Note: Descriptions are shown in the official language in which they were submitted.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
1
IMIDAZOPYRAZINES AS PROTEIN KINASE INHIBITORS
Field of the Invention
The present invention relates to imidazo[1,2-a]pyrazine compounds useful as
protein kinase inhibitors, regulators or modulators, pharmaceutical
compositions
containing the compounds, and methods of treatment using the compounds and
compositions to treat diseases such as, for example, cancer, inflammation,
arthritis,
viral diseases, neurodegenerative diseases such as Alzheimer's disease,
cardiovascular diseases, and fungal diseases. The present compounds are
especially
useful as Aurora kinase inhibitors.
Background of the Invention
Protein kinases are a family of enzymes that catalyze phosphorylation of
proteins, in particular the hydroxyl group of specific tyrosine, serine, or
threonine
residues in proteins. Protein kinases are pivotal in the regulation of a wide
variety of
cellular processes, including metabolism, cell proliferation, cell
differentiation, and cell
survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be
manifested by a deregulation of the cell division cycle in one of two ways -
making
stimulatory genes hyperactive or inhibitory genes inactive. Protein kinase
inhibitors,
regulators or modulators alter the function of kinases such as cyclin-
dependent
kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase
kinase 3 (GSK3beta), Checkpoint (Chk) (e.g., CHK-1, CHK-2 etc.) kinases, AKT
kinases, JNK, and the like. Examples of protein kinase inhibitors are
described in
W002/22610 Al and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236.
The cyclin-dependent kinases are serine/threonine protein kinases, which are
the driving force behind the cell cycle and cell proliferation. Misregulation
of CDK
function ocdurs with high frequency in many important solid tumors. Individual
CDK's,
such as, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like,
perform distinct roles in cell cycle progression and can be classified as
either Gl, S, or
G2M phase enzymes. CDK2 and CDK4 are of particular interest because their
activities are frequently misregulated in a wide variety of human cancers.
CDK2
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
2
activity is required for progression through G1 to the S phase of the cell
cycle, and
CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to
maintain the proper sequence of cell cycle events and allow the cell to
respond to
insults or to proliferative signals, while the loss of proper checkpoint
control in cancer
cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at
the
level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene
activation
(cyclin E). Many reports have demonstrated that both the coactivator, cyclin
E, and
the inhibitor, p27, of CDK2 are either over- or underexpressed, respectively,
in breast,
colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma,
ovarian, and other cancers. Their altered expression has been shown to
correlate
with increased CDK2 activity levels and poor overall survival. This
observation makes
CDK2 and its regulatory pathways compelling targets for the development of
cancer
treatments.
A number of adenosine 5'-triphosphate (ATP) competitive small organic
molecules as well as peptides have been reported in the literature as CDK
inhibitors
for the potential treatment of cancers. U.S. 6,413,974, col. 1, line 23- col.
15, line 10
offers a good description of the various CDKs and their relationship to
various types of
cancer. Flavopiridol (shown below) is a nonselective CDK inhibitor that is
currently
undergoing human clinical trials, A. M. Senderowicz et al, J. Clin. Onco/.
(1998) 16,
2986-2999.
CH3
N
HO~~~``,
HO O
I \ I
cl
OH 0
Other known inhibitors of CDKs include, for example, olomoucine (J. Vesely et
al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al,
Eur. J.
Biochem., (1997) 243, 527-536). U.S. 6,107,305 describes certain pyrazolo[3,4-
b]
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
3
pyridine compounds as CDK inhibitors. An illustrative compound from the '305
patent
is:
I \
/
0 0
"
N N
H
K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162
disclose certain aminothiazole compounds as CDK inhibitors.
Imidazopyrazines are known. For example, U.S. 6,919,341 (the disclosure of
which is
incorporated herein by reference) and US2005/0009832 disclose various
imidazopyrazines. Also being mentioned are the following: W02005/047290;
US2005/095616; W02005/039393; W02005/019220; W02004/072081;
W02005/014599; W02005/009354; W02005/005429; W02005/085252;
US2005/009832; US2004/220189; W02004/074289; W02004/026877;
W02004/02631 0; W02004/022562; W02003/089434; W02003/084959;
W02003/051346; US2003/022898; W02002/060492; W02002/060386;
W02002/028860; JP (1986)61-057587; J. Burke et al., J. Biological Chem., Vol.
278(3), 1450-1456 (2003); and F. Bondavalli et al, J. Med. Chem., Vol. 45
(22), 4875-
4887 (2002).
Also made reference to are US 2004/0220189 (published November 4, 2004);
US 2005/0009832 (published January 13, 2005); US 2006/0084650 (published April
20, 2006) which describe kinase inhibitors, and
US 2006/0106023 (published May 18, 2006) which describe imidazopyrazines as
cyclin dependent kinase inhibitors. In addition, US 2007/0117804 (published
May 24,
2007), describes imidazopyrazines as protein kinase inhibitors of the
following
structure:
A compound of the Formula:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
4
R' R2
R
1\~
NY`N
R3.IN.H
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
-C(O)NR5R6, -N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1_3
NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties
which
can be the same or different each moiety being independently selected from
the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6;
R' is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl
can be
unsubstituted or substituted with one or more moieties which can be the same
or different each moiety being independently selected from the group
consisting
of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -
CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2,
-NR5R6 (wherein the R5 and R6, together with the N of said
-NR5R6, form a heterocyclyl ring), -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5,
-
C(O)OR5, -C(O)R5 and -OR5;
R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl,
arylalkyl and
heteroaryl can be unsubstituted or optionally independently be substituted
with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of halo, amide, alkyl,
alkenyl,
alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of
said -NR5R6, form a heterocyclyl ring), -CN, arylalkyl,
-CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl
and heterocyclyl;
R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
- said alkyl shown above for R3 can be unsubstituted or substituted with one
or
more moieties which can be the same or different each moiety being
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
independently selected from the group consisting of -OR5, alkoxy,
heteroaryl, and -NR5R6;
- said aryl shown above for R3 is unsubstituted, or optionally substituted, or
optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or
5 heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, cycloalkyl
and heteroarylalkyl can be unsubstituted or optionally independently
substituted with one or more moieties which can be the same or different
each moiety being independently selected from alkyl, -OR5, -N(R5R6)
and
-S(O2)R5; and
- said heteroaryl shown above for R3 can be unsubstituted or optionally
substituted, or optionally fused, with one or more moieties which can be
the same or different with each moiety being independently selected
from the group consisting of halo, amino, alkoxycarbonyl, -OR5, alkyl, -
CHO, - NR5R6, -S(02)N(R5R6),
-C(O)N(R5R6), -SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
heterocyclenyl, and heterocyclyl;
R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl; and
R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl;
further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be
joined
together with the N of said -NR5R6 to form a cyclic ring.
Another series of protein kinases are those that play an important role as a
checkpoint in cell cycle progression. Checkpoints prevent cell cycle
progression at
inappropriate times, such as in response to DNA damage, and maintain the
metabolic
balance of cells while the cell is arrested, and in some instances can induce
apoptosis
(programmed cell death) when the requirements of the checkpoint have not been
met.
Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in
G2,
prior to entry into mitosis.
One series of checkpoints monitors the integrity of the genome and, upon
sensing DNA damage, these "DNA damage checkpoints" block cell cycle
progression
in G, & G2 phases, and slow progression through S phase. This action enables
DNA
repair processes to complete their tasks before replication of the genome and
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
6
subsequent separation of this genetic material into new daughter cells takes
place.
Inactivation of CHK1 has been shown to transduce signals from the DNA-damage
sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which
promotes
mitotic entry, and abrogate G2 arrest induced by DNA damage inflicted by
anticancer agents or endogenous DNA damage, as well as result in preferential
killing
of the resulting checkpoint defective cells. See, e.g., Peng et al., Science,
277, 1501-
1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91,
865-
867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature,
363,
368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell., 5, 147-160 (1994).
Selective manipulation of checkpoint control in cancer cells could afford
broad
utilization in cancer chemotherapeutic and radiotherapy regimens and may, in
addition, offer a common hallmark of human cancer "genomic instability" to be
exploited as the selective basis for the destruction of cancer cells. A number
of
factors place CHK1 as a pivotal target in DNA-damage checkpoint control. The
elucidation of inhibitors of this and functionally related kinases such as
CDS1/CHK2, a
kinase recently discovered to cooperate with CHK1 in regulating S phase
progression
(see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-
1897
(1998)), could provide valuable new therapeutic entities for the treatment of
cancer.
Another group of kinases are the tyrosine kinases. Tyrosine kinases can be of
the receptor type (having extracellular, transmembrane and intracellular
domains) or
the non-receptor type (being wholly intracellular). Receptor-type tyrosine
kinases are
comprised of a large number of transmembrane receptors with diverse biological
activity. In fact, about 20 different subfamilies of receptor-type tyrosine
kinases have
been identified. One tyrosine kinase subfamily, designated the HER subfamily,
is
comprised of EGFR (HER1), HER2, HER3 and HER4. Ligands of this subfamily of
receptors identified so far include epithelial growth factor, TGF-alpha,
amphiregulin,
HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type
tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR,
and IR-R.
The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit
and
FLK-II. The FLK family is comprised of the kinase insert domain receptor
(KDR), fetal
liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine
kinase-1
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
7
(flt-1). For detailed discussion of the receptor-type tyrosine kinases, see
Plowman et
al., DN&P 7(6): 334-339, 1994.
At least one of the non-receptor protein tyrosine kinases, namely, LCK, is
believed to mediate the transduction in T-cells of a signal from the
interaction of a cell-
surface protein (Cd4) with a cross-linked anti-Cd4 antibody. A more detailed
discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8,
2025-
2031 (1993). The non-receptor type of tyrosine kinases is also comprised of
numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak,
Jak,
Ack, and LIMK. Each of these subfamilies is further sub-divided into varying
receptors. For example, the Src subfamily is one of the largest and includes
Src, Yes,
Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been
linked
to oncogenesis. For a more detailed discussion of the non-receptor type of
tyrosine
kinases, see Bolen, Oncogene, 8:2025-2031 (1993).
In addition to its role in cell-cycle control, protein kinases also play a
crucial role
in angiogenesis, which is the mechanism by which new capillaries are formed
from
existing vessels. When required, the vascular system has the potential to
generate
new capillary networks in order to maintain the proper functioning of tissues
and
organs. In the adult, however, angiogenesis is fairly limited, occurring only
in the
process of wound healing and neovascularization of the endometrium during
menstruation. On the other hand, unwanted angiogenesis is a hallmark of
several
diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related
macular
degeneration, and cancer (solid tumors). Protein kinases which have been shown
to
be involved in the angiogenic process include three members of the growth
factor
receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor
receptor
2, also known as KDR (kinase insert domain receptor) and as FLK 1); FGF-R
(fibroblast growth factor receptor); and TEK (also known as Tie-2).
VEGF-R2, which is expressed only on endothelial cells, binds the potent
angiogenic growth factor VEGF and mediates the subsequent signal transduction
through activation of its intracellular kinase activity. Thus, it is expected
that direct
inhibition of the kinase activity of VEGF-R2 will result in the reduction of
angiogenesis
even in the presence of exogenous VEGF (see Strawn et al, Cancer Research, 56,
3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
8
mediate signal transduction. Millauer et al, Cancer Research, 56, 1615-1620
(1996).
Furthermore, VEGF-R2 appears to have no function in the adult beyond that of
mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of
the
kinase activity of VEGF-R2 would be expected to exhibit little toxicity.
Similarly, FGFR binds the angiogenic growth factors aFGF and bFGF and
mediates subsequent intracellular signal transduction. Recently, it has been
suggested that growth factors such as bFGF may play a critical role in
inducing
angiogenesis in solid tumors that have reached a certain size. Yoshiji et al.,
Cancer
Research, 57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed in
a number of different cell types throughout the body and may or may not play
important roles in other normal physiological processes in the adult.
Nonetheless,
systemic administration of a small molecule inhibitor of the kinase activity
of FGF-R
has been reported to block bFGF-induced angiogenesis in mice without apparent
toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998).
TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only
on endothelial cells which has been shown to play a role in angiogenesis. The
binding
of the factor angiopoietin-1 results in autophosphorylation of the kinase
domain of
TEK and results in a signal transduction process which appears to mediate the
interaction of endothelial cells with peri-endothelial support cells, thereby
facilitating
the maturation of newly formed blood vessels. The factor angiopoietin-2, on
the other
hand, appears to antagonize the action of angiopoietin-1 on TEK and disrupts
angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997).
The kinase, JNK, belongs to the mitogen-activated protein kinase (MAPK)
superfamily. JNK plays a crucial role in inflammatory responses, stress
responses,
cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity can be
activated
by various stimuli, including the proinflammatory cytokines (TNF-alpha and
interleukin-
1), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging
chemicals,
radiation, and Fas signaling. Results from the JNK knockout mice indicate that
JNK is
involved in apoptosis induction and T helper cell differentiation.
Pim-1 is a small serine/threonine kinase. Elevated expression levels of Pim-1
have been detected in lymphoid and myeloid malignancies, and recently Pim-1
was
identified as a prognostic marker in prostate cancer. K. Peltola, "Signaling
in Cancer:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
9
Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser.
D Osa
- Tom. 616, (August 30, 2005),
http://kiriasto.utu.fi/iulkaisupalvelut/annaalit/2004/D616.html. Pim-1 acts as
a cell
survival factor and may prevent apoptosis in malignant cells. K. Petersen Shay
et al.,
Molecular Cancer Research 3:170-181 (2005).
Yet another group of kinases are Aurora kinases. Aurora kinases (Aurora-A,
Aurora-B, Aurora-C) are serine/threonine protein kinases that have been
implicated in
human cancer, such as colon, breast and other solid tumors. Aurora-A (also
sometimes referred to as AIK) is believed to be involved in protein
phosphorylation
events that regulate the cell cycle. Specifically, Aurora-A may play a role in
controlling
the accurate segregation of chromosomes during mitosis. Misregulation of the
cell
cycle can lead to cellular proliferation and other abnormalities. In human
colon cancer
tissue, Aurora-A, Aurora-B, Aurora-C have been found to be over-expressed
(see,
Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell
Biol.
143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
There is a need for effective inhibitors of protein kinases, especially Aurora
kinases, in order to treat or prevent disease states associated with abnormal
cell
proliferation. Moreover, it is desirable to have kinase inhibitors, especially
small-
molecule compounds that may be readily synthesized.
Summary of the Invention
In its many embodiments, the present invention provides a novel class of
imidazo[1,2-a]pyrazine compounds, methods of preparing such compounds,
pharmaceutical compositions comprising one or more such compounds, methods of
preparing pharmaceutical formulations comprising one or more such compounds,
and
methods of treatment, prevention, inhibition or amelioration of one or more
diseases
associated with protein kinases using such compounds or pharmaceutical
compositions.
In one aspect, the present invention provides compounds represented by
Formula I:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
R' R2
R~N
1\~
NN
R3.IN.H
Formula I
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
5 -C(O)NR5R6, -N(R5)C(O)Rs, heterocyclyl, heteroaryl substituted with (CH2)1_3
NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties
which
can be the same or different each moiety being independently selected from
the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6;
10 R' is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl
can be
unsubstituted or substituted with one or more moieties which can be the same
or different each moiety being independently selected from the group
consisting
of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -
CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2,
-NR5R6 (wherein the R5 and R6, together with the N of said
-NR5R6, form a heterocyclyl ring), -S(O)R5, -S(02)R5, -CN, -CHO, -SR5,
-
C(O)OR5, -C(O)R5 and -OR5;
R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl,
arylalkyl and
heteroaryl can be unsubstituted or optionally independently be substituted
with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of halo, amide, alkyl,
alkenyl,
alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of
said -NR5R6, form a heterocyclyl ring), -CN, arylalkyl,
-CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl
and heterocyclyl;
R3 is heterocyclyl-(CR'R8)n-X, heterocyclenyi-(CR'R$)n-X, heteroaryl-(CR7 R$)õ-
X or
aryl-(CR'R$)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl-
or aryl- moieties of said R3 can be unsubstituted or substituted with one or
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
11
more moieties, independently selected from the group consisting of -CONRSR6,
-OR5 and alkyl,
n is 1-6,
X is selected from the group consisting of -NR5R6, -OR5, -SO-R5, -SR5, S02R5,
heteroaryl, heterocyclyl and aryl, wherein said heteroaryl or aryl can be
unsubstituted or substituted with one or more moieties, independently
selected from the group consisting of -0-alkyl, alkyl, halo, or NR5R6;
R' and R 8 are each independently hydrogen, alkyl, heterocyclyl, aryl,
heteroaryl
or cycloalkyl;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylaikoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2,
alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH,
hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, wherein each of
said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl,
heteroaryl,
heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl,
-S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2,
alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH,
hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl can be
unsubstituted or substituted with one or more moieties independently
selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl,
cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
alkyl, hydroxyalkyl, and aminoalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl,
cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
alkyl, hydroxyalkyl, aminoalkyl, -alkyl-OC(O)alkyl, -alkylOC(O)cycloalkyl,
-alkylOC(O)aryl, -alkylOC(O)aralkyl, -alkylOC(O)NR5aryI, -
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
12
alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, -
alkylOC(O)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, -
alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyi, -
alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, -
alkylC(O)ONR5aryl, -alkylC(O)ONR5alkyl, -alkylC(O)ONR5heterocyclyl, -
alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, -
alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl wherein each
of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl,
heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl,
heterocyclenylalkyl, heterocycloalkylalkyl, -alkyl-OC(O)alkyl, -
alkylOC(O)cycloalkyl, -alkylOC(O)aryl, -alkylOC(O)aralkyl, -
alkylOC(O)NR5aryl, -alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, -
alkylOC(O)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, -
alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyl, -
alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, -
alkylC(O)ONR5aryi, -alkylC(O)ONR5alkyl, -alkylC(O)ONR5heterocyclyl, -
alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, -
alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl,can be
unsubstituted or substituted with one or more moieties independently
selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl,
cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
alkyl, hydroxyalkyl, aminoalkyl, amino, aminodialkyl, aminocycloalkyl,
halo, trihaloalkyl, dihaloalkyl, and monohaloalkyl;
further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be
joined together with the N of said -NR5R6 to form a cyclic ring or bridged
cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be
unsubstituted or substituted with one or more moieties, which can be the
same or different, independently selected from the group consisting of
hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -
C02-alkyl, -C02-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
13
heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl,
aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl,
spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-
alkyl, heterocyclyl, heterocyclenyl, halo, trihaloalkyl, dihaloalkyl, CN and
monohaloalkyl.
The compounds of Formula I can be useful as protein kinase inhibitors. The
compounds of Formula I can also be useful as Aurora kinase inhibitors. The
compounds of Formula I can be useful in the treatment and prevention of
proliferative
diseases, for example, cancer, inflammation and arthritis, neurodegenerative
diseases
such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal
diseases.
Detailed Description
In an embodiment, the present invention provides imidazopyrazine compounds,
especially imidazo[1,2-a]pyrazine compounds which are represented by
structural
Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrug
thereof,
wherein the various moieties are as described above.
In another embodiment, the present invention provides compounds
represented by Formula I:
R' R2
R~N
~1\
N Y`N
R3.IN.H
Formula I
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R is H, CN, -NR5R6, cycloalkenyl, heterocyclenyl, -C(O)NR5R6, -N(R5)C(O)R6, or
alkyl
substituted with one or more moieties which can be the same or different each
moiety being independently selected from the group consisting of -OR5 and -
NR5R6;
R' is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl
can be
unsubstituted or substituted with one or more moieties which can be the same
or different each moiety being independently selected from the group
consisting
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
14
of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -
C(O)NR5R6 and -OR5;
R2 is H, halo, or heteroaryl, wherein said heteroaryl can be unsubstituted or
substituted with one or more moieties which can be the same or different each
moiety being independently selected from the group consisting of halo, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
R3 is heterocyclyl-(CR'R8),-X, heterocyclenyl-(CR'R$)n-X, heteroaryl-(CR'R$)n-
X or
aryI-(CR'R$)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl-
or aryl- moieties of said R3 can be unsubstituted or substituted with one or
more moieties, independently selected from the group consisting of -CONR5R6,
-OR5 and alkyl,
n is 1,
X is selected from the group consisting of, -NR5R6, -OR5, -SO-R5 and -SR5,
R' and R 8 are each independently hydrogen or alkyl;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2,
alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and
hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylaikoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or
substituted with one or more moieties independently selected from the
group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl,
arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl,
heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and
aminoalky;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl,
cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl,
cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl can be unsubstituted or substituted with one or
5 more moieties independently selected from the group consisting of alkyl,
alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl,
cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl,
heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -
alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl;
10 further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally
be
joined together with the N of said -NR5R6 to form a cyclic ring or bridged
cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be
unsubstituted or substituted with one or more moieties, which can be the
same or different, independently selected from the group consisting of
15 hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -
C02-alkyl, -C02-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl,
heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl,
aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl,
spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-
alkyl, heterocyclyl, and heterocyclenyl.
In an embodiment, R, R' and R2 are not all H simultaneously.
In another embodiment, in Formula I, R2 is unsubstituted heteroaryl or
heteroaryl substituted with alkyl.
In another embodiment, in Formula I, R2 is heteroaryl substituted with alkyl.
In another embodiment, in Formula I, R2 is pyrazolyl.
In another embodiment, in Formula I, R2 is pyrazolyl substituted with alkyl.
In another embodiment, in Formula I, R2 is 1-methyl-pyrazol-4-yl.
In another embodiment, in Formula I, R is H.
In another embodiment, in Formula I, R is CN.
In another embodiment, in Formula I, R is -C(O)NR5R6.
In another embodiment, in Formula I, R is -C(O)NH2.
In another embodiment, in Formula I, R is heterocyclenyl.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
16
In another embodiment, in Formula I, R is tetrahydropyridinyl.
In another embodiment, in Formula I, R is 1,2,3,6-tetrahydropyridinyl.
In another embodiment, in Formula I, R is alkyl substituted with one or more
moieties which can be the same or different each moiety being independently
selected
from the group consisting of -OR' and -NR5R6.
In another embodiment, in Formula I, R is alkyl substituted with one or more -
NR5R6.
In another embodiment, in Formula I, R is alkyl substituted with -NH2.
In another embodiment, in Formula I, R is alkyl substituted with -NH(methyl).
In another embodiment, R is unsubstituted alkyl.
In some embodiments, both R and R' are not H simultaneously.
In another embodiment, in Formula I, R3 is heteroaryl-CH2-X, wherein X is -
OR5, -SOR5, -NR5R6, or -SR5; R5 is hydrogen, -alkylN(alkyl)2,
heterocyclylalkyl or
heterocyclenylalkyl; or R5 and R6 can optionally be joined together with the N
of said -
NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring
or bridged
cyclic ring can be unsubstituted or substituted one or more moities, which can
be the
same or different, independently selected from the group consisting of
hydroxyl, alkyl,
alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl,
heterospirocyclenyl, heterospiroaryl and -CO2alkyl.
In another embodiment, in Formula I, R3 is heteroaryl-CH2-X or heteroaryl-
CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl,
hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl,
heteroarylalkyl,
or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -
alkylN(alkyl)2; or R5
and R6 can optionally be joined together with the N of said -NR5R6 to form a
cyclic ring
or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be
unsubstituted or substituted one or more moities, which can be the same or
different,
independently selected from the group consisting of hydroxyl, alkyl, alkoxyl,
alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl,
heterospirocyclenyl,
heterospiroaryl and -CO2alkyl.
In another embodiment, in Formula I, R3 is heteroaryl-CH2-X, wherein the
5
heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONRR6,
wherein X
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
17
is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined
together with the N
of said -NR5R6 to form a cyclic ring.
In another embodiment, in Formula I, R3 is aryl-CH2-X, wherein the aryl of
said
aryl-CH2-X is substituted with alkyl, wherein X is heterocyclyl.
s
~op, / SrX gs,
t / x
In another embodiment, in Formula I, R3 is s-N X, ,
N ~~.`
S' \
X ~ ~ X
x m
or wherein X is selected from the rou
9 P
consisting of, -NR5R6, -OR5 -SO-R5 and -SR5,
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2,
alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and
hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylaikoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or
substituted with one or more moieties independently selected from the
group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl,
arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl,
heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and
aminoalky;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl,
cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
- heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl,
cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl can be unsubstituted or substituted with one or
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
18
more moieties independently selected from the group consisting of alkyl,
alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl,
cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl,
heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -
alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl;
further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be
joined together with the N of said -NR5R6 to form a cyclic ring or bridged
cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be
unsubstituted or substituted with one or more moieties, which can be the
same or different, independently selected from the group consisting of
hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -
C02-alkyl, -C02-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl,
heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl,
aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl,
spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-
alkyl, heterocyclyl, and heterocyclenyl.
In another embodiment, in Formula I, R3 is isothiazole, thiophene or
pyrimidine
substituted with:
N H3C
~j ~
CH3 HgC y H3C~CH3, r~- ~- ~~- ~ i
~
N ~ N N
N
H3CO V \ Q 2O , , , OH, , HO
N /+
N N N
CH1 N ~ Or
I / f f f f 1 0 1
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
19
~~ ~,
N r
N NJ~
~ N~ N
~ I J CH3 N N c~ ~ ON
, H3C ~,
OH
O s 0= S\-\ OH
N- N- N
OH,
-~~
OH,
N
OH
O\_ OH OH
_ -~ OH k($-o_
N
Or HO1",O
r
N
Or HO,,,_",o
In another embodiment, in Formula I, R3 is pyrimidinyl substituted with
heterocyclylmethyl.
In another embodiment, in Formula I, R3 is pyrimidinyl substituted with
morpholinylmethyll or pyrrolidinylmethyl.
In another embodiment, in Formula I, R3 is phenyl substituted with
heterocyclylalkyl, wherein said heterocyclylalkyl can be unsubstituted or
substituted
with one or more moieties, which can be the same or different, each moiety
being
independently selected from the group consisting of alkyl.
In another embodiment, in Formula I, R3 is phenyl-CHmethyl-X or phenyl-CH2-
X , wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl
wherein said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl can
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
be unsubstituted or substituted with one or more moieties, which can be the
same or
different, each moiety being independently selected from the group consisting
alkyl.
In another embodiment, in Formula I, R3 is phenyl substituted with
heterocyclylmethyl, wherein said phenyl group is further substituted with
alkyl.
5 In another embodiment, in Formula I, R3 is phenyl substituted with
piperidinylmethyl, morpholinylmethyl or thiomorpholinylmethyl, wherein said
phenyl
group is further substituted with methyl.
s
N ls~cS
In another embodiment, in Formula I, R3 is x , N or
;is s
x,wherein X is heterocyclyl wherein said heterocyclyl can be
10 unsubstituted or substituted with one or more moieties, which can be the
same or
different, each moiety being independently selected from the group consisting
of
hydroxyl, alkyl, hydroxyalkyl, alkoxyl, -CO2alkyl, arylalkyl, aryl,
alkoxyalkyl, and
heterocyclyl.
N,, N
In another embodiment, in Formula I, R 3 is x wherein X is heterocyclyl
15 wherein said heterocyclyl can be unsubstituted or substituted with one or
more
moieties, which can be the same or different, each moiety being independently
selected from the group consisting of alkyl.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r"l' N
~ 1\
NY`N
R3. IN,H
20 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2
is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
21
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together
with
the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -
SR5, -
C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -
alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl,
heterocyclenylalkyl, cycloalkyl,
cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl,
hydroxyalkyl,
alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined
together with the N
of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said
cyclic ring or
bridged cyclic ring can be unsubstituted or substituted one or more moities,
which can
be the same or different, independently selected from the group consisting of
hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl,
heterospirocyclyl,
heterospirocyclenyl, heterospiroaryl and -CO2alkyl; wherein R5 and R6 are as
defined
above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R`~N
/~ j\
NYN
R3~ N. H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together
with
the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -
SR5, -
C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -OR5, heterocyclyl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
22
-N(Rs)C(O)N(RsRs), -N(R syC(O)ORs, -(CH2)1_3-N(R s R s)and -NR s R s ; R, is
H; R s
is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is
substituted
with alkyl or -CONR5R 6, wherein X is -NR5Rs or R 5 and R 6 are optionally
joined
together with the N of said -NR5R6 to form heterocyclyl; wherein R 5 and R 6
are as
defined above.
In another embodiment, this invention discloses a. compound of the formula:
R' R2
R'rlk N
N N
R3.N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, -C(O)OH, -C(O)NH2, -NR5R 6 (where R 5 and R 6 form a cyclic amine
together with
the N of said -NR5R 6), -CN, arylalkyl, -CH2OR5, -S(O)R 5, -S(02)R5, -CN, -
CHO, -SR 5,
-
C(O)ORs, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -ORs, heterocyclyl,
-N(R5)C(O)N(R5R 6), -N(Rs)-C(O)ORs, -(CH2)1_3-N(R5R6 ) and -NR5Rs; R' is H; R3
is isothiazole, thiophene or pyrimidine substituted with:
r~=
N^~';` N N H3C N
CH3 C" v C ~ Y ~
3 3 V H C~CH3
f f f f f 3 t
r5
N N N
N
YO
H3C V \ (0) N
ZO O H3C
OH, , HO
N /+
N
N5- S
N / ~ c H3CNy 6'1,
(s) \~ ~ Z O
f 7
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
23
~~ ~,
N r
N NJ>
N~
hN I I CH3 N H3C ~, ~,
OH
~~OH
~ O-\ - S 0= S
~ N
OH,
-~~
OH,
or HO~ ; wherein R5 and R 6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R`
~ \
N~/j`N
R3. IN.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together
with
the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -
SR5, -
C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is phenyl-CHmethyl-X or phenyl-CH2-X, wherein said phenyl of each of said
phenyl-
CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl,
further
wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl
wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and
R6 are
as defined above.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
24
In another embodiment, this invention discloses a compound of the formula:
R' R2
R
NN
R3.N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together
with
the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -
SR5, -
C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is
S gs s
/ ~~ ~
~\(X / X x`~i X i
S-r, :N X or
P~
0--,\Xwherein X is selected from the group consisting of, -NR5R6, -OR5 -SO-R5
and -SRS,
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-
alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2,
alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and
hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl,
heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylaikoxyl, -S-
alkylheterocyclyl, heterocyclyl and heterocyclenyl can be unsubstituted
or substituted with one or more alkyl,
R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl,
cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-
alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl,
cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl,
5 heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl and
heterocycloalkylalkyl can be unsubstituted or substituted with one or
more alkyl,
further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be
joined together with the N of said -NR5R6 to form a cyclic ring or bridged
10 cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can
be
unsubstituted or substituted with one or moieties, which can be the same
or different, independently selected from the group consisting of
hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -
C02-alkyl, -C02-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl,
15 heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl,
aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl,
spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-
alkyl, heterocyclyl, and heterocyclenyl.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r"j' N
~ \
N~/j`N
20 R3~ IN, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
heteroaryl, wherein said heteroaryl can be unsubstituted or substituted with
one or
more moieties which can be the same or different each moiety being
independently
selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl,
cycloalkyl,
25 aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine
together with
the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -
SR5, -
C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or
alkyl
substituted with one or more moieties which can be the same or different each
moiety
being independently selected from the group consisting of -OR5, heterocyclyl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
26
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is,
S ~ S'N V S-N N
N N~ ~ S-N N
Q O N~ IS NOH ~
, OH, S , ,
O
TNN NS'N N s~s'
~O O S S-N N S O-\N
10~.N.~ , - , ~, ,
_1,N ' N
S 0=S
N - ~ r N o / N S i N / N
C?, O_
HN
'NJ~ ~ ~5~~ ~N
, N , or
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
l\
N
Y`N
R3. N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
pyrazolyl,
wherein said pyrazolyl can be unsubstituted or substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -
C(O)OH, -
C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of
said -
NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)ORS,
-
C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl
substituted with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -
alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl,
heterocyclenylalkyl, cycloalkyl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
27
cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R 6 is hydrogen, alkyl,
hydroxyalkyl,
alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined
together with the N
of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said
cyclic ring or
bridged cyclic ring can be unsubstituted or substituted one or more moities,
which can
be the same or different, independently selected from the group consisting of
hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl,
heterospirocyclyl,
heterospirocyclenyl, heterospiroaryl and -CO2alkyl, wherein R5 and R6 are as
defined
above; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R\~N
T/ 1\
~ Y`N
N
RO, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
pyrazolyl,
wherein said pyrazolyl can be unsubstituted or substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -
C(O)OH, -
C(O)NH2, -NR5R6 (where R5 and R 6 form a cyclic amine together with the N of
said -
NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5,
-
C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl
substituted with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)ORs, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is
heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is
substituted with
alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6
are
optionally joined together with the N of said -NR5R6 to form heterocyclyl;
wherein R5
and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
~
N N
R3.TN.H
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
28
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
pyrazolyl,
wherein said pyrazolyl can be unsubstituted or substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -
C(O)OH, -
C(O)NH2, -NR5R6 (where R5 and R 6 form a cyclic amine together with the N of
said -
NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5,
-
C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl
substituted with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is isothiazole, thiophene or pyrimidine substituted with:
r~.
H3C
QN^s,'r N
CH3 H C~CH3
3 r e e t 3 r
~- _2
~~- ~ /~
N N r~ r~ N N
N
H3CO V \ Q
YO , OH, , HO
N /+
+
N r~- P
/ / - c HsC~
No
CH3 ~Ns~ ~ I O
t t t t , t t t
N [-~' r~_
N
N hN 15 t H3C CH3
OH
~ O_ ~ ~~OH
N~J~ ~ N- N- ~~N~-~ N
, OH,
-~~
OH,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
29
N
or HO,/0 ; wherein RS and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
NN
R3~N, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
pyrazolyl,
wherein said pyrazolyl can be unsubstituted or substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -
C(O)OH, -
C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of
said -
NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5,
-
C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl
substituted with
one or more moieties which can be the same or different each moiety being
independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1_3-N(R5R6) and -NR5R6; R' is H; R3
is
phenyl-CHmethyl-X or phenyl-CH2-X, wherein said phenyl of each of said phenyl-
CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl,
further
wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl
wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or
thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and
R6 are
as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R
1\~
NN
R3. IN,H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
pyrazolyl,
wherein said pyrazolyl can be unsubstituted or substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -
C(O)OH, -
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of
said -
NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(02)R5, -CN, -CHO, -SR5, -C(O)OR5,
-
C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl
substituted with
one or more moieties which can be the same or different each moiety being
5 independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R' is H; R3
is,
S ~
S N~~~ N N g s~, QOH, SN O ~ S, ,
O
S-N N S
N S-N N S
N O ~S N
~ 1SN ~ 1SN
N S s 0=S ~
n
I N.J NJ S N O-~No ~N_ S/ N- N_
HN
N _N S / N
10 N N i , and ~N
wherein R5 and R 6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' Rz
R\T"J' N
\
1Y`N
N
R3.N, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
15 pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or
more moieties
which can be the same or different each moiety being independently selected
from the
group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)ORs, -
(CH2)1_3-
N(R5R6) and -NR5R6; R' is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X,
wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl,
arylalkyl,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
31
heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -
alkylSH, R6 is
hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6
can
optionally be joined together with the N of said -NR5R6 to form a cyclic ring
or bridged
cyclic ring, wherein said cyclic ring or bridged cyclic ring can be
unsubstituted or
substituted one or more moities, which can be the same or different,
independently
selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl,
hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl,
heterospiroaryl and
-CO2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
1\~
NN
RT N, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -
(CH2)1_3-
N(R5R6) and -NR5R6; R' is H; and R3 is heteroaryl-CH2-X, wherein the
heteroaryl of
said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -
NR5R6, R5
is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N
of said -
NR5R6 to form heterocyclyl.
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'I')' ' N
j_ \1
NN
R3.N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-
H-pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -
(CH2)1_3-
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
32
N(R5R6) and -NR5R6; R' is H; R3 is isothiazole, thiophene or pyrimidine
substituted
with:
N H3C N
N^~ ~
CH3 C ~ H c cH ~
3 r 3 r > > 3 3e
,-- ~ ~~' ~
r N N N
N I
N N \ I
H3CO
YO co O HsC OH, HO
r ~ N /+
N
N + H3C~
(N) N
NO
3 , s ,o o
N
N N-?
