent-4-ynyl 0.28
46 23 H Homoprenyl 0.37
68 28 F Pent-4-ynyl 0.36
All values represent the average of at least three independent observations.
The standard errors of the mean (SEM)
are 6-11 % of the mean value.
[0087] Although these compounds exhibited improvements in potency over
previously reported Hsp90 inhibitors,
they proved to be poorly water-soluble, especially with the 2-iodo
substituent. This hampered their
formulation, and rendered them insufficiently orally bioavailable. We
therefore sought to incorporate
ionizable amino groups in the N(9) side-chain of the inhibitor. The
introduction of the amino group not
106
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
only improved the water solubility, but also increased the potency. The
highest potencies were obtained
when the amino N atom was separated by 2 or 3 methylene units from the purine
ring, and was further
substituted with a bulky alkyl group. The most active compound in the 3-atom
linker series proved to be the
tert-butylamine (HER-2 ICSO = 140 4:15 nM), while in the 2-atom linker series
the neopentylamine (HER-2
IC50 = 90 =L 10 nM) showed optimal activity.
[0088] Example 319 Examination of ability of amine derivatives to inlubit cell
growth
Amines were tested for their ability to inhibit cell-growth, using a
previously described assay to quantify cell
proliferation. In brief, MCF-7 breast cancer cells were incubated for 5 days
with the test compound, and then treated
with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-
sulfophenyl)-2H-tetrazolium). The MTS
reagent is reduced only by metabolically active cells to the formazan dye, and
the number of live cells was deduced
by spectrophotometry (490 nM). The MTS IC50 was defined as the concentration
of Hsp90 inhibitor that gave rise to
50% less new live cells compared to an untreated culture. In this assay, the
control 17-AAG had an MTS IC50 of 32
:h 4 nM, and the standard error of the mean (SEM) associated with this assay
ranged from 9-21 fo of the mean value.
The 8-(sulfanyl)adenines proved to be inhibit cell growth with MTS IC5o values
typically in the 200-500 nM range,
which is roughly within 1 logarithmic unit of the gold standard 17-AAG.
NH2 ~ / ~ UMe
N -
eN- ~~--S
N
HN(CH2)n
R
HER-2 MTS
Cmpd # ID n R IC50 [AM] a ICso [ M] s
PU24FC1 3b 1.7 1.2
309 4 0.29 0.7
108 37 3 Et2CH- 0.21 0.2
109 38 3 EtMeCH- 0.21 0.2
126 39 3 i-Pr- 0.18 0.6
95 40 3 t-Bu- 0.14 0.2
89 41 2 i-Bu- 0.10 0.2
132 42 2 t-BuCHa- 0.09 0.5
(a) For the HER-2 degradation assay, the values represent the average of at
least three independent observations,
and the standard errors of the mean (SEM) are 6-11 Jo of the mean value. (b)
For the growth inhibition assay, the
values represent the average of at least three independent observations, and
the standard errors of the mean (SEM)
are 9-21% of the mean value.
100891 Example 320 Selectivity assessment
The selectivity of 132 for Hsp90 over other ATP-binding proteins was assessed
with a panel of human kinases
(Aurora-A, CHK2, IKKc; MAPKl, MAPK2, MEK1, PDKI, P1k3, PI-3K, c-Raf, c-Src),
none of which were
significantly inhibited at 10 M.
107
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0090] Example 321 In vivo pharmacokinetics
Perhaps the most important feature of the amine compounds, besides their
potency, was their dramatically increased
water-solubility. Once converted to their H3PO4 salt, these amines provided
excellent water solubility (>10 mg/mL,),
and were readily administered in standard aqueous solutions. For animal
studies, they were formulated in a
phosphatidylcholine/water dispersion. The pharn-iacokinetics of these
compounds was determined in Balb/C mice.
When the compounds were administered orally at 100 mg/kg, peak plasma
concentrations (C,,,,x) between 4.8 and
9.7 Ag/mL (10-19 M) were achieved. The plasma concentrations peaked at T,,,,
= 30 min, indicating rapid
absorption, and dropped below the detection limit (0.5 g/mL, 1 M) after 1-4
h to give, when integrated over a 4 h
period, AUC values of 240 to 680 min= g/mL (equivalent to 8-22 M-hr). The
effect of the solubility on the oral
bioavailability was striking, and the %F increased from <10% for the pentyne
derivative to 14-97% for the amines
95, 89, 108, 109, 126, 132 and 132. When administered intravenously at 10
mg/kg, these amines were cleared at the
rate of 33-131 mL/min/kg, which is quite high compared to the total liver
blood flow (90 mL/min/kg for nuce). We
did not determine, however, if the clearance was due to rnetabolism,
distribution, or inadequate protein binding. By
analogy with the structurally related adenines, it is also possible that the
inhibitors 95, 89, 108, 109, 126, 132
accumulate in the tumor to concentrations exceeding those in the plasma. In
spite of their high clearance at 10
mg/kg, the oral bioavailability of compounds 126, 95, and 132 at 100 mg/kg was
equal or greater than 50%,
suggesting that the clearance was saturated at 100 mg/kg.