\ ~ J cH3 N N c~ ~ O~-N
H3C ~f
OH
-\ OH
- / O-~ S 0=S
/N , /N \1 , OH, I ,
-~~
OH,
N
or HO,/o ;wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r"j' N
l\
N
Y`N
R3.N, H
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
33
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-
H-pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -
(CH2)1-3-
N(R5R6) and -NR5R6; R' is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X, wherein
said
phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted
or
substituted with alkyl, further wherein X is piperazinyl, piperadinyl,
pyrrolidinyl,
morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl,
pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or
substituted with
alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r"l' N
~ \
NYL`N
R3.IN.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more
moieties
which can be the same or different each moiety being independently selected
from the
group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -
(CH2)1-3-
~ ~,
N
S-N N
S-N N S
N
N(R5R6) and -NR5R6; R' is H; R3 is, O, OH, 0
S N os' S- N S'N N
O
SN OH INJ , Cb,
O
~e NJ
`
O S S N N S NON N O N
ilr
`-".N
~ N ,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
34
N N HN
0 S N
S s S
S N ON_ N_ N_ N~ ~~
N
SON
and
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r)' N
~1\
N ~/`N
R3. IN.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yl; R is unsubstituted alkyl; R' is H; R3 is heteroaryl-CH2-X or
heteroaryl-
CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl,
hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl,
heteroarylalkyl,
or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -
alkylN(alkyl)2; or R5
and R6 can optionally be joined together with the N of said -NR5R6 to form a
cyclic ring
or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be
unsubstituted or substituted one or more moities, which can be the same or
different,
independently selected from the group consisting of hydroxyl, alkyl, alkoxyl,
alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl,
heterospirocyclenyl,
heterospiroaryl and -CO2alkyl; wherein R5 and R 6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
~ 1\~
NN
R3" N, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yi; R is unsubstituted alkyl; R' is H; R3 is heteroaryl-CH2-X,
wherein the
5
heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONRR6,
wherein X
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R 6 are optionally joined
together with the N
of said -NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'~" N
~
N\\/l~'N
R3.~N.H
5 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2
is 1-
H-pyrazol-4-yl; R is unsubstituted alkyl; R' is H; R3 is isothiazole,
thiophene or
pyrimidine substituted with:
r~- ~~- ~~-
^P. N N H3C N
CY CH3 C" Q ~CH
3 3 HC 3f
3 f
r~- /+ r~/ /-s
N N N N
N ~
N
H3CO aOHYO ~
0 , , H3C~ , 0 , HO
N /+
N ~- N
1 N ~- H3C~
N/ O
CH3 ~N $~ ~/ ~ I c 0
10 ,
~~ ~-
N r CN) N
I
/I CH3 N N
H3C ~~f
OH
~ 0= S ~/OH
O~_N\J~ ~ N- N- \~~N~ N
, OH, I ,
-~~
OH,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
36
N
or HO_/o ; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R
1\~
NN
R3. N, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-
H-pyrazol-4-yl; R is unsubstituted alkyl; R' is H; R3 is phenyl-CHmethyl-X or
phenyl-
CH2-X, wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X
can
be unsubstituted or substituted with alkyl, further wherein X is piperazinyl,
piperadinyl,
pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl,
piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted
or
substituted with alkyl;
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'r"j" N
~ ~
N \/1'N
R3.~N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
'-e
S-N N
S-N N~
pyrazol-4-yl; R is unsubstituted alkyl; R' is H; and R3 is, oH,
~ S N N N SN N
S
'/I~ 1 .4:; N
S'N OH, S ,
0
NJ
''~'
S ` ^>- , iss'
O N~ ~S/-N N S N O~ N ~ ~ ~`O ~.~N
~,S , ,, ~OCN.~ N~-N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
37
N N HN
S OS N S N S
S N ON_ N_ ~Nj' N~'
SON
and
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'rlk N
~ \
N~/1`N
R3 IN.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yl; R is methyl, R' is H; R3 is heteroaryl-CH2-X or heteroaryl-
CHMethyl-X,
wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl,
arylalkyl,
heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -
alkylSH, R6 is
hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6
can
optionally be joined together with the N of said -NR5R6 to form a cyclic ring
or bridged
cyclic ring, wherein said cyclic ring or bridged cyclic ring can be
unsubstituted or
substituted one or more moities, which can be the same or different,
independently
selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl,
hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl,
heterospiroaryl and
-CO2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R'~" N
~
N~N
R3.N.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
pyrazol-4-yl; R is methyl, R' is H; R3 is heteroaryl-CH2-X, wherein the
heteroaryl of
said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -
NR5R6, R5
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
38
is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N
of said -
NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R
NY`N
R3.IN.H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-
H-pyrazol-4-yl; R is methyl, R' is H; R3 is isothiazole, thiophene or
pyrimidine
substituted with:
N/\~ r~= r~~ ~~~
r.
CY/~s,:' N H3C
v ~CH3~
CH3 C Hc
~
3 f 3 ) f f 3 f
~~ _
r~- ~- r / S Ir y
N N N
N
H,c0 N I~ I I/
0 H3C1.10 OH c0) HO Y
) f ) ) , ) ) )
N /+
~ji
~7 I N H3C
C:) O
CH `~ ~ / ~ / ~ - `'
3 S f~ f f f f f o
r7
N
c ) -1N N-/
~ N N -~~ -~ ' \ ~ -=
\ I J CH3 N
H3C
OH
- / O-~ S 0= S /OH
N~ ~ _ ~N_ ~~ ~~ NI
OH,
-~~
OH,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
39
N
or HO"/ v .
In another embodiment, this invention discloses a compound of the formula:
R' R2
R~N
~ ~
N \/1'N
R3"TN, H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-
H-pyrazol-4-yl; R is methyl, R' is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X,
wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be
unsubstituted or substituted with alkyl, further wherein X is piperazinyl,
piperadinyl,
pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl,
piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted
or
substituted with alkyl.
In another embodiment, this invention discloses a compound of the formula:
R' R2
R
~
N N
R3.~N".H
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is
1-H-
~ :~ I ,~
S-N N
S-N N~ S
N
pyrazol-4-yl; R is methyl, R' is H; R3 is, ~O , OH, 0 ,
S S- N S'N N
N N ~ ~'J
S, , N , - ,
S-N OH3
O
N
s~ T1,~ S N N S N O ~~ ~O ~ I` N
O ~,S ~N ~ ~ N `N~.N D
> > \' ,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
.
~N HN
~
s N O-\_ N- ~S=/ N- O N- ~(=S I~~~Gs
N
N N
SN
and N
In another embodiment, this invention discloses a compound of the formula:
H
N- N
N
NY `N
HNI
S-N NR5R6
5 or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R5
is alkyl; R6
is selected from the group consisting of alkoxyalkyl, hydroxyalkyl,
cycloalkyl, wherein
said cycloalkyl is substituted by hydroxyalkyl; or R5 and R6 together with the
N of said
-NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one
or more
moieties independently selected from the group consisting of alkoxyalkyl,
10 hydroxyalkyl, and alkyl.
In another embodiment, this invention discloses a compound of the formula:
H
N- N
N
NY _N
HNI ~
/
S-N NR5R6
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R5 is
methyl,
ethyl, or propyl; R6 is selected from the group consisting of ethoxyethyl, 1,1-
15 dimethylhydroxyethyl, cyclopentyl, cyclohexyl, wherein each of said
cyclopentyl and
cyclohexyl is substituted by hydroxymethyl; or R5 and R6 together with the N
of said -
NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one or
more
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
41
moieties independently selected from the group consisting of ethoxymethyl,
methoxymethyl, hydroxymethyl, and methyl.
Non-limiting examples of compounds of Formula I include:
H
N_ N H
N_ N_N H I N'N
N `N ~N \ \ ~
~N \ ~N1 \ ~N \ N~N ~N1~ \
NN NYN N~N HN ~\~ NY`N
HTN HN~ ^ HN~ S-' N HN 7 ~)--\ TS~-N/--~N ~
S-N S-N / / \ g-N// N
0, - , \--/ ,
HN-N
HN-N
N- H N
N~N
N N`N NH `N ~N N N
~N ` N\ N HN 1 S N HN 1 N
N,
Nl~)-_N N~
N
HN
T_\/ HN~ HN~ ~ S 0=S
S-N N _ ~-\ 1~ }-\
S N 0~_ S-N 0~_No N-, ~N-
~, N ,,
N_ ~
H3C ~ H H
H3C CH3 CH3 N'N N- N
H3CN \ \ ~ I
NYN Nj
N ~N \ N
FfN S. ~ S. NN ~ -N
~ IN CH3 IN l I
N~ No HN\ /S~N ~ ~gNH
L N , N
H H
N-N N-N
\ I \ I
H
N-N
HN-N ~N \ N \ \ I
H N~N N~N ~N \
N N HN H N ^ N` ~N
/
T --\ ~
NY N S-N N S-N N HN_ õ
N S NH ~~ S/-N ~N
~N~ , \, OMe, ~OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
42
H H
N'N H H N-N
\'N N-N
I
N
N
NN N N \ I \
HN N~N N~N N~N
/ HN1/\ HN ~ HN
N ~
S-N ( t r~ ~
--~
/\ S-N iI-<, g
H H H
N'N H N,N N-N
N'N I I
N
NY `N ~N` N~N ~ N~N
NI~/1N HN N HN N
HN ~
N HNNrN/~ S S
S-N N~ No N
<\~
S-N 6 O
> > > O
s H H N' N
N- N
H3C`Y^N SN N
N/~ H3C ~ N~ H3C~N NY 'N
N N\~N N~N HN ~
HN`Y ^ H~N"~ HN I~ COyEt S'NkOH
1/ /}-\
S N OH, S'N OH,
~ N e ~
H
H N-\ `N \ ,N N
H "fO"~'N '-rN N
N~I_N Nllz~-- N
N N
T
HN,, HN` HN
~~--N S'N N S-N N S-N N
\~ ~, OH,
H
N'N
H H
N~N N,N
I \TN I
lN N'^~N N
N~ ~/ N HN N
N
~ OH
~
HN O S-N N HN
S-N N \- S-N> OH
\~/
~ ~ ~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
43
N-N N-N H
N'N
N N ~
NN N7` ~N \ N
OH N
HN HN /0 HN
S-N S-N S_N
H
N'N
N,N
I
~l
f N NY~
'N
NN '
HN
HN O
S N N S-N H N- N_ a
\r \r ~N \ N \ ~N \
~N \ NN N~
N N~T N
N N
HN r HN~ HN ~/ HN1/\
\ I- S-N S-N S-N N
S-N OH F
CF3 F F, CF3,
H N_ \'r \ -r H
\ r N-
I N \ ~N \ ~N \ N
N~N N~N N~N
N1--l-- N
HN HN1/\ HN~ HN
Q-\ ~~ /-
S-N aF S-N N~ F S-N N S N
/ F
F
F 0 ,
H H H
N,
N_
\r \_r \r
a
~N
N~ ~N NY'l N
N NY N N I
HN N HN~
i
/ N / HN~ S-N N
S-N N ~Fo\--
F ~F S-N N S-N N , ~/ 'F, ~''F, F
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
44
a~r
H H N`
N'N N-
~N \ \ I \ r
N
N N N \
HN N N` ~ N~N
N N T
HN,,r HN~
No HN ~ ~\O S_N S-N HN-\-F
S /
N FJ or
H
N'N
H ( N_
N
~ N \
~N \ N ~ _\
N~N N NY _N
HN ~N HN S H%~N
S- N
N ~ ~ N
- ~ - ~ - ~
H H
H N-N N' H
N'N \ I \ ~ N'r
N~ N\ N N- \T^
HN N
N N N~
HN ~/ HN rN OMe HN ~
S-N S N N/ N/ ~ S'N N/ \ OMe
H H
H N'N H N,N
~~N \ ~ N-N I
~N
N N I` ~N \ I- N\
NN ~ N N~ NN
Y HN N
HN
s-N r\ s N N/ \ S N r\ sN
N _
OMe, Me0 ~ F, HN Br,
H
N-N N-N N'f`1 N-
N
N \ -
N NY N Nll)zN NY N
HN ~
/ HN ~ HN ~ HN
F r
S-N S_N / \ S N S N
N N N
ci, - , - 1
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
H
N'N
H
N' ' N N
~
I N NY N
NN
HN TS- HN~ ~ N +
S-N bN1X NMeZ O,N~ \
and -
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
As used above, and throughout this disclosure, the following terms, unless
otherwise indicated, shall be understood to have the following meanings,
including
5 any possible substitutions of the stated groups or moieties:
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or
branched and comprising about 1 to about 20 carbon atoms in the chain.
Preferred
10 alkyl groups contain about 1 to about 12 carbon atoms in the chain. More
preferred
alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched
means
that one or more, lower alkyl groups such as methyl, ethyl or propyl, are
attached to a
linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6
carbon
atoms in the chain which may be straight or branched. "Alkyl" may be
unsubstituted or
15 optionally substituted by one or more substituents which may be the same or
different,
each substituent being independently selected from the group consisting of
halo, alkyl,
aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., =N-
OH), -
NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -O-C(O)-alkyl, -O-C(O)-aryl,
-O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of
suitable alkyl
20 groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-
carbon double bond and which may be straight or branched and comprising about
2 to
about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to
about
12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon
atoms in
25 the chain. Branched means that one or more, lower alkyl groups such as
methyl, ethyl
or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about
2 to
about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl"
may
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
46
be unsubstituted or optionally substituted by one or more substituents which
may be
the same or different, each substituent being independently selected from the
group
consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-
limiting
examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-
methylbut-
2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom
from an alkyl group that is defined above. Non-limiting examples of alkylene
include
methylene, ethylene and propylene.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-
carbon triple bond and which may be straight or branched and comprising about
2 to
about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to
about
12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in
the chain. Branched means that one or more, lower alkyl groups such as methyl,
ethyl
or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about
2 to
about 6 carbon atoms in the chain which may be straight or branched. Non-
limiting
examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-
methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one
or more
substituents which may be the same or different, each substituent being
independently selected from the group consisting of alkyl, aryl and
cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising
about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
The
aryl group can be optionally substituted with one or more "ring system
substituents"
which may be the same or different, and are as defined herein. Non-limiting
examples
of suitable aryl groups include phenyl and naphthyl.
"Bridged cyclic ring" is a hydrocarbon ring such as cycloalkyl, cyclenyl, or
aryl
or heteroatom containing ring such as, heterocyclyl, heterocyclenyl, or
heteroaryl as
described herein, that contains a bridge, which is a valence bond or an atom
or an
unbranched chain of atoms connecting two different parts of the ring. The two
tertiary
carbon atoms connected through the bridge are termed "bridgeheads".
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system
comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring
atoms,
in which one or more of the ring atoms is an element other than carbon, for
example
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
47
nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls
contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted
by one or
more "ring system substituents" which may be the same or different, and are as
defined herein. The prefix aza, oxa or thia before the heteroaryl root name
means that
at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A
nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding
N-oxide.
"Heteroaryl" may also include a heteroaryl as defined above fused to an aryl
as
defined above. Non-limiting examples of suitable heteroaryls include pyridyl,
pyrazinyl,
furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl,
isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,
triazolyl, 1,2,4-
thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
imidazo[1,2-
a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
benzimidazolyl,
benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-
triazinyl,
benzothiazolyl and the like. The term "heteroaryl" also refers to partially
saturated
heteroaryl moieties such as, for example, tetrahydroisoquinolyl,
tetrahydroquinolyl and
the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and
alkyl are
as previously described. Preferred aralkyls comprise a lower alkyl group. Non-
limiting
examples of suitable aralkyl groups include benzyl, 2-phenethyl and
naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as
previously described. Preferred alkylaryls comprise a lower alkyl group. Non-
limiting
example of a suitable alkylaryl group is tolyl. The bond to the parent moiety
is through
the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising
about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.
Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The
cycloalkyl can be
optionally substituted with one or more "ring system substituents" which may
be the
same or different, and are as defined above. Non-limiting examples of suitable
monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl and
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
48
the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-
decalinyl,
norbomyl, adamantyl and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an
alkyl
moiety (defined above) to a parent core. Non-limiting examples of suitable
cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system
comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10
carbon
atoms which contain at least one carbon-carbon double bond. Preferred
cycloalkenyl
rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be
optionally
substituted with one or more "ring system substituents" which may be the same
or
different, and are as defined above. Non-limiting examples of suitable
monocyclic
cycloalkenyis include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and
the like.
Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an
alkyl moiety (defined above) to a parent core. Non-limiting examples of
suitable
cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the
like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are
fluorine,
chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-
aromatic ring system which, for example, replaces an available hydrogen on the
ring
system. Ring system substituents may be the same or different, each being
independently selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylaikenyl,
heteroarylalkynyl,
alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,
aroyl, halo,
nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio,
aralkylthio,
heteroaralkylthio, cycloalkyl, heterocyclyl, amide, -CHO, -O-C(O)-alkyl, -O-
C(O)-aryl, -
O-C(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), oxime (e.g.,
=N-OH), YjY2N-, YIY2N-alkyl-, YlY2NC(O)-, Y1Y2NSO2- and -SO2NYjY2, wherein Y,
and Y2 can be the same or different and are independently selected from the
group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system
substituent"
may also mean a single moiety which simultaneously replaces two available
hydrogen
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
49
on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples
of
such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which
form
moieties such as, for example:
O0 co 0~0 and
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an
alkyl moiety (defined above) to a parent core. Non-limiting examples of
suitable
heteroaryis include 2-pyridinylmethyl, quinolinylmethyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring
system comprising about 3 to about 10 ring atoms, preferably about 5 to about
10 ring
atoms, in which one or more of the atoms in the ring system is an element
other than
carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There
are no
adjacent oxygen and/or sulfur atoms present in the ring system. Preferred
heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or
thia before
the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur
atom
respectively is present as a ring atom. Any -NH in a heterocyclyl ring may
exist
protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the
like;
such protections are also considered part of this invention. The heterocyclyl
can be
optionally substituted by one or more "ring system substituents" which may be
the
same or different, and are as defined herein. The nitrogen or sulfur atom of
the
heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide
or S,S-
dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings
include
piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
thiazolidinyl, 1,4-
dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the
like.
'"HeterocyclyP' may also mean a single moiety (e.g., carbonyl) which
simultaneously
replaces two available hydrogen on the same carbon atom on a ring system.
Example
of such moiety is pyrrolidone:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
H
N
O
"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an
alkyl moiety (defined above) to a parent core. Non-limiting examples of
suitable
heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
5 "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system
comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring
atoms,
in which one or more of the atoms in the ring system is an element other than
carbon,
for example nitrogen, oxygen or sulfur atom, alone or in combination, and
which
contains at least one carbon-carbon double bond or carbon-nitrogen double
bond.
10 There are no adjacent oxygen and/or sulfur atoms present in the ring
system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The
prefix aza,
oxa or thia before the heterocyclenyl root name means that at least a
nitrogen, oxygen
or sulfur atom respectively is present as a ring atom. The heterocyclenyl can
be
optionally substituted by one or more ring system substituents, wherein "ring
system
15 substituent" is as defined above. The nitrogen or sulfur atom of the
heterocyclenyl can
be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-
limiting examples of suitable heterocyclenyl groups include 1,2,3,4-
tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-
tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-
pyrrolinyl, 2-
20 imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,
dihydrooxadiazolyl,
dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,
fluorodihydrofuranyl, 7-
oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the
like.
"Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which
simultaneously
replaces two available hydrogen on the same carbon atom on a ring system.
Example
25 of such moiety is pyrrolidinone:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
51
H
N
I
O
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked
via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this
invention,
there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well
as
there are no N or S groups on carbon adjacent to another heteroatom. Thus, for
example, in the ring:
4
2
5 1 1
N
H
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the
moieties:
N O
H and N OH
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl
are
as previously described. Preferred alkynylalkyls contain a lower alkynyl and a
lower
alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting
examples
of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and
alkyl are as previously described. Preferred heteroaralkyls contain a lower
alkyl group.
Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-
ylmethyl. The bond to the parent moiety is through the alkyl.
"Spiro ring systems" have two or more rings linked by one common atom.
Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl,
spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl. The spiro
ring systems
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
52
can be optionally substituted by one or more ring system substituents, wherein
"ring
system substituent" is as defined above. Non-limiting examples of suitable
spiro ring
9 10 1
2
8 CXD3
systems include 7 6 4
1 1
HNOD 7 I 5 I
spiro[4.5]decane, 8-azaspiro[4.5]dec-2-ene, and
spiro[4.4]nona-2,7-diene.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously
defined.
Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable
hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the
various groups are as previously described. The bond to the parent moiety is
through
the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of
suitable
acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously
described. The bond to the parent moiety is through the carbonyl. Non-limiting
examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously
described. Non-limiting examples of suitable alkoxy groups include methoxy,
ethoxy,
n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through
the
ether oxygen.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously
described. Non-limiting examples of suitable aryloxy groups include phenoxy
and
naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as
previously described. Non-limiting examples of suitable aralkyloxy groups
include
benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is
through
the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously
described. Non-limiting examples of suitable alkylthio groups include
methylthio and
ethylthio. The bond to the parent moiety is through the sulfur.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
53
"Arylthio" means an aryl-S- group in which the aryl group is as previously
described. Non-limiting examples of suitable arylthio groups include
phenylthio and
naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as
previously described. Non-limiting example of a suitable aralkylthio group is
benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of
suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The
bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of
suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
The
bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a
suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent
moiety
is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(02)- group. Preferred groups are those in
which the alkyl group is lower alkyl. The bond to the parent moiety is through
the
sulfonyl.
"Arylsulfonyl" means an aryl-S(02)- group. The bond to the parent moiety is
through the sulfonyl.
The term "substituted" means that one or more hydrogen on the designated
atom is replaced with a selection from the indicated group, provided that the
designated atom's normal valency under the existing circumstances is not
exceeded,
and that the substitution results in a stable compound. Combinations of
substituents
and/or variables are permissible only if such combinations result in stable
compounds.
By "stable compound' or "stable structure" is meant a compound that is
sufficiently
robust to survive isolation to a useful degree of purity from a reaction
mixture, and
formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the
specified
groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for
a
compound refers to the physical state of said compound after being isolated
from a
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
54
synthetic process (e.g. from a reaction mixture), or natural source or
combination
thereof. Thus, the term "purified", "in purified form" or "in isolated and
purified form" for
a compound refers to the physical state of said compound after being obtained
from a
purification process or processes described herein or well known to the
skilled artisan
(e.g., chromatography, recrystallization and the like) , in sufficient purity
to be
characterizable by standard analytical techniques described herein or well
known to
the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is assumed to have
the
sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that
the group is in modified form to preclude undesired side reactions at the
protected site
when the compound is subjected to a reaction. Suitable protecting groups will
be
recognized by those with ordinary skill in the art as well as by reference to
standard
textbooks such as, for example, T. W. Greene et al, Protective Groups in
organic
Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one
time
in any constituent or in Formula I, its definition on each occurrence is
independent of
its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any
product
which results, directly or indirectly, from combination of the specified
ingredients in the
specified amounts.
Prodrugs and solvates of the compounds of the invention are also
contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V.
Stella,
Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series,
and
in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,
American
Pharmaceutical Association and Pergamon Press. The term "prodrug" means a
compound (e.g., a drug precursor) that is transformed in vivo to yield a
compound of
Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the
compound.
The transformation may occur by various mechanisms (e.g., by metabolic or
chemical
processes), such as, for example, through hydrolysis in blood. A discussion of
the
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
use of prodrugs is provided by T. Higuchi and W. Stella, Pro-drugs as Novel
Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in
Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
Pergamon Press, 1987.
5 For example, if a compound of Formula (I) or a pharmaceutically acceptable
salt, hydrate or solvate of the compound contains a carboxylic acid functional
group, a
prodrug can comprise an ester formed by the replacement of the hydrogen atom
of
the acid group with a group such as, for example, (Cl-C8)alkyl, (C2-
C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-
10 methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-
(alkoxycarbonyloxy)ethyl
having from 4 to 7 carbon atoms, 1 -methyl-1 -(alkoxycarbonyloxy)ethyl having
from 5
to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms,
1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-
phthalidyl, 4-
15 crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Cl-C2)alkylamino(C2-
C3)alkyl (such
as P-dimethylaminoethyl), carbamoyl-(Cj-C2)alkyl, N,N-di (Cl-C2)alkylcarbamoyl-
(C1-
C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the
like.
Similarly, if a compound of Formula (I) contains an alcohol functional group,
a
prodrug can be formed by the replacement of the hydrogen atom of the alcohol
group
20 with a group such as, for example, (CI-C6)alkanoyloxymethyl, 1-((Cl-
C6)alkanoyloxy)ethyl, 1-methyl-1-((CI-C6)alkanoyloxy)ethyl, (Cl-
C6)alkoxycarbonyloxymethyl, N-(Cl-Cs)alkoxycarbonylaminomethyl, succinoyl, (Cl-
C6)alkanoyl, a-amino(Cl-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-
aminoacyl, where each a-aminoacyl group is independently selected from the
naturally
25 occurring L-amino acids, P(O)(OH)2, -P(O)(O(CI-Cs)alkyl)2 or glycosyl (the
radical
resulting from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug
can be formed by the replacement of a hydrogen atom in the amine group with a
30 group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R
and R'
are each independently (Cl-Clo)alkyl, (C3-C7) cycloalkyl, benzyl, or R-
carbonyl is a
natural a-aminoacyl or natural a-aminoacyl, -C(OH)C(O)OY' wherein Y' is H, (Cl-
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
56
C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (CI-C4) alkyl and Y3 is P-
Cs)alkyl,
carboxy P-Cs)alkyl, amino(Cj-C4)alkyl or mono-N--or di-N,N-(Cj-
C6)alkylaminoalkyl,
-C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N,N-(Cj-
C6)alkylamino
morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as
solvated forms with pharmaceutically acceptable solvents such as water,
ethanol, and
the like, and it is intended that the invention embrace both solvated and
unsolvated
forms. "Solvate" means a physical association of a compourid of this invention
with
one or more solvent molecules. This physical association involves varying
degrees of
ionic and covalent bonding, including hydrogen bonding. In certain instances
the
solvate will be capable of isolation, for example when one or more solvent
molecules
are incorporated in the crystal lattice of the crystalline solid. "Solvate"
encompasses
both solution-phase and isolatable solvates. Non-limiting examples of suitable
solvates include ethanolates, methanolates, and the like. "Hydrate" is a
solvate
wherein the solvent molecule is H20.
One or more compounds of the invention may optionally be converted to a
solvate. Preparation of solvates is generally known. Thus, for example, M.
Caira et al,
J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the
solvates of the antifungal fluconazole in ethyl acetate as well as from water.
Similar
preparations of solvates, hemisolvate, hydrates and the like are described by
E. C.
van Tonder et al, AAPS PharmSciTech., 50), article 12 (2004); and A. L.
Bingham et
al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves
dissolving the inventive compound in desired amounts of the desired solvent
(organic
or water or mixtures thereof) at a higher than ambient temperature, and
cooling the
solution at a rate sufficient to form crystals which are then isolated by
standard
methods. Analytical techniques such as, for example I. R. spectroscopy, show
the
presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe
an
amount of compound or a composition of the present invention effective in
inhibiting
the above-noted diseases and thus producing the desired therapeutic,
ameliorative,
inhibitory or preventative effect.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
57
The compounds of Formula I can form salts which are also within the scope of
this invention. Reference to a compound of Formula I herein is understood to
include
reference to salts thereof, unless otherwise indicated. The term "salt(s)", as
employed
herein, denotes acidic salts formed with inorganic and/or organic acids, as
well as
basic salts formed with inorganic and/or organic bases. In addition, when a
compound
of Formula I contains both a basic moiety, such as, but not limited to a
pyridine or
imidazole, and an acidic moiety, such as, but not limited to a carboxylic
acid,
zwitterions ("inner salts") may be formed and are included within the term
"salt(s)" as
used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable)
salts are preferred, although other salts are also useful. Salts of the
compounds of the
Formula I may be formed, for example, by reacting a compound of Formula I with
an
amount of acid or base, such as an equivalent amount, in a medium such as one
in
which the salt precipitates or in an aqueous medium followed by
lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates,
benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides,
lactates,
maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates,
propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,
toluenesulfonates (also known as tosylates,) and the like. Additionally, acids
which are
generally considered suitable for the formation of pharmaceutically useful
salts from
basic pharmaceutical compounds are discussed, for example, by P. Stahl et al,
Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and
Use.
(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977)
66(l) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217;
Anderson
et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York;
and in
The Orange Book (Food & Drug Administration, Washington, D.C. on their
website).
These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as
sodium, lithium, and potassium salts, alkaline earth metal salts such as
calcium and
magnesium salts, salts with organic bases (for example, organic amines) such
as
dicyclohexylamines, t-butyl amines, and salts with amino acids such as
arginine,
lysine and the like. Basic nitrogen-containing groups may be quartemized with
agents
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
58
such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides
and
iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates),
long chain
halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides
(e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically
acceptable salts within the scope of the invention and all acid and base salts
are
considered equivalent to the free forms of the corresponding compounds for
purposes
of the invention.
Pharmaceutically acceptable esters of the present compounds include the
following groups: (1) carboxylic acid esters obtained by esterification of the
hydroxy
groups, in which the non-carbonyl moiety of the carboxylic acid portion of the
ester
grouping is selected from straight or branched chain alkyl (for example,
acetyl, n-
propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl),
aralkyl (for
example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for
example,
phenyl optionally substituted with, for example, halogen, C1_4alkyl, or Cl-
4alkoxy or
amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example,
methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl);
(4)
phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate
esters
may be further esterified by, for example, a C1_20 alcohol or reactive
derivative thereof,
or by a 2,3-di (Cr,24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may
exist in their tautomeric form (for example, as an amide or imino ether). All
such
tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and,
therefore, exist in different stereoisomeric forms. It is intended that all
stereoisomeric
forms of the compounds of Formula (I) as well as mixtures thereof, including
racemic
mixtures, form part of the present invention. In addition, the present
invention
embraces all geometric and positional isomers. For example, if a compound of
Formula (I) incorporates a double bond or a fused ring, both the cis- and
trans-forms,
as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers
on the basis of their physical chemical differences by methods well known to
those
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
59
skilled in the art, such as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the enantiomeric
mixture
into a diastereomeric mixture by reaction with an appropriate optically active
compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid
chloride),
separating the diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of the
compounds
of Formula (I) may be atropisomers (e.g., substituted biaryls) and are
considered as
part of this invention. Enantiomers can also be separated by use of chiral
HPLC
column.
It is also possible that the compounds of Formula (I) may exist in different
tautomeric forms, and all such forms are embraced within the scope of the
invention.
Also, for example, all keto-enol and imine-enamine forms of the compounds are
included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the
like)
of the present compounds (including those of the salts, solvates, esters and
prodrugs
of the compounds as well as the salts, solvates and esters of the prodrugs),
such as
those which may exist due to asymmetric carbons on various substituents,
including
enantiomeric forms (which may exist even in the absence of asymmetric
carbons),
rotameric forms, atropisomers, and diastereomeric forms, are contemplated
within the
scope of this invention, as are positional isomers (such as, for example, 4-
pyridyl and
3-pyridyl). (For example, if a compound of Formula (I) incorporates a double
bond or a
fused ring, both the cis- and trans-forms, as well as mixtures, are embraced
within the
scope of the invention. Also, for example, all keto-enol and imine-enamine
forms of
the compounds are included in the invention.) Individual stereoisomers of the
compounds of the invention may, for example, be substantially free of other
isomers,
or may be admixed, for example, as racemates or with all other, or other
selected,
stereoisomers. The chiral centers of the present invention can have the S or R
configuration as defined by the IUPAC 1974 Recommendations. The use of the
terms
"salt", "solvate", "ester", "prodrug" and the like, is intended to equally
apply to the salt,
solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers,
positional isomers, racemates or prodrugs of the inventive compounds.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
The present invention also embraces isotopically-labelled compounds of the
present invention which are identical to those recited herein, but for the
fact that one
or more atoms are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number usually found in nature.
Examples of
5 isotopes that can be incorporated into compounds of the invention include
isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as
2H,
31õI, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S,18F, and 36CI, respectively.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled
with
3H and14C) are useful in compound and/or substrate tissue distribution assays.
10 Tritiated (i.e., 3H) and carbon-14 (i.e.,14C) isotopes are particularly
preferred for their
ease of preparation and detectability. Further, substitution with heavier
isotopes such
as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting
from
greater metabolic stability (e.g., increased in vivo half-life or reduced
dosage
requirements) and hence may be preferred in some circumstances. Isotopically
15 labeled compounds of Formula (I) can generally be prepared by following
procedures
analogous to those disclosed in the Schemes and/or in the Examples herein
below, by
substituting an appropriate isotopically labeled reagent for a non-
isotopically labeled
reagent.
Polymorphic forms of the compounds of Formula I, and of the salts, solvates,
20 esters and prodrugs of the compounds of Formula I, are intended to be
included in the
present invention.
The compounds according to the invention have pharmacological properties; in
particular, the compounds of Formula I can be inhibitors, regulators or
modulators of
protein kinases. Non-limiting examples of protein kinases that can be
inhibited,
25 regulated or modulated include cyclin-dependent kinases (CDKs), such as,
CDK1,
CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein
kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases, Chk
kinases (such as Chkl and Chk2), tyrosine kinases, such as the HER subfamily
(including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulin
30 subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the PDGF
subfamily
(including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-
II), the
FLK family (including, for example, kinase insert domain receptor (KDR), fetal
liver
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
61
kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine
kinase-1 (flt-1)),
non-receptor protein tyrosine kinases, for example LCK, Src, Frk, Btk, Csk,
Abl,
Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK, growth factor receptor tyrosine
kinases
such as VEGF-R2, FGF-R, TEK, Akt kinases, Aurora kinases (Aurora A, Aurora B,
Aurora C) and the like.
The compounds of Formula I can be inhibitors of protein kinases such as, for
example, the inhibitors of the checkpoint kinases such as Chkl, Chk2 and the
like.
Preferred compounds can exhibit IC50 values of less than about 5pm, preferably
about
0.001 to about 1.0 pm, and more preferably about 0.001 to about 0.1 pm. The
assay
methods are described in the Examples set forth below.
The compounds of Formula I can be useful in the therapy of proliferative
diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases,
neurological/neurodegenerative disorders, arthritis, inflammation, anti-
proliferative
(e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
Many of
these diseases and disorders are listed in U.S. 6,413,974 cited earlier,
incorporated
by reference herein.
More specifically, the compounds of Formula I can be useful in the treatment
of
a variety of cancers, including (but not limited to) the following:
tumor of the bladder, breast (including BRCA-mutated breast cancer,
colorectal,
colon, kidney, liver, lung, small cell lung cancer, non-small cell lung
cancer, head and
neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix,
thyroid,
prostate, and skin, including squamous cell carcinoma;
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy
cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma;
chronic lymphocytic leukemia ("CLL"),
acute and chronic myelogenous leukemia, myelodysplastic syndrome and
promyelocytic leukemia;
fibrosarcoma, rhabdomyosarcoma;
head and neck, mantle cell lymphoma, myeloma;
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
62
astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors,
astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors
("GIST") and
schwannomas;
melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and
Kaposi's
sarcoma.
Due to the key role of kinases in the regulation of cellular proliferation in
general, inhibitors could act as reversible cytostatic agents which may be
useful in the
treatment of any disease process which features abnormal cellular
proliferation, e.g.,
benign prostate hyperplasia, familial adenomatosis polyposis, neuro-
fibromatosis,
atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis,
restenosis
following angioplasty or vascular surgery, hypertrophic scar formation,
inflammatory
bowel disease, transplantation rejection, endotoxic shock, and fungal
infections.
Compounds of Formula I may also be useful in the treatment of Alzheimer's
disease, as suggested by the recent finding that CDK5 is involved in the
phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749).
Compounds of Formula I may induce or inhibit apoptosis. The apoptotic
response is aberrant in a variety of human diseases. Compounds of Formula I,
as
modulators of apoptosis, will be useful in the treatment of cancer (including
but not
limited to those types mentioned hereinabove), viral infections (including but
not
limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and
adenovirus),
prevention of AIDS development in HIV-infected individuals, autoimmune
diseases
(including but not limited to systemic lupus, erythematosus, autoimmune
mediated
glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel
disease, and
autoimmune diabetes mellitus), neurodegenerative disorders (including but not
limited
to Alzheimer's disease, AIDS-related dementia, Parkinson's disease,
amyotrophic
lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and
cerebellar
degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury
associated with myocardial infarctions, stroke and reperfusion injury,
arrhythmia,
atherosclerosis, toxin-induced or alcohol related liver diseases,
hematological
diseases (including but not limited to chronic anemia and aplastic anemia),
degenerative diseases of the musculoskeletal system (including but not limited
to
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
63
osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis,
multiple
sclerosis, kidney diseases and cancer pain.
Compounds of Formula I, as inhibitors of kinases, can modulate the level of
cellular RNA and DNA synthesis. These agents would therefore be useful in the
treatment of viral infections (including but not limited to HIV, human
papilloma virus,
herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
Compounds of Formula I may also be useful in the chemoprevention of cancer.
Chemoprevention is defined as inhibiting the development of invasive cancer by
either
blocking the initiating mutagenic event or by blocking the progression of pre-
malignant
cells that have already suffered an insult or inhibiting tumor relapse.