Pharmacokinetic parameters of selected amines.
IV Parameters pn ParamatPrc
Cmpd # Compound Cl T1/2 Vss C. T. AUC T1/2 %F
[mL/min/kg] [h] [Llkg] [gS/rriU [h] [min- g/mL] [h] [%]
108 37 69 0.5 2_4 5.8 0.5 590 0.6 42
109 38 33 1.3 3.4 4.8 0.5 380 0.7 28
126 39 62 4.2 22 4.7 0.5 450 1.5 55
95 40 131 1.6 24 6.7 0.5 680 0.9 97
89 41 47 0.3 0.4 6.7 0.5 290 0.3 14
132 42 64 0.4 1.6 9.5 0.5 760 0.5 50
The compounds were formulated as H3PO4 salts in a phosphatidylcholine/water
dispersion and delivered
intravenously (IV) at 10 mg/kg or orally (PO) at 100 mg/kg. Plasma
concentrations were measured at six time points
over 4 hours, and the pharmacokinetic parameters were determined using non-
compartmental methods (WinNonlin
Professional, Version 4.1). The terminal half-life was calculated using 3-4
data points.
[0091] This is to our knowledge the first time that pharmacologically relevant
concentrations of Hsp90 inhibitors
have been achieved via the oral route, and these results suggested that these
inhibitors may be orally active. For
instance, a C,,,. = 5.8 p.g/mL. (108) corresponds to a concentration of 12 AM,
which is approximately 50-fold higher
than the concentrations required to either induce HER-2 degradation in MCF-7
cells (HER-2 IC50 = 0.21 iLM) or to
inhibit the proliferation of MCF-7 cells (MTS IC5o= 0.2 EcM). The plasma
concentration of the anvnes 95, 89, 108,
109, 126, 132 remained above 1 M, the detection limit, for 1-4 h.
[0092] Example 322 In vivo induction of the degradation of Hsp90 clients
These anunes provided a good combination of potency, ease of formulation, and
bioavailability, but displayed
relatively high clearance values in mice. We next verified the ability of the
arbitrarily chosen amine 89 to induce the
degradation of Hsp90 clients in vivo. Nude mice were implanted with A549 lung
cancer cells, a cell line dependent
on the Hsp90 clients Raf-1 and Akt for cell proliferation, and were
administered a single oral dose of 89=H3PO4
108
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
(200 mg/kg). The mice were sacrificed at 6, 24, or 48 hrs, the tumors were
harvested, and Hsp90 client proteins were
visualized by Westem blot. The levels of the Hsp90 clients HER-2 and pHER-2
significantly decreased at 6 h, then
gradually reached their normal value after 24-48 h (Fig. la). The levels of
the Hsp90 clients pAKT and pRaf, and
the downstream kinase pERK decreased less dramatically, and were lowest at 24
h. Upregulation of the chaperone
Hsp70, a response characteristic of Hsp90 inhibition, was evident and lasted
24-48 h. As expected, the kinase PI-
3K, which is not an Hsp90 client, was not affected. These pharmacodynamic data
underscore an added benefit of
targeting Hsp90, since exposing tumor cells to an Hsp90 inhibitor for a few
hours is sufficient to induce the
degradation of the client proteins. Once degraded, those client proteins
require 6-48 hours to accumulate back to
their normal levels, and even if the Hsp90 inhibitor is rapidly cleared as 89,
its pharmacological effect can be long
lasting. This behavior differs significantly from that of most ATP-competitive
kinase inhibitors which, once cleared,
allow their target to immediately resume its function.
[0093] Example 323 Xenograft model
The pharmacodynamic effect of amine 126 was examined in a N87 xenograft model
(Fig. lb), N87 being a stomach
cancer cell line expressing high HER-2levels. Mice were administered 126=H3P04
orally at two different regimens
(2 x 100 or 2 x 200 mg/kg/day) for three days, and were sacrificed 24 h after
the last dosing. Oral administration of
126=H3P04 at 2 x 200 mg/kg/day induced the degradation of the Hsp90 clients
Akt, pAkt, Raf-1, pRaf, cdk6, and
pRb to levels comparable to those obtained witlr 17-AAG injected
intraperitoneally once daily at 90 mg/kg/day. The
levels of HER-2 and pHER-2 decreased only partially, probably reflecting the
fact that HER-2 and pHER-2 are
degraded and re-expressed faster (<24 h) than other Hsp90 clients. A 126=H3P04
dose of 2 x 100 mg/kg/day was still
effective at degrading Akt, pAkt, Raf-1, pMEK, cdk6, and pRb, but promoted
little or no degradation of HER-2,
pHER-2, and pRaf.
[0094] Example 324 Repression of tumor growth
Next, the ability of a subset of amines (109, 126, and 132) to repress tumor
growth was examined in murine
xenograft models using the N87 stomach cancer cell line, which grew in mice
more reproducibly than the A549 cell
line. Cornpounds 109=H3P04 and 126=H3P04 were delivered orally at 200
mg/kg/day (once daily, 5 days/week), in
the same experiment (Fig. 2a). Tumor growth inhibition was observed for both
compounds, but with a lower
statistical significance for 109=H3PO4 (p=0.07) compared to 126=H3PO4
(p=0.03). At these doses, neither mortality
nor weight loss was observed. Similarly, the compound most active in the HER-2
degradation assay, 132=H3PO4i
was tested in a separate experiment (Fig. 2b), at 200 mg/kg/day but with a
different schedule (2 x 100 mg/kg/day, 5
days/week), and also showed statistically significant (p= 0.02) tumor growth
inhibition, and no overt toxicity.
The chaperone Hsp90 is a target of interest for the treatment of cancer
because of its central regulatory role.
Inhibition of Hsp90 induces the degradation of several client proteins, and
shuts down multiple oncogenic pathways,
which in turn affects a number of critical steps implicated in the genesis of
a tumor (proliferation, angiogenesis,
acquired immortality, evasion of apoptosis, and metastasis). The simultaneous
modulation of various oncogenic
effects should reduce the likelihood of the tumor acquiring resistance to
Hsp90 inhibitors. In addition, the existence
of an activated form of Hsp90 in cancer cells offers the possibility to
develop inhibitors selective for malignant cells.
Compounds of the present invention as purine-based inhibitors of Hsp90 have
been optimized, reaching 90 nM
potency as in the HER-2 degradation assay and 200 nM in in vitro growth
inhibition assays. The introduction of an
amino group in the side-chain dramatically improved their aqueous solubility
(>10 mg/kg for their H3P04 salts),
which greatly facilitated their formulation for oral delivery. In niice, the
oral bioavailability of the compounds of the
109
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
present invention ranged from 14-97%. These amines reached high plasma
concentrations (C,,,a,= 10-19 AM; oral
dose of 100 mg/kg) but were cleared rapidly (CI=33-131 mL/min/kg; intravenous
dose of 10 mg/kg). When
administered orally to mice bearing A549 tumor xenografts (200 mg/kg),
compounds of the present invention
induced the pharmacodynamic response expected from Hsp90 inhibitors:
degradation of the client proteins HER-2,
pHER-2, pAKT and pRaf and up-regulation of Hsp70. Similarly, in a murine N87
xenograft model, oral
administration of compounds of the present invention (2 x 200 mg/kg/day)
induced the degradation of Hsp90 clients
but not of PI-3K. Furthermore, in the N87 model, compounds of the present
invention inhibited tumor growth orally
at 200 mg/kg/day. These are the first Hsp90 inhibitors reported to inhibit
tumor growth upon oral administration, but
high doses are currently necessary. Further work is necessary to improve the
potency and clearance of these
compounds, and to exaniine alternate xenogra$ models.
[0095] Example 325 Optimization of benzolothiopurine analogs
The structure activity relationship data of the substituted benzolothiopurine
analogs is summarized below. The 7'-
substitutent is essential for inhibitory activity. When 7'-CI (5) was moved to
alternate sites on the aryl ring (6'-Cl
(179) or 5'-Cl (2) or 4'-Cl (3)), the activity dropped from 200 nM to as much
as 20 uM. Moreover, replacing the Cl-
substituent at the 7'-position with various moieties dramatically affected the
potency of Her-2 degradation. For
example, HER-2 degradation activity of the 7'-halide, 7'-OCH3 and 7'-CH3
substituted benzolothio purine analogs
range from 180 to 330 nM, with the 7'-chloro exhibiting the best activity.
Replacement of the 7'-OCH3 group with
longer alkyl ethers such as 7'-OCH2CH3, reduced the activity by 500 fold.