Compounds of Formula I may also be useful in inhibiting tumor angiogenesis
and metastasis.
Compounds of Formula I may also act as inhibitors of cyclin dependent kinases
and other protein kinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP
kinase, EGF
receptor, PDGF receptor, IGF receptor, P13 kinase, weel kinase, Src, Abl and
thus be
effective in the treatment of diseases associated with other protein kinases.
Another aspect of this invention is a method of treating a mammal (e.g.,
human) having a disease or condition associated with kinases (e.g., CDKs, CHK
and
Aurora kinases) by administering a therapeutically effective amount of at
least one
compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester
or
prodrug of said compound to the mammal.
A preferred dosage is about 0.001 to 1000 mg/kg of body weight/day of the
compound of Formula I. An especially preferred dosage is about 0.01 to 25
mg/kg of
body weight/day of a compound of Formula I, or a pharmaceutically acceptable
salt,
solvate, ester or prodrug of said compound.
The compounds of this invention may also be useful in combination
(administered
together or sequentially) with one or more of anti-cancer treatments such as
radiation
therapy, and/or one or more anti-cancer agents different from the compound of
Formula I. The compounds of the present invention can be present in the same
dosage unit as the anti-cancer agent or in separate dosage units.
Another aspect of the present invention is a method of treating one or more
diseases associated with a kinase (such as CDK, CHK and Aurora), comprising
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
64
administering to a mammal in need of such treatment: an amount of a first
compound,
which is a compound of Formula 1, or a pharmaceutically acceptable salt,
solvate,
ester or prodrug thereof; and an amount of at least one second compound, the
second
compound being an anti-cancer agent different from the compound of Formula 1,
wherein the amounts of the first compound and the second compound result in a
therapeutic effect.
Non-limiting examples of suitable anti-cancer agent is selected from the group
consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal
doxorubicin (e.g.,
Caelyx , Myocet , Doxil ), taxotere, taxol, etoposide, irinotecan, camptostar,
topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,
methoxtrexate,
temozolomide, cyclophosphamide, SCH 66336, R115777 , L778,123 , BMS 2146628
,
Iressa , Tarceva , antibodies to EGFR, antibodies to IGFR (including, for
example,
those published in US 2005/0136063 published June 23, 2005), KSP inhibitors
(such
as, for example, those published in WO 2006/098962 and WO 2006/098961;
ispinesib, SB-743921 from Cytokinetics), centrosome associated protein E
("CENP-
E") inhibitors (e.g., GSK-923295), Gleevec , intron, ara-C, adriamycin,
cytoxan,
gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,
Chlorambucil,
Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,
leucovirin,
ELOXATINTM, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,
Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin,
Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone
propionate, Testolactone, Megestrolacetate, Methylprednisolone,
Methyltestosterone,
Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,
Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,
Amsacrine,
Procarbazine; Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole,
Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin,
herceptin, Bexxar, bortezomib ("Velcade"), Zevalin, Trisenox, Xeloda,
Vinorelbine,
Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225 ,
satriplatin, mylotarg, Avastin, Rituxan, panitubimab, Sutent, sorafinib,
Sprycel
(dastinib), nilotinib, Tykerb (lapatinib) and Campath.
If formulated as a fixed dose, such combination products employ the
5 compounds of this invention within the dosage range described herein and the
other
pharmaceutically active agent or treatment within its dosage range. For
example, the
CDC2 inhibitor olomucine has been found to act synergistically with known
cytotoxic
agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897. Compounds of
Formula I
may also be administered sequentially with known anticancer or cytotoxic
agents
10 when a combination formulation is inappropriate. The invention is not
limited in the
sequence of administration; compounds of Formula I may be administered either
prior
to or after administration of the known anticancer or cytotoxic agent. For
example, the
cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is
affected by the
sequence of administration with anticancer agents. Cancer Research, (1997) 57,
15 3375. Such techniques are within the skills of persons skilled in the art
as well as
attending physicians.
Accordingly, in an aspect, this invention includes combinations comprising an
amount of at least one compound of Formula I, or a pharmaceutically acceptable
salt,
solvate, ester or prodrug thereof, and an amount of one or more anti-cancer
20 treatments and anti-cancer agents listed above wherein the amounts of the
compounds/ treatments result in desired therapeutic effect.
Another aspect of the present invention is a method of inhibiting one or more
Aurora kinases in a patient in need thereof, comprising administering to the
patient a
therapeutically effective amount of at least one compound of Formula 1 or a
25 pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more Aurora kinases in a
patient in
need thereof, comprising administering a therapeutically effective amount of
at least
one compound of Formula 1 or a pharmaceutically acceptable salt, solvate,
ester or
30 prodrug thereof.
Yet another aspect of the present invention is a method of treating one or
more
diseases associated with Aurora kinase, comprising administering to a mammal
in
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
66
need of such treatment an amount of a first compound, which is a compound of
Formula 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug
thereof;
and an amount of at least one second compound, the second compound being an
anti-cancer agent, wherein the amounts of the first compound and the second
compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more Aurora kinases in a
patient in
need thereof, comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising in combination at least one
pharmaceutically
acceptable carrier and at least one compound according to Formula 1, or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the Aurora kinase to be inhibited can be Aurora A,
Aurora B and/or Aurora C.
Another aspect of the present invention is a method of inhibiting one or more
Checkpoint kinases in a patient in need thereof, comprising administering to
the
patient a therapeutically effective amount of at least one compound of formula
1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more Checkpoint kinases in a
patient
in need thereof, comprising administering a therapeutically effective amount
of at least
one compound of formula 1 or a pharmaceutically acceptable salt, solvate,
ester or
prodrug thereof.
Yet another aspect of the present invention is a method of treating one or
more
diseases associated with Checkpoint kinase, comprising administering to a
mammal in need of such treatment an amount of a first compound, which is a
compound of formula 1, or a pharmaceutically acceptable salt, solvate, ester
or
prodrug thereof; and an amount of at least one second compound, the second
compound being an anti-cancer agent, wherein the amounts of the first
compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more Checkpoint kinases in a
patient
in need thereof, comprising administering a therapeutically effective amount
of a
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
67
pharmaceutical composition comprising in combination at least one
pharmaceutically
acceptable carrier and at least one compound according to formula 1, or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be Chkl
and/or Chk2.
Another aspect of the present invention is a method of inhibiting one or more
cyclin dependent kinases in a patient in need thereof, comprising
administering to the
patient a therapeutically effective amount of at least one compound of formula
1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more cyclin dependent kinases
in a
patient in need thereof, comprising administering a therapeutically effective
amount of
at least one compound of formula 1 or a pharmaceutically acceptable salt,
solvate,
ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or
more
diseases associated with cyclin dependent kinase, comprising administering to
a
mammal in need of such treatment an amount of a first compound, which is a
compound of formula 1, or a pharmaceutically acceptable salt, solvate, ester
or
prodrug thereof; and an amount of at least one second compound, the second
compound being an anti-cancer agent, wherein the amounts of the first compound
and
the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more cyclin dependent kinases
in a
patient in need thereof, comprising administering a therapeutically effective
amount of
a pharmaceutical composition comprising in combination at least one
pharmaceutically acceptable carrier and at least one compound according to
formula
1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be CDK1
and/or CDK2.
Another aspect of the present invention is a method of inhibiting one or more
tyrosine kinases in a patient in need thereof, comprising administering to the
patient a
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
68
therapeutically effective amount of at least one compound of Formula 1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or
slowing
the progression of, a disease associated with one or more tyrosine kinases in
a
patient in need thereof, comprising administering a therapeutically effective
amount of
at least one compound of Formula 1 or a pharmaceutically acceptable salt,
solvate,
ester or prodrug thereof.
Another aspect of the present invention is a method of treating one or more
diseases associated with tyrosine kinase, comprising administering to a mammal
in
need of such treatment an amount of a first compound, which is a compound of
Formula 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug
thereof;
and an amount of at least one second compound, the second compound being an
anti-cancer agent, wherein the amounts of the first compound and the second
compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more tyrosine kinases in a
patient in
need thereof, comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising in combination at least one
pharmaceutically
acceptable carrier and at least one compound according to Formula 1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the tyrosine kinase can be VEGFR (VEGF-R2), EGFR,
HER2, SRC, JAK and/or TEK.
Another aspect of the present invention is a method of inhibiting one or more
Pim-1 kinases in a patient in need thereof, comprising administering to the
patient a
therapeutically effective amount of at least one compound of Formula 1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or
slowing
the progression of, a disease associated with one or more Pim-1 kinases in a
patient
in need thereof, comprising administering a therapeutically effective amount
of at least
one compound of Formula 1 or a pharmaceutically acceptable salt, solvate,
ester or
prodrug thereof.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
69
Another aspect of the present invention is a method of treating one or more
diseases associated with Pim-1 kinase, comprising administering to a mammal in
need of such treatment an amount of a first compound, which is a compound of
Formula 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug
thereof;
and an amount of at least one second compound, the second compound being an
anti-cancer agent, wherein the amounts of the first compound and the second
compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing
the
progression of, a disease associated with one or more Pim-1 kinases in a
patient in
need thereof, comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising in combination at least one
pharmaceutically
acceptable carrier and at least one compound according to Formula 1 or a
pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
The pharmacological properties of the compounds of this invention may be
confirmed by a number of pharmacological assays. The exemplified
pharmacological
assays which are described herein below have been carried out with compounds
according to the invention and their salts, solvates, esters or prodrugs.
This invention is also directed to pharmaceutical compositions which comprise
at least one compound of Formula I, or a pharmaceutically acceptable salt,
solvate,
ester or prodrug of said compound and at least one pharmaceutically acceptable
carrier.
For preparing pharmaceutical compositions from the compounds described by
this invention, inert, pharmaceutically acceptable carriers can be either
solid or liquid.
Solid form preparations include powders, tablets, dispersible granules,
capsules,
cachets and suppositories. The powders and tablets may be comprised of from
about
5 to about 95 percent active ingredient. Suitable solid carriers are known in
the art,
e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose.
Tablets,
powders, cachets and capsules can be used as solid dosage forms suitable for
oral
administration. Examples of pharmaceutically acceptable carriers and methods
of
manufacture for various compositions may be found in A. Gennaro (ed.),
Remington's
Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton,
Pennsylvania.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
Liquid form preparations include solutions, suspensions and emulsions. As an
example may be mentioned water or water-propylene glycol solutions for
parenteral
injection or addition of sweeteners and opacifiers for oral solutions,
suspensions and
emulsions. Liquid form preparations may also include solutions for intranasal
5 administration.
Aerosol preparations suitable for inhalation may include solutions and solids
in
powder form, which may be in combination with a pharmaceutically acceptable
carrier,
such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted,
10 shortly before use, to liquid form preparations for either oral or
parenteral
administration. Such liquid forms include solutions, suspensions and
emulsions.
The compounds of the invention may also be deliverable transdermally. The
transdermal compositions can take the form of creams, lotions, aerosols and/or
emulsions and can be included in a transdermal patch of the matrix or
reservoir type
15 as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally or intravenously.
Also contemplated are delivery methods that are combinations of the above-
noted delivery methods, Such methods are typically decided by those skilled in
the art.
20 Preferably, the pharmaceutical preparation is in a unit dosage form. In
such
form, the preparation is subdivided into suitably sized unit doses containing
appropriate quantities of the active component, e.g., an effective amount to
achieve
the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or
25 adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to
about 50
mg, more preferably from about 1 mg to about 25 mg, according to the
particular
application.
The actual dosage employed may be varied depending upon the requirements
of the patient and the severity of the condition being treated. Determination
of the
30 proper dosage regimen for a particular situation is within the skill of the
art. For
convenience, the total daily dosage may be divided and administered in
portions
during the day as required.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
71
The amount and frequency of administration of the compounds of the invention
and/or the pharmaceutically acceptable salts thereof will be regulated
according to the
judgment of the attending clinician considering such factors as age, condition
and size
of the patient as well as severity of the symptoms being treated. A typical
recommended daily dosage regimen for oral administration can range from about
1
mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four
divided doses.
Another aspect of this invention is a kit comprising a therapeutically
effective
amount of at least one compound of Formula I, or a pharmaceutically acceptable
salt,
solvate, ester or prodrug of said compound and a pharmaceutically acceptable
carrier,
vehicle or diluent.
Yet another aspect of this invention is a kit comprising an amount of at least
one compound of Formula I, or a pharmaceutically acceptable salt, solvate,
ester or
prodrug of said compound and an amount of at least one anticancer therapy
and/or
anti-cancer agent listed above, wherein the amounts of the two or more
ingredients
result in desired therapeutic effect.
The invention disclosed herein is exemplified by the following preparations
and
examples which should not be construed to limit the scope of the disclosure.
Alternative mechanistic pathways and analogous structures will be apparent to
those
skilled in the art.
Where NMR data are presented, 1 H spectra were obtained on either a Varian
VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and
are
reported as ppm down field from Me4Si with number of protons, multiplicities,
and
coupling constants in Hertz indicated parenthetically. Where LC/MS data are
presented, analyses was performed using an Applied Biosystems API-100 mass
spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron,
33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min -
95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The retention time and observed
parent ion are given.
The following solvents and reagents may be referred to by their abbreviations
in parenthesis:
Thin layer chromatography: TLC
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
72
dichloromethane: CH2CI2
ethyl acetate: AcOEt or EtOAc
methanol: MeOH
trifluoroacetate: TFA
triethylamine: Et3N or TEA
butoxycarbonyl: n-Boc or Boc
nuclear magnetic resonance spectroscopy: NMR
liquid chromatography mass spectrometry: LCMS
high resolution mass spectrometry: HRMS
milliliters: mL
millimoles: mmol
microliters: l
grams: g
milligrams: mg
room temperature or rt (ambient): about 25 C.
dimethoxyethane: DME
The synthesis of the inventive compounds is illustrated below. Also, it should
be noted
that the disclosure of commonly-owned U.S. 6,919,341 and U.S. Appl. No.
11/598186
is incorporated herein by reference.
EXAMPLE 1
NIS, DMF I
60 C, 95% NBr
Part B N' IN
N^ Br 1.25 equiv NaSMe ~N~ _Br Sl~
N N
7 MeOH, rt, 95% N~
N cat. Pd(PPh3)4, K2C03
Br S~ Part A trimethylboroxine, DMF
100 C, 90% N
N~N
Part C
S~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
73
N NIS, DMF N
(, ~1V N </ _ ~ `1
N 60 C, 95% NN
S~ Part D SNI
SEM
N,N SEM
cat. PdCI2(dppf) I / N,N
K3PO4, boronate 1I /
DME, water N ~CPBA, DCM
100 C, 60-75% N~N rt, 90% N~ N
Part E S~ Part F o S O
I
Part A: Prepared according to US20060106023 (Al).
Part B: To a solution of compound from Example 1, Part A (2.00 g, 8.19 mmol)
in DMF
(50 mL) was added N-iodosuccinimide (1.84 g, 8.19 mmol). The reaction mixture
was
stirred at 60C for 16 hours. The mixture was cooled to 25C and concentrated.
The
residue was dissolved in DCM with a small amount of methanol and then loaded
on.
the column. Purification by column chromatography (Si02, 40% ethyl
acetate/hexanes) afforded compound 4 as a white solid 2.30 g (76%). 'H-NMR
(400-
MHz, DMSO-d6) 6 8.3 (s, 1 H), 7.8 (s, 1 H), 2.6 (s, 3H). HPLC-MS tR = 1.87 Min
(UV
254nm). Mass calculated for formula C7H5BrIN3S 370.01, observed LC/MS m/z
370.9
(M+H).
Part C: A suspension of bromide from Part B (45.6 g), Pd(PPh3)4 (10.8 g),
potassium
carbonate (77.4 g), trimethylboroxine (46.9 g) and potassium carbonate (77.4
g) in
DMF (410 mL) was heated overnight under nitrogen at 105C. After cooling, the
mixture was diluted with ethyl acetate (1 L), washed with brine (2 x 500 mL),
dried
(magnesium sulfate), filtered, concentrated and purified by chromatography on
silica
gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%).
Part D: To a DMF (400 mL) solution of compound from Example 1, Part C (21.8 g)
was added N-iodosuccinimide (26.9 g) and the resulting mixture was heated
overnight
at 60C. The mixture was concentrated and water (400 mL) was added. After
stirring 1
hr at rt, saturated sodium carbonate was added (250 mL) and subsequently
stirred an
additional 30 min at rt. The mixture was filtered, washed with water, methanol
(100
mL) and the filter cake was dried overnight under vacuum. A brown solid was
obtained
(31.4 g, 87%).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
74
Part E: A flask was charged with iodide from Part D (1.00 equiv), Bpin-
compound 5a
(1.3 equiv), PdCI2(dppf) (0.1 equiv) and potassium phosphate monohydrate (3.0
equiv). After purging the flask with argon, 1,4-dioxane (50 mL) and water (5)
were
added and the resulting mixture was heated at 80C ovemight (23 h). The
reaction was
cooled to room temperature. EtOAc was added to the reaction mixture and
filtered
through Celite. After concentration the residue was purified by column
chromatography (silica gel, 25% EtOAc/hexane) to give the title compound.
Part F: To a solution of compound from Example 1, Part E (1.0 equiv) in DCM
(10 mL)
was added m-CPBA (2.05 equiv) in one portion. The resulting mixture was
stirred at
room temperature for 30 min. The mixture was concentrated and then partitioned
between EtOAc and water. The organic layer was washed with NaHCO3 (sat. aq.,
twice), brine and dried (Na2SO4). After concentration, the title compound was
obtained
and used in the next step directly without further purification.
EXAMPLE 2
~S N02 S N02
~
N\ ~ N\
HO2C Me02C
1 2
To a solution of 1' (1.04 g, 5.98 mmol) in 20 mL of DMF, was added K2CO3 (2.48
g,
17.9 mmol) and Mel (1.27 g, 8.96 mmol). The reaction was stirred at room
temperature overnight. It was diluted with 200 mL of 50% EtOAc/hexanes and
washed with water (200 mL) and brine (100 mL). The organic was concentrated.
To
the residue was added 20 mL of hexanes. The solid was collected by filtration
to give
2. The filtrate was concentrated and purified by column eluting with 25%
EtOAc/hexanes to give additional amount of 2. The combined yield of 2 is 1.05
g. 'H
NMR (400 MHz, CDCI3) 6 8.37 (s, 1 H), 4.05 (s, 3H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
EXAMPLE 3
C02Me C02Me
N
~
02N S H2N N
S
2 3
To a solution of 2 (260 mg, 1.38 mmol) in 6 mL of AcOH was added iron powder
(774
5 mg, 13.8 mmol). The reaction mixture was heated at 70-75 C for 12 min. The
mixture was cooled to room temperature and then added 20 mL of MeOH. The
resulting mixture was filtered through celite (the celite was rinsed with
additional
amount MeOH). The filtrate was concentrated to remove most of AcOH. To the
residue was added 15 mL of 20% MeOH/CH2CI2 followed by 20 mL of saturated
10 aqueous NaHCO3. The mixture was stirred until it stops bobbling. The
mixture was
extracted by EtOAc (60 mL x 2), dried over Na2SO4, and then concentrated. To
the
residue was added 5 mL of ether followed by 5 mL of hexanes. The solid was
collected by filtration to give 160 mg of crude 3 which contains a little
acylated amine
but pure enough for the sulfone displacement reaction. The filtrate was
purified by
15 column with 20% of AcOEt/ CH2CI2 to give additional 30 mg of 3. 'H NMR (400
MHz,
CDCI3) 6 6.85 (s, 1 H), 4.61 (brs, 2H), 3.92 (s, 3H).
EXAMPLE 4
SEM
SEM N-N
C02Me N~N \ ~
Br /
~ N + Br , --~ NI`
H2N S~ N1~ NN
N\/'N
3 HN
S02Me COZMe
S-N
4
20 To a solution of compound 3 (89 mg, 0.56 mmol) and 6-bromo-8-
methanesulfonyl-3-
[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1,2-a]pyrazine
(258 mg,
0.55 mmol) in 2 mL of DMF, was added NaH (60% dispersion in oil, 44 mg, 1.1
mmol).
The reaction was stirred at room temperature for 15 min. It was quenched with
5 mL
of saturated aqueous NH4CI and diluted with 30 mL of water. The solid was
collected
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
76
by filtration, washed with water and MeOH. It was dried under vacuum to give
255 mg
of compound 4. 'H NMR (400 MHz, DMSO-d6) b 8.85 (s, 1 H), 8.22 (s, 1 H), 8.15
(s,
1 H), 7.96 (s, 1 H), 7.62 (s, 1 H), 5.50 (s, 2H), 3.85 (s, 3H), 3.60 (t, 2H),
1.83 (t, 2H),
0.00 (s, 9H).
EXAMPLE 5
SEM
SEM SEM N-N
N \'N
/ I \
BrN N Stey
Step A N N
N
N N N N
HN HN
S C02Me S C02Me S-N OH
N N
4 5
Step A: To a solution of 4 (76 mg, 0.14 mmol) in 6 mL of THF was added
Pd(PPh3)4
(16 mg, 0.014 mmol) and 0.35 mL of MeZnCI (2 M solution in THF, 0.69 mmol).
The
reaction was stirred at 80 C for 20 min. It was cooled to room temperature
and
quenched by adding 0.5 mL of MeOH. It was diluted with 30 mL of CH2CI2 and
washed with 20 mL of 0.5 N aqueous HCI solution. The solvent was removed under
vacuum. The residue was purified by flash chromatography eluting with 5%
MeOH/CH2CI2 to give 50 mg of 5-{6-methyl-3-[1-(2-trimethylsilanyl-
ethoxymethyl)-1 H-
pyrazol-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-isothiazole-3-carboxylic acid
methyl
ester contaminated by a small amount of triphenylphosphine oxide.
Step B: The above crude material was dissolved in 5 mL of THF. To the solution
was
added 0.5 mL of LiBHEt3 (1 M solution in THF). The reaction was stirred at
room
temperature for 30 min. It was quenched by adding 5 mL of saturated aqueous
NH4CI
solution. The mixture was extracted by 30 mL of CH2CI2. The organic was
concentrated and purified by flash chromatography eluting with 5% MeOH/CH2CI2
to
give 25 mg of compound 5. NMR (400 MHz, CDCI3) 6 7.90 (s, 1 H), 7.82 (s, 1 H),
7.60
(s, 1 H), 7.48 (s, 1 H), 6.90 (s, 1 H), 5.55 (s, 2H), 4.75 (brs, 2H), 3.65 (t,
2H), 2.50 (s,
3H), 1.00 (t, 2H), 0.00 (s, 9H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
77
EXAMPLE 6
SEM
N`N SEM
N'N
N \ -- N
N\\/'N
NY-1-- N
~HN
S-N OH /
S-N OMs
6
To a solution of compound 5 (200 mg, 0.438 mmol) in 20 mL of THF, was added
triethylamine (0.21 mL, 1.5 mmol) and methanesulfonylchloride (0.10 mL, 1.3
mmol).
5 The reaction was stirred at room temperature for 30 min. It was quenched by
adding 1
mL of MeOH. The solution was diluted by 30 mL of CH2CI2, washed consecutively
with 15 mL of 2 N aqueous HCI, water, and brine. The solvent was removed under
vacuum to give 230 mg of crude compound 6 which was used in further
transformations without further purification.
EXAMPLE 7
SEM SEM SEM
~ N'N N'N
N
N \ I \ I
N Step A N Step B _\
N YN1` N
~ ~ -i N~ N N
N I
HN HN HN
50~~
/ S-N N3 NH2
OMs 3 z
6 7
Step A: Mixture of compound 6 (17 mg, 0.032 mmol) and sodium azide (15 mg,
0.23
mmol) in 1 mL of DMF was heated at 70 C for 3 h. It was cooled to room
temperature
and added 10 mL of water. The resulting solid was collected by filtration and
purified
by flash chromatography eluting with 5% MeOH/CH2CI2 to give 12 mg of (3-
azidomethyl-isothiazol-5-yl)-{6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-
1 H-
pyrazol-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
78
Step B: The above material was dissolved in 3 mL of MeOH. To the solution was
added 15 mg of 10% wt. Pd/C. The mixture was stirred under H2 (1 atm) for 1 h.
It
was filtered through celite. The filtrate was concentrated under vacuum to
give 12 mg
of compound 7. NMR (400 MHz, CDCI3) 6 7.88 (s, 1H), 7.80 (s, 1H), 7.60 (s,
1H),
7.47 (s, 1 H), 6.86 (s, 1 H), 5.55 (s, 2H), 4.00 (brs, 2H), 3.65 (t, 2H), 2.50
(s, 3H), 1.00
(t, 2H), 0.00 (s, 9H).
EXAMPLE 8
SEM H
N'N
N I
N N
N N
Y-1--
HN
NHN
S-N NH
2
S-N NH2
7 8
To a solution of compound 7 (12 mg, 0.026 mmol) in 2 mL of THF heated at 70
C,
was added 0.5 mL of 4 N HCI in dioxane. To the resulting mixture was added
MeOH
until it became homogeneous. The reaction was stirred at 70 C for 1 h and
then
cooled to room temperature. The solid was collected by filtration and washed
with
ether to give 9 mg of compound 8 as its HCI salt form. NMR (400 MHz, CD3OD) 6
8.23 (s, 1 H), 8.20 (s, 2H), 8.03 (s, 1 H), 7.20 (s, 1 H), 4.22 (s, 2H), 2.59
(s, 3H). HPLC-
MS tR = 1.82 min (UV 254nm). Mass calculated for formula C14H14N$S 326.1;
observed
MH+ (LCMS) 327.2 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
79
EXAMPLE 9
SEM SEM H
N-N N, N'N
N
\
N Step N \ Step B' N
N
N_~ N N_ N N
~
~ HN
HN HN
S-N N-
S-N NH2 S-N N-
7 1 9
Step A: To a solution of compound 7 (9 mg, 0.02 mmol) in 1 mL of MeOH/CH2CI2
(1:1), was added formaldehyde (40% wt. in water, 6 mg, 0.2 mmol). It was
stirred at
room temperature for 15 min when NaBH4 (16 mg, 0.4 mmol) was added in two
portions. The mixture was purified by flash chromatography eluting with NH4CI
(aq.)/MeOH/CH2CI2 (1:5:190) to give 5 mg of (3-dimethylaminomethyl-isothiazol-
5-yl)-
{6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1,2-
a]pyrazin-8-yl}-amine.
Step B: The above material was then dissolved in 2 mL of THF. The resulting
solution
was heated at 70 C when 0.5 mL of 4 N HCI in dioxane was added. To the
resulting
mixture was added 1 mL of MeOH. The reaction was stirred at 70 C for 1 h and
then
cooled to room temperature. Most of the solvent was removed under vacuum. To
the
residue was added 5 mL of ether. The solid was collected by filtration and
washed
with ether to give 5 mg of compound 9 as its HCI salt form. NMR (400 MHz,
CD3OD)
6 8.21 (s, 1 H), 8.18 (s, 2H), 8.08 (s, 1 H), 7.30 (s, 1 H), 4.42 (s, 2H),
2.95 (s, 6H), 2.59
(s, 3H). HPLC-MS tR = 2.04 min (UV 254nm). Mass calculated for formula
C16H18N8S
354.1; observed MH+ (LCMS) 355.2 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
EXAMPLE 10
SEM SEM
N-N N- N
\ I \ I
N N
N~N N~N
HN HN
CHO
S-N OH S-N
5 10
To a solution of compound 5 (2.50 g, 5.47 mmol) in 100 mL of THF, was added
0.3
5 mL of water followed by Dess-Martin periodinane (6.96 g, 16.4 mmol). The
reaction
was stirred at room temperature for 30 min. The solid was filtered off. The
filtrate was
diluted with 200 mL of CH2C12, and washed with 100 mL of saturated aqueous
NH4CI
solution. The organic was dried over anhydrous Na2SO4 and then concentrated.
To
the residue was added 30 mL of acetonitrile. The solid was collected by
filtration to
10 give 2.05 g of compound 10. NMR (400 MHz, DMSO-d6) 6 12.38 (s, 1 H), 9.84
(s, 1 H),
8.60 (s, 1 H), 8.11 (s, 1 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 7.55 (s, 1 H),
5.50 (s, 2H), 3.60 (t,
2H), 2.45 (s, 3H), 1.83 (t, 2H), 0.00 (s, 9H).
EXAMPLE 11
SEM SEM H
N- % N N-N N'N
\ I \ I \ ~
Step A Step B
N \ ~ I N - ~Nl~
N \~N N~N N~ 'N
HN CHO HN HN
/
S-N S-N N S-N N
10 11
Step A: A solution of compound 10 (100 mg, 0.220 mmol) and pyrrolidine (156
mg,
2.20 mmol) in 14 mL of CH2CI2 was stirred at room temperature for 20 min. To
the
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
81
solution was added two drops of acetic acid, followed by NaBH4 (67 mg, 1.8
mmol).
The resulting mixture was stirred at room temperature for 5 min when 3 mL of
MeOH
was added. The stirring was continued for additional 20 min. The reaction was
quenched by adding 15 mL of saturated aqueous NaHCO3 solution. After diluted
with
20 mL of CH2CI2, the organic was isolated. The solvent was removed under
vacuum.
The residue was purified by flash chromatography eluting with NH4CI
(aq.)/MeOH/CH2CI2 (1:10:190) to give 98 mg of {6-methyl-3-[1-(2-
trimethylsilanyl-
ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(3-pyrrolidin-1-
ylmethyl-
isothiazol-5-yl)-amine. NMR (400 MHz, CDCI3) 6 7.88 (s, 1 H), 7.81 (s, 1 H),
7.60 (s,
1 H), 7.48 (s, 1 H), 6.96 (s, 1 H), 5.55 (s, 2H), 3.80 (s, 2H), 3.65 (t, 2H),
2.70 (brs, 4H),
2.50 (s, 3H), 1.85 (brs, 4H), 0.96 (t, 2H), 0.00 (s, 9H).
Step B: To a solution of {6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-
pyrazol-4-
yl]-imidazo[1,2-a]pyrazin-8-yl}-(3-pyrrolidin-1-ylmethyl-isothiazol-5-yl)-
amine (98 mg,
0.19 mmol) in 8 mL of THF heated at 70 C, was added 2 mL of 4 N HCI in
dioxane.
To the resulting mixture was added MeOH until it became homogeneous. The
reaction was stirred at 70 C for 1 h and then cooled to room temperature. To
the
mixture was added 3 mL of ether. The solid was collected by filtration and
washed
with ether to give 79 mg of compound 11 as its HCI salt form. NMR (400 MHz,
CD3OD) 6 8.18 (s, 2H), 8.13 (s, 1 H), 8.00 (s, 1 H), 7.22 (s, 1 H), 4.50 (s,
2H), 3.62-3.68
(m, 2H), 3.06-3.15 (m, 2H), 2.58 (s, 3H), 1.95-2.22 (m, 4H). HPLC-MS tR = 2.03
min
(UV 254nm)= Mass calculated for formula C1$H2ON$S 380.2; observed MH+ (LCMS)
381.2 (m/z).
EXAMPLE 12
By essentially the same procedure set forth in Example 11, only replacing
pyrrolidine with other respective aliphatic amines- in step A, compounds shown
in
column 2 of Table 1 were prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
82
SEM SEM H
N-N N-N N'N
Step A Step B
N \ --- I N \ -~ Nl~
N \~N N`\ ~N N~
HN
CHO HN HN
S-N S-N N-R2 S-N N-R2
R~ R,
12
TABLE I
LCMS
HPLC
Example Column 2 MW MH+
MS tR
m/z
H
N'N
\ I
N
12-1 NY-1--- N 382.5 383.2 2.15
HN~
~~ / --~
S-N N--\
H
N-N
I \
N
12-2 NY-1-N 408.5 409.2 2.31
HN~
S-N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
83
H
N'N
N
12-3 NY-,-- N 396.5 229.2 1.49
HN'
r / --~
S-N N~
`-0
H
N'
N
N
12-4 NY-,-- N 394.5 395.2 2.18
HN
S-N N
H
N'N
N
12-5 N 408.5 409.2 2.26
HN~^
~~ /--\
S-N N
H
N'
I N
N
12-6 N~ N 424.5 425.2 1.95
HN\ ^
~/ /
S-N N
OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
84
H
N'N
N
12-7 N~N 408.5 409.2 2.35
HN~ ^
~~ /--\
S-N N
\__/
N,
N
12-8 N~ N 409.5 410.2 1.76
HN~ ^
~~ /~--\
S-N N~
~N
H
N'N
N
12-9 N 424.5 425.2 2.18
HN
S-N N
OMe
H
N'
I N
~N \
12-10 N-)-- N 410.5 411.2 2.04
HN~
S-N aOH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
H
N'
I N
N
12-11 NY-,-- N 412.5 413.2 2.23
HN~
S-N N~
~S
H
N'N
N
12-12 N N 430.5 431.2 2.35
HN~
S-N
b
/N
H
N-N
N
N`\/'N
12-13 HN~ 444.6 445.2 2.40
ih
S-N N
b
H
N'
I N
N
12-14 NY-1--- N 422.5 423.2 2.50
HN~
S-N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
86
H
N'N
\ I
N
12-15 NY-,-- N 448.6 449.2 2.69
HN\ ^
~/ /
S-N N
H
N'N
12-16 N \
IN ; - N 428.5 429.2 2.34
HN~ ^
'(~ /
S-N N
H
N'N
12-17 N
NYl-- N 445.5 446.2 1.76
HN'
r / --~
S-N N
~ \
-N
H
N'
I N
'-e'N
12-18 N~N 442.5 443.2 2.39
HN\
~//
S-N N
b
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
87
H
N'
I N
N
12-19 NY-,-- N 408.5 409.2 2.15
HN\
S-N N
H
N'N
N
12-20 N~N 466.6 467.3 2.23
HN~
S'N N
O~
O
H
N,
I N
N
12-21 NY-1- N 466.6 467.3 2.24
HN~
O
S-N a-o
H
N'N
N'Ilf~ N
12-22 N~N 422.5 423.2 2.41
HN~
~~ /~----~
S-N 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
88
H
N'N
\ I
N
12-23 NY-1--- N 442.5 443.2 3.51
HN~ ^ -
/~
S N N
H
N'N
N
12-24 NY-,-- N 408.5 409.2 2.32
HN
S-N N '
H
N'N
N
12-25 Nj,)'- N 448.5 449.2 2.65
HN~
/~--~
S-N N
N'
I N
~N \
12-26 N) N 424.5 425.2 2.07
HN S-N aj OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
89
H
N'N
N~~
NY'N
12-27 HN 484.6 485.3 2.79
S-N N
H
N'
I N
N
12-28 NY-,-- N 470.6 471.3 2.60
HN\
S-N N
H
N'N
N
12-29 NY-,-- N 428.5 429.2 3.27
HN
S-N to
N- N
I
N
12-30 NY-,-- N 382.17 393.17 1.97
HN\ ^
~/ /
S-N -~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
H
N'N
N \
12-31 N~N 396.18 397.18 2.01
HN~
S N --~
N'N
N \
12-32 N~N 410.20 411.20 2.04
HN~ ^
~~ /~
S-N N-~-
\
H
N'
I N
\
N
12-33 N N 422.20 423.20 2.52
HN\ ^ ~
~S/-N~N
H
N'N
N
12-34 NY~-- N 396.18 397.18 2.25
HN\
S-NN-~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
91
H
N'
I N
NI_
12-35 NN 406.17 407.17 2.24
HN /^
S_NN
H
N-N
12-36 N~N 438.20 439.20 2.36
HN
O
S-N
H
N'N
N
12-37 HN N 442.19 443.19 2.30
Y\lr o
S-N N~
O
H
N'
N
N
12-38 N\~ N 398.16 399.16 2.12
O
HN
S_N~--\N--/'
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
92
EXAMPLE 13
SEM
SEM N%
- N
% N
C02Me `N
N + / --~ ~ \
H2N SN NN
N
3 N HN
S02Me C02Me
S-N
13
By essentially the same procedure set forth in Example 4, only replacing 6-
bromo-8-
methanesulfonyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-
imidazo[1,2-
a]pyrazine with 8-methanesulfonyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-
pyrazol-
4-yl]-imidazo[1,2-a]pyrazine, compound 13 was prepared. NMR (400 MHz, DMSO-d6)
b 8.66 (s, 1 H), 8.22 (d, 1 H), 8.21 (s, 1 H), 8.03 (s, 1 H), 7.82 (d, 1 H),
5.58 (s, 2H), 3.96
(s, 3H), 3.69 (t, 2H), 3.40 (s, 1 H), 0.95 (t, 2H), 0.02 (s, 9H).
EXAMPLE 14
SEM SEM
N- N N~N
\ I \ I
N N
N N NJIL-- N
HTN HN
C02Me
S-N S-N OH
13 14
To a solution of compound 13 (830 mg, 1.76 mmol) in 50 mL of CH2CI2 stirred at
0 C,
was added 7.05 mL of LiBHEt3 (1 M solution in THF). The reaction was stirred
at room
temperature for 10 min. It was quenched by adding saturated aqueous NH4CI
solution. The organic was separated and washed with saturated aqueous NaHCO3
solution. The solvent was removed under vacuum. To the residue was added 10 mL
of MeOH. The solid was collected by filtration to give 530 mg of compound 14.
NMR
(400 MHz, CD3OD) 6 8.38 (s, 1H), 7.98 (s, 1H), 7.97 (d, 2H), 7.78 (s, 1H),
7.69 (d,
2H), 7.15 (s, 1 H), 5.55 (s, 2H), 4.62 (s, 2H), 3.66 (t, 2H), 0.92 (t, 2H),
0.00 (s, 9H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
93
EXAMPLE 15
SEM SEM
`N `N
N \ -~ N
N T\--- N NY-,-- N
HN HN
CHO
/
y /
S-N N OH S-N
14 15
To a solution of compound 14 (258 mg, 0.582 mmol) in 20 mL of THF, was added
0.05 mL of water followed by Dess-Martin periodinane (740 mg, 1.75 mmol). The
reaction was stirred at room temperature for 1.5 h. The solid was filtered
off. The
filtrate was diluted with 100 mL of CH2CI2, and washed with water and brine.
The
solvent was removed under vacuum, the residue was purified by flash
chromatography eluting with 5% of MeOH/CH2CI2 to give 230 mg of compound 15.
EXAMPLE 16
SEM SEM H
N-N N-N N'N
Step A Step B ^
~ \N N r~_ N
NN N N~/1`\N
HN HN H'N
/
f / CHO
S-N S-N N-R2 S-N N-R2
R~ R,
16
By essentially the same procedure set forth in Example 11, compounds shown in
column 2 of Table 2 were prepared by replacing compound 10 with compound 15,
and
15 replacing pyrrolidine with other respective aliphatic amines in step A.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
94
TABLE 2
LCMS
Example Column 2 MW MH+ HPLC
MS tR
m/z
H
N'N
N
16-1 N~N 394.5 395.2 2.02
HN~
S-N 0-
H
N'N
\
~N \
16-2 N~ N 394.5 395.2 2.13
HN~
S-N N
H
N'N
N
~
16-3 N~ N 434.6 435.2 2.50
HN~
S-N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
H
N'N
N
~
16-4 Nl N 428.5 429.2 2.22
HN S-N
H
N'
I N
N
16-5 Nj,'I'-N 408.5 409.2 2.18
HN S-N N
H
N'
( N
N
~
16-6 N~ N 408.5 409.2 2.21
HN S-N
N'
I N
N
16-7 N'~'-N 381.2 382.2 2.55
HN\
S'N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
96
H
N'N
N
16-8 NY-I--N 366.14 367.14 2.43
HN~ ^
~~ /-~
S-N N
0
1) Walsh R.J.A.; Wooldridge, K. R. H. J. Chem. Soc. Perkin Trans. 1972, 1247.
EXAMPLE 17
SEM SEM SEM SEM
N'N N,N N-N N-N
I I I I
N Part A N Part B Part C N
N~ ~)~ \ Y~N \ -~ ~ \
N N1\_N N~N N~N
HN S~N S N S, N S
1~N SEM" I/N SEM" 1 ~N SEM"
CO2CH3 COZCH3 OH p S--O
~ 2 3 4
SEM H
\'N \'N
Pa-~ N Pa
E
YN
NN N I N
"N S H`TN~g
SEM
TL /N N
R r{
O O
5 6
Part A: A solution of ester (2.38 g, 4.91 mmol, 1 equivalent) in DMF (40 mL)
was
treated with NaH (60% dispersion in oil, 1.5 equivalents) for 20 min at rt, at
which
time, the reaction mixture was cooled to -10C and 2-
(trimethylsilyl)ethoxymethyl
chloride ( 0.87 mL, 1 equivalent) added to the reaction mixture. The resulting
solution
was allowed to slowly warm to rt and continued to stir at rt for a further 1
h. LC-MS
analysis indicated the reaction was complete. The reaction was quenched with
methanol (15 mL), diluted with ethyl acetate (300 mL) and washed with sat.
sodium
bicarbonate, water, brine, dried (sodium sulfate) and concentrated.
Purification by
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
97
column chromatography (Si02 40% ethyl acetate / hexanes) afforded the desired
product as a yellow solid 1.2 g (40%). HPLC-MS tR = 2.79 Min (UV 254,m). Mass
calculated for formula C27H41 N7O4SSi2 615.25, observed LC/MS m/z 616.2 (M+H).
Part B: To a solution of compound from Part A (1.2 g, 1.90 mmol, 1 equivalent)
in THF
(100 mL) was added superhydride solution (4 equivalents) at rt. The resulting
solution
was stirred at rt for 30 minutes at which time LC-MS analysis indicated the
reaction
was complete. The reaction was quenched with sat. aq. ammonium chloride and
then
extracted with dichloromethane (x2). The combined organic layers were dried
(sodium
sulfate) and concentrated. Purification by column chromatography (Si02 60 %
ethyl
acetate / hexanes) afforded alcohol as a clear oil (47%). HPLC-MS tR = 2.49
Min (UV
254nm). Mass calculated for formula C26H41 N7O3SSi2 587.25, observed LC/MS m/z
588.3 (M+H).
Part C: A solution of alcohol from Part B (0.52 g, 0.88 mmol, 1 equivalent) in
DCM (15
mL) was treated with triethylamine (1.5 equivalents) for 15 min at OC (ice-
bath), at
which time, methanesulfonyl chloride (1.2 equivalents) was added to the
reaction at
OC. The resulting solution was allowed to slowly warm to rt and continued to
stir at rt
for a further 3h. LC-MS analysis indicated the reaction was complete. The
reaction
mixture was diluted with ethyl acetate (100mL) and washed with water, brine,
dried
(anh. sodium sulfate) and concentrated to afford mesylate as a red/brown oil
0.59 g
(100%) which was used without further purification. HPLC-MS tR = 2.66 Min (UV
254nm). Mass calculated for formula C27H43N7O5S2Si2 665.23, observed LC/MS m/z
666.1 (M+H).
Part D: A solution of the respective alcohol (3 equivalents) in THF (1.5 mL)
was
treated with NaH (60% dispersion in oil, 2 equivalents) for 15 min at rt, at
which time,
mesylate from Part C (40 mg, 0.06 mmol, 1 equivalent) was added to the
reaction
mixture. After stirring at rt for 1 h, LC-MS analysis indicated the reaction
was complete.
The reaction was quenched with sat. aq. ammonium chloride and then extracted
with
ethyl acetate (twice). The combined organic layer was dried (sodium sulfate)
and
concentrated to afford crude ether, which was used without further
purification.
Part E: A solution of compound from Part D in 1,4-dioxane (1 mL) was treated
with 4N
HCI in 1,4-dioxane solution (1 mL) at 60C for 10 min at which time HPLC-MS
indicated that the reaction was complete. The solvent was removed and the
residue
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
98
was purified by Prep-LC. Conversion to a hydrochloric salt afforded compounds
listed
in Table 3.
TABLE 3
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
H
N'N
N
17-1 NY-,-- N 398.2 399.2 2.55
HN\
S-NO-N\_ /
N
\
H
N-I N
~N \
N1-1-- N 438.2 439.3 2.79
17-2
HN` ^
~
~S-N~O-\_N~J
H
N-I N
\
17-3 N~N 426.2 427.3 2.68
HN\
~S-N~O-~-
N
H
N'
I N
N
Y`
17-4 N N I 440.2 441.2 2.75
HN
S_N
N-\
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
99
H
N'N
I
N
17-5 Nyl-- N 424.2 425.2 2.59
HN~
S N~- O
N
N'N
N
NY`N
17-6 HN S, 412.2 413.2 2.54
N
O
HN-N
I
N
NN
17-7 HN S/ N 424.2 425.2 2.61
O
DN
HN-N
N
17-8 N~N 410.1 411.1 1.113
H N 1 S%N 0
~_O
~j
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
100
HN-N
N
N~N 424.1 425.2 1.290
17-9
HN S,
N
HN-N
N
17-10 NN 396.1 397.1 1.103
HN S,
~_N
N 0HN-N
~N \
17-11 N I 438.2 439.1 1.343
H N 1 S%N O
~_O
N
HN-N
~N \
17-12 Nyl N 377.1 378.2 1.94
H N
1 /N
N /-' N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
101
HN-N
N
17-13 N~N 377.1 378.2 2.65
HN S,
N
NJ
HN-N
N
17-14 Ny'N 394.1 395.2 3.96
HN S,
~ /N 0
N
HN-N
. \~
N
17-15 Nyl-:::~ N 409.1 410.8 3.17
HN
/N O
NH
HN-N
N
N~ 'N
17-16 480.2 481.3 3.54
HN S,
~ /N
N
JN
HN
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
102
HN-N
N
17-17 "~" 423.2 424.3 3.15
HN
1 /N O
~NN-
HN-N
N
17-18 H IN s, 438.2 439.1 3.32
/" 0~
N _~/
HN-N
~N \
N~_N
17-19 438.2 439.1 3.32
HN S,
1 /N O
A N
HN-N
N
N~_N
17-20 HN S 452.2 453.3 3.55
1 /N O
N
/ `
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
103
HN-N
N
N~_N
17-21 HN s, 452.2 453.1 3.55
1 /N O
N
H
N-
\ I,
N
N~
17-22 N 405.1 406.2 2.57
HN SE N
N
N i~
0~~~!/
H
a
5~' N
NY
17-23 N I 482.0 483.3 2.98
HN S'
i(Br
No/
0
HN-N
~N \
N~N 410.1 411.1 2.77
17-24
H N 1S,
/N O
N~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
104
H
N- N
~N \
17-25 N11-1-- N 424.1 425.1 3.06
HN
S-N O
O
HN-N
N
N~N 487.1 488.4 3.82
17-26
HN 1 /N S~
N
~-~`,~-CH3
0
HN-N
N
N~ N 451.2 452.2 3.40
17-27
HN S1 /N O
O
N \,JN- \
CH3
HN-N
N
17-28 N~ N 408.2 409.6 3.87
HN ,
1 /N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
105
H
N-N
N
N~
17_29 N 530.3 531.3 3.34
HN S.
, /N
N
0
H
N'
I N
\
N
N\/ '
17-30 N T 418.5 419.2 3.00
HN S
y ~N
N ~
O
H
N'N
N
17-31 N~N 473.1
/ \
HN N _
S-N N
O~O
H
N- N
N
17-32 N Y-,-- N 473.1
HN
/
~
S-N ~
0 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
106
H
a
N
17-33 N ~ N 473.1
HN
/
S-N ~
O O
H
N-N
N
17-34 NY-,-- N 465.2
NH
HN
S-N 2
O O
H
N-
~N \
17-35 N~N 467.1
HN
S- N~
O2~NHAc
O
H
N-
N
17-36 N Y-,-- N 445.1
HN~
~' } N~
S-N N ~
0 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
107
H
N-A'
N
17-37 Nyl-- N 445.1
HN
_
~
S N ~
p\p N
H
N- N
N
17-38 NY-,-- N 445.1
HN ~
S-N ~ \
o 0
H
N-N
NI_
17-39 N Y'' N 445.1
HN
S-N ~
N
O p
H
N-~
\
N
N Y `N
17-40 HN ~ 472.1
S-NhN
O
,O
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
108
H
N-N
~ I
N
"N 457.1
17-41
HN
s "- N-0
O N
H
N-
5:;~' N
"Yl-- N 409.1
17-42
HN~
S-N ON
H
N-
N
"Y-,-- N 451.2
17-43
HN
S N
O N
I
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
109
EXAMPLE 18
SEM SEM SEM SEM
N'N N N- N N- N
i I I I
I/~N Part ' f/^N \ Part B N Pa rt~ I~ N
N'Y _N N)lj--N N - N N YN
HN S, N S N S, N S,
1 ~ N SEM I/N SEM 1 ~N SEM ~~NO /
CO2CH3 OH S~o
COZCH3 O
SEM H
\'N \'N
PaRO' N Part E N NY N NY`N
SEM S HN S
~ /N ~ /N
R R
O O
By essentially the same procedures given in Preparative Example 17, compounds
given in Table 4 can be prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
110
TABLE 4
MS
Example Column 2 Exact m/z HPLC
mass (M+H) MS tR
H
N-N
N
NY-`N
18-1 HN S, N 412.2 413.2 2.36
O
N~
HN-N
N
N~N
18-2 HN S, 426.2 427.1 2.71
N
HN-N
~N
NN
18-3 HN 1 S, 400.1 401.1 2.47
N
S
/ N-
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
111
HN-N
\ I
vl~ N
N111N
18-4 HN S, 416.1 417.1 2.23
1 1N
0=S
/ N-
EXAMPLE 19
I I
H3C\ N~ H3CN
NN N11 _N
SO2CH3 HN
IN
CO2CH3
Example 19 was prepared in similar manner to Example 4. 'H NMR (300 MHz,.
DMSO-d6) 6 12.4 (bs, 1 H), 7.81 (s, 1 H), 7.75 (s, 1 H), 7.59 (s, 1 H), 3.85
(s, 3H), 2.49
(s, 3H).
EXAMPLE 20
I I
H3CN~ H3CN~
N `N --' N
~/ Y `N
HNI N SEM N I N
CO2CH3 CO2CH3
Example 20 was prepared in similar manner to Example 17, Part A. 'H NMR (300
MHz, CDCI3) 6 7.81 (s, 1 H), 7.73 (s, 1 H), 7.63 (s, 1 H), 6.61 (s, 2H), 3.98
(s, 3H), 3.74
(t, J = 8 Hz, 2H), 2.62 (s, 3H), 0.94 (t, J = 8 Hz, 2H), -0.83 (s, 9H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
112
EXAMPLE 21
I I
H3CN~ H3CN~
NY N Nj~N
S E M N N SEM' N I N
CO2CH3 CHO
To a stirring solution of ester (2.40 g, 4.40 mmol) in tetrahydrofuran (96 mL)
at -78 C
was added DIBAL-H (1M in dichloromethane, 11.0 mL, 11.0 mmol) dropwise. The
mixture was stirred at -78 C for 3 hours at which time thin layer
chromatography
(30% ethyl acetate/hexanes) indicated the reaction was complete. The mixture
was
quickly poured into stirring saturated aqueous sodium potassium tartrate and
stirred at
room temperature for 14 hours. The mixture was extracted with ethyl acetate
(2x250
mL), the organic layers were combined, washed with brine (100 mL), dried over
magnesium sulfate, filtered, and concentrated under reduced pressure affording
compound 21 as a yellow solid 2.20 g (97%). 'H NMR (300 MHz, CDCI3) 8 9.99 (s,
1 H), 7.74 (s, 1 H), 7.73 (s, 1 H), 7.65 (s, 1 H), 6.60 (s, 2H), 3.74 (t, J =
8 Hz, 2H), 2.64
(s, 3H), 0.94 (t, J = 8 Hz, 2H), -0.07 (s, 9H).
EXAMPLE 22
I I
H3C\ N~ H3CN~
NI/`N NY _N
SEM' N I N SEM' N I S`N
CHO No
To a stirring solution of aldehyde (1.30 g, 2.52 mmol), piperidine (257 mg,
3.02 mmol),
and acetic acid (150 L, 2.52 mmol) in 1,2-dichloroethane (17 mL) at room
temperature was added sodium triacetoxyborohydride (801 mg, 3.78 mmol) in one
portion. The mixture was stirred at room temperature for 2 hours at which time
thin
layer chromatography (40% ethyl acetate/hexanes) indicated the reaction was
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
113
complete. The reaction was quenched with 1 N sodium hydroxide (25 mL) and
stirred
for 20 minutes. The mixture was extracted with chloroform (3X20 mL), the
organic
layers were combined, dried over sodium sulfate, filtered, and concentrated
under
reduced pressure. Afforded compound 22 as a yellow solid 1.35 g (92%). 'H NMR
(300 MHz, CDCI3) S 7.70 (s, 1 H), 7.59 (s, 1 H), 7.23 (s, 1 H), 6.58 (s, 2 H),
3.72 (t, J = 8
Hz, 2H), 3.62 (s, 2H), 2.58 (s, 3H), 2.47 (m, 4H), 1.58 (m, 6H), 0.93 (t, J =
8 Hz, 2H), -
0.086 (s, 9H).
EXAMPLE 23
I I
H3C ^N~( H3CN~
N\~N NN
SEM N I N SEM N I S`N
/ H3
CHO N
E
Example 23 was prepared in a similar manner to example 22 with the
substitution of
3-methylpiperidine for piperidine. 'H NMR (300 MHz, CDCI3) S 7.70 (s, 1H),
7.59 (s,
1 H), 7.23 (s, 1 H), 6.58 (s, 2H), 3.72 (t, J = 8 Hz, 2H), 3.62 (s, 2H), 2.85
(m, 2H), 2.59
(s, 3H), 1.98 (m, 1 H), 1.65 (m, 6H), 0.93 (t, J 8 Hz, 2H), 0.84 (d, J 6 Hz,
3H), -
0.076 (s, 9H).
EXAMPLE 24
I I
H3CN~ H3C~N~
N~N NN
SEM N N SEM N I N
CHO No
Example 24 was prepared in a similar manner to example 23 with the
substitution of
pyrrolidine for piperidine. 1 H NMR (300 MHz, CDCI3) 6 7.70 (s, 1 H), 7.59 (s,
1 H), 7.23
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
114
(s, 1 H), 6.58 (s, 2H), 3.77 (s, 2H), 3.72 (t, J = 8 Hz, 2H), 2.61 (m, 4H),
2.59 (s, 3H),
1.81 (m, 4H), 0.92 (t, J = 8 Hz, 2H), -0.90 (s, 9H).
EXAMPLE 25
I I
H3C\ N~ H3CN
N N --~ N~ N/
T =2 HCl
SEM- N S` HN
, IN , IN
No No
A solution of iodide from Example 24 (20 mg, 0.035 mmol) in 1,4-dioxane (1 mL)
was
treated with 4N HCI in 1,4-dioxane (1 mL). The mixture was sonicated at room
temperature for 2.5 hours, at which time HPLC indicated the reaction was
complete.
The mixture was concentrated under reduced pressure and the resulting residue
was
purified by prep-HPLC and conversion to the hydrochloride salt afforded
compound 25
as a white solid 15 mg (83%). 'H NMR (300 MHz, CD3OD) S 7.88 (s, 1H), 7.79 (s,
1 H), 7.17 (s, 1 H), 4.51 (s, 2H), 3.71 (m, 2H), 3,22 (m, 2H), 2.57 (s, 3H),
2.07 (m, 4H).
HPLC tR = 4.83 min (UV 254 nm). Mass calculated for formula C15H IN6S 440.03;
observed MH+ (MS) 441.5 (m/z).
EXAMPLE 26
I I
H3C\ ^N H3C` ^N~
N~N/ N`\'/N
~ =HCl
SEMN f HN
/ N C fN H3
E
N N
Example 26 was prepared in a similar manner to example 25. 'H NMR (300 MHz,
CD3OD) S 7.87 (s, 1 H), 7.79 (s, 1 H), 7.22 (s, 1 H), 4.39 (s, 2H), 3.52 (m,
2H), 2.96 (m,
1 H), 2.70 (m, 1 H), 2.57 (s, 3H), 1.90 (m, 4H), 1.21 (m, 1 H), 0.99 (d, J = 6
Hz, 3H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
115
HPLC tR = 5.06 min (UV 25A,m). Mass calculated for C H21IN6S 468.3; observed
MH+
(MS) 469.7 (m/z).
EXAMPLE 27
The compounds shown in column 2 of Table 5 were prepared as follows:
R2
R\ N~ RN3
N\~N N\)
N
~ T = HCl
SEM' N I S`N ~ I S`N
R1 R,
A flask containing the prepared aryl iodide scaffolds (compound from Example
22, 23,
or 24, 1 equivalent), commercially available or readily prepared in 1 to 3
steps
aryl/heteroaryl/alkyl boronic acid/ester/boroxine or aryl/heteroaryl/alkyl
magnesium
bromide or aryl/heteroaryl/alkyl zinc chloride (1.5 - 3 equivalents),
potassium
phosphate or potassium carbonate (2- 3 equivalents) and Pd(PPh3)4 or PdCl2dppf
(0.05 - 0.10 equivalents) was evacuated, backfilled with nitrogen and
repeated. 1,4-
Dioxane or N,N-dimethylformamide or 1,2-dimethoxyethane (1 - 3 mL) was added
and the mixture was stirred at 50 - 130 C until reaction was complete as
judged by
thin layer chromatography (ethyl acetate/hexanes) or HPLC. The mixture was
diluted
with water (3 - 10 mL) and extracted with ethyl acetate (2-3 x 10-30 mL). The
organic
layers were combined, washed with brine (15 - 30 mL), dried over magnesium
sulfate,
filtered, concentrated, and purified by column chromatography (Si02, ethyl
acetate/hexanes). The product obtained was dissolved in 1,4-dioxane (1 mL) and
treated with 4 N HCI in 1,4-dioxane (1 mL) and sonicated at room temperature
for 1-5
hours, at which time HPLC indicated the reaction was complete. The mixture was
concentrated under reduced pressure and the resulting residue was purified by
prep-
HPLC and conversion to the hydrochloride salt afforded compounds 27-1 to 27-7.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
116
TABLE 5
MS
Example Column 2 MW MH+ HPLC
tR
m/z
CH3
N~
H3C\-
T/_ ,\
N~-`N
27-1 HN_, S I328.4 329.1 3.52
N
N' I
H3C ~J
CH3
H3CN
N y~'-N
27-2 ~ S 370.5 371.1 4.34
IN
No
CH3
H3C~N
~ 1 \
N\\ T/ '-N
27-3 HN S 356.4 357.4 3.98
, ~N
No
H3C%
N' N
H3C-T~ N
27-4 N11)'-N 408.5 409.6 4.21
HN
, /N
No
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
117
CH3
H3C\ N~
~/_
NY`N
27-5 HN' s, 356.4 357.4 3.91
~ N CH3
N
CH3
H3C\
_IN
NYI\ `N
27-6 HN 342.4 343.2 3.71
C
~N
ND
N- NH
H3C ~
~
H3C\ N CH3
~
27-7 N N 422.5 423.2 3.87
HN s
I'N
No
EXAMPLE 28
CF3
H3C\ ~N H3C\ N~
NY-' N/ N N =HCl
SEM' N S, HN S,
~ N /N
ON N
0
A mixture of iodide (60 mg, 0.103 mmol), trimethyl(trifluoromethyl)silane (44
mg, 0.308 mmol), copper iodide (73 mg, 0.385 mmol), potassium fluoride (15 mg,
0.257 mmol), and anhydrous DMF (1.0 mL) was degassed with nitrogen then heated
at 80 C in a sealed tube overnight. The mixture was cooled to room
temperature,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
118
diluted with water (30 mL), and extracted with ethyl acetate (100 mL). The
organic
layer was dried over sodium sulfate, filtered, concentrated under reduced
pressure,
and purified by column chromatography (Si02, 90:10:0.25 methylene
chloride/methanol/concentrated ammonium hydroxide). The resulting residue was
dissolved in anhydrous 1,4-dioxane (1mL) and 4 M HCI in dioxane (1 mL) was
added.
The resulting solution was sonicated at room temperature for 2 hours and
concentrated under reduced pressure to dryness. Purification by preparative
HPLC
and conversion to the hydrochloride salt afforded the title compound as an off-
white
solid 3.1 mg (6%). 'H NMR (300 MHz, CD3OD) 6 8.07 (s, 1 H), 7.85 (s, 1 H),
7.24 (s,
1 H), 4.40 (s, 2H), 3.61 (d, J = 12.3 Hz, 2H), 3.07 (t, J= 12.3 Hz, 2H), 2.55
(s, 3H),
1.75-2.03 (m, 5H), 1.56 (m, 1H). HPLC tR = 7.19 min. Mass calculated for
formula
C17H19F3N6S 396.13; observed MH+ 397.2 (m/z).
EXAMPLE 29
I C1
H3CIN N\ H3CN\ /
N 1 N NN =HCl
SEM' N S~ HN S,
~ N N
O 0
A mixture of iodide (100 mg, 0.171 mmol) in anhydrous THF (2.0 mL) was
cooled to -78 C and n-butyl lithium (2.5 M solution in hexanes, 89 pL, 0.222
mmol)
was added dropwise. After stirring for 15 minutes a solution of
hexachloroethane (45
mg, 0.188 mmol) in THF (1.0 mL) was added dropwise. After stirring the
reaction at -
78 C for 30 minutes the solution was quenched with a saturated aqueous
solution of
ammonium chloride (3.0 mL) and warmed to room temperature. The reaction was
concentrated under reduced pressure, extracted with ethyl acetate (50 mL) and
the
organic layer dried over sodium sulfate, filtered, concentrated under reduced
pressure, and purified by column chromatography (Si02, 90:10:0.25 methylene
chloride/methanol/concentrated ammonium hydroxide). The resulting residue was
dissolved in anhydrous 1,4-dioxane (1mL) and 4 M HCI in dioxane (1 mL) was
added.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
119
The resulting solution was sonicated at room temperature for 2 hours and
concentrated under reduced pressure to dryness. Purification by preparative
HPLC
and conversion to the hydrochloride salt afforded the title compound as an off-
white
solid 30 mg (40%). ' H NMR (300 MHz, CD3OD) 6 7.80 (s, 1 H), 7.73 (s, 1H),
7.22 (s,
1H), 4.39 (s, 2H), 3.59 (d, J = 12.3 Hz, 2H), 3.08 (t, J= 12.3 Hz, 2H), 2.55
(s, 3H),
1.75-2.03 (m, 5H), 1.56 (m, 1 H). HPLC tR = 4.79 min. Mass calculated for
formula
C16H19CIN6S 362.11; observed MH+ 363.7 (m/z).
EXAMPLE 30
I C1
H3C\ N~ H3C\ ~N~
N/ N1~ N =HCl
SEM.N S, HN S~
~ N ~ N
N N
CH3 CH3
Example 30 was prepared in a similar manner as Example 29. 'H NMR (300 MHz,
CD3OD) b 7.77 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 4.39 (s, 2H), 3.47-3.67 (m,
2H),
2.97 (m, 1 H), 2.71 (m, 1 H), 2.55 (s, 3H), 1.77-2.01 (m, 4H), 1.20 (m, 1 H),
1.00 (d, J=
6.4 Hz, 3H). HPLC tR = 4.98 min. Mass calculated for formula C17H21CIN6S
376.12;
observed MH+ 377.6 (m/z).
EXAMPLE 31
I Br
H3CIN N\ / H3C~N\ /
N N NN =HCl
SEM' N S, HN S~
N
~ 1 N 1,
ON N
0
Example 31 was prepared in a similar manner to compound 29 with the
substitution of
tetrachlorodibromoethane for hexachloroethane. 'H NMR (300 MHz, CD3OD) 6 7.84
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
120
(s, 1 H), 7.83 (s, 1 H), 7.25 (s, 1 H), 4.41 (s, 2H), 3.61 (d, J = 12.3 Hz,
2H), 3.08 (t, J=
12.3 Hz, 2H), 2.57 (s 3H), 1.77-2.03 (m, 5H), 1.55 (m, 1 H). HPLC tR = 5.19
min.
Mass calculated for formula C16H19BrNsS 406.06; observed MH+ 407.4 (m/z).
EXAMPLE 32
F
/
N `T` /NHZ N `T\/N \ I
B I N , B ~N 0
O O
To a solution of aminopyrimidine (100 mg, 0.452 mmol) in anhydrous pyridine
(2.0
mL) was added 3-fluorobenzoyl chloride (72 mg, 0.452 mmol). After stirring at
room
temperature overnight, the reaction was concentrated under reduced pressure,
diluted
with water (30 mL), and extracted with methylene chloride (100 mL). The
organic
layer was dried over sodium sulfate, filtered and concentrated to afford the
title
compound as an off-white solid 124 mg (80%). 'H NMR (300 MHz, CDCI3) 6 8.95
(s,
2H), 8.72 (s, 1 H), 7.66-7.72 (m, 2H), 7.49 (m, 2H), 1.36 (s, 12H).
EXAMPLE 33
/ F
H
N NH2 N N \ I F
BY BY
O, ,N G N 0
i i
O O
Prepared in a similar manner as compound 31 affording the title compound as an
off-
white solid 131 mg (80%). 'H NMR (300 MHz, CDCI3) 6 8.93 (s, 2H), 8.65 (s,
1H),
7.83 (m, 1 H), 7.69 (m, 1 H), 7.30 (m, 1 H), 1.34 (s, 12H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
121
EXAMPLE 34
-N
H3C\ N H3C` N H3C\ N
N~ N~ N=HCl + N~ =HCl
SEM- N ~ S, ~, IN
~ ~N I ~N
a a a
A mixture of iodide (60 mg, 0.103 mmol), tri-n-butyl(pyridyl)tin (57 mg, 0.154
mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane
adduct (8
mg, 0.0103 mmol), and potassium fluoride (18 mg, 0.309 mmol) in anhydrous 1,4-
dioxane (1.0 mL) was degassed with nitrogen then heated at 85 C in a sealed
tube
overnight. The mixture was cooled to room temperature, diluted with water (30
mL),
and extracted with ethyl acetate (2 x 100 mL). The organic layer was then
separated,
dried over sodium sulfate, filtered, concentrated under reduced pressure to
residue,
and purified by column chromatography (Si02, 90:10:0.25 methylene
chloride/methanol/ concentrated ammonium hydroxide). The resulting residue was
then dissolved in anhydrous 1,4-dioxane (1mL) and 4 M HCI in dioxane (1 mL)
was
added. The resulting solution was sonicated at room temperature for 2 hours
and
then concentrated under reduced pressure to dryness. Purification by
preparative
HPLC and conversion to the hydrochloride salt afforded de-halogenated product
3.2
mg (10%) as an off-white solid: 'H NMR (300 MHz, CD3OD) 6 8.23 (s, 1H), 8.13
(s,
2H), 7.29 (s, 1 H), 4.55 (s, 2H), 3.72 (br s, 2H), 3.29 (m, 2H), 2.61 (s, 3H),
2.05-2.18
(m, 4H). HPLC tR =3.49 min. Mass calculated for formula C15H16N6S 314.13;
observed MH+ 315.2 (m/z).
Also afforded coupling product 5.0 mg (10%) as an off-white solid: 'H NMR (300
MHz, CD3OD) 6 8.95 (s, 1 H), 8.86 (d, J = 5.1 Hz, 1 H), 8.50 (s, 1 H), 8.28
(t, J = 7.5 Hz,
1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 6.3 Hz, 1 H), 7.26 (s, 1 H),
4.54 (s, 2H), 3.74
(m, 2H), 3.29 (m, 2H), 1.99-2.30 (m, 4H). HPLC tR =4.80 min. Mass calculated
for
formula C20H21N7S 391.16; observed MH+ 392.5 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
122
EXAMPLE 35
H3C\ ^N \ N
H3C
N y ~
N~ ~N N =HCl
HN
SSEM N I N f IN
CO2CH3 CO2CH3
Sodium borohydride (3 mg, 0.073 mmol) was added to a room temperature
suspension of iodide (15 mg, 0.037) in methanol (1 mL). The reaction was
allowed to
stir for 30 minutes then quenched with water (20 mL). The mixture was diluted
with
diethyl ether (20 mL) and the phases were allowed to separate. The organic
layer
was dried (sodium sulfate), filtered and concentrated to afford a protected de-
halogenated intermediate. The reduced product (7 mg, 0.017 mmol) was subjected
to
the acidic conditions outlined previously to afford the title compound as a
yellow solid
2 mg (17%). 1 H NMR (300 MHz, CD3OD) 6 7.94 (s, 1 H), 7.90 (s, 1 H), 7.74 (s,
1 H),
7.55 (s, 1 H), 3.94 (s, 3H), 2.50 (s, 3H). HPLC tR = 4.67 min (UV 254nm)= Mass
calculated for formula C12HI1N502S 289.06; observed MH- (ESI MS) 288.0 (m/z).
EXAMPLE 36
I I
H3CN g3C_ ^N~
NN N
7 --~ =HCl
SEM N HN
, /N f IN
No No
Example 36 was prepared in a similar manner to Example 31. 'H NMR (300 MHz,
CD3OD) 6 7.72 (s, 1 H), 7.69 (s, 1 H), 7.15 (s, 1 H), 4.38 (s, 2H), 3.69-3.52
(m, 2H),
3.17-2.96 (m, 2H), 2.54 (s, 3H), 2.06-1.70 (m, 5H), 1.65-1.44 (m, 1 H). HPLC
tR = 5.00
min (UV 254nm). Mass calculated for formula C16H191N6S 454.04; observed MH+
(ESI
MS) 455.0 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
123
EXAMPLE 37
I CN
H3C\ N H3C\ ^N~(
N~N/ --~ NN
=HCl
SEMN ' HN
~ /N ~ IN
No N_ )
Pd2(dba)3 (5 mg, 0.005 mmol) was added to a room temperature solution of
DPPF (6 mg, 0.103 mmol) in N,N'-dimethylformamide (1 mL) and stirred for 10
minutes. The mixture was then added to a solution of iodide (60 mg, 0.103
mmol),
Zn(CN)2 (12 mg, 0.103 mmol) in N,N'dimethylformamide (4 mL). The reaction was
heated to 150 C in the microwave for 30 minutes, cooled to room temperature
then.
concentrated to dryness. Purification of the resultant residue by flash
chromatography.
(Si02; 12 g; 10% methanol in methylene chloride) afforded impure nitrile as a
yellow
solid. The impure nitrile (22 mg, 0.045 mmol) was dissolved in 2 N HCI (4 mL)
without
further purification. The resultant solution was sonicated at 45 C for 2
hours. Upon
completion, the reaction was concentrated to dryness. Purification of the
resultant
residue by prep-HPLC afforded the title compound as a white solid 8 mg (18%).
'H
NMR (300 MHz, CD3OD) b 8.22 (s, 1 H), 7.93 (s, 1 H), 7.22 (s, 1 H), 4.40 (s,
2H), 3.73-
3.52 (m, 2H), 3.20-2.97 (m, 2H), 2.55 (s, 3H), 2.06-1.71 (m, 5H), 1.66-1.42
(m, 1 H).
HPLC tR = 4.50 min (UV 254nm). Mass calculated for formula C17H19N7S 353.14;
observed MH+ (ESI MS) 354.3 (m/z).
EXAMPLE 38
SCH3
H3C\T5^N~ H3C ^ N \
N) Y`,~
N --- N~N
1 =HCl
SEM'N S. HN S~
( N , IN
No N
o
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
124
A mixture of iodide (70 mg, 0.12 mmol), Pd(dppf)C12 (9 mg, 0.012 mmol),
sodium tert-butoxide (35 mg, 0.36 mmol) and sodium thiomethoxide (17 mg, 0.24
mmol) was flushed with nitrogen then dissolved into 1,4-dioxane (5 mL). The
solution
was heated to 95 C in the microwave for 90 minutes. The reaction was cooled
to
room temperature, diluted with ethyl acetate (100 mL), and filtered through
celite. The
organic layer was washed with water (50 mL) and brine (50 mL) then dried
(sodium
sulfate), filtered and concentrated to dryness. Purification of the resultant
residue by
prep-HPLC afforded the protected thiomethylether. The thiomethylether (35 mg,
0.07
mmol) was subjected to the reaction conditions outlined in example 110 to
afford the
title compound as a white solid 6 mg (11%). 'H NMR (300 MHz, CD3OD) 6 8.28 (s,
1 H), 8.25 (s, 1H), 7.34 (s, 1H), 4.43 (s, 2H), 3.68-3.52 (m, 2H), 3.18-2.98
(m, 2H),
2.67 (s, 3H), 2.49 (s, 3H), 2.05-1.71 (m, 5H), 1.65-1.44 (m, 1 H). HPLC tR =
4.74 min
(UV 254nm). Mass calculated for formula C17H22N6S2 374.13; observed MH+ (ESI
MS)
375.3 (m/z).
EXAMPLE 39
SEt
H3C\ N \\ H3C ^ N \
N/~
N
=HCl
SEMN S. HN1S"~ ~N No N
~
A combined mixture of iodide (70 mg, 0.12 mmol), sodium thioethoxide (20 mg,
0.24 mmol), Pd(dppf)C12 (9 mg, 0.012 mmol) and sodium tert-butoxide (35 mg,
0.36
mmol) was flushed with nitrogen gas then dissolved into 1,4-dioxane (5 mL).
The
reaction was heated to 95 C and stirred for 72 hours. The reaction was then
cooled
to room temperature, diluted with ethyl acetate (100 ml), and filtered through
celite.