Similarly, replacing the 7'-Cl with 7'-H
reduced the activity 25 fold. Disubstitution (6', 7'-dichloro) resulted in a
140 fold loss of activity compared with
mono substituted analog. The entirety of these results suggests that the ATP-
binding site of Hsp90 is very sensitive
to subtle changes at the 7'-position.
Structure activity relationships of the benzothiozole moiety.
NH2
e N N --
5
N N N
S
R
Compound # Compound # R" HER-2 ICso(nM)
178 1 H 5000
181 3 4'-Cl 15000
180 2 5'-Cl 20000
179 4 6'-Cl 7000
232 5 7'-Cl 180
171 6 7'-Br 330
175 7 7'-F 200
172 8 7'-Me 300
185 9 7'Cl, 6'-Cl 25000
173 10 7'-OCH3 190
174 11 7'-OCHZCH3 100000
110
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
[0096] Example 326 Optimization of the 9-N-alkyl substituent
Analysis of the N-alkyl substituent shows that both the cheniical nature of
the linker at the 9-position as well as its
length affect the biological activity. Compounds with 2- to 4- carbon linkers
at the 9-position give sirnilar activities,
even when substituted with various functional groups, including alcohols,
esters and some amines. Increasing the
length of the alkyl linker beyond 4 carbons decreased the activity.
Surprisingly, among the amine substituents,
addition of a tertiary-butyl methyl amine to the 2 -carbon linker resulted in
significant improvement in HER-2
degradation activity (35 nM) over other amine substituents. Moreover, addition
of a diethyl phosphate group to the
2-carbon alcohol also showed similar improvement in HER-2 degradation activity
(30 nM). It would seem that two
carbon linkers provide the optimal scaffold.
Structure activity relationships of the 9-N-alkyl position.
NHZ
N N ~ S
N N N
R S
. / ~
cl
Compound # Compound # R HER-2
229 12 -CHaCH3 200
231 13 -CH2CHZCH3 250
232 5 -CH2CHZCHaCH3 180
233 14 -CH2CH2CH2CH2CH3 700
244 15 -CH2CH2OH 300
245 16 -CHZCH2CHZOH 150
246 17 -CHZCHZCHaCHZOH 150
241' 18 -CHaCH2OZCCH3 150
242 19 -CHICH2CHZO2CCH3 90
243 20 -CHZCH2CHaCH2OZCCH3 130
204 21 -CHa CHaPO(OCH2CH3)z 30
284 22 -CH2CHZCHaCH2CN 110
270 23 -CH2CH2-morpholine 250
265 24 -CH2CHaNHC(CH3)3 140
247 25 -CHZCHaNHCHZC(CH3)3 35
264 26 -CH2CH2NHCHCH2CHZ 110
266 27 -CH2CH2CH2NHCH(CH3)2 170
253 28 -CH2CHZCH2NHC(CH3)3 150
[0097) Example 327 Substituting the benzolothiozole with a pyridothiazole ring
Although, the benzothiozole compounds exhibited acceptable potencies in the
HER-2-degradation assay, as a class,
they were poorly soluble in aqueous media and were subsequently shown to have
low oral bioavailability. In an
attempt to increase overall oral bioavailability for this class of compounds,
we introduced an additional ionizable
moiety by substituting the benzolothiozole with a pyridothiazole ring. The HER-
2 degradation activity of the most
active members of this series was determined. In accordance with the SAR data
shown for the benzothiol series, the
best analogs contained a 2-carbon linker substituted with the diethyl
phosphate moiety.
Structure activity relationships of the pyridothiazole moiety.
111
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
NH2
N N
y--s
N N N
R' S
R" N
Compound # R' R" HER-2
207 29 -CH2CH2CH2CH3 Br 400
202 30 -CH2CH2PO (OCH2CH3)2 Br 28
177 31 -CH2CH2CH2CH3 Cl 280
206 32 -CH2CH2PO (OCHaCH3)2 Cl 30
205 33 -CH2CH2CH2 02C CH3 Cl 170
[0098] Example 328 Solubility analysis
Comparison of the ethyl-diethyl phosphate analog 206 from the pyridinothiazol
series with its benzothioazol analog
204 in a panel of solubility parameters including solubility in simulated
gastric fluid, simulated intestinal fluid, and
serum, the pyridinothiazol derivative was significantly more soluble in all
three solutions.