The filtrate was washed with water (50 mL) and brine (50 mL) then dried
(sodium
sulfate), filtered and concentrated to dryness. Purification of the resultant
residue by
flash chromatography (Si02; 12 g; 0% to 10% methanol in methylene chloride)
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
125
afforded a thioethylether intermediate as a yellow solid. The thioethylether
(10 mg,
0.019 mmol) was subjected to the reaction conditions outlined in example 110
to
afford the title compound as a white solid 2 mg (4%). 'H NMR (300 MHz, CD3OD)
6
8.32 (s, 1 H), 8.28 (s, 1 H), 7.35 (s, 1 H), 4.43 (s, 2H), 3.68-3.55 (m, 2H),
3.17-3.01 (m,
2H), 2.90 (q, J = 7.3 Hz, 2H), 2.67 (s, 3H), 2.07-1.71 (m, 5H), 1.65-1.42 (m,
1 H), 1.28
(t, J = 7.3 Hz, 3H). HPLC tR = 5.27 min (UV 254nm). Mass calculated for
formula
C18H24N6S2 388.15; observed MH+ (ESI MS) 389.7 (m/z).
EXAMPLE 40
0 DPPA / Et3N O~y N S Part B N Na104 / OSOq
HO ~ i S t-BuOH / 80 C OI -j ~B~ ~Sn t Bu ~ ~S Dioxane: H20 (3;1)
Br `N O N~ 2,6rLutidine / rt
N Part A 1,4dioxane/
Pd(0) Part C
H RR1-NH / NaBH(OAc)3 / R
O~N S H CH3COOH (cat.)DCM / O H RI ~ TMSI / DCM H N ~
\ O ~N O NaBH4 O N~SN R 20 min 2S~N-R
X\ ~ ~ i Part D N Part E N
H
N'N
NaH/DMSO I
H N
0
N'N N\ ~N ~~ I
\ T
HN 6 N
N_ IN
Y ~N
1 O 0=S=0
Part A: To a stirred solution of 2-Bromo-thiazole-5-carboxylic acid (2.0 g,
9.615 mmol)
in t-Butanol (30 mL) and triethyl amine (1.5 mL, 10.57 mmol) was added
diphenylphosphoryl azide (2.9 g, 10.57 mmol) and reaction mixture was heated
to 80
C and stirred for 12 hrs, LCMS showed the complete disappearance of the
starting
material. Reaction mixture was cooled to room temp., solvent removed under
vacuum,
water (100 mL) added and extracted with ethyl acetate (3 x 100 mL). Organic
layer
was washed with water, brine, dried over sodium sulfate and concentrated,
crude
material was passed through small pad of silica gel and resultant (2-Bromo-
thiazol-5-
yl)-carbamic acid tert-butyl ester (solid) was used as such in the next step,
yield 2.5 g
(90%). 'H NMR (400 MHz, DMSO-d6 6 7.10 (s, 1 H), 7.05 (s, 1 H), 1.51 (s,
9H).Mass
calculated for formula C8H11 BrN2O2S 277.97; observed MH+ (LCMS) 279.0 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
126
Part B: To a stirred solution of (2-Bromo-thiazol-5-yl)-carbamic acid tert-
butyl ester
(2.5 g, 8.9928 mmol) in 1,4-dioxane (20.0 mL) were added tributy(vinyl)tin
(2.9 mL,
9.892 mmol), 2,6-di-tert-butyl-4-methylphenol (cat. amt) and
tetrakis(triphenyl
phosphine) palladium(0) (506.0 mg, 0.4496 mmol). The reaction mixture was
heated
to 100 C and stirred for 12 hrs, LCMS showed the complete disappearance of
the
starting material. Reaction mixture was cooled to room temp, filtered and
solid washed
with ethyl acetate, combined filtrate (organic solvent) was removed under
vacuum,
crude material was purified using biotage HPLC using hexane / ethyl acetate
gradient
0.0 to 100 % to yield (2-Vinyl-thiazol-5-yl)-carbamic acid tert-butyl ester
(solid) 1.1 g
(54%). 1 H NMR (400 MHz, CDCI3 b 7.27 (d, J = 12.7 Hz,2H), 7.19 (brs, 1 H),
6.84-6.77
(m, 1H), 6.87 (d, J = 17.0 Hz, 1H), 5.43 (d, J = 10.5 Hz,1 H), 1.52 (s, 9H).
Mass
calculated for formula CjoH14N202S 226.08; observed MH+ (LCMS) 227.1 (m/z).
Part C: To a stirred solution of (2-Vinyl-thiazol-5-yl)-carbamic acid tert-
butyl ester (0.76
g, 2.857 mmol) in 1,4-dioxane : water (30 : 9 mL), were added sodium periodate
(2.5
g, 11.43 mmol) osmium tetroxide (2.5% solution in 2-propanol) (0.5 mL) and 2,6-
lutidine (0.663 mL, 5.714 mmol) and reaction mixture was stirred for 4 hrs,
LCMS
showed the almost disappearance of the starting material. Reaction mixture was
diluted with water (100 mL) and extracted with ethyl acetate, organic layer
was
washed with water, brine, dried over sodium sulfate and concentrated under
high
vacuum to yield aidehyde 710 mg (92%). Crude product was used as such in the
next
reaction. 1 H NMR (400 MHz, DMSO-d6 6 11.45 (s, 1 H), 9.76 (s, 1 H), 7.58 (s,
1 H),
1.40 (s, 9H). Mass calculated for formula C9H12N203S 228.06; observed MH+
(LCMS)
229.1 (m/z).
Part D: To a stirred solution of (2-Formyl-thiazol-5-yl)-carbamic acid tert-
butyl ester
(0.76 g, 2.857 mmol) in 1,2-dichloroethane(10 mL) were added Morpholine (250
mg,
1.1135 mmol) triacetoxysodium borohydride (472 mg, 2.227 mmol) and Cat amount
acetic acid (three drops) and stirred for two hrs at room temp. To the
reaction mixture
was added sodium borohydride (126 mg, 3.3405 mmol) and stirred for one hrs.
LCMS
showed the disappearance of the starting material. Reaction mixture was
diluted with
water (100 mL) and extracted with dichloromethane, organic layer was washed
with
water, brine, dried over sodium sulfate and concentrated under high vacuum to
yield
(2-Morpholin-4-ylmethyl-thiazol-5-yl)-carbamic acid tert-butyl ester 298 mg
(91 %).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
127
Crude product was used as such in the next reaction. Mass calculated for
formula
C14H25N303S 315.43; observed MH+ (LCMS) 300.3 (m/z).
Part E: To a stirred solution of (2-Morpholin-4-ylmethyl-thiazol-5-yl)-
carbamic acid tert-
butyl ester (80.0 mg, 0.268 mmol) in dichloromethane(5 mL) was added
iodotirmethylsilane ( 44 pL, 0.321 mmol) and stirred for 10 min. LCMS showed
the
disappearance of the starting material. Reaction mixture was diluted with
water (10
mL), 1 N aqueous NaOH solution (5 mL) and extracted with 10% 2-propanol in DCM
(3
x 25 mL) and organic layer dried over sodium sulfate and concentrated under
high
vacuum to yield 2-Morpholin-4-ylmethyl-thiazol-5-ylamine 30.0 mg (56%). Crude
product was used as such in the next reaction. Mass calculated for formula
C8H13N3OS 199.27; observed MH+ (LCMS) 200.1 (m/z).
Part F: To a stirred solution of 2-Morpholin-4-ylmethyl-thiazol-5-ylamine
(30.0 mg,
0.151 mmol) in DMSO (2.5 mL) was added 8-Methanesulfonyl-6-methyl-3-(1 H-
pyrazol-4-yl)-imidazo[1,2-a]pyrazine ( 25.0 mg, 0.09045 mmol) followed by NaH
60%
in mineral oil (48 mg, 1.206 mmol) and stirred for 30 min. LCMS showed the
disappearance of the starting material. Reaction mixture was quenched 1:1
mixture of
acetonitriie and saturated ammonium chloride (10 mL), and extracted with 10% 2-
propanol in DCM (3 x 25 mL) and organic layer was concentrated under high
vacuum
to yield crude [6-Methyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-
morpholin-
4-ylmethyl-thiazol-5-yl)-amine which was subsequently purified by Agilent
reverse
phase HPLC using formic acid method to yield 10 mg (28%). HPLC-MS (10 min
method) tR = 2.06 min (UV 254nm). Mass calculated for formula C18H2ON8OS
396.47;
observed MH+ (LCMS) 397.5 (m/z).
The compounds shown in Table 6 were prepared using procedures described
in Example 40.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
128
TABLE 6
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
H
\ N,N
I
N
N~N 396.47 397.5 2.06
40-1 ^ 'NH
S
0
H
N.N
40-2 NY'L'N 394.50 395.5 2.38
/^~,-NH
N\ '
S
CN
H
N-N
380.47 381.5 2.25
40-3 "~ N
HN
'*I Q-J
g H
N'
I N
408.52 409.2 2.56
40-4 "y)--N ~
HN N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
129
H
N'
~ N
" ~N 409.51 410.3 2.14
40-5 "N J
HN S N
c"
N
H
N-N
I
" 422.55 423.5 2.74
40-6 "N
~N~NH
H
N'N
Nl--'--N
422.55 423.3 2.75
40-7 N~N S v NH
~
HN-N
N N
"` ~N 449.58 450.3 1.85
40-8 ~(
N s NH
4\ 1
N
H
N-~ N
`~" 382.49 383.2 2.28
40-9 NY `N
/-N\-/ S NH
\~ D, -
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
130
H
N'N
HN
435.55 436.44 1.78
40-10 NY N
N g NH
\-~ J
N
H
N' N
^ I
LN>
~" 463.60 464.27 1.90
40-11 ~ "~N
N NH
N
H
N' N
I
-" 411.53 412.25 1.76
40-12 NY N
~NL< g NH
~
N
H
N-N
40-13 ~N 422.55 423.28 2.74
"~ $ NH
\\ ~
N
EXAMPLE 41
O 0
HO -11/ ~ --, H3CO ~ ~
S N02 S N02
To a solution of 5-nitrothiophene-3-carboxylic acid (5.00 g, 28.88 mmol) in
dimethylformamide (40 mL) was added potassium carbonate (11.98 g, 86.71 mmol)
and iodomethane (2.70 mL, 43.37 mmol). The reaction mixture was stirred at RT
for
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
131
16 hr. After the starting material had been consumed, the reaction was diluted
with
50% ethyl acetate/hexanes (350 mL) and extracted with H20 (350 mL). The
organic
layer was washed with brine (150 mL) and concentrated. Hexanes (50 mL) was
added to the solid and concentrated again to yield 5.456 g (99%) of product.
'H NMR
(400 MHz) CDCI3 6 8.30 (s, 1 H), 8.25 (s, 1 H), 3.93 (s, 3H). Mass calculated
for
formula C6H5NO4S 187.17; observed M4H+ (MS) 191.15 (m/z)
EXAMPLE 42
O O
H3CO ~ ~ H3CO ~ ~
g N02 g NHZ
To a solution of the nitro-ester (1.006 g, 5.375 mmol) in TFA (15 mL), Fe
powder (1.5135 g, 27.10 mmol) was slowly added to the round bottom flask. The
reaction was heated to 60 C for 45 min at which time TLC (1:1, ethyl acetate
to
hexanes) showed consumption of starting material. The reaction was diluted
with
ethyl acetate and the Fe was filtered off. The filtrate was neutralized with
aqueous
Na2CO3 and allowed to stir for 1 hr. The aqueous layer was extracted with
EtOAc.
The organic layer was washed with brine, dried over Na2SO4, and concentrated
to
give 0.701 g (83%) of a yellow solid. 'H NMR (400 MHz) CD3OD 6 7.29 (s, 1 H),
6.44
(s, 1 H), 3.79 (s, 3H). Mass calculated for formula C6H7NO2S 157.19; observed
MH+
(LCMS) 158.1 (m/z).
EXAMPLE 43
NE N NEM
O N
\ I
H3C OCH3
N + HgC\ ^N
N\" ~~N H2N S ~N/\
~
0=S=0 NH
H3C H3CO2C
Cys
A solution of the sulfone (1.27 g, 3.11 mmol) and 2-aminothiophene-4-
carboxylate methyl ester (0.701 g, 4.46 mmol) in DMF (35 mL) were treated with
NaH
(60% dispersion in oil, 0.402 g, 10.05 mmol) at room temperature until mass
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
132
spectrometry and thin layer chromatography (50% ethyl acetate/hexanes)
indicated
that the reaction was complete. Saturated ammonium chloride (15 mL) and water
(50
mL) were added to the reaction. The reaction was stirred for 10 minutes. The
precipitated solid was collected via filtration to yield the desired product.
'H NMR (400
MHz) CDCI3 b 8.78 (s, 1 H), 7.88 (s, 1 H), 7.82 (s, 3H), 7.68 (s, 1 H), 7.58
(s, 1 H), 7.44
(s, 1 H), 7.16 (s, 3H), 5.54 (s, 2H), 3.87 (s, 3H), 3.67 (t, 2H), 2.46 (s,
3H), 0.97 (t, 2H),
0.01 (s, 9H). Mass calculated for formula C22H28N6O3SSi 484.65; observed MH+
(MS)
485.1 (m/z).
EXAMPLE 44
SEM SEM
N- N N- N
\ I \ I
H3C N H3~ N
N\~N N\~N
NH TNH
H3CO2C H02C Cy
S S
A solution of the ester prepared in Example 43 (0.565 g, 1.17 mmol) in THF (10
mL) and MeOH (3 mL) was treated with solid NaOH (9 pellets) followed by H20 (5
mL). The reaction was stirred vigorously at room temperature for 16 hr. The
THF and
MeOH were removed in vacuo and the residue was extracted with EtOAc (3 x 20
mL).
The aqueous phase was brought to a pH of 3-4 with aqueous HCI. The acidified
aqueous phase was extracted with EtOAc (5 x 20 mL) and concentrated in vacuo
to
give 0.393 g(71 %) of the desired carboxylic acid.
EXAMPLE 45
SEM SEM
N,N N-N
\ I \ I
Hs~N HsC~ N
NYI-- N N),)'-N
~ NH HN O
HOZC--
L S. S HN-O
A solution of the carboxylic acid (prepared in Example 4) (0.054 g, 0.115
mmol)
in DMF (3 mL) was treated with amine (0.03 mL, 0.262 mmol), NMM (0.07 mL,
0.637
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
133
mmol) and then HATU (0.141 g, 0.372 mmol). The reaction was stirred at room
temperature for 16 hr. Water (15 mL) was added and the reaction was stirred
for 10
minutes. The precipitated solid was collected via filtration to yield 0.038 g
(60%) of the
desired amide. 'H NMR (400 MHz) CDCI3 6 9.13 (s, 1H), 7.86 (s, 1H), 7.80 (s,
3H),
7.54 (s, 1 H), 7.41 (s, 1 H), 7.31 (s, 1 H), 7.08 (s, 3H), 5.83 (d, 1 H), 5.53
(s, 2H), 3.93
(m, 1H), 3.67 (t, 2H), 2.44 (s, 3H), 1.70 (m, 10H), 0.96 (t, 2H), 0.00 (s,
9H). Mass
calculated for formula C27H37N7O2SSi 551.78; observed MH+ (MS) 552.1 (m/z).
By essentially the same procedure set forth in Example 45, only substituting
the
amines shown in Column 2 of Table 7, the compounds in Column 3 were prepared:
TABLE 7
MH+ LCMS
Example Column 2 Column 3 MW m/z MS tR
SEM
N-N
\I
N H3C~N \
45-1 N~)--N 523.7 524.1
HN 0
S ~ N
SEM
N-N
N H3C~ N
45-2 CJ NN 539.7 540.2
HN O
S I/ No
0
SEM
N-I N
N H3~ N
45-3 ( ) NYI-- N 552.8 553.3
N HN S
I TL ~
O ~~N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
134
SEM
N
H3~N
45-4 H N~ 497.7 498.3 4.16
N
~N~
HN S
~ /
N
O
N.
I N
H2N Hs~N
I'
45-5 N 537.8 538.1
HN S
NH
O ~
SEM
N, N
H ~~OH H3~N ~
45-6 2N N~N 513.7 514.3
HN S
H
N~~OH
0
N.
~ I N
HgC N
_`~
45-7 ~~OMe N7 N 527.7 528.2
HzN HN S
O~
NH
~
OMe
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
135
SEM
I
H3 C-~N
H N~N~ Ni-)- N
45-8 2 ~ S 540.8 541.2
I/
NH
O ~
/ N-
SEM
N,N
H3C-~-N \
45-9 NH N."~N 497.7 498.1
2 ~
HN S
N,_,,-
O
SEM
N- N
H3 N
45-10 H2N N. ~N 511.7 512.1
HN ~V S
0 SEM
N, N H3 N
45-11 N~ N\~N 525.7 526.1
H HN ~V S
~
N~
0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
136
SEM
N- I N
H3~N~
NN
45-12 HN 541.7 542.2
NH
O ---\
\
SEM
N-~ N
H3C~
i~ N
\
45-13 NN HS 554.8 555.3
Oi
N
~
N-
/
SEM
N-N
OH FbCT~~- N \
45-14 N~N 553.8 554.2
HN S
N
0 OH
H N
SEM
I N
OH H3 ~N
45-15 HN N1-1- N 557.7 558.2
pH HN S
/
O N
\-~
OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
137
SEM
N.N
H H3 C-~N
45-16 i_,N N~N 568.8 569.2
I HN /
IN
0 SEM
N, N
OMe ~~N
45-17 HN Nll)zz:N 585.8 586.2
OMe HN ~-OMe
~ N
0 OMe
SEM H3N
~
N~
N 584.8 585.2
45-18 H
HN S
N
~
OH N
O \--\
/ N-
NEM
N
H3N
45-19 HN,~OMe N1-1-- N 555.8 556.3 4.37
l HN S
0
\ t Me
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
. ; '
138
EXAMPLE 46
SEM H
N-N N-N
\ I \ I
H3 N HsN
N),),-N N 'I~")-- N 10 HN O HN
-O
S // HN--O S /HN
To a solution of the amide (0.038 g, 0.069 mmol) in dichloromethane (4 mL)
was added lithium aluminum hydride (0.029 g, 0.775 mmol) and ethyl ether (0.8
mL).
The reaction mixture was stirred at RT for 10 min then refluxed at 40 C for 5
hr. The
reaction was monitored by mass spectrometry. Upon consumption of the starting
amide, the reaction was cooled to RT and quenched with H20 (2 mL). The
reaction
was diluted with DCM and filtered. The filtrate was washed with H20 (<_ 8 mL).
The
organic layer was concentrated to give 0.019 g (52 %) of the amine. The above
amine
in THF was further treated with 4 N HCI/dioxane at 60 C for 1 hr. Upon
cooling to RT,
Et20 was added and the mixture was stirred for 10 min. The precipitated solid
was
collected giving 13.9 mg (96 % yield) of the desired amine.
By essentially the same procedure set forth in Example 46, the following
compounds shown in Column 2 of Table 8 were prepared:
TABLE 8
LCMS
Example Column 2 MW MH+ LCMS
m/z MS tR
H`N, N
H3C\ N \
46-1 N`Jzz': N 395.5 396.2 2.06
HN 'S ^O
C / Nr J
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
139
H.N`N
H3C~N
46-2 N\ 379.5 381.2 2.12
HN S
~ / N
H`N, N
H3CN ~
46-3 N~N 381.5 382.2 2.03
HN g ~
~/
.N`N
H3C~ N
\
46-4 N -
T'Lz:N 367.5 368.2 1.95
HN S
N
,_r
H
N'
~ N
/
46-5 H3N N 353.4 354.2 1.97
HN
N' N
\ I
H3~N
46-6 N1-1- N 408.5 409.2 1.77
HN
5=/ q
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
140
H,N`N
H3~N \
46-7 N`~N 393.5 394.2 2.06
HN S
N
H.N`N
H3C ,
N 369.4 370.2 1.76
46-8 N N
~
HN S
I ~ H
N`~OH
H, N,N
H3C
46-9 ~ ~N 383.5 384.2 1.78
HN S
C~ H
N--"OMe
H.N`N
H3C-Tl~ N
46-10 N~N 396.5 397.2 1.52
HN S
N
H, N,N
H3C\ N
46-11 N` ~N 353.4 354.2 1.79
HN S
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
141
H.N`N
\ 1
H3C N
46-12 ~ ~N 397.5 398.2 1.93
HN S
N
H.N`N
H3C-rl~ N
46-13 N.~N 410.5 411.2 1.76
HNI S
N
H.N`N
46-14 H3CY`N 409.5 410.2 1.94
N'lljz'N
HN S
~N_ rOH
H.N`N
46-15 H3C -T~~ N 413.5 414.2 1.87
N~N
HN S H
OH
H`N`N
H3C-fo~ N
46-16 NN 424.6 425.2 1.80
HN S /
I'-"-"Ni
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
142
H`N'N
H3C~N
46-17 N~N 441.6 442.2 2.23
HN S ~OMe
OMe
H,N`N
\ I
H3C_rl~ N
\
46-18 N~N OH 440.6 441.2 1.78
HN S
N
EXAMPLE 47
O O O __N
+ NOH O I
CI
Ethyl 4-chloro-3-oxobutanoate (14.15 g, 86 mmol), cyanoacetic acid (8.00 g, 86
mmol), NH4OAc (1.32 g, 17.2 mmol), AcOH (2.46 mL, 43 mmol), and benzene (40
mL) was stirred overnight at reflux with a Dean-Stark trap. The mixture was
cooled to
room temperature, diluted with EtOAc, washed with sat. NaHCO3, brine, dried
with
Na2SO4, and concentrated to afford crude product 1 (9.29g, 58%). HPLC-MS tR
=1.67
Min (UV 254nm). Mass calculated for M+ 187.0, observed LC/MS m/z 188.1(M+H).
EXAMPLE 48
UN
iN
O-/
CI I
H2N S O
Morpholine (580 uL, 6.65 mmol) was added dropwise to a mixture of ethyl 3-
(chloromethyl)-4-cyanobut-3-enoate (622 mg, 3.33 mmol) and S-flakes (116 mg,
3.63mmol) in EtOH (5 mL). The reaction stirred at room temperature overnight.
The
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
143
mixture was concentrated. The mixture was diluted with EtOAc, washed with
brine,
dried with Na2SO4, and concentrated to afford crude product. Purification by
Prep-LC
afforded the title compound (182 mg, 20%). HPLC-MS tR = 0.80 Min (UV 2wm).
Mass
calculated for M+ 270.1, observed LC/MS m/z 271.1(M+H).
EXAMPLE 49
SEM
N.N
SEM
N (0) N \ 1
N N~N O
N H2N ~ ~ HN NJ
NT\~N S O\1 To
S02Me O
O \--
A solution of ethyl 5-amino-3-(morpholinomethyl)thiophene-2-carboxylate (61.0
mg,
0.225 mmol) and sulfone (71.0 mg, 0.173 mmol) in DMF (2 mL) was treated with
NaH
(60% dispersion in oil, 20.9 mg, 0.521 mmol) at room temperature. The mixture
was
stirred at room temperature until LCMS indicate the reaction was complete. The
reaction mixture was diluted with EtOAc, washed with sat NH4CI, dried with
Na2SO4,
and concentrated to afford title compound. HPLC-MS tR = 1.79 Min (UV 254nm).
Mass
calculated for M+ 597.2, observed LC/MS m/z 598.3(M+H).
EXAMPLE 50
SEM
N, I N NE 1 N
N
N
N N O HN CD
N H~ -y ~
g
To -~
3/O O ~
A solution of i-PrMgCi in THF (0.78 uL, 1.56 mmol) was added dropwise to a
solution
of crude compound from example 49 (104.2 mg, 0.173 mmol) and diethylamine (91
uL, 0.782 mmol) in THF (3 mL) at -20 C. The mixture was slowly warmed up to
room
temperature and stirred at this temperature until LCMS indicate the reaction
was
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
144
complete. The reaction mixture was cooled to 0 C and quenched with Sat. NH4C1.
The reaction mixture was extracted with EtOAc and the organic layer was dried
with
Na2SO4 and concentrated to afford crude product 4. HPLC-MS tR = 1.81 Min (UV
254nm). Mass calculated for M+ 624.3, observed LC/MS m/z 625.3(M+H).
EXAMPLE 51
`
SEM NH
N- N N
N\ O N~ N O
H~ N --~ HN
TN N ~ N
S
N
O
-- O \--
4N HCI in dioxane (1 mL) was added to crude compound 4 (17mg, 0.027 mmol) at
0 C. The mixture was warmed to room temperature and stirred at this
temperature
until LCMS indicate the reaction was complete. Concentration and purification
by
Prep-LC and conversion to a hydrochloric salt afforded the title compound.
HPLC-MS
tR = 1.14 Min (UV 254nm). Mass calculated for M+ 494.2, observed LC/MS m/z
495.2(M+H).
By essentially the same procedure, compounds given in Column 2 of Table 9 can
be
prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
145
TABLE 9
LCMS
Example Column 2 MW MH+ LCMS
MS tR
m/z
H
N.N
~ j
51-1 HN "~~ 524.1 525.1 1.09
N
S
0 k--/s
N- I N
'-r-N
51-2 "ly)' N<- 478.2 479.2 1.32
HN N
s
N
O ~
H
N-~ "
~N \
51-3 H~N ~ 490.2 491.2 1.35
N
i
S
N
O
EXAMPLE 52
/ ~ / ~
HOzC S CO2H HOZC S NHBOC
A solution of thiophene-2,5-dicarboxylic acid (2.73 g, 15.84 mmol),
diphenylphosphoryl azide (3.41 mL g, 15.84 mmol) and triethylamine (4.4 mL,
31.68
mmol) in tert-butanol (80 mL) was heated at refluxing 5h. The reaction mixture
was
cooled to room temperature and then concentrated to afford the crude title
compound.
HPLC-MS tR =1.52 Min (UV 254nm). Mass calculated for M+ 243.0, observed LC/MS
m/z 244.1(M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
146
EXAMPLE 53
2 HO C N S
O
Et3N (1261.6 uL, 9.05 mmol) was added at 0 C to a mixture of 5-tert-
Butoxycarbonylamino- thiophene-2-carboxylic acid (550 mg, 2.26mmol), EDCI
(1086
mg, 5.65 mmol) , and piperidine (447 uL, 4.52 mmol) in DMF (6ml). The reaction
mixture was warmed up to room temperature and stirred at this temperature
ovemight.
The mixture was diluted with EtOAc, washed with brine (2X), dried over Na2SO4
and
concentrated to afford crude residue. Purification by Biotage afforded
compound 2
(368 mg, 53%). HPLC-MS tR =1.89 Min (UV 254nm). Mass calculated for M+ 310.1,
observed LC/MS m/z 311.2(M+H). HPLC-MS tR =2.4 Min (UV 254nm).
EXAMPLE 54
~ 1N C'-\ JJ.-NHBOC N N
HZ
S O O
Compound from Example 53 (90 mg, 0.29 mmol) was stirred in 20% TFA / CH2CI2
solution (5 mL) at room temperature for 1.5 hrs. The reaction mixture was
concentrated to afford compound 3. The crude product was used without further
purification. HPLC-MS tR =1.16 Min (UV 254nm). Mass calculated for M+210.0,
observed LC/MS m/z 211.1(M+H).
EXAMPLE 55
SEM
SEM N,N
N-N I
Y~\N
+ ~N \ N\
\ NHZ ~N
ON S NN ~
HN
0 SO2Me
s ~
O No
A solution of crude material from Example 54 and sulfone (98.0 mg, 0.241 mmol)
in
DMF (2 mL) was treated with NaH (60% dispersion in oil, 29.0 mg, 0.725 mmol)
at
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
147
room temperature. The mixture was stirred until LCMS indicate the reaction was
complete. The reaction mixture was diluted with EtOAc, washed with sat NH4CI,
dried
with Na2SO4, and concentrated to afford crude product 4. Purification by
Biotage
afforded the title compound (82 mg, 63%). HPLC-MS tR = 2.30 Min (UV 254,1m).
Mass
calculated for M+ 537.2, observed LC/MS m/z 538.2(M+H).
EXAMPLE 56
SEM SEM
; - ; ,
N "I -
N
N Y-I-- N N-N
0
HN HN
S /
N No
O
To a solution of the amide (47.6 mg, 0.089 mmol) in dichloromethane (5 mL) was
added lithium aluminum hydride (39.9 mg, 1.0 mmol) and ethyl ether (1 mL). The
reaction mixture was stirred at room temperature for 10 min then refluxed at
40 C
until LCMS indicate the reaction was complete. The reaction was cooled to room
temperature and quenched with H20 (0.5 mL). The reaction was diluted with
dichloromethane, dried over Na2SO4 and concentrated to afford crude title
compound.
HPLC-MS tR = 1.52 Min (UV 254nm). Mass calculated for M+ 523.2, observed LC/MS
m/z 524.2 (M+H).
EXAMPLE 57
SEM H
\r N
N_
N
HN _ HN
S / S
No No
4N HCI in dioxane (2mL) was added to crude compound from example 56 at 0 C.
The
mixture was warmed to room temperature and stirred at this temperature until
LCMS
indicate the reaction was complete. Concentration afforded crude title
compound.
Purification by Prep-LC and conversion to a hydrochloric salt afforded the
title
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
148
compound. HPLC-MS tR = 0.91 Min (UV 2Wm). Mass calculated for M+ 393.1,
observed LC/MS m/z 394.1 (M+H).
By essentially the same procedure, the compounds in Table 10 were prepared.
TABLE 10
LCMS
Example Column 3 MW MH+ HPLC MS
m/z tR
N-N
57-1 ~" \ 411.1 412.1 1.05
YN
HN ~
S ~
N~~
~JS
N-N
57-2 ~N 381.1 382.0 0.88
~N
HN
S I-/N /-
H
N-N
57-3 ~" 461.1 462.1 1.08
Y'N
HN
CF3
S /~
N )
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
149
H
N'N
~~Nl \
NY`N
57-4 HN 491.1 492.1 1.41
CF3
OH
N-N
/ N
57-5 N~N 421.2 422.0 1.04
HN
S
N
H
N,
57-6 ~" 437.2 438.3 1.20
N
HN O-
S
No
H
N'N
\ I
~N \
57-7 N~N 409.1 410 1.00
HN
SIN
OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
150
EXAMPLE 58
s~ s~
N N
H3CN H3C` N
N~N Nl,'J'-N
SO2CH3 HNO
S-N OCH3
To a solution of 8-methanesulfonyl-6-methyl-3-thiazol-2-yl-imidazo [1, 2-a]
pyrazine (0.070 g; 0.24 mmol) and 5-amino-3-carbomethoxy-isothiazole (0.039g;
0.25
mmol) in dimethyl formamide (DMF; 0.8 mL) was added sodium hydride (NaH; 60%
in
oil; 0.024 g). The reaction mixture was stirred at room temperature for 0.5 hr
and then
quenched with saturated aqueous solution of ammonium chloride (NH4CI). Diluted
with more water and filtered. The filter cake was washed with water and
hexanes. The
filter cake was dried in vacuo to obtain the title compound as yellow solid
(0.078 g;
87%). ' H NMR (400 MHz, DMSO-d6): 8.85 (s, 1 H), 8.42 (s, 1 H), 8.1 (s, 1 H),
7.9 (s,
1 H), 7.65 (s, 1 H), 3.85 (s, 3H) 2.5 (s, 3H). HPLC-MS tR = 4.35 (UV254nm).
Mass Calc.
for C15H12N602S2 372.04; obsd MH+ (LCMS) 373.2 (m/z).
EXAMPLE 59
s~ s~
- N - N
N H3C5;"'_N\
H3C-Ir
N~N N (Y1'N
~
HN~O H N
S-N OCH3 S-N OH
A solution of lithium triethylborohydride (Super Hydride; 1 M in THF; 0.32 mL)
was added dropwise to a solution of the methyl ester (0.03 g; 0.08 mmol) in
dry THF
(0.8 mL). After stirring at room temperature for 1.5 hr, the reaction mixture
was
quenched with saturated aqueous NH4CI solution (8 mL) and diluted with water.
Small
amount of the precipitated yellow solid was filtered and washed with water and
ether.
The solid was dried in vacuo to obtain -10 mg (36%) of the alcohol. 'H NMR
(400
MHz, DMSO-d6): 8.8 (s, 1 H), 8.4 (s, 1 H), 8.1 (s, 1 H), 7.9 (s, 1 H), 7.2 (s,
1 H), 5.4 (t,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
151
1 H). 4.5 (d, 2H), 2.5 (s, 3H). HPLC-MS tR = 2.98 (UV254nm). Mass Calc. for
C14H12N6OS2 344.05; obsd MH+ (LCMS) 345.2 (m/z).
EXAMPLE 60
s~ s~
H3C\ ^N H3C\ N
- N N
NY N NY N
HN O O
S-~OCH3 S-~OCH3
A solution of ester (0.113 g; 0.3 mmol) in DMF (1.5 mL) was treated with NaH
(60% in oil; 0.03 g; 0.76 mmol) followed by 2-(Trimethylsilyl) ethoxymethyl
chloride
(SEM-CI; 0.1 mL; 0.61 mmol). The reaction mixture was stirred at room
temperature
for 3 hr and quenched with saturated aqueous NH4CI and water. The precipitated
yellow solid was collected by filtration, washed with water and dried. The
title
compound was obtained as yellow solid (0.142 g; 92%). 'H NMR (400 MHz, CDCI3):
9.1 (s, 1 H), 8.1 (s, 1 H), 7.98 (s, 1 H), 7.8 (s, 1 H), 7.4 (s, 1 H), 6.65
(s, 2H), 4.0 (s, 3H),
3.78 (t, 2H), 2.65 (s, 3H), 1.0 (t, 2H), 0.0 (s, 9H). HPLC-MS tR = 5.98
(UV254nm). Mass
Calc. for C21 H26N6O3S2Si 502.13; obsd MH+ (LCMS) 503.3 (m/z).
EXAMPLE 61
s s~
H3C\ N H3C_ N
- N - N
NJ,)" N
O NY
Si-,O,-, N N I S-N OCH3 S-OH
A solution of lithium triethylborohydride (Super Hydride; 1 M in THF; 1 mL)
was
added dropwise to a solution of the methyl ester 2 in dry THF. After stirring
at room
temperature for 1 hr, the reaction mixture was quenched with saturated aqueous
NH4CI solution (8 mL) and saturated aqueous solution of Rochelle salt. The
organic
product was extracted with dichloromethane (CH2CI2), washed with water and
brine.
Concentration in vacuo gave -120 mg (100%) of the alcohol. HPLC-MS tR = 4.22
(UV254nm). Mass Calc. for C20H26N6O2S2Si 474.13; obsd MH+ (LCMS) 475.3 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
152
EXAMPLE 62
s~ s~
N N
H3CN H3CN
N Nj>'- N
OvN iSi,-,,-,O,-, N ~ CHO
S N OH I S N
Dess-Martin periodinane (0.147 g; 0.35 mmol) was added to a solution of
alcohol (0.11 g; 0.23 mmol) in dry THF and stirred at room temperature for 40
minutes. The reaction mixture was diluted with 30 mL of CH2CI2, washed with
saturated sodium bicarbonate (NaHCO3) solution, water and dried. Concentration
furnished a yellow solid which was re-dissolved in CH2CI2 and filtered. The
filtrate was
concentrated to obtain 120 mg of crude title compound as a yellow solid which
was
used as is in the next step. 'H NMR (400 MHz, CDCI3): 10 (s, 1 H), 9.1 (s, 1
H), 8.1 (s,
1 H), 7.98 (s, 1 H), 7.78 (s, 1 H), 7.4 (s, 1 H), 6.6 (s, 2H), 3.78 (t, 2H),
2.65 (s, 3H), 1.0 (t,
2H), 0.0 (s, 9H). HPLC-MS tR = 6.14 (UV254nm). Mass Calc. for C20H24N6O2S2Si
472.12; obsd MH+ (LCMS) 473.3 (m/z).
EXAMPLE 63
s~ sN
H3C\ ^N \ H3C~N
- N
(_ ~\ NY `N
NY 'N I
N
~Si~iO~ SN ~ CHO S_N N
I
A solution of aldehyde (0.05 g; 0.1 mmol) and piperidine (0.05 mL; 0.5 mmol)
in
CH2CI2 (1 mL) was treated with glacial acetic acid (AcOH; 1 drop) and stirred
at room
temperature (RT) for 3 hr. Solid sodium borohydride (NaBH4; 0.016 g; 0.42
mmol) was
added and the reaction mixture was cooled in an ice/brine bath (-5 C) and
methanol
(0.2 mL) was added dropwise. After stirring at low temperature for 30 minutes,
the
reaction was quenched with saturated NH4CI and extracted into CH2CI2. The
organic
extract was washed with saturated NH4CI, water and brine. Removal of solvent
gave
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
153
the crude product which was purified by preparative thin layer chromatography
(Prep
TLC) using CH2CI2 with 4% CH3OH and 1% ammonium hydroxide. The title
compound was isolated as yellow film (25 mg; 45%). 'H NMR (400 MHz, CDCI3):
9.1
(s, 1 H), 8.1 (s, 1 H), 7.98 (s, 1 H), 7.4 (s, 1 H),7.3 (s, 1 H), 6.6 (s, 2H),
3.8 (t, 2H), 3.6 (s,
2H), 2.65 (s, 3H), 2.5 (br-s, 4H),1.7 (br-s, 4H), 1.45 (br-s, 2H), 0.98 (t,
2H), 0.0 (s, 9H).