Gastric Intestinal Serum
Compound # (PH 2.0) (PH 6.5) (PH 7.4)
ml Aglml ml
204 21 98.5 * *
206 32 124 38.3 14
242 19 220 16 9
243 20 46 3 *
253 28 * 137.7 198.7
173 10 35 2 18
284 22 58.7 4.4 31.3
247 25 * 6 4.9
270 23 * * *
264 26 245 21 59
*-unable to determine due to degradation
[0099] Example 329 In vivo pharmacokinetics measurements of key compounds
Compounds 242 and 264 also showed biologically relevant concentrations in
simulated gastric, intestinal and serum
solutions and as a result, 242, 264 and 206 were selected for fiuther
examination in vivo. Pharmacokinetic
measurements obtained in mice after oral administration at 100 mg/kg are shown
below.
Mouse PK PO Mouse PK PO
Compound # Cmax at 100 mg/kg AUC at 100mg/kg PO
ng/mL n mL*min
206 32 BLD BLD
242 19 603 62592
264 26 4479 430511
BLD-Below level of detection
112
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
Compound 264 was rapidly absorbed reaching a C-max of 4513 ng/m130 min after
dosing (see figure 3) with half
life estimated at 90 minutes. Concentrations for compound 242 were
significantly lower than 264. Surprisingly,
despite its increased solubility over its benzothiazole analog, concentrations
for 206 were not increased and
remained below the level of detection perhaps as a result of poor permeability
properties.
[00100) Example 330 In vivo efficacy in the N87 xenograft model of human
stomach cancer
From the sum total of the structure activity data and the pharmaceutics
properties in the above studies, compound
264 was notable because it was potent in the HER-2 degradation assay, orally
bioavailable and had a reasonable
half-life in the mouse. As a result, it was selected for further evaluation in
vivo for efficacy in the N87 xenograft
model of human stomach cancer. Briefly, N87 tumor fragments were implanted
subcutaneously into the flank of
athymic nude mice. When the tumors reached an average of 100 mm3 in size, mice
were randomized into groups of
10. Compound 264 was administered orally at 200 mg/kg 5 days /week and on day
39 of this study 56% tumor
growth inhibition was observed for 264 as compared with the control group (see
figure 4). The observed tumor
growth inhibition was statistically significant (p< 0.05) when analyzed using
the t-test.
[00101] Hsp90 inhibitors have rapidly become targets of interest for treating
cancer as evidenced by numerous
recent reports. The ATP-binding site of Hsp90 is amenable to compound
optimization and drug
development. The compounds of the present invention indicate that the
phosphate-binding pocket of the
ATP-binding site is large enough to accommodate bicyclic ring systems.
However, the ring substitution
requirements are very specific, with the 7'-halogens out-performing all other
substitution patterns. The
bicyclic ring moieties provide the increase in potency necessary for effective
inhibition of tumor cell
growth while also providing the improvements in pharmaceutics properties
required for in vivo activity via
the oral route of administration. Since Hsp90 perforrns a key role not only in
regulating proteins associated
with oncology pathways, but also in neuropathy and inflammation, it is likely
that Hsp90 inhibitors of the
class presented here will have additional utility.
* * *
[00102] The foregoing examples are not limiting and merely illustrative of
various aspects and embodiments of the
present invention. All documents cited herein are indicative of the levels of
skill in the art to which the
invention pertains and are incorporated by reference herein in their
entireties. None, however, is adniitted
to be prior art.
[00103] One skilled in the art will readily appreciate that the present
invention is well adapted to carry out the
objects and obtain the ends and advantages mentioned, as well as those
inherent therein. The methods and
compositions described illustrate preferred embodiments, are exemplary, and
are not intended as limitations
on the scope of the invention. Certain modifications and other uses will occur
to those skilled in the art,
and are encompassed within the spirit of the invention, as defined by the
scope of the claims.
[00104] The invention illustratively described herein suitably may be
practiced in the absence of any element or
elements, limitation or limitations which is not specifically disclosed
herein. The terms and expressions
which have been employed are used as terms of description and not of
limitation, and there is no intention
in the use of such terms and expressions of excluding any equivalents of the
features shown and described,
or portions thereof. It is recognized that various modifications are possible
within the scope of the
113
CA 02634723 2008-06-20
WO 2007/075572 PCT/US2006/048250
invention claimed. Thus, it should be understood that although the present
invention has been specifically
disclosed by preferred embodiments, optional features, modifications and
variations of the concepts herein
disclosed may be resorted to by those skilled in the art, and that such
modifications and variations are
considered to be within the scope of this invention as defined by the
description and the appended claims.
[00105] In addition, where features or aspects of the invention are described
in terms of Markush groups or other
grouping of alternatives, those skilled in the art will recognize that the
invention is also thereby described
in terms of any individual member or subgroup of members of the Markush group
or other group, and
exclusions of individual members,as appropriate, or by proviso.
[00106] Other embodiments are within the following claims.
114