HPLC-MS tR = 3.82 (UV254nm). Mass Calc. for C25H35N7OS2Si 541.21; obsd MH+
(LCMS) 542.3 (m/z).
EXAMPLE 64
sN sN
H3CN H3C N
~~ 1
NY N NYN
N HN
jSI
S-N S-N
A solution of compound from Example 63 (0.013 g; 0.02 mmol) in 0.5 mL of
THF was treated with HCI in dioxane (4M; 0.5 mL) and placed in an oil bath at
70 C.
After heating for 30 min, a precipitate formed which dissolved upon adding 0.5
mL of
methanol. The reaction mixture was heated at a bath temperature of 70 C for an
additional 1 hr. The contents of the reaction were cooled to RT and all the
volatiles
were removed on a rotary evaporator. The residue was suspended in THF and
triturated with ether. The precipitate was collected by filtration, washed
with - 10 mL of
ether and dried in air (0.5 hr) and in vacuo (16 hr) to furnish 10 mg (93%) of
the title
compound as a yellow solid. ' H NMR (400 MHz, CD3OD): 9.0 (s, 1 H), 8.3 (s, 1
H), 8.05
(s, 1 H), 7.7 (s, 1 H), 7.25 (s, 1 H), 4.4 (s, 2H), 3.6 (d, 2H), 3.1 (t, 2H),
2.6 (s, 3H), 2.0 (d,
2H), 1.85 (t, 4H), 1.6 (t, 1 H). HPLC-MS tR = 2.96 (UV254nm). Mass Calc. for
C19H21 N7S2
411.13; obsd MH+ (LCMS) 412.2 (m/z).
Compounds in the Table 11 were prepared as per above examples:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
154
TABLE 11
Example Structure MW LCMS HPLC
MH+ (m/z) MS tR
s^1
N
59-1 H3C 344.05 345.2 2.98
N
N
HN
QOH
S
59-2 H'C~~N 343.06 344.2 2.78
NY 'N
HN`
S-NOH
S
N
H3C /
64-1 i~ ^ 411.13 412.2 2.96
Y'N < J
HNN
S-N
S
N
64-2 H3C " 397.11 398.2 3.11 N N Y'N
HNN
S-N
s-
H3C N
64-3 ~ i~ 413.11 414.2 2.86
Y'N
HNN
S-N
N
64-4 H3C~N 411.13 412.2 2.99
N 7\-J-- N 0
HNN
S-N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
155
s
ci \ I
64-5 H'c~N 444.09 445.2 3.29
N\~N 0
HNN
i
S-N
EXAMPLE 65
$i~O N- N N-N
~ N- N H2N ~O
\ I I~ NJ H3CTl-'N Part B H3CN
H3C\ N NN N 'N
N\/~N Part A HN ~ /~ HIN r
SOZCH3 J
)4; NJO I ~ N~/
Part A: Lithium hexamethyldisilazide (1 M in THF; 0.18 mL) was added to an
amber
solution of 4-morpholin-4-ylmethyl phenylamine (0.013g; 0.068 mmol) and 8-
methanesulfonyl-6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-
yl]-
imidazo[1, 2-a]pyrazine (0.025g; 0.061 mmol) in 2 mL of THF at RT resulting in
a
burgundy solution. After stirring at RT for 20 minutes, the reaction mixture
was
quenched with saturated aqueous NH4CI solution. The contents were diluted with
ethyl acetate and washed with water and brine. The crude material from the
organic
extract was purified by prep TLC (5% methanol-CH2CI2) to obtain the title
compound
as pale yellow oil (0.025 g; 80%). 'H NMR (400 MHz, CDCI3): 8 (s, 1 H), 7.9
(d, 2H),
7.85 (s, 1 H), 7.8 (s, 1 H), 7.5 (s, 1 H), 7.4 (s, 1 H), 7.35 (d, 2H), 5.55
(s, 2H), 3.75 (br-s,
4H), 3.7 (t, 2H), 3.5 (br-s, 2H), 2.5 (br-s, 2H), 2.4 (s, 3H), 1.6 (br-s, 2H),
0.95 (t, 2H),
0.0 (s, 9H). HPLC-MS tR = 3.05 (UV254nm). Mass Calc. for C27H37N7O2Si 519.27;
obsd
MH+ (LCMS) 520.3 (m/z).
Part B: The compound from Part A (0.025g; 0.048 mmol) was suspended in dry THF
and treated with HCI in dioxane (4M; 1 mL) and heated in an oil bath set to 70
C for
15 minutes when a white precipitate was formed. Methanol was added to dissolve
some of the solid and the reaction mixture was continued to be heated for 45
minutes
more. After cooling to RT, the volatiles were removed on the rotary
evaporator. The
residue was suspended in THF and the precipitated solid was collected by
filtration,
washed with ether and dried in vacuo overnight. The title compound was
isolated as a
beige solid (14 mg; 78%). All the analogues in Table 12 were similarly
prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
156
TABLE 12
Example Structure MW LCMS HPLC
MH+ (m/z) MS tR
N- N
65-1 H3C~N 389.19 390.2 1.7
NN
HTN
N
N- N
\ I
65-2 H3C -eN \ 389.19 390.2 1.76
NY 'N
HN
/ N
(DO
S
1
65-3 H3C -J-~"~1N 405.16 406.2 2.38
NY ~N
HN ~
I NJ
N- N
65-4 Br"ro~:.'N 451.11 452.2 2.51
NY 'N
HN
N
N-N
65-5 H3C~N 387.22 388.2 1.85
N'N
H'N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
157
Na
65-6 H3C~N \ 459.24 460.3 2.03
NY~N
HN I ) aC02Et
NN- N
\I
65-7 B~N 437.1 438.2 2.38
NY'N
HN N
N- N
\I
65-8 H3C -1-:-"N 373.2 374.2 1.65
NY 'N
HN N
H
a
65-11 Br~N 452.11 453.3 1.93
NYN
HN I )zz~ rNH
N- N
\ 1
65-12 H3C -10~" N \ 388.21 389.2 1.59
NY'N
HN X~~ rNH
Na
65-13 H3C ~N \ 402.23 403.2 1.51
N`/'N
H~N /
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
158
N- N
65-14 H3C -rN \ 416.24 417.2 1.54
NII N
HN )~~ ^NJ
I N( f
H ~/
N- N
65-15 Br~N \ 467.1 468.3 2.27
N T\/'N
HN I: O
r ^
N- N
65-16 H3C~N 403.21 404.2 1.9
NY N
HN ~ ^O
Nr.J
N-N
65-17 H3CN 390.19 391.2 1.36
NY 'N
HN N
EXAMPLE 66
Si'\'O~
I \- N H2N I \ \~N \~N
v `COZCH3 Br /
Br\ N
T1~ N\~N N -N
NY'N 1" I
Part A Part B
SOZCH3 HNI \ HN I \
~ CO CH
2 3 ~ COyCHg
Part A: A solution of 4-Amino-2-methyl-benzoic acid methyl ester (0.33 g; 2
mmol;
prepared from commercially available 4-nitro-2-methyl-benzoic acid) and 8-
methanesulfonyl-6-bromo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-
yl]-
imidazo[1, 2-a]pyrazine (0.472 g; 1.0 mmol) was treated with LiHMDS (1M in
THF; 2
mL) at RT. The resulting burgundy solution was stirred at RT for 20 minutes
and then
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
159
quenched with saturated aqueous NH4CI solution. Standard work up as described
for
Example 65 and flash silicagel chromatography (25% EtOAc in CH2CI2) provided
the
title compound as pale yellow foam (0.48 g; 86%).
NMR (400 MHz, CDCI3): 8.18 (s, 1 H), 8 (d, 1 H), 7.9 (s, 1 H), 7.85 (d, 1 H),
7.78 (s, 1 H),
7.7 (s, 1 H), 7.62 (s, 1 H), 7.58 (s, 1 H), 5.5 (s, 2H), 3.9 (s, 3H), 3.65 (t,
2H), 2.6 (s, 3H),
0.98 (t, 2H), 0.0 (s, 9H). Mass Calc. for C24H29BrN6O3Si 556.13; Obsd MH+ (CI-
MS)
557 / 559 (m/z).
Part B: A solution of compound from Part A (0.48 g; 0.86 mmol) in 2 mL of dry
THF
was treated with a solution of dimethyl zinc (2M; 4 mL) dropwise. After the
effervescence ceased, solid Pd(PPh3)4 was added and the reaction was flushed
with
nitrogen, fitted with a reflux condenser and heated in an oil bath at 65-70 C.
After 0.5
hr, the reaction mixture had turned from yellow orange to deep red and after 4
more
hours, it had become an opaque black. TLC (25% EtOAc- CH2CI2) indicated the
formation of a slightly more polar spot. The reaction was cooled to RT,
quenched with
saturated aqueous NH4CI solution and extracted with EtOAc. Flash silicagel
chromatography of the crude material gave the 6-methyl title compound as
yellow
solid (0.38 g; 90%). NMR (400 MHz, CDCI3): 8.1 (s, 1 H), 8 (d, 1 H), 7.9 (d, 1
H), 7.85
(s, 1 H), 7.8 (s, 1 H), 7.7 (s, 1 H), 7.58 (s, 1 H), 7.4 (s, 1 H), 5.5 (s,
2H), 3.9 (s, 3H), 3.65
(t, 2H), 2.65 (s, 3H), 2.4 (s, 3H), 0.98 (t, 2H), 0.0 (s, 9H). Mass Calc. for
C25H32N6O3Si 492.23; Obsd MH+ (CI-MS) 493.11 (m/z).
EXAMPLE 67
~ i ~~'O~ ~iiO~ R
N- N N-N N-N
\ I \ I \ I
H3C\ ^N H3C\ ^N H3C\ ^N
N~N N~ 'N N
HN HN HN
[ / ( / N' 1
C02CH3 CHO
Part A: Ester was first reduced to the alcohol using LiBEt3H in THF at RT and
subsequently oxidized using Dess-Marin periodinane to the aidehyde as
described
previously. The reductive amination of aldehyde with various secondary amines
was
carried out provided SEM-protected title compound. Removal of the SEM
protecting
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
160
group was carried out under conditions described previously. In a similar
manner,
other tertiary amines listed in Table 13 were also prepared by the similar
reaction
scheme with the corresponding secondary amines followed by removal of the SEM
protecting group.
TABLE 13
Example Structure MW LCMS HPLC
MH+ (m/z) MS tR
N- N
67-1 H3C~N 401.23 402.2 1.87
NY 'N
HN I N
N- N
1
67-2 H3C~N 403.21 404.2 1.71
NY 'N
HN
I,:,::~
N
N- N
67-3 H3C~N 419.19 420.2 1.95
N T\/'N
HN
I X,,z S
N- N
67-4 H3C -f--"' N 415.25 416.2 2.0
NY
_HNOCQ
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
161
EXAMPLE 68
NH2 NHCbz
r\
N~NN iN
Et0 OEt EtO~OEt
The substrate (1 g, 5.07 mmol) was dissolved in THF:H20 (12 mL, 1:1, v/v) and
treated with K2C03 (1.4 g, 10.15 mmol) at room temperature. Then benzyl
chloroformate (0.79 ml, 5.58 mmol) in THF (2 mL) was slowly added. The mixture
was
stirred for 16 h. It was diluted with ethyl acetate (25 mL). The two layers
were
separated, and the aqueous layer was extracted with ethyl acetate (2 x 25 mL).
The
combined organic layer was washed with brine (1 x 30 mL), dried (Na2SO4),
filtered
and evaporated under reduced pressure to give the crude product which was
purified
by column chromatography (SiO2) eluting ethyl acetate-hexane.
EXAMPLE 69
NHCbz NHCbz
r\
N~N~N
EtO OEt O
The substrate acetal (1.2 g, 3.64 g) was dissolved in acetone (20 mL), and
treated
with 1 N aqueous HCI (2 mL) at room temperature, and the mixture was stirred
for 7 h.
Then acetone was evaporated off, and the residue was diluted with saturated
aqueous
NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 30
mL).
The combined organic layer was washed with brine (1 x 30 mL), dried (Na2SO4),
filtered and evaporated under reduced pressure to give the crude product as
solid
which was used in the next step without any further purification.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
162
EXAMPLE 70
NHCbz NHCbz NH2
r~ r~ I \
ON~ N N~N N~NI~
~ V
The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H (2 eq.) in
1,2-
dichloroethane was stirred at room temperature for 2 h. Then sodium
borohydride (3
eq.) was added and the mixture was stirred for 30 min at which point LC-MS
analysis
indicate complete consumption of starting material to product. Then the
reaction was
quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until
two
clear layer separated. The organic layer was washed with water, brine, dried
(Na2SO4), filtered and concentrated under reduced pressure to give the
product.
The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1
atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was
evaporated under reduce pressure to give the crude product.
EXAMPLE 71
NHCbz NHCbz NH2
Part A r~ Part B r~
N\/ N NT N N~N
O N N
Part A: The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in
1,2-
dichloroethane was stirred at room temperature for 2 h. Then sodium
borohydride (3
eq.) was added and the mixture was stirred for 30 min at which point LC-MS
analysis
indicate complete consumption of starting material to product. Then the
reaction was
quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until
two
clear layer separated. The organic layer was washed with water, brine, dried
(Na2SO4), filtered and concentrated under reduced pressure to give the
product.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
163
Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd/C at
1
atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was
evaporated under reduce pressure to give the crude product.
EXAMPLE 72
NHCbz NHCbz NH2
/~ Part A 6-~ Part B 6~
N\/ N N~N N~N
N~ N
OJ ~
~O ~O
Part A: The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in
1,2-
dichloroethane was stirred at room temperature for 2 h. Then sodium
borohydride (3
eq.) was added and the mixture was stirred for 30 min at which point LC-MS
analysis
indicate complete consumption of starting material to product. Then the
reaction was
quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until
two
clear layer separated. The organic layer was washed with water, brine, dried
(Na2SO4), filtered and concentrated under reduced pressure to give the
product.
Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd/C at
1
atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was
evaporated under reduce pressure to give the crude product.
EXAMPLE 73
N'NSEM N'NSEM N-NH
NHZ
R_ N Part A R_ ~N \ Part B RN
+
N\)-- N N\~N NYl- N
SOZMe RR1 HN CN R' HN I~R'
z N, i N-N R2 N RZ
Part A: The substrate (1 eq.) and amine (1.5-2 eq.) was dissolved in DMSO
under
argon, and treated with NaH (5 eq., 60% dispersion in oil). After 30 min, LC-
MS
analysis indicated complete consumption of starting material. The reaction was
quenched by addition of saturated aqueous NH4CI-acetonitrile (1:1, v/v). The
two
layers were separated, and the aqueous layer was extracted with ethyl acetate.
The
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
164
combined organic layer was washed with brine, dried (Na2SO4), filtered and
concentrated under reduced pressure to give the crude product.
Part B: The substrate was dissolved in 4N HCI in dioxane, and stirred at room
temperature for 30 min. The solvent was then evaporated, and the residue was
purified by Prep-LC. Conversion to hydrochloride salt afforded the product as
solid.
TABLE 14
LCMS HPLC MS
Example Column MW MH+ m/z tR
'NH
73-1 N\~N
H 375.4 376.1 0.83
1N ~
N' N
NH
73-2 NN 389.4 390.2 1.05
HN C N fD
N
'NH
73-3 NN 391.4 392.1 0.78
HN
3O
NH
rN
73-4 N~N 361.4 362.2 0.74
HN
~N
'NH
rN
73-5 N\~N
H 375.4 376.2 0.85
iN N
NND
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
165
'NH
rN
73-6 N~N 377.4 378.3 0.87
HN C
EXAMPLE 74
~N' Part A (~~N~~ Part B Part C N
~ 'N ~ N~N N~N
NYN - NY
HN S HN S
HN S HN I S N I iN \
OH CHO
COZCH3
Part A: By essentially the same procedure as described for Example 1 and 13.
Part B: To a solution of compound from Example 74, Part A (0.16 g, 0.57 mmol)
in
THF (20 mL) and water (0.025 mL) was added Dess-Martin periodinane (3
equivalents). The resulting solution was stirred at rt for 1.5h at which time
LC-MS
analysis indicated the reaction was complete. The reaction mixture was
diluted: with
dichloromethane (75 mL), washed with water, dried (sodium sulfate) and
concentrated. Purification by column chromatography (Si02 10% methanol / DCM)
afforded the title compound as a yellow solid 0.08 g (49%). HPLC-MS tR = 1.59
Min
(UV 254nm). Mass calculated for formula C13H11 N5OS 285.07, observed LC/MS m/z
286.1 (M+H).
Part C: To a solution of compound from Part B (30 mg, 0.105 mmol, 1
equivalent), 3-
methylpiperidine (10 equivalents) in dichloromethane:methanol (5:1) (3 ml) was
added
acetic acid (1 drop). The resulting solution was stirred at rt for 30 minutes,
and then
sodium borohydride (8 equivalents) added to the reaction. The reaction mixture
was
stirred at rt for 1 hour at which time LC-MS analysis indicated the reaction
was
complete. The reaction was quenched with sat. aq. sodium bicarbonate and then
extracted with dichloromethane (x2). The combined organic layer was dried
(sodium
sulfate) and concentrated. Purification by Prep-LC and conversion to a
hydrochloric
salt afforded the title compound. HPLC-MS tR = 3.73 Min (UV 254nm). Mass
calculated
for formula C19H24N6S 368.18, observed LC/MS m/z 369.2 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
166
EXAMPLE 75
7~N N
Part A
N ` N 0- Ny N
HN g HN S
/N
CHO No
Part A: To a solution of compound 1 (30 mg, 0.105 mmol, 1 equivalent),
piperidine (10
equivalents) in dichloromethane:methanol (5:1) (3 ml) was added acetic acid (1
drop).
The resulting solution was stirred at rt for 30 minutes, and then sodium
borohydride (8
equivalents) added to the reaction. The reaction mixture was stirred at rt for
1 h at
which time LC-MS analysis indicated the reaction was complete. The reaction
was
quenched with sat. aq. sodium bicarbonate and then extracted with
dichloromethane
(x2). The combined organic layer was dried (sodium sulfate) and concentrated.
Purification by Prep-LC and conversion to a hydrochloric salt afforded
compound 2.
HPLC-MS tR = 3.47 Min (UV 254nm). Mass calculated for formula C18H22N6S
354.16,
observed LC/MS m/z 355.1 (M+H).
EXAMPLE 76
SEM
SEM N-N
N-N I
I H2N
N NaH / DMF/ RT - N
~
NN O 93% HN S`
O
0=S=0 Step A /N
O
O
SEM H
N-N N-N
\ I ~ >~OH
N
H
1) LAH, THF (66%) 3) K2CO3 / 80 C (65%)
N7\Ij--N NY)'-N
2) MsCI / Et3N (85%) HN I S N 4) 4M HCI, dioxane (95%) HN ~ SN
Step B ~
Step C ~OH
OMs N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
167
Step A: Sodium hydride (60% dispersion in mineral oil, 6.68 g, 3.40 equiv) was
slowly
added in one portion to a stirring mixture of compound sulfone (20.0 g, 1.00
equiv)
and aminoisothiazole (11.5 g, 1.20 equiv, as HCI salt) in DMF (490 mL) at room
temperature (with aid of a room temperature water bath). Reaction was allowed
to stir
for 1 hour at which time HPLC analysis indicated the reaction was complete.
The
reaction was carefully quenched with saturated aqueous sodium bicarbonate (200
mL)
and then diluted with water (1 L). This mixture was stirred for 20 minutes at
room
temperature, and then the resulting precipitate was collected by filtration,
washed with
water (200 mL), and dried under high vacuum for 16 hours. The resulting waxy
solid
was dissolved in 1.8 L of 1:1 chloroform : methanol, dried over sodium
sulfate, filtered,
and concentrated under reduced pressure to give the title compound (22.3 g,
93%) as
a dark yellow solid. 1 H NMR (300 MHz, DMSO-d6) b 12.3 (bs, 1 H), 8.60 (s, 1
H), 8.10
(s, 1 H), 7.88 (s, 2H), 7.59 (s, 1 H), 5.51 (s, 2H), 3.85 (s, 3H), 3.63 (d, J
= 8 Hz, 2H),
2.48 (s, 3H), 0.88 (d, J = 8 Hz, 2H), -0.026 (s, 9H). Mass calculated for
formula
C21H27N7O3SSi 485.63; observed MH+ (MS) 486.6 (m/z).
Step B: A mixture of compound from Step A (4.27g, 3.73 mmol) was dissolved in
180
mL of THF. The resulting solution was cooled to 0 C and LiAIH4 powder (2.6 g,
68.5
mmol) was carefully added. The cooling bath was removed and the reaction was
stirred at RT under a N2 atmosphere for 1.5 hr. The reaction was cooled to 0 C
and
carefully quenched by the sequential addition of 2.6 mL of H20; 2.6 mL of 15 %
NaOH
(aq); 7.8 mL H20. After stirring for 10 min, the reaction was filtered through
a very thin
pad of Celite (rinsing with THF, EtOAc and DCM). Concentration of the filtrate
yielded
a light yellow solid. Pure alcohol (2.66 g, 66 % yield) was obtained via
triturating with
MeOH and used directly in Step C.
Step B (Alternative procedure; e.g. Example 76-39): A solution of 4,4-
difluoropiperidine hydrochloride (25.1 mg, 0.16 mmol) in THF (2.0 mL) was
added
NaH (60% dispersion in mineral oil, 12 mg, 0.30 mmol). The mixture was stirred
under a N2 atmosphere at room temperature for 10 min, then mesylate (31.4 mg,
0.06
mmol) and Nal (4 mg, 0.03 mmol) were added to the reaction flask. The reaction
was
heated at 80 C under a N2 atmosphere for 8 hr. The reaction was cooled to
room
temperature and 15 mL of saturated NH4CI (aq) solution was added. The reaction
was diluted with dichloromethane (20 mL) and the layers were separated. The
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
168
aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic
phase
was washed with 15 mL of saturated NaHCO3 (aq), then brine (15 mL). The
organic
phase was dried over NaSO4 and concentrated in vacuo. Purification via
preparative
TLC (10% MeOH/CH2CI2) gave 19.7 mg (60% yield) of the title compound.
Step C: A mixture of compound from Step B (2.40 g, 4.49 mmol), amine (1.57 g,
13.46
mmol), and Nal (63.0 mg, 0.449 mmol) in 45 mL of THF was heated at 80 C for
12 h.
It was diluted with 200 mL of CH2CI2, and washed with 100 mL of saturated
aqueous
NaHCO3 solution, then with brine (100 mL). The solvent was removed under
vacuum.
The residue was purified by flash chromatography eluting with 5% to 10%
MeOH/CH2CI2 to give 1.68 g of the title compound. 'H NMR (400 MHz, CDCI3) b
9.49
(brs, 1 H), 7.89 (s, 1 H), 7.82 (s, 1 H), 7.60 (s, 1 H), 7.49 (s, 1 H), 6.86
(s, 1 H), 5.54 (s,
2H), 3.79 (brs, 3H), 3.67 (t, J = 8.3 Hz, 2H), 3.36 (s, 2H), 2.65-2.80 (m,
2H), 2.50 (s,
3H), 1.11 (s, 6H), 1.02(t, J = 7.1 Hz, 2H), 0.96 (t, J = 8.2 Hz, 2H), 0.01 (s,
9H). To a
solution of Sem-protected compound (2.0 g, 3.6 mmol) in 36 mL of MeOH/CH2CI2
(1:1) stirred at 80 C, was added 36 mL of 4 N HCI in dioxane. The reaction
was
stirred at 80 C for 30 min. After it was cooled to the room temperature, 120
mL of
ether was added. The solid was collected by filtration, washed with ether and
dried
under vacuum to give 2.0 g of the title compound as its HCI salt form. Mass
calculated
for formula C20H26N$OS 426.2; observed MH+ (LCMS) 427.2 (m/z).
Using essentially the same procedures as described for Example 76, the
following
compounds were prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
169
TABLE 15
LCMS
Example Column 2 EM MH+ HPLC
m/z MS tR
H
N-N
N1\
NY`
76-1 N I 426.2 427.2 2.28
HN~
S N N--\-
O\.-
NV
N
76-2 N~N 426.2 427.2 2.21
HN~
S-N N
OH
NV
~N \
76-3 NY-1- N 452.2 453.2 2.26
HN S-N N
\ OH
N'
I N
\
N
76-4 N)-)- N 466.3 467.3 2.48
HN--
r / --~
S-N N
\ OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
170
N,N
\ I
N
NY-,-- N 452.2 453.2 2.35
76-5
HN^
iS~_ N~--~N
N'
I N
N
NN 440.2 441.2 2.39
76-6
HN
OH
S-N N~
N'
I N
~N \
76-7 NN 438.1 439.1 1.81
HN`
S_N~N OH
H
N'N
N
76-8 N~N 438.1 439.1 1.03
HN` /OH
'(i
S-N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
171
N'N
\ I
N
76-9 N~N 452.2 453.3 1.48
HN O
S_N N =
N'
~ N
N
76-10 NY-1-- N 452.2 453.1 1.48
HN
S- 0
N'
I N
N
NN 452.2 453.3 1.35
76-11
HN~^
~S~-N~N
H
NV
N
76-12 N~N 452.2 453.2 1.36
HN~^
~S~-N~-\N
''.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
172
H
4N-~
\
N
76-13 NY'L-- N 452.2 453.2 1.041
HN~
,
~ /--~
S'N N
OH
H
N-
N
76-14 N~N 424.2 425.2 1.091
HN,r /~--~
S'N N
/
OH
H
N-
~N \
76-15 \ I,
N)-,-- N 410.2 411.2 1.048
HN,r /~--~
S-N /N
OH
H
N'N
~N \
76-16 N~N 426.2 427.1 1.16
HN
S-N N~
~
HO O
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
173
H
N-
N
NY-`~ N
.76-17 HN 476.2 477.3 2.69
S-N
N N
~
H
N-
76-18 \ I ,
~N \
NY~- N 424.2 425.2 2.15
HN
S-N N--\_O,
H
ci
~N \
76-19 NY-,-- N 426.2 427.2 2.21
HN
S-N N-~~
OH
H
N-
76-20 ~ N \
NN 412.2 413.1 1.086
HN
S'N N
/ OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
174
H
N-~
\
N
76-21 N~N 438.2 439.1 1.090
HN,r /~---\
S'N N
/
H
N-
N
76-22 NY-,-- N 424.2 425.2 1.162
HN~
~~ /~--~
S-N /N
1
H
N-~
N
452.2 453.3 1.286
76-23 NY-,-- N
HN
S'N N
/
I
H
N-
\I,
N
76-24 NYl-- N 424.2 425.2 1.12
HN,,
S-N /N.
OEt
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
175
H
N -
N
NY _N
76-25 HN~ 462.2 463.2 2.62
S'N N
O
,N
N-{\
H
N-
N
NY-,-- N 452.2 453.2 2.58
76-26
HN~
S-NN
b
H
N-
N
NY)-- N 466.2 467.3 2.74
76-27
HN~
S-N
0 H
N-
~N \
76-28 N)--l- N 438.2 439.2 2.39
HN~
S~- N~--\N -\_
6 O,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
176
H
N-
N
Nyl-- N 466.2 467.2 1.553
76-29
HN~
/~--~
S'N N
O
H
N-
N
NY-,-- N 436.2 437.2 1.16
76-30
HN~
S'N N
-O H
H
N-
N
76-31 NY-1--- N 438.2 439.1 1.48
HN
S-N N.,,,7
OEt
H
4N-~
"e'N
76-32 NYl- N 466.2 467.3 2.62
HN~
/~--~
S'N N
~ OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
177
H
N-
\I'
N
76-33 NY-1- N 454.2 455.0 0.910
HN~
~~ /~--~
S'N N
OH
H
N-
N
N~
76-34 N 468.2 469.1 1.031
HN~
S'N N
/
O
H
N-
76-35 ~N \
N~N 468.2 469.1 1.232
HN~
1' /
S'N N
` OH
H
N-
N
76-36 N 354.1 355.2 2.03
N
HN~
1' /
S-N HN-\
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
178
H
a
N
76-37 N~N 398.2 399.2 1.95
HN~
S-N HN
HO
H
N-~
\
N
76-38 NY)- N 480.2 481.3 2.46
HN
S-N
CF3 OH
H
N-^I
\ I'
N
N~ N 430.1 431.2 2.64
76-39
HN
S-N~-~
qF
F
H
N-
N
76-40 N Y _ N 412.2 413.2 2.53
HN~
1S'-NN
F
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
179
H
N-
N
76-41 NY-,-- N 462.2 463.3 2.99
HN
S-NaCF3
H N-
\I,
N
76-42 N~N 448.1 449.2 3.33
H N CF3
S-N
H
N-
~ N \
76-43 N~N 398.1 399.2 2.41
HN~
S-N N
F
H
N-
e N
76-44 Ny),- N 378.1 379.2 2.43
HN~
S-N
H
N-
N
76-45 N~N 430.1 431.2 2.45
HN~
S-N~a F
F
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
180
H
N-
\I,
N
N)-)-- N 462.2 463.3 2.62
76-46
HN~
S-N~- N
- \
C F3
H
N-~
\
N
76-47 N)--1- N 416.1 417.2 2.37
HN
S-N N F
a
F
H
N-
N
76-48 NY)--- N 424.2 425.2 1.105
HN,~^
,
S-N
O
H
N-~
\
N
76-49 N 412.2 413.2 2.48
~ N
HN~
S~-N~-
QF
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
181
H
a
N 422.1 391.2 2.27
76-50 N
T N
HN
TS-N~HN-\-C F3
H
N-A1
\i-
NT~N
76-51 N)-,-- N 390.1 391.2 2.27
HN
S-NHN-\
r F
F
H
a
N
Y _
76-52 N N 518.1 519.3 3.32
HN
S-N~-\~N-\_CF3
F3CH
N-
N
76-53 NY-,-- N 402.1 403.2 2.39
HN
5-N~- N
~F
F
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
182
H
N-~
\
N
76-54 N Y~-- N 398.1 399.2 2.37
HN
S-N
N
H
N-A'
\I,
N
76-55 NY-1--- N 398.1 399.2 2.37
HN
S-N~- N
F
H
N-
N
76-56 Ni-)-- N 444.2 445.2 2.61
HN~ F
'S'-N~HN--&F
H
N-^I
"e'N
76-57 NY-,-- N 448.1 449.2 3.27
HN ~
;CF3
S-N N
"-r
\
~N \
N~N
76-58 467.2 468.4 3.90
HN~
S-N N~\
(\_N
0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
183
H
N-
N
N~N
76-59 HN~\ 466.2 467.4 3.59
S-N
S N O
~
/
N
0
H
N-
~N
NY
76-60 N 473.1 474.2 3.67
HN
S-N ~I~\
(\-N). S .O
c~
H
N-
\I7~N \
N~
76-61 N 535.2 536.3 4.42
HN~
S-N ON, .O
0 Ph
H
N-
\
~N \
76-62 N~N 409.1 410.4 3.31
HN~
~S~-N~--~
NH
H
N-
\I,
~N
N~
76-63 N 423.2 424.1 3.24
HN
NO
>
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
184
"-r
\
~N \
NN
76-64 HN489.2 490.4 4.64
S-N C)
N
0
F
H
N`
~N \
76-65 N 437.2 438.2 3.45
HN
S-N CN
11--o
H
N-
N
NY N
76-66 HNy 462.2 463.3 3.17
iI~
S-N N~
~
F O-
F
H
N-
'-T~N
N)-)-- N
76-67 HN466.2 467.2 3.56
S-N C N HN,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
185
H
N-
~N \
NY _N
76-68 HN467.2 468.1 3.44
S-N ~1~
-N~
O
~O
H
4N-~
\
~N \
NY _N
76-69 HN473.2 474.3 3.92
~
S-N ~-~
N
H
N-1
\ I.
~N \
76-70 N-)-- N 423.2 424.2 3.38
HN~
S-N C--o
N
N-
~N \
NY N
76-71 HN477.2 478.2 3.56
S-N N-
\-N)
~D
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
186
H
"`
~N \
NY
7g_72 N 499.2 500.5 3.91
HN
S-N CN
Ph
H
"`
~N \
"Y N
76-73 439.2 440.6 3.14
HN~
S-N CN
OH
H
N-
76-74 ~N \
N 384.1 385.1 0.981
HN~
S-NHN-\
`-\OH
H
"`I
\
~N \
76-75 "N 412.2 413.2 0.932
HN~
S-NHN
\ OH
H
"`
370.1 371.2 0.788
76-76 N` N
HN~
1S'-NI HN--\-OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
187
H
N-
~N \
76-77 "~N 422.2 423.3 1.224
HN~
~S-N~-
H
N-N
\ I
~N \
"Y)-- N 419.2 420.3 3.69
76-78
HN~
S-N~-
~
CN
H
N-
~N \
"Yl-- N 451.2 452.3 3.46
76-79
HN~
S-N
N HAc
H
N-~
\
"T~N
"~" 444.1 445.5 3.65
76-80
HN~
S-N
(\-~ O
0
H
N-
N
"r)-- " 495.2 496.8 4.63
76-81
HN~
~~ /~--~
S-N
qPh
NC
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
188
H
N-
N
NYl-- N
76-82 HN~ 451.2 452.4 3.48
S-N
O
H
H
N-
~N \
NY
76-83 N 450.2 451.2 2.81
HN
S-N
H
N-
",T~N
N~
76-84 N 437.2 438.2 1.76
HN~
S-N
N-
/
H
N-N
\ I
~N \
76-85 N -)'N 452.1 453.2 2.97
HN,
S-N I-
OH
CF3
H
N,N
~N
76-86 N~N 411.5 411.2 2.38
HN~
S-N N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
189
H
N'N
N
76-87 NY-1- N 424.1 425.2 1.09
HN\ ^
~S/-N~HN
HO
H
N'N
I
Nl\
NY`N
76-88 HN 453.2 454.3 0.86
S_N a
OH
H
N'N
N
NY`N
76_89 432.1 433.1 1.05
HN
Y~S-- \N
N-N
/
H
N'N
N
76-90 N 429.1 430.2 0.99
HN~ ^
~S~-N~- \N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
190
N-N
I
N
76-91 N~N 438.1 439.1 0.97
HN\ ^
S/-
~N~
/ N
OH
H
N-
N
76-92 NYl-- N 448.1
HN
S- N~N
~/ -CF3
N-N
H3C~
76-93 Nlrt'N 480.2 481.3 3.33
HN
S-N j --\__
\ OEt
CF3
N-N
NI_
76-94 N ~ N 462.2
HN
~--~ F3
S-nj
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
191
H
\ ~r
H3C~I N
N'Y N
76-95 HN 444.2
S-N N
\~ F
F
H
a
H3C~I N
N'Y
76-96 N 426.2
HN
S-N~aF
H
a
N
H3C e
INY N
~ 476.2
76-97 HN
S-N aCF3
H
N-
N
76-98 N yl-- N 436.1
HN
S-N~- N-\
( CF3
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
192
H
N-~
\
N
76_99 N N 404.1
Y
HN
S-NHN
CH3
F F
H
N-~
\
N
NY N
76-100 HN~ 448.2
S-N
-CH3
F
HO
H
N-~
\
H3CN
76-101 N I 490.1
HN
S-N N-\
(\ CF3
CF3
H
N-~
\
~N \
76-102 N~ N 478.2
HN\^ OH
~S/-N~N CF3
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
193
H
N-~
\
N
NY N
76-103 HN477.2 478.3 1.85
S-N Q
N
H
N
N \
76-104 N N 546.3
Y
HN~
S- N~N
Ph
Ph
H
N-~
\
N
NY N
76-105 HN ~ 463.2
S-N N
~ N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
194
H
N-~
N
N~N 468.2
76-106
HN
S-N~- N
OH
Ph
N-~
N
"Y N
76-107 HN -r 476.2
S-N N
N
H
N-
N
"yl-- N 423.2
76-108
HN
S-N~Q,--NH
2
H
N-~
~N \
N Y _N
76-109 ""~ 554.2
S-N
OH
CF3
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
195
H
a
N
76-110 N~ N 378.1 379.2 2.43
HN
S-N ~
/
N-N
N
76-111 N~ 408.1 409.2 2.59
T N
HN
S-NHN-\
CF3
H
N-N
I N
Nl,'I--N 506.2 507.3 2.59
76-112
HN~
S-N N
CF3 OH
N-N
H3C"
"yl-- " 484.2 485.3 2.54
76-113
HN~
S-N N
COZEt
F
H
N-N
\I
H3C\ ^N
76-114 7N::;~- N 382.1
HN\ ^
'S~/-N~N
OH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
196
H
N-N
H3C\ ^N
76-115 ~NYl- N 391.1 392.2 2.01
HN`
S- NN
q
CN
H
N- N
H3C\ N
76-116 NYl- N
HN\ ^
~S/-N~N
~q
F
N-N
H3C\ ^N
TNY N
76-117
HN
S-N N~
L_ I\OMe
N-N
\ I
H3C~N
NY'N
76-118 ~ ~~
HN`
S-N N
~q
OiPr
H
N-
H3C\~N
76-119 N 1"\--- N 366.1
HN\^
S-N N
D
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
197
N-
H3C\^
N 'N
TY N
76-120 h0''467.2
S-N N
CN
H
N
N
Y
76-121 N N 442.2
HN~
~S~- N~- ~N
POH
F
H
N-
H3CN
76-122 NN 380.2
HN~^ =
S- N~- N
~
H
N-~
~
N \
H3C-
76-123 NN 394.2
HN
S- N~-\N
Et
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
198
H
N-
H3C~N
76-124 "'IY)- N 400.1
HN
S- N~ N
CI
H
N-
H3C~N
76-125 "N 444.1
HN
S-N~N
Br
H
N-
H3C-r,7~N
" N
76-126 HNr-,~~ 467.2
S-N N
F
H
N-
H3C~N ~
I"'~N 450.1
76-127
HN
S-N~N
OH
CF3
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
199
H
N-
H3C Yl~N
NY N
76-128 HN451.2
S-N N
q
QO
Example 76-1: 'H NMR (400 MHz, CD3OD) b 8.24 (s, 1 H), 8.23 (s, 2H), 8.07 (s,
1 H),
7.35 (s, 1 H), 4.57 (d, J = 12.8 Hz, 2H), 3.81 (t, J = 4.8, 2H), 3.57 (q, J =
14.0, 6.8 Hz,
2H), 3.52 (m, 2H), 3.41 (m, 2H), 2.60 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.21
(t, J = 6.8
Hz, 3H). HPLC-MS tR = 2.28 min (UV 254nm). Mass calculated for formula
C20H26N80S
426.2; observed MH+ (LCMS) 427.2 (m/z).
Example 76-2: 'H NMR (400 MHz, CD3OD) 6 8.31 (s, 1 H), 8.29 (s, 2H), 7.32 (s,
1 H),
4.88 (d, 1 H), 4.46 (d, J= 16.1 Hz, 1 H), 3.82 (d, J= 12.3 Hz, 1 H), 3.71 (d,
J= 12.3 Hz,
1 H), 3.64 (m, 1 H), 2.65 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.31 (t, J =
7.1 Hz, 3H).
HPLC-MS tR = 2.26 min (UV 254nm).
Example 76-3: 'H NMR (400 MHz, CD3OD) 6 8.16 (s, 2H), 8.13 (s, 1H), 7.99 (s,
1H),
7.25 (s, 1 H), 4.72 (d, J = 15.6 Hz, 1 H), 4.53 (t, J = 15.6, 1 H), 3.66 (s,
2H), 3.61 (m,
1 H), 3.40 (m, 1 H), 2.57 (s, 3H), 1.33-0.95 (8H), 1.17 (t, J= 6.8 Hz, 3H).
HPLC-MS tR =
2.26 min (UV 254nm). Mass calculated for formula C20H26N80S 452.2; observed
MH+
(LCMS) 453.2 (m/z).
Example 76-4: 'H NMR (400 MHz, CD3OD) 6 8.16 (s, 2H), 8.15 (s, 1H), 8.00 (s,
1H),
7.21 (s, 1 H), 4.95 (d, J= 16.0 Hz, 1 H), 4.35 (d, J= 16.8 Hz, 1 H), 4.07 (d,
J= 12.4 Hz
1 H), 3.82 (d, J = 12.8 Hz 1 H), 3.52 (m, 2H), 2.57 (s, 3H), 1.96-1.58 (10H),
1.26 (t, J =
6.8 Hz, 3H). HPLC-MS tR = 2.48 min (UV 254nm). Mass calculated for formula
C20H26N80S 466.3; observed MH+ (LCMS) 467.3 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
200
Example 76-5: 'H NMR (400 MHz, CD3OD) b 8.28 (s, 1 H), 8.25 (s, 2H), 8.10 (s,
1 H),
7.39 (s, 1 H), 4.65 (d, J = 14.0 Hz, 1 H), 4.52 (d, J = 10.8 Hz, 1 H), 4.24
(d, J = 14.0 Hz
1 H), 3.85 (d, J = 18.0 Hz 1 H), 3.65-3.44 (4H), 2.65 (s, 3H), 1.97-1.58 (6H),
1.29 (t, J =
7.2 Hz, 3H). HPLC-MS tR = 2.35 min (UV 254nm). Mass calculated for formula
C20H26N80S 452.2; observed MH+ (LCMS) 453.2 (m/z).
Example 76-6 'H NMR (400 MHz, CD3OD) 6 8.21 (s, 3H), 8.03 (s, 1 H), 7.23 (s, 1
H),
4.38 (d, J = 5.6 Hz, 1 H), 3.79 (d, J = 5.4 Hz, 1 H), 3.63 (d, J = 12.4 Hz 1
H), 3.53 (m,
1H), 3.10 (m, 1H), 2.58 (s, 3H), 1.34 (s, 6H), 0.87 (t, J = 6.2 Hz, 3H). HPLC-
MS tR =
2.39 min (UV 254nm). Mass calculated for formula C20H26N80S 440.2; observed
MH+
(LCMS) 441.2 (m/z).
Example 76-7: 'H-NMR (400 MHz, CD3OD ) 6 8.33 m (3H), 8.15 s (1H), 7.41 s
(1H),
4.80 (d, 2H), 4.15 (d, 2H), 4.06 (d, 2H), 3.62 (d, 2H), 3.58 (m, 1 H), 2.68
(d, 3H), 2.21
(m, 1 H), 1.81 (m , 6H) and 1.45 (s, 3H). HPLC-MS tR =1.80Min (UV 254nm). Mass
calculated for formula C21 H26N80S 438.55, observed LC/MS m/z 439.1 (M+H).
Example 76-8: 'H-NMR (400 MHz, DMSO-d6) 6 12.73 bs (1H), 9.2 bs (1H), 8.28 s
(2H), 8.09 s (1 H), 8.08 s (1 H), 7.36 s (1 H), 4.71 m (1 H), 4.05 m (1 H),
3.82 m (1 H),
3.63 m (1 H), 3.25 m (2H), 1.97 m (1 H), 1.65 m (6H) and 1.30 s (3H).
Example 76-9: 'H-NMR (400 MHz, DMSO-d6) S 8.28 (1H), 8.25 (2H), 8.08 (1 H),
7.32
(1 H), 4.71 (1 H), 4.08 (1 H), 3.84 (1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3 H),
2.17 (2 H),
1.87-1.73 (6 H), 1.45 (3 H).
Example 76-10: 'H-NMR (400 MHz, DMSO-d6 ) S 8.28 (1H), 8.25 (2H), 8.08 (1 H),
7.32 (1 H), 4.71 (1 H),4.08(1 H),3.84(1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3
H), 2.17 (2
H), 1.87-1.73 (6 H), 1.45 (3 H).
Example 76-11: 'HNMR (400 MHz, CD3OD) S 8.20 (s, 2H), 8.14 (s, 1 H), 8.03 (s,
1 H),
7.25 (s, 1 H), 4.48 (d, 1 H), 4.37 (d, 1 H), 3.46 (s, 3H), 2.91-3.60 (m, 6H),
2.62 (s, 3H),
1.40 - 1.89 (m, 4H), 0.92 (s, 3H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
201
Example 76-12: 'HNMR (400 MHz, CD3OD) S 8.20 (s, 2H), 8.14 (s, 1 H), 8.03 (s,
1 H),
7.25 (s, 1 H), 4.48 (d, 1 H), 4.37 (d, 1 H), 3.46 (s, 3H), 2.91-3.60 (m, 6H),
2.62 (s, 3H),
1.40 - 1.89 (m, 4H), 0.92 (s, 3H).
Example 76-40:1 H NMR (400 MHz, CD3OD) S 8.28 (s, 1 H), 8.25 (s, 2H), 8.10 (s,
1 H),
7.38 (s, 1 H), 4.59 (s, 2H), 3.3-3.9 (m, 4H), 2.64 (s, 3H), 2.3-2.5 (m, 4H).
Example 76-42: 'H NMR (400 MHz, CD3OD) b 8.13 (broad s, 2H), 7.85 (s, 1 H),
7.78
(s, 1 H), 7.15 (s, 1 H), 4.10 (d, J - 14 Hz, 1 H), 3.96 (d, J -14 Hz, 1 H),
3.54-3.66 (m,
1 H), 3.07-3.17 (m, 1 H), 2.62-2.72 (m, 1 H), 2.53 (s, 3H), 1.82-2.21 (m, 4H).
EXAMPLE 77
~OH OH
H2N H
A mixture of iodoethane (52.5 g, 336.5 mmol) and 2-amino-2-methyl-l-propanol
(30.0
g, 336.5 mmol) was stirred at 60 C for 15 min. It was diluted with 500 mL of
ether,
and basified by adding 5 N aqueous NaOH until it reaches pH =10. The organic
layer
was separated. The aqueous layer was extracted with ether (500 mL X 3). The
combined organic was washed sequentially with 100 mL of water, and 100 mL of
brine, then dried over anhydrous Na2SO4. The solvent was removed to provide 20
g
of the crude product, which was purified by recrystallization in 150 mL of
hexanes to
give 13 g of a white solid. The solid was further purified by sublimation
under reduced
pressure to give 12 g of the title compound. 'H NMR (400 MHz, CDCI3) b 3.28
(s, 2H),
2.54 (qt, J = 7.1 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H), 1.07 (s, 6H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
202
EXAMPLE 78
1. LiAIHa +
C C02H OH N OH
HCI. H 2. CbzCI, K2CO3 Cbz Cbz
3. Chiral Separation
Peak 1 Peak 2
Step A
Pd(OH)2, H2 C>--O
OH
O
Cbz Step B Cbz Step C H
Peak 1
or Peak 2
Step A: The substrate (10 g) was suspended in THF (200 mL). Then lithium
aluminum
hydride solution (110 mL, 2M in THF) was slowly added. The mixture was stirred
at
room temperature for 12 h. The solution was cooled to 0 C, and saturated
aqueous
Na2SO4 (200 mL) was slowly added. The mixture was filtered through Celite, and
filtercake was washed with ethyl acetate (400 mL). The organic layer was
washed with
water (200 mL) and brine (200 mL). The organic layer was dried (anhydrous
Na2SO4),
filtered and evaporated to give the amino alcohol (6.9g). The amino alcohol
(6.9 g)
was dissolved in THF (80 mL) and water (80 mL) at room temperature. The
potassium
carbonate (14.76 g) was added. Then benzyl chloroformate (8.28 mL) in THF (40
mL)
was added dropwise. The mixture was stirred at room temperature for 30 min.
Solvent
was evaporated off under reduced pressure, and ethyl acetate (100 mL) was
added.
Two layers were separated, and the aqueous layer was extracted with ethyl
acetate (2
x 100 mL). The combined organic layer was washed with brine (200 mL), dried
(Na2SO4), filtered and evaporated under reduced pressure to give the crude
product
which was purified by column chromatography. The racemic aminoalcohol was
chirally
separated by SFC HPCL method. Then enatiomers corresponding to peak 1 and peak
2 were separately taken forward to prepare the corresponding building blocks.
Step B: The alcohol from Step A (1.936 g) was dissolved in dichloromethane (80
mL),
and treated with proton sponge (8.32 g) at room temperature. Then
trimethyloxonium
tetrafluoroborate (5.69 g) was added. The mixture was stirred for 1 h. The
reaction
was quenched with saturated aqueous ammonium chloride solution (100 mL). The
two
layers were separated, and the aqueous layer was extracted with
dichloromethane (2
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
203
x 100 mL). The combined organic layer was washed sequentially with
hydrochloric
acid (200 mL, 1 N), saturated sodium bicarbonate solution (200 mL), brine (200
mL),
dried (Na2SO4), filtered and evaporated under reduced pressure to give the
crude
product which was purified by column chromatography.
Step C: The enantiomerically pure methyl ether from Step B in EtOH was treated
with
Pd(OH)2 on carbon (20% wt) and stirred in hydrogen atmosphere at atmospheric
pressure at room temperature for 2 h. The mixture was filtered off, and the
filtrate was
evaporated under reduced pressure to give the amine.
EXAMPLE 79
0
1. LDA, THF; Mel 1. NaH, Mel, DMF
JOEt OH O
N 2. LiBHEt3 N 2. 20% TFA/DCM N
i i
Boc Step A Boc Step B
1. CBZCI, K2CO3 20% Pd(OH)2
2. Chiral Separation N,, O N O- N O-
~ Step D H
Step C Cbz Cbz
Step A: At -78 C, ester (6359 mg, 24.7 mmol) in THF (50m1) was added dropwise
to
LDA (1.8 M in THF, 27.5 ml, 49.4 mmol) in THF (200m1). The reaction mixture
was
slowly warmed up to room temperature and stirred at that temperature
overnight. The
reaction was cooled to 0 C and quenched with saturated NH4CI solution. The
mixture
was diluted with H20 and extracted with EtOAc (x2). The combined organic layer
was
dried over anhydrous Na2SO4 and concentrated. Purification by column
chromatography afforded the title compound (6221 mg, 93%). LCMS tR =2.27 Min.
Mass calculated for, M+ 271.1, observed LC/MS m/z 216.1 (M+H-C4H8). To a
solution
of ester (4659 mg, 17.2 mmol) in THF (300 ml) was added LiBHEt3 (69 ml, 1 M in
THF). The reaction was stirred at room temperature for 30 min. It was quenched
by
adding saturated NH4CI. The mixture was extracted with CH2CI2. The combined
organic layer was dried over anhydrous Na2SO4 and concentrated. Purification
by
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
204
column chromatography afforded the title compound (3032mg, 77%). LCMS tR =1.82
Min. Mass calculated for, M+ 229.1, observed LC/MS m/z 174.1 (M+H-C4H8).
Step B: NaH (1324 mg, 60% dispersion in mineral oil, 33.1 mmol) was added
portion
wise to a mixture of compound from Step A and Mel (3.3 ml, 52.9 mmol) in DMF
(66
mL) at 0 C. The reaction mixture was slowly warmed up to room temperature and
stirred at that temperature ovemight. The reaction was cooled to 0 C and
quenched
with saturated NH4CI solution. The mixture was diluted with H20 and extracted
with
EtOAc (x2). The combined organic layer was dried over anhydrous Na2SO4 and
concentrated. Purification by column chromatography afforded the title
compound
(2633 mg, 82%). LCMS tR =2.32 Min. Mass calculated for, M+ 243.1, observed
LC/MS m/z 188.1 (M+H-C4H8). A solution of compound 4 (901 mg, 3.71 mmol) was
stirred in 20 % TFA in CH2CI2 (20 mL) at 0 C for 30 min and then room
temperature
for 15 min. The reaction mixture was concentrated. The crude residue was used
for
example without further purification. LCMS tR =0.26 Min. Mass calculated for,
M+
143.1, observed LC/MS m/z 144.1 (M+H).
Step C: CbzCl (604 ul, 4.08 mmol) in THF (1 ml) was added to a mixture of
compound
from Step B and K2CO3 (1125 mg, 8.15 mmol) in THF (20 ml) and H20 (20 ml) at 0
C.
After stirring at room temperature for 30 min, the reaction mixture was
extracted with
EtOAc (x2). The combined organic layer was dried over anhydrous Na2SO4 and
concentrated. Purification by column chromatography afforded the titlte
compound
(965mg, 94%). LCMS tR =2.28 Min (UV 254nm). Mass calculated for, M+ 277.1,
observed LC/MS m/z 278.1 (M+H). The title amines were chirally separated
utilizing a
Gilson GX-281 liquid handling system with HPLC capabilities. Separation was
accomplished with the following conditions: Chiral Technologies Chiral PAK AD
column (5 x 50 cm; 20 p); flow = 50 mUmin; 7.5% isopropanol in hexanes
(isocratic);
observed at 210 nm.
Step D: The enatiomerically pure isomers from Step C were dissolved in (1
mmol, 277
mg) in EtOH (6 ml) was mixed with 20% Pd(OH)2 (51 mg) and stirred under H2
balloon
at room temperature for 2h. Filtration through celite and concentration
afforded the
title compound, which was used for next step without further purification.
LCMS tR
=0.26 Min. Mass calculated for, M+ 143.1, observed LC/MS m/z 144.1 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
205
EXAMPLE 80
SEM SEM H
- N,N
-" \N \~
N N 2N HCI, dioxane N
N N\~N N~N
StepA
T Step B HN SHN SHN SI/ O`R
~OH ~ ~OR ~
N\-- N~
\--
Step A: The parent compounds were prepared from Example 76-2 using acid
chlorides, acids, ureas and isocyanates using standard reaction conditions.
Step B: Sem-protected material from Step A was dissolved in 1,4-dioxane (1 mL)
and
treated with 4 N HCI in 1,4-dioxane (1 mL). then heated at 60C for 1 hr.. The
mixture
was concentrated under reduced pressure and the resulting residue was purified
by
prep-HPLC and conversion to the hydrochloride salt afforded the title compound
as a
colorless solid.
Using essentially the same procedures as described for Example 80, the
following
compounds were prepared.
TABLE 16
LCMS
HPLC
Example Column 2 MW MH MS tR
m/z
H
N-
N
80-1 N N 468.2 469.3 2.62
HN ,
I /
N ~
~O 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
206
H
N-
N
80_2 N N 510.3 511.3 3.12
HN g~
N
-rO O
H
N-AI
\ I ,
N
Y
80-3 N N f 496.2 497.3 2.98
HN S,
/
N
~O O
H
\ `I
N
N Y N
80-4 496.2 497.3 2.98
HN S,
y
L /
N
-rO O
H
N-AI
~N \
80-5 N N 482.2 483.3 2.82
Y
HN S.
/
N ~
rO O
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
207
H
N-AI
\ ,
N
NY N
80-6 ' 494.2 495.3 2.83
HN S~
I
N
~O O
H
N -
\ ,
N
Y
80-7 N N f 530.2 531.3 3.34
HN S~
i
N
~O O
H
N-AI
N
N Y N
80-8 I 508.2 509.3 3.03
HN gI
N
-rO O
H
N-
\I,
N
N~
N 510.3 511.3 3.08
80-9
HN gI
N
C o
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
208
H
N-
\I'
N
N~
N
80-10 525.3 526.3 2.21
HN S~
H2N
N
~O O
H
a
N
~
80-11 N N 508.2 509.3 2.87
HN g~
I
N
-rO 0
H
N-~
\
N
80-12 N N 509.2 510.3 1.85
HN gI
N N H2
-rO O
H
a
~N \
80-13 N N 525.3 526.3 2.37
HN g~
,,,NH2
I /
N
-rO 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
209
H
N-~
\
N
80-14 N N 539.3 540.3 2.86
Y
HN SI
,,,NH2
N
~O O
H
N
\
N
N~N 550.3 551.3 3.56
80-15
HN gI /
N
-rO O
H
N-^I
\ I ,
N
80-16 N N 497.2 498.3 2.65
Y
HN gI
\N~
N
~O O
H
a
N
Nll)'-N 536.3 537.3 3.27
80-17
HN gI /
N
--rO 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
210
H
N-
N
~
80-18 N N 522.3 523.3 2.98
HN SI
N
-rO O
H
N-
N
80-19 N N 483.2 484.2 2.25
Y
HN SI
~NH2
N
,rO
H
N'N
~N \
N N
80-20 HN ~_\ 539.3 540.3 2.65
S-N
ol-~~
NH2
H
N-
I N
~N \
NY N
80-21 HN` 557.2 558.2 2.53
S-N
NH2
O
SMe
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
211
H
N'N
N
N Y _N
yf- -~ 573.3 574.2 2.74
80-22 HN
i
S-N
NH2
0
Ph
H
N
N \
N N
80-23 HN 523.2 524.2 2.38
S-N
N
H
N-N
~N \
NY N
80-24 HN 497.2 498.3 2.29
S-Nl~
NH2
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
212
H
'N
N
NN
80-25 HN ~ 511.2 512.3 2.28
~N~
S~-
NH2
O
H
N
~N \
NY N
80-26 HN 484.2 485.3 2.77
S-N
~
Olp
I
H
N-N
~N \
NY N
80-27 HN 512.2 513.3 3.03
S-Nh
H
N-N
~N \
NY N
498.2 499.3 2.65
80-28 HNY
'S-NI~ ~
Ol
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
213
H
N-N
N
NY N
HN 551.3 554.3 1.98
80-29 ~ /
S-N
N
c )
O
H
N-
\f.
N
N Y _N
HN S 540.3 541.3 3.21
80-30 /
S-N \ O~
H
N-N
~N \
NY N
\ 511.2 512.2 3.32
80-31 HN Yl
S-N
pINH
~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
214
H
~N \
NY _N
HN
80-32 S_ N 563.2 564.2 3.36
pINH
F
H
N-N
~N \
N Y _N
80-33 HN S 583.3 584.2 3.52
o
HN o
O
O
H
N'N
N
NY N
80-34 HN531.2 532.2 2.99
S-N
p I ~N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
215
H
N-
~N \
N Y N
80-35 HN s, 569.2 570.2 3.16
iN `
N/\ O
~OH
~N
O '
O ~
H
N'N
N
NY
80-36 HN N 664.4 665.3 6.22
S-Nl~
p )14
H
N-N
N
NY N
80-37 HN 497.2 498.2 3.09
S-Nh
pINH
H
~N \
NY N
80-38 HN r ~/ 511.2 512.2 3.32
S-N
pINH
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
216
H
N \
N Y N
HN
80-39 S N 525.3 526.2 3.56
pINH
H
N-
~N \
NY N
80-40 HN 525.3 526.2 3.53
S-Nl~
pl NH
H
'N
\ I
N
NY N
80-41 HN 576.2 577.3 3.29
S-N
CF
3
0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
217
EXAMPLE 81
SEM
SEM N'
N
H2N N NaH / DMF/ RT ~N \
N
~
NY'~-N O O Step A HN S,0==0 \ ~ ~N
I O
O\
SEM H
N- -
1) LAH, THF N 1) amine, K2CO3 / 80 C 5:P'N
NN NN
2) MsCI / Et3N
HN S2) 2N HCI, dioxane HN S.
Step '
p Step C
C0Ms NRZ
Step A: The starting sulfone was prepared by essentially the same procedure
described in Example 6 except that ethylboronic acid or cyclopropylboronic
acid was
used. Final products listed in Table 17 were obtained by using the procedures
described for Example 76.
TABLE 17
LCMS
Example Column 2 MW MH+ HPLC
MS tR
m/z
H
N-
\I'
N
81-1 N N 440.2 441.2 1.21
Y
HN
I
N
/r0H
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
218
H
N-
\ I,
N
N ~ _N
81 _2 HN 440.2 441.2 1.29
I/
N
O --\
H
N-
\ I ,
N
81-3 N Y~- N 422.2 423.1 1.26
HN g~
/
N
H
N-
\ I,
N
NY
81-4 N I 424.2 425.2 1.29
HN g~
~ k
N
H
\ `I
N \
81-5 NY-,-- N 436.2 437.2 1.34
HN g~
~ N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
219
H
\~r
N
81-6 N~N 492.2 493.3 3.34
HN
, /N
N OH
H
\~r
N \
81-7 N~N 478.2 479.3 3.17
H N
, /N
N OH
H
N`
N \
81-8 NYl-- N 494.2 495.3 2.93
HN IgO
/N
N OH
H
N`
N
81-9 NY-1--- N 434.2 435.3 3.08
H N g~
, /N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
220
H
\ `I
N
81-10 N~N 408.2 409.3 2.86
HN g~ N
N
~
H
N-
N
81-11 N N 422.2 423.3 2.97
HN g~
N
N
H
N-
~ f.
N
81-12 N N 434.2 435.3 3.07
Y `
HN g, N
N
H
N-N
81-13 N N 436.2 437.3 3.12
~
HN
/N
N
-A~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
221
H
N'N
~ N \
~
81-14 N N 432.2 433.3 2.98
HN S~
, /
N
H
\~r
N
81-15 N N 452.2 453.3 2.97
HN S~
E / N
N
HO\~
H " \
N-
\ f'
N
N Y _
81-16 N 452.2 453.3 3.15
HN g~
T N - /O
N
H
N-
N
81-17 NY-1- N 434.2 435.3 3.07
HN S~ / N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
222
H
\~r
N \
81-18 N Y ' N 448.2 449.3 3.29
HN gI N
N
~
H
N`
N
NY_
81-19 N 478.2 479.3 3.35
HN g~
t N
N
EXAMPLE 82
<N. ,SEM N, ,SEM <JNH
N N Step A ~N \ Step B ~N \
NY-1--- N NN --~ N` N
HN N~T SNHNY S~
~ ~N ~ ~N y ~N
R
OMs NH
Step A: The title compound was prepared using as described for Example 7
except
that t-butylamine was used.
Step B: To a solution of the product of Step A (1 equivalent) in THF (3 mL)
was added
DIEA (3 equivalents), and the respective trifilate (1.2 equivalents) at room
temperature. The reaction was heated at reflux until consumption of starting
material
was observed by LC-MS analysis. The solution was cooled to room temperature
and
concentrated under reduced pressure. Purification by column chromatography
(Si02,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
223
30% ethyl acetate/dichloromethane) afforded the desired coupled intermediate.
This
material was dissolved in 1,4-dioxane, HCI (4N in dioxane) was added and the
mixture
was sonicated until such time that HPLC indicated no starting material
remained. The
mixture was concentrated under reduced pressure, purified by prep-HPLC, and
conversion to the hydrochloride salt afforded the title compounds as off-white
solids in
Table 18.
TABLE 18
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
tNH
H3C\ ^N
101-1 N 464.2 465.1 5.22
HN S
f IN
/-CF3
N
k
N'NH
H3C\
N
101-2 S 446.2 447.2 4.09
HNT IN
/-CHF2
EXAMPLE 83
N, , SEM N, , SEM N-
~ N N NH
N Step A 5:;'N \ Step B N
NY-- N NY-`N NY N
HN ' H N ' HN SI IN I IN N
OMs SCH3 S02CH3
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
224
Step A: Sodium thiomethoxide (39 mg, 3.00 equiv) was added to a stirring
mixture of
mesylate prepared in example 7(100 mg, 1.00 equiv) and sodium iodide (14 mg,
0.50
equiv) in DMF (6 mL) at room temperature. The resulting mixture was allowed to
stir
for 2.5 hours at which time LC-MS analysis indicated the reaction was
complete. The
reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and
then
extracted with dichloromethane (2 x 70 mL). The combined organics were dried
over
anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to
afford
the title compound as a yellow solid, 100 mg (>99%).
Step B: m-Chloroperbenzoic acid (66 mg, 2.05 equiv) was added to a stirring
solution
of compound from Step A (91 mg, 1.00 equiv) in dichloromethane (3 mL) at room
temperature. The mixture was allowed to stir for 2 hours at which time thin
layer
chromatography indicated the reaction was complete. The mixture was diluted
with
ethyl acetate (40 mL) and then washed with saturated aqueous sodium
bicarbonate
(15 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. This material was dissolved in 1,4-
dioxane,
HCI (4N in dioxane) was added and the mixture was sonicated until such time
that
HPLC indicated no starting material remained. The mixture was concentrated
under
reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride
salt
afforded the title compound as an off-white solid, 18 mg (27%). 'H NMR (300
MHz,
DMSO-d6) S 12.19 (s, 1 H), 8.24 (s, 2H), 7.96 (s, 1 H), 7.83 (s, 1 H), 7.28
(s, 1 H), 4.61
(s, 2H), 3.01 (s, 3H), 2.53 (s, 3H). HPLC tr = 4.04 min (UV 254nm). Mass
calculated for
C15H15N702S2 389.1; observed MH+ (MS) 390.7 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
225
EXAMPLE 84
/ F Step A c(0,N11IIII) F Step BO / I F S~p C F
--' ~ S N -~ H2N S I N
O O O 0
SEM SEM H
SEM \ -
\~r 1
Step D~N \ Step E N Step F~N
N_ 1\N N
+ ~N \ -- N~N NN N
Y ` HN ~ HN
S02Me S/ F S/ F HN ~/ F
NNo S No
Step A: EtN(iPr)2 (10.55 mL, 60.69 mmol) was added at 0 C to acid (2953 mg,
20.23
mmol, prepared according to Bioorganic & Medicinal Chemistry, 11(20), 4333-
4340;
2003), EDCI (5817 mg, 30.34 mmol), HOBT (4100 mg, 30.34 mmol) and piperidine
(2398 uL, 24.28 mmol) in DMF (100 mL). After stirring at room temperature
overnight,
the crude reaction material was diluted with EtOAc and washed with brine (2X).
The
organic layer was dried over Na2SO4, filtered, and concentrated to give the
crude
product which was chromatographed to give the product amide. HPLC-MS tR =1.57
Min (UV 254nm)=Mass calculated for formula, M+ 213.0, observed LC/MS m/z 214.1
(M+H).
Step B: Powdered KNO3 (1100.8 mg, 10.89 mmol) was added portionwise to a
stirred
solution of amide (927.6 mg, 4.356 mmol) in conc. H2SO4 (20 mL) at 0 C. After
stirring
at 0 C for 30 min, the reaction mixture was poured onto ice. Extraction with
CH2CI2
and the combined organic lawyer was washed with H20, dried over Na2SO4 and
concentrated. Purification by column chromatography afforded first the
undesired
nitration product 545.5 mg (48.5%), HPLC-MS tR = 1.79 Min (UV 254nm)= Mass
calculated for M+ 258.0, observed LC/MS m/z 259.1(M+H),'HNMR (400 MHz, CDCI3)
6 7.58 (d, 1 H, J = 0.4 Hz), 3.67 (m, 4H), 1.73 (m, 6H), then the desired
nitration
product 435.6 mg (38.8%), HPLC-MS tR = 1.68 Min (UV 254nm). Mass calculated
for M+
258.0, observed LC/MS m/z 259.1(M+H).1 H NMR (400 MHz, CDC13) 6 8.37 (d, 1H, J
= 3.2 Hz), 3.67 (m, 4H), 1.71 (m, 6H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
226
Step C: To a solution of nitroamide (435.6 mg, 1.69 mmol) in HOAc (20 mL) was
added iron powder (471.5 mg, 8.44 mmol). The reaction mixture was heated at 70
C
for 30 min. The mixture was cooled to room temperature and concentrated to
dryness. To the residue was added 30mL of 20% MeOH/CH2CI2 followed by 20 mL of
saturated aqueous NaHCO3. The mixture was stirred until it stoped bobbling.
The
mixture was extracted by EtOAc (x 2), dried over Na2SO4, and then
concentrated. The
crude amine was used for displacement reaction without further purification.
HPLC-
MS tR = 1.32 Min (UV 254nm). Mass calculated for M+ 228.0, observed LC/MS m/z
229.1(M+H).
Step D: A solution of crude amine from Step C (491.5 mg, 2.156 mmol) and
sulfone
(292 mg, 0.719 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in
oil,
172.5 mg, 4.312 mmol) at room temperature. The mixture was stirred until LCMS
indicated the reaction was complete. The reaction mixture was diluted with
EtOAc,
washed with sat NH4CI, dried with Na2SO4, and concentrated to afford crude
product
4. Purification afforded compound 4. HPLC-MS tR = 2.503 Min (UV 254nm). Mass
calculated for M+ 555.2, observed LC/MS m/z 556.3(M+H).
Step E: To a solution of the amide from Step D (120 mg, 0.216 mmol) in
dichloromethane (12 mL) was added lithium aluminum hydride (86.4 mg, 2.162
mmol)
and ethyl ether (3 mL) at 0 C. The reaction mixture was stirred at room
temperature
until LCMS indicate the reaction was complete. The reaction was quenched with
H20
(86 uL), 3N NaOH (86 uL) and H20 (264 uL). The reaction was filtered and
concentrated to afford crude compound 5. HPLC-MS tR = 1.738 Min (UV 254nm).
Mass
calculated for M+ 541.2, observed LC/MS m/z 542.2 (M+H).
Step F: 4N HCI in dioxane (3mL) was added to crude product from Step E at 0 C.
The
mixture was stirred at room temperature until LCMS indicated the reaction was
complete. Concentration afforded crude product. Purification by Prep-LC and
conversion to a hydrochloric salt afforded the title compound. HPLC-MS tR =
0.923
Min (UV 254nm). Mass calculated for M+ 411.1, observed LC/MS m/z 412.2 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
227
EXAMPLE 85
H
N-
\
N
N~/ N
HN -~/
S
N
By essentially the same procedure given in Example 84, the title compound can
be
prepared. HPLC-MS tR = 1.005 Min (UV 254nm). Mass calculated for M+ 425.1,
observed LC/MS m/z 426.2 (M+H).
EXAMPLE 86
SEM
N-
NEM
~ IJV /N
A / ~ I+ B c
OZN I IO HZN _O N ~ -- N\~N
II S~ T
O 0 HN
SO2Me
O
O
SEM SEM NEM
N-
D I` F
N N
~ ---- N~N E - NY-,--N - N
H N ~ H N HN _ N~N
S/ S HN ~
OH O Na F S / ^
}-F
Step A: To a solution of nitroester (2285 mg, 12.22 mmol) in HOAc (55 mL) was
added iron powder (6825 mg, 122.20 mmol). The reaction mixture was heated at
75 C for 10 min. The mixture was cooled to room temperature and then added 200
mL of MeOH. The resulting mixture was filtered through celite (the celite was
rinsed
with additional amount MeOH). The filtrate was concentrated to remove most of
AcOH. To the residue was added 50 mL of 20% MeOH/CH2CI2 followed by saturated
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
228
aqueous NaHCO3 until it stoped bubbling. The mixture was extracted by EtOAc (x
2),
dried over Na2SO4, and then concentrated. The crude amine was used without
further
purification. HPLC-MS tR = 1.07 Min (UV 254,m). Mass calculated for M+
157Ø0,
observed LC/MS m/z 158.1(M+H).
Step B: To a solution of the aminoester (850 mg, 5.414 mmol)) and sulfone from
Example 1 (1 equivalent, 1469 mg, 3.609 mmol) in DMSO (36 mL) was treated with
NaH (60% dispersion in oil, 14.43 mmol, 577 mg) at room temperature
portionwise.
After 10 min, LC-MS analysis of the reaction indicated the reaction was
complete.
While cooling by water bath, the reaction was quenched with sat. NH4C1
dropwise (5
ml) and then added H20 (160 ml) extracted with ethyl acetate (2x). The
combined
organic layers were washed with brine and dried (sodium sulfate). Evaporation
and
purification by column chromatography (0 to 100% EtOAc/Hexane) afforded title
compound (1492 mg, 85%). HPLC-MS tR = 2.41 Min (UV 254nm). Mass calculated for
M+ 484.1, observed LC/MS m/z 485.2 (M+H).
Step C: To a solution of the product of Step B (206 mg, 0.4271 mmol) in THF (8
mL)
was treated with DIBAL (1.0 M in CH2C12, 2.56 mL) at -78 C dropwise. After
stirring at
-78 C for 4.5h, LCMS indicated the existence of small amount of starting
material..
Two more equivalents DIBAL (0.85 mL) were added. After stirring at -78 C for
another
0.5 h, brine (6 mL) was added portionwise at -78 C to quench the excess
reagents.
The reaction mixture was extracted with CH2CI2 (3X). Evaporation of solvent
and
purification by column chromatography (0 -> 100% 2% MeOH in EtOAc/Hexane)
afforded alcohol (153 mg, 79%). HPLC-MS tR = 2.01 Min (UV 254nm). Mass
calculated
for M+ 456.1, observed LC/MS m/z 457.1 (M+H).
Step D: To a solution of alcohol from Step C (537 mg, 1.17 mmol) in THF (26
mL),
was added H20 (0.078 mL) followed by Dess-Martin periodinane (599 mg, 1.41
mmol) at 0 C. The reaction was stirred at room temperature until LCMS
indicated the
reaction was complete. The reaction mixture was diluted with CH2CI2, and
washed
with saturated aqueous NH4CI solution. The organic was dried over anhydrous
Na2SO4 and then concentrated. Purification by column chromatography afforded
aldehyde (237.1 mg, 44%). HPLC-MS tR = 2.15 Min (UV 254nm). Mass calculated
for
M+ 454.1, observed LC/MS m/z 455.1 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
229
Step E: To a mixture of aldehyde (94 mg, 0.21 mmol) and 4-fluoropiperidine
hydrochloride (58 mg, 0.41 mmol) in DCE (10 mL) was added DIEA (144 uL, 0.828
mmol), followed by NaBH(OAc)3 (139 mg, 0.62 mmol). The reaction mixture was
stirred at room temperature ovemight and then diluted with CH2CI2, and washed
with
saturated NaHCO3 solution. The organic was dried over anhydrous Na2SO4 and
then
concentrated. The crude product was used without purification for next step.
HPLC-
MS tR = 1.57 Min (UV 254,1m). Mass calculated for M+ 541.2, observed LC/MS m/z
542.2 (M+H).
Step F: 4N HCI in dioxane (5mL) was added to crude amine at 0 C. The mixture
was
stirred at room temperature until LCMS indicated the reaction was complete.
Concentration and purification by Prep-LC the title compound. HPLC-MS tR =
0.89
Min (UV 254nm). Mass calculated for M+ 411.1, observed LC/MS m/z 412.1 (M+H).
EXAMPLE 87
H
N -
\ I ,
N
NY _N
HN ~
S ~
Na F
F
By essentially the same procedure as Example 86, the title compound can be
prepared. HPLC-MS tR = 0.97 Min (UV 254nm). Mass calculated for M+ 429.1,
observed
LC/MS m/z 430.1 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
230
EXAMPLE 88
H
N- N
N
NY N
HNI l S F N F
By essentially the same procedure as Example 86, the title compound can be
prepared. HPLC-MS tR = 0.99 Min (UV 254nm). Mass calculated for M+ 443.1,
observed
LC/MS m/z 444.1 (M+H).
EXAMPLE 89
SEM SEM SEM SEM
-~'
Br B
~/~N N c F / N
T~` l- N N -)- N N N N Y-,-- N
N Y
SMe SMe SMe SOZMe
SEM SEM
N-~ F
a
N F
+ H2N ~ D N` ~ E - F NN ---
S~COZMe ~ N HN
N HN
-COZMe
~
S-N S_N OH
SEM H
F a
F F N \ G N
N\/ N N~N
HiN HN
S-N OMs S N N
Part A: A mixture of 6-bromo compound (4562 mg, 10.39 mmol), PdCl2dppf (424.3
mg, 0.519 mmoL), Cul (296.9 mg, 1.56 mmol) and tributyl(1-ethoxyvinyl)tin
(5617 uL,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
231
16.627 mmol) in CH3CN (100 mL) was refluxing until LCMS indicate the reaction
was
complete. 1 N HCI (15 mL) was added and the mixture was stirred until LCMS
indicate
the conversion to ketone. The reaction mixture was diluted with EtOAc, washed
with
sat NH4C1, dried with Na2SO4, and concentrated. Purification afforded ketone
(3200
mg, 76%). HPLC-MS tR = 2.32 Min (UV 254nm)= Mass calculated for M+ 403.1,
observed LC/MS m/z 404.2 (M+H).
Part B: Bis(2-methoxyethyl)aminosulfur trifluoride (2745 uL, 14.89 mmoL) was
added
dropwise to ketone from Part A (600 mg, 1.489 mmoL) in CH2CI2 (1 mL) at 0 C.
The
mixture was stirred at room temperature for 1 week and then carefully added
dropeise
to Sat NaHCO3 solution. The mixture was extracted with CH2CI2 and the organic
layer
was dried over Na2SO4, and concentrated. Purification afforded di-fluoro
compound.
HPLC-MS tR = 2.52 Min (UV 254nm). Mass calculated for M+ 425.1, observed LC/MS
m/z 426.2 (M+H).
Part C: m-CPBA (1515.7 mg, 6.76 mmoL) was added to a solution the product of
Part
B (1307 mg, 3.07 mmoL) in CH2CI2 (31 mL). After stirring at room temperature
for 2h,
the reaction mixture was diluted with EtOAc, washed with sat NaHCO3, dried
with
Na2SO4, and concentrated. The sulfone (5-A) was used directly without further
purification. HPLC-MS tR = 2.17 Min (UV 254nm). Mass calculated for M+ 457.1,
observed LC/MS m/z 458.0 (M+H).
Part D: To a solution of the aminoisothiazole (400 mg, 2.53 mmol) and sulfone
from
Part C (964 mg, 2.11 mmol) in DMF (13 mL) was treated with NaH (60% dispersion
in
oil, 4.64 mmol, 186 mg) at room temperature. The mixture was stirred until
LCMS
indicate the reaction was complete. The reaction mixture was diluted with
EtOAc,
washed with sat NH4CI, dried with Na2SO4, and concentrated. Purification
afforded
the displacement product (438.5 mg, 39%). HPLC-MS tR = 2.22 Min (UV 254nm).
Mass
calculated for M+ 535.1, observed LC/MS m/z 536.1 (M+H).
Part E: To the solution of ester (406.5 mg, 0.759 mmol) in THF (39 mL) was
added
LiBHEt3 (3.79 mL, 1 M solution in THF). The reaction was stirred at room
temperature
for 30 min. It was quenched by adding saturated aqueous NH4CI (15 mL). The
mixture was extracted by 30 mL of CH2CI2. The organic was concentrated and the
crude alcohol was used for next step without further purification. HPLC-MS tR
= 1.99
Min (UV 254nm). Mass calculated for M+ 507.1, observed LC/MS m/z 508.1 (M+H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
232
Part F: To a solution of crude alcohol from Part E in THF (40 mL), was added
triethylamine (365 uL, 2.62 mmol) and methanesulfonylchloride (173 uL, 2.23
mmol).
The reaction was stirred at room temperature for 30 min. It was quenched by
adding
MeOH. The solution was diluted by 30 mL of CH2CI2, washed consecutively with
15
mL of 2 N aqueous HCI, water, and brine. The solvent was removed under vacuum
to
give crude mesylate which was used in next transformations without further
purification. HPLC-MS tR = 2.35 Min (UV 254nm)= Mass calculated for M+ 585.1,
observed LC/MS m/z 586.1 (M+H).
Part G: A mixture of crude compound (30mg, 0.051 mmol), 3-methyl piperidine
(24 uL,
0.205 mmol), EtN(iPr)2 (54 uL, 0.307 mmol) and Nal (1 mg) in THF (2ml) was
heated
at 80 C for 1 h and 10 min. The mixture was cooled dot room temperature and
then
concentrated. 4N HCI in dioxane (3mL) was added to crude displacement product
at
0 C. The mixture was stirred at room temperature until LCMS indicated the
reaction
was complete. Concentration and purification afforded compound 5-1. HPLC-MS tR
=
1.27 Min (UV 254nm). Mass calculated for M+ 458.1, observed LC/MS m/z 459.1
(M+H).
By essentially the same procedure given in Example 89, the compounds listed in
Table 19 can be prepared.
Table 19
LCMS MH+ HPLC
Example Column 2 MW m/z MS tR
H
N'N
F F
N_ \
89-2 N~IN 444.1 445.1 1.20
HN~ ^ ~
'(S~-N~- 0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
233
H
N'N
F F
i I N_
89-3 N~IN 458.1 459.1 1.26
HN S-N
N- I N
F F
~N
89-4 NY-,-- N 502.2 503.2 1.18
HN` ^
S-NN
OH
H
N'
I N
F
N
89_5 Nl,)'-N 516.2 517.2 1.23
HN` ^
NQ OH
H
N'
I N
F F
~N
89_6 NY-,-- N 502.2 503.2 1.36
HN S-N ~~J -
O-l
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
234
H
N'N
F F
NI_
89-7 N~N 432.1 433.1 1.19
HN~ ^
S(~ N~- \N--\
H
N'N
F F
N
89-8 NY-1- N 518.1 519.1 1.20
HN O
i
S-N N
\ HO
H
N'
I N
F F
i I N
89-9 N~ N 446.1 447.1 1.22
HN~
S`N N-~
H
N'
~ N
F F
~ I N
NY-1--- N 472.1 43.2 1.34
89-10
HN
S-N~--\N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
235
N-N
F F
,
N
NN 476.1 477.1 1.19
89-11
HN~
S N N-~
p
\,-
H
N'
I N
F F
N
89-12 NY-1--- N 456.1 457.1 1.13
HN~ ^
~S~-Nk-\N
H
N'
I N
F F
~N
89-13 N~N 476.1 477.1 1.06
HN~ pH
S NN-Y
H
N'
I N
F F
j~N
89-14 N~N 460.1 461.2 1.13
HN~ ^
S(~~N~N4L
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
236
H
N'N
F F
N
89-15 NN 458.1 459.2 1.26
HN\ ^
~S/-N~N
EXAMPLE 90
SEM SEM SEM SEM
- N-r `~' \ -N
~
N Step A ~N \ Step B ~N \ Step C- N
I _ -- - 1/
NN NY'L-- N N~N NN
SEM"N 1/ SEMN SEM"N i SEM"N
~S-NOMs S-N CN S_NH2 S-OH
Step A: To a solution of mesylate (1.1 g, 1.65 mmol) in DMSO (20 mL) at room
temperature was added Nal (280 mg, 1.88 mmol) and NaCN (300 mg, 6.12 mmol).
The mixture was stirred at 60 C for 1 h. It was diluted with 200 mL of EtOAc
and
washed with water (200 mL X 2). The solvent was removed under vacuum. The
residue was purified by column chromatography (Si02, 60% EtOAc/hexanes) to
afford
980 mg of the title compound. 'H NMR (400 MHz, CDCI3) b 7.90 (s, 1 H), 7.82
(s, 1 H),
7.63 (s, 1 H), 7.58 (s, 1 H), 7.20 (s, 1 H), 6.61 (brs, 2H), 5.56 (s, 2H),
3.88 (s, 2H), 3.75
(t, 2H), 3.65 (t, 2H), 2.53 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.07 (s,
9H).
Step B: A solution of compound from Step A (530 mg, 0.889 mmol) in 30 mL of
CH2CI2 was cooled to 0 C. To this was slowly added DIBAL-H solution (1 M in
CH2CI2, 3.56 mL, 3.56 mmol). The reaction was stirred at 0 C for 20 min. It
was
quenched with 1 mL of MeOH, and the resulting solution was stirred at room
temperature with 50 mL of saturated Rochelle salt solution for 2 h. The
organic layer
was isolated and the solvent was removed under vacuum. The residue was
purified
by column chromatography (Si02, 10% 7N NH3 in MeOH/ CH2CI2) to give 450 mg of
the title compound. 'H NMR (400 MHz, CDCI3) 6 7.90 (s, 1H), 7:83 (s, 1H), 7.63
(s,
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
237
1 H), 7.58 (s, 1 H), 7.05 (s, 1 H), 6.65 (brs, 2H), 5.55 (s, 2H), 3.75 (t,
2H), 3.65 (t, 2H),
3.16 (t, 2H), 2.95 (t, 2H), 2.52 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08
(s, 9H).
Step C: A solution of compound from Step B (400 mg, 0.667 mmol) and NaOAc (400
mg, 4.88 mmol) in 20 mL of AcOH was stirred at 60 C. To this was slowly added
t-
butyl nitrite (1.40 mL, 11.8 mmol). The reaction was stirred at 60 C for 20
min. It was
cooled to room temperature and added 20 mL of CH2CI2. The solid was filtered
off,
and the solvent in the filtrate was removed under vacuum. The residue was
diluted
with 100 mL of CH2CI2 and washed with 50 mL of saturated NaHCO3 aqueous
solution. The organic portion was concentrated. The residuw was dissolved in
10 mL
of MeOH. To this solution was added a solution of NaOH (200 mg) in 1 mL of
water.
After stirred at room temperature for 30 min, it was diluted with 100 mL of
CH2CI2 and
washed with 100 mL of brine. The solvent was removed under vacuum. The residue
was purified by column chromatography (Si02, 75% EtOAc/hexanes) to give 240 mg
of
the title compound. ' H NMR (400 MHz, CDCI3) b 7.90 (s, 1 H), 7.81 (s, 1 H),
7.63 (s,
1 H), 7.58 (s, 1 H), 7.05 (s, 1 H), 6.65 (brs, 2H), 5.57 (s, 2H), 4.03 (t,
2H), 3.75 (t, 2H),
3.65 (t, 2H), 3.01(t, 2H), 2.52 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s,
9H).
EXAMPLE 91
SEM SEM SEM H
, \ , N, \ -
N- r
N St--~~N Step Step N \ ~N NN
N N N~ ~ N
HN
SEM"N SEM i/ SEM"N
S'N OH S-N OMs 1-N N S SN
0
S
Step A: To a solution of Example 90 (200 mg, 0.333 mol) in 10 mL of THF, was
added
NEt3 (84 mg, 0.830 mmol) followed by methanesulfonyl chloride (76.4 mg, 0.667
mmol). The reaction was stirred at room temperature for 20 min. It was
quenched by
adding 10 mL of water and diluted with 50 mL of CH2CI2. The mixture was washed
with 20 mL of 0.5 N aqueous HCI solution. The organic was dried over anhydrous
Na2SO4. The solvent was removed under vacuum. The residue was purified by
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
238
column chromatography (Si02, 70% EtOAc/hexanes) to give 180 mg of the title
compound.
Step B: A mixture of mesylate from Step A (42 mg, 0.062 mmol), thiomorpholine
(16
mg, 0.16 mmol), K2CO3 (8.5 mg, 0.062 mmol) and a trace amount of Nal in 1.5 mL
of
THF was stirred at 80 C for 24 h. It was cooled to room temperature. The
solvent
was removed under vacuum. The residue was purified by column chromatography
(Si02, 5% 7 N NH3 in MeOH/CH2CI2) to give 37 mg of the title compound. 'H NMR
(400 MHz, CDCI3) b 7.88 (s, 1 H), 7.81 (s, 1 H), 7.64 (s, 1 H), 7.57 (s, 1 H),
7.05 (s, 1 H),
6.64 (brs, 2H), 5.55 (s, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 2.64-3.08(m, 8H),
2.52 (s, 3H),
0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H).
Step C: To a solution of product from Step B (37 mg, 0.054 mmol) in 2 mL of
THF/MeOH (1:1) stirred at 80 C, was added 0.5 mL of 4 N HCI in dioxane
solution.
The reaction was stirred at 80 C for 30 min. It was cooled to room
temperature and
diluted with 2 mL of THF and 1 mL of ether. The solid was collected by
filtration and
washed with ether to give 26 mg of the title compound as its HCI salt form.
HPLC-MS
tR = 2.21 min (UV 254nm). Mass calculated for formula C19H2ON$OS 426.1;
observed
MH+ (LCMS) 427.2 (m/z).
By essentially the same procedure set forth in Example 91 only replacing
thiomorpholine with other respective aliphatic amines in Step B, compounds
shown in
column 2 of Table 20 were prepared.
TABLE 20
LCMS
HPLC
Example Column 2 MW MH+
MS tR
m/z
H
N'
I N
\
91-1 NN 410.5 411.2 1.95
N
HN ~
S N
N \-j
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
239
N-N
91-2 N\ N 396.5 397.2 2.38
~N
HN ~
S-N N
H
N'
I N
91-3 N N 408.5 409.2 2.51
N
HN
N No
N- I N
\
N
91-4 NY-,-- N 426.5 427.2 2.29
HN
NNo
N'
I N
~N \
91-5 Yl- N OEt 440.6 441.2 2.52
HN
S- N ~NJ
/
H
NV
~N \
91-6 NY-,-- N 424.6 425.2 2.60
HN
S-NJJJ
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
240
N,
I N
N
91-7 NY-1-- N 422.5 423.2 2.46
HN ~
S- N
H
N'
~ N
~N \
91-8 N~N 476.5 477.3 2.62
HN ~~_
/~ \_N~CF
SN
EXAMPLE 92
SEM SEM H
SEM
% N, Y Y
'r \ N Step AN Step B N N
"
N St ~
N _~
- N ~ " " N
NyL- N
" SEM~N SEM-" HN Y
SEM" Z CHO S_
N Br SN O S-N O
S-" Br ON N
0
Step A: To a solution of carbon tetrabromide (170 mg, 0.512 mmol) in 4 mL of
CH2CI2
stirred at 0 C, was added PPh3 (267 mg, 1.02 mmol). The reaction was stirred
at 0
C for 15 min when the aidehyde (200 mg, 0.341 mmol) was added. The resulting
solution was further stirred at 0 C for 15 min. It was quenched with 10 mL of
saturated NaHCO3 aqueous solution. The mixture was extracted by 20 mL of
CH2CI2.
The aqueous phase was further extracted by CH2CI2 (10 mL X 2). The combined
organics were concentrated and further purified by column chromatography
(Si02,
50% EtOAc/hexanes) to give 150 mg of the title compound.
Step B: A stirred solution of compound from Step A (40 mg, 0.054 mmol) and
pyrrolidine (30 mg, 0.43 mmol) in 0.6 mL of DMSO and 0.15 mL of water was
stirred
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
241
at 100 C for 3 h. It was cooled to room temperature and diluted with 15 mL of
CH2CI2. The content was washed with water, saturated aqueous NaHCO3 and brine
sequentially. The organic was concentrated and purified by column
chromatography
(Si02, 3.5% 7 N NH3 in MeOH/ CH2CI2) to give 20 mg of the title compound. 'H
NMR
(400 MHz, CDCI3) b 7.88 (s, 1 H), 7.81 (s, 1 H), 7.64 (s, 1 H), 7.57 (s, 1 H),
7.18 (s, 1 H),
6.62 (brs, 2H), 5.55 (s, 2H), 3.90 (s, 2H), 3.75 (t, 2H), 3.67 (t, 2H), 3.45-
3.62 (m, 4H),
2.52 (s, 3H), 1.35-1.63 (m, 6H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s, 9H).
Step C: A solution of compound from Part B (20 mg, 0.029 mmol) in 1 mL of THF
and
2 mL of TFA was stirred at 60 C for 2 h. The solvent was removed under
vacuum.
The residue was dissolved in 2 mL of THF. To the stirred solution was added 1
mL of
1 M HCI in ether.The solid was collected by filtration and washed with ether
to give 10
mg of the title compound as its HCI salt form. HPLC-MS tR = 2.55 min (UV
254nm).
Mass calculated for formula C19H2ON80S 408.2; observed MH+ (LCMS) 409.2 (m/z).
By essentially the same procedure set forth in Example 92, only replacing
pyrrolidine with other respective aliphatic amines in Step B, compounds shown
in
column 2 of Table 21 were prepared.
TABLE 21
LCMS
HPLC
Example Column 2 MW MH+
MS tR
m/z
N- I N
N
92-1 N`~N 422.5 423.2 2.83
H~N' n
0
S N No
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
242
H
N-
I N
N
92-2 Nyj'-N 436.5 437.2 3.15
HN
S N N~
O
N-
I N
N
92-3 NN 410.5 411.2 2.82
HN
S-N N
O
H
N-
I N
~N \
92-4 N\ ~N 440.5 441.2 2.92
H~N' ~
_ S
S N N
O
H
N
92-5 N \ ~ \ 424.1
N
HN 5:
SN
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
243
EXAMPLE 93
SE
H
SEM
%
SE N, \ '~1 `
N'~v
~ ~N N
N Step A I N Step B' N, Step C N\~N
N~ ~ -- N Y_ N `r
~N I I
SEM"N i HN ~
SEM"N1/\ SEMN1/\ /
S_N
S'N N
/
S'N Br bo
S'N OMs .
Step A: To a solution of mesylate (560 mg, 0.841 mmol) in 16 mL of acetone was
added LiBr (730 mg, 8.41 mmol). The mixture was stirred at room temperature
for 1.5
h. It was diluted with 100 mL of CH2CI2 and washed with brine (100 mL). The
solvent
was removed under vacuum. The residue was purified by column chromatography
(Si02, 40% EtOAc/hexanes) to give 506 mg of the title compound. 6 7.88 (s, 1
H), 7.81
(s, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.30 (s, 1 H), 6.70 (brs, 2H), 5.57
(s, 2H), 4.55 (s,
2H), 3.78 (t, 2H), 3.68 (t, 2H), 2.56 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -
0.08 (s, 9H).
Step B: To a solution of compound from Step A (40 mg, 0.061 mmol) in 1.5 mL of
THF, was added 2-tri-n-butylstannylpyridine (45 mg, 0.12 mmol), and Pd(PPh3)4
(17
mg, 0.015 mmol). The reaction was stirred at 80 C in a sealed vial for 16 h.
The
solvent was removed under vacuum. The residue was purified by column
chromatography (Si02, 3% 7 N NH3 in MeOH/ CH2CI2) to give 32 mg of crude title
compound contaminated by triphenylphosphine oxide. This material was used in
Step
C without further purification.
Step C: The product of Step B was dissolved in 2 mL of MeOH/THF (1:1) at 80
C. To
this solution was added 0.5 mL of 4 N HCI in dioxane. The reaction was stirred
at 80
C for 30 min. It was cooled to room temperature and diluted with 1 mL of THF.
The
solid was collected by filtration and washed with THF and ether to give 15 mg
of the
title compound as its HCI salt form. 6 8.8(d, 1 H), 8.86 (t, 1 H), 8.10 (s,
3H), 7.92-8.08
(m, 3H), 7.22 (s, 1 H), 4.60 (s, 2H), 2.58 (s, 3H). HPLC-MS tR = 2.00 min (UV
254nm).
Mass calculated for formula C19H16N8S 388.1; observed MH+ (LCMS) 389.2 (m/z).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
244
By essentially the same procedure set forth in Example 93, only replacing 2-
tri-
n-butylstannylpyridine with other respective stannyl reagents in Step B,
compounds
shown in column 2 of Table 22 were prepared.
TABLE 22
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
H
N'
I N
N
93-1 NY-,-- N 402.1
HN TN,
N
H
N'
~ N
N
93-2 NY-,-- N 402.1
HN ~
/
S-N
N
H
N'
I N
N
93-3 NY-,-- N 402.1
HN
S-N
N
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
245
H
N'
~ N
N
93-4 N N 402.1
HN
S-N
N
H
N-
N
93-5 Nl,),-N 418.1
HN ~
/ OMe
S-N N/ ~
H
N'
I N
\
N
93-6 N N 418.1
HN ~
/
S-N N/
OMe
H
N-N
~N \
93-7 N~N 418.1
HN
/
S-N
OMe
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
246
H
N'
I N
N
93-8 N N 418.1
HN
S-N
N
MeO
H
N-
N
93-9 N~N 406.1
HN
/
S-N N/ \
F
H
N'N
\ I
N
93-10 N~N 466.1
HN
/
S-N
Br
H
N'N
~N \
93-11 N~N 422.1
HN
/
S-N
CI
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
247
H
N'
N
N
93-12 Nyl-- N 406.1
HN ~N/ F
S- / ~
N
H
N'N
N
93-13 NN 466.1
HNS-~
/ r
N
N
H
N'N
N
93-14 N 422.1
/ CI
HNS-~
N
N
H
N'N
N
93-15 N ~ N 431.2
HN ~
/
S-N N/ ~
NMe
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
248
H
N-I N
N
93-16 NY-1-- N 404.1
HN ~
S-N O +~ \
~-N
EXAMPLE 94
SEM SEM SEM
\~r N-r N-r
N Step A ~N Step B N
~
N
NY-L--N N)--1-N N
SEM"N SEM"N SEM"N ~ OH
CHO S- ~ S- /
N N N
MeS
SEM SEM H
N-N ~
o I
N Step C ~N \ Step D N
I' NN
NN NN
T 7 HN SMe
SEMN OH SEM"N i SMe r /
S- / S_ S'N N
N N N
MeS
Step A: To a mixture of 10 mL of THF/DMF (1:1)was added NaH (39.3 mg, 1.64
mmol). It was cooled to -10 C and a solution of trimethylsulfonium iodide
(334 mg,
1.64 mmol) in 5 mL of DMSO was then slowly added. To the resulting mixture was
added aldehyde. The reaction was stirred at room temperature for 40 min. It
was
quenched with ice water, and diluted with 50 mL of CH2CI2. The mixture was
washed
with water and brine. The solvent was removed under vacuum. The residue was
purified by column chromatography (Si02, 40% EtOAc/hexanes) to give 390 mg of
the
title compound. 6 7.90 (s, 1 H), 7.82 (s, 1 H), 7.67 (s, 1 H), 7.59 (s, 1 H),
7.10 (s, 1 H),
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
249
6.80 (brd, 1 H), 6.56 (brd, 1 H), 5.57 (s, 2H), 4.02-4.10 (m, 1 H), 3.78 (t,
2H), 3.69 (t,
2H), 3.07-3.25 (m, 2H), 2.58 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s,
9H).
Step B: A solution of compound from Step A (270 mg, 0.450 mmol) in 4 mL of DMF
was treated with sodium methanethiolate (100 mg, 1.43 mmol). The reaction was
stirred at room temperature for 30 min. It was diluted with 15 mL of water.
The
mixture was extracted with EtOAc (20 mL x 3). The combined organics were
washed
with brine (20 mL) and then concentrated. The residue was purified by column
chromatography (Si02, 70% EtOAc/hexanes) to give 220 mg of the title compound.
6
7.90 (s, 1 H), 7.82 (s, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.21 (s, 1 H),
6.76 (brd, 1 H), 6.56
(brd, 1 H), 5.57 (s, 2H), 4.94 (m, 1 H), 3.40-3.80 (m, 5H), 2.80-3.15 (m, 2H),
2.58 (s,
3H), 2.12 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H).
Step C: To a solution of compound from Step B (30 mg, 0.046 mol) in 1 mL of
THF,
was added NEt3 (14 mg, 0.14 mmol) followed by methanesulfonyl chloride (16 mg,
0.14 mmol). The reaction was stirred at room temperature for 15 min. It was
quenched by adding 2 mL of water and diluted with 15 mL of CH2CI2. The mixture
was washed with 10 mL of 0.2 N aqueous HCI solution. The organic was dried
over
anhydrous Na2SO4 and then concentrated. The residue was treated with Nal (10
mg,
0.071 mmol) and piperidine (13 mg, 0.15 mmol) in 1 mL of THF. The resulting
mixture
was stirred at 80 C for 12 h. It was diluted with 15 mL of CH2CI2 and washed
with 15
mL of saturated aqueous NaHCO3 solution. The solvent was removed under vacuum,
and the residue was purified by column chromatography (Si02, 3% 7 N NH3 in
MeOH/
CH2CI2) to give 12 mg of the title compound.
Step D: To a solution of compound from Step C (12 mg, 0.017 mmol) in 1 mL of
THF/MeOH (1:1), was added 0.5 mL of 4 N HCI in dioxane. The reaction was
stirred
at 80 C for 1 h. It was cooled to room temperature and diluted with 10 mL of
ether.
The solid was collected by filtration and washed with ether to give 8 mg of
the title
compound as its HCI salt form. HPLC-MS tR = 2.88 min (UV 254nm). Mass
calculated
for formula C21H26N$S2 454.2; observed MH+ (LCMS) 455.3 (m/z).
By essentially the same procedure set forth in Example 94, only replacing
piperidine with other respective aliphatic amines in Step B, compounds shown
in
column 2 of Table 23 were prepared.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
250
TABLE 23
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
N- N
94-1 N 440.6 441.2 2.57
N T\l-- N
HN ~
S_\' N ~--SMe
N- N
94-2 N 468.6 469.3 2.83
N\~N
HTN N
S N SMe
EXAMPLE 95
By essentially the same procedure set forth in Example 94, only replacing
sodium methanethiolate with sodium benzenethiolate in Step A, and employing
the
respective aliphatic amines to replace piperidine in Step B, compounds shown
in
column 2 of Table 24 were prepared.
TABLE 24
LCMS
Example Column 2 MW MH+ HPLC
m/z MStR
H
N'
N
95-1 N ^ 516.7 517.3 3.23
NN ~ 1
HTN ` J
S_ N SPh
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
251
H
N'
I N
95-2 N 502.6 503.3 3.09
N T\'t-- N ~
HN ~
S_\~ N ~SPh
H
N'
~ N
95-3 N 530.7 531.3 3.23
YN
HN N
S N SPh
EXAMPLE 96
SEM SEM
N \`r `
N
N \ ~ ~ \
NyL-- N NY~'-N
SEM-N SEM-N OH
~CHO
S'N S'N SO2Me
A stirred solution of dimethylsulfone (281 mg, 2.99 mmol) in 5 mL of DMF was
treated with sodium t-butoxide (287 mg, 2.99 mmol) at room temperature for 5
min.
Aldehyde was then added. The reaction was stirred at room temperature for 15
min.
It was quenched with saturated aqueous NH4CI solution (5 mL). The mixture was
diluted with 50 mL of water and extracted with 50 mL of EtOAc/hexanes (1:1),
followed by 25 mL of EtOAc. The combined organic phase was washed with brine
and then concentrated. The residue was purified by column chromatography
(Si02,
50% EtOAc/hexanes) to give 270 mg of the title compound. b 7.90 (s, 1 H), 7.82
(s,
1 H), 7.68 (s, 1 H), 7.60 (s, 1 H), 7.20 (s, 1 H), 6.67 (brs, 2H), 5.55 (s,
2H), 5.34-5.47
(brs, 1 H), 3.90-3.98 (brs, 1 H), 3.78 (t, 2H), 3.68 (t, 2H), 3.10 (s, 3H),
2.58 (s, 3H),
0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
252
By essentially the same procedure set forth in Step B and Step C in Example
96, compounds shown in column 2 of Table 25 were prepared.
TABLE 25
LCMS
Example Column 2 MW MH+ HPLC
m/z MS tR
H
N'
N
N
96-1 N~N 472.6 473.3 2.23
HN N
Me
S N SO
O
N'N
N
96-2 N` ~N 0 486.6 487.3 2.62
HN N
Me
S_N S O
O
N'
N
N
"N ~ 500.6 501.3 2.75
96-3 N\' N
HN
Me
S_N SO
0
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
253
EXAMPLE 97
SEM SEM SEM H
`~' -~' ` ~~ `N
ci ci
N Step A N Step B N Step N
N N N N NN N~N
HN
SEMN SEM"N~, I CHO SEM'N i/ _
/ /r S
S-N OH S-N S-N RN-R2 N R`~-R2
,
~
The compounds shown in column 2 of Table 24 were prepared according to the
above
reaction scheme and employing the following general procedures.
Step A: To a stirred solution of compound alcohol (1.00 g, 1.70 mmol) in 20 mL
of
THF, was added Dess-Martin periodinane (1.84 g, 4.26 mmol) and a trace amount
of
water. The reaction was stirred at room temperature for 40 min. It was diluted
with
200 mL of-CH2CI2, and washed with water and brine. The organic was dried over
anhydrous Na2SO4. The solvent was removed under vacuum. The residue was
purified by column chromatography (Si02, 40% EtOAc/hexanes) to give 250 mg of
the
title compound.
Step B: To a solution of compound from Step A (0.05 mmol) in 1 mL of
CH2CI2/MeOH
(1:1) was added the respective amine (5 equivalent) and a trace amount of
trifluoroacetic acid. The mixture was stirred at room temperature for 30 min
when
NaBH4 (10 equivalent) was added. The stirring was continued for additional 10
min.
The reaction was quenched with saturated aqueous NH4CI solution. The mixture
was
extracted with CH2CI2. The organic was concentrated and the residue was
purified by
column chromatography (Si02, 5% 7 N NH3 in MeOH/ CH2CI2) to give title
compound.
Step C: To a solution of compound from Step B(0.05 mmol) in 1 mL of THF/MeOH
(1:1), was added 1 mL of 4 N HCI in dioxane. The reaction was stirred at 80 C
for 30
min. It was cooled to room temperature and diluted with 10 mL of ether. The
solid
was collected by filtration to afford compound 97-1 and 97-2, respectively.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
254
TABLE 26
LCMS
Example Column 2 MW MH+ HPLC
MS tR
m/z
H
N'N
CI \ I
N
97-1 N~N 428.9 429.2 2.63
HN~
S-N~-~N
H
N'N
CI \ I
N
97-2 NY-1- N 446.9 447.2 2.68
HN\
~S/-NN
F
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
255
EXAMPLE 98
SEM SEM
N CH3MgBr N Et3N / MsCI
~ THF/RT N THF
SEMN H Part A SEMN ~/
Part B
S-N 0 S-N OH
R
SEM Part C N`
\~r \
1)R1R2N/THF/A N
N
2) 4N-HCI- Dioxane NY N
NY N THF-CH30H I
RN
SEMN~~^ Part D 10-3 (R = SEM) ~
S,N N.R
S-N OMs YX (R = H) R2
Part A: To a solution of the isothiazole-aldehyde (534 mg; 0.9 mmol) in
anhydrous
THF (9 mL) was added methyl magnesium bromide (3M; 1.8 mL) at room
temperature. After stirring for 20 min, the reaction mixture was quenched with
5 mL of
saturated aqueous NH4CI solution and diluted with CH2CI2. The organic layer
was
washed with water and brine. The aqueous layer was back extracted with CH2CI2.
The
combined organic layers were dried over sodium sulfate and concentrated to
obtain
the crude product. Flash silica gel chromatography (EtOAc: CH2CI2 = 2:1) gave
the
desired carbinol as a white solid (460 mg; 84%) along with unreacted aidehyde
(50
mg). 'H-NMR (CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H); 7.55 (s, 1 H);
7.1 (s, 1 H);
6.75-6.65 (br-dd, 2H); 5.55 (s, 2H); 4.95 (t, J = 3 Hz, 1 H); 3.8 (t, J = 6
Hz, 2H); 3.7 (t, J
= 6 Hz, 2H); 2.55 (s, 3H); 1.6 (d, J = 3 Hz, 3H); 1.0 (m, 2H); 0.05 (s, 9H); -
0.05 (s, 9H).
Part B: Triethylamine (136mg; 1.35mmol) and methanesulfonyl chloride (88 mg;
0.77
mmol) were added to a solution of the carbinol from Part A (232 mg; 0.39 mmol)
in 12
mL of THF at room temperature. After 10 min, the reaction was quenched with
water
and diluted with CH2CI2. The organic layer was washed with water and brine,
dried
over Na2SO4_and concentrated to obtain crude product. Rapid elution with
CH2CI2:
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
256
EtOAc (2:1) from a flash silica gel column gave the desired mesylate as white
solid
(268 mg; 100%). 'H-NMR (CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H);
7.55 (s, 1 H);
7.3 (s, 1 H); 6.7 (br-s, 2H); 5.85 (q, J = 4 Hz, 1 H); 5.55 (s, 2H); 3.8 (t, J
= 6 Hz, 2H); 3.7
(t, J = 6 Hz, 2H); 2.95 (s, 3H); 2.6 (s, 3H); 1.85 (d, J = 4 Hz, 3H); 1.0 (m,
2H); 0.05 (s,
9H); -0.05 (s, 9H).
Part C: A solution of the mesylate (40 mg; 0.06 mmol) in 2 mL of anhydrous THF
was
treated with hexamethyleneimine (15 mg; 0.15 mmol) plus a catalytic amount of
Nal
and the mixture was heated at reflux in an oil bath (80 C; 20 h). The reaction
mixture
was cooled to room temperature and diluted with water and CH2CI2. The organic
layer
was washed with water, brine and dried over Na2SO4. Concentration in vacuo
gave
the crude product. Purification was carried out on flash silica gel column,
eluting the
product with CH2CI2 containing 2-4% of 7N-Ammonia in methanol. The desired di-
SEM protected amine product was obtained as a colorless film (31 mg; 75%).1H-
NMR
(CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H); 7.55 (s, 1 H); 7.3 (s, 1
H); 6.6 (br-s, 2H);
5.55 (s, 2H); 4.0 (br-s, 1 H); 3.8 (t, J = 6 Hz, 2H); 3.7 (t, J = 6 Hz, 2H);
2.8 (br-s, 4H);
2.6 (s, 3H); 1.75-1.5 (m, 11 H); 1.0 (m, 2H); 0.05 (s, 9H); -0.05 (s, 9H).
Part D: To a solution of the above di-SEM protected amine from Part C (31 mg;
0.045
mmol) in 0.2 mL of THF and 0.2 mL of CH3OH was added 4N-HCI in dioxane (0.2
mL). The resulting mixture was heated at 80 C in an oil bath for 30 min and
then
allowed to cool to room temperature. THF (2 mL) was added to the reaction
mixture
and the precipitated product was collected by filtration. The filer cake was
washed with
THF and ether and dried under vacuum to obtain the title product as white
solid (23
mg)-
By using appropriate Grignard reagents in the first step and appropriate amine
in the
third step in the procedures described above, all the target compounds listed
in Table
1 were prepared and characterized.
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
257
TABLE 27
LCMS
HPLC
Example Structure EM MH+
MS tR
m/z
H
\ `I
N
98-1 N-?- N 422.2 423.2 2.46
HN~ ,~
~~ /~--~
S'N N
H
I
N
98-2 NY-1- N 398.2 399.2 2.06
HN~
S-N HN
HO
H
\ `I
N
N~N 426.2 427.2 2.13
98-3 HN
S'N N
~ HO
H
N-
~ N \
98-4 N~N 396.2 397.2 2.57
HN~
S-N N--\
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
258
H
\ `I
98-5 '-T~N 422.2 423.2 2.74
N~N
HN
S'N N
H
\ `I
N
98-6 N,N 436.2 437.2 2.86
HN ~
S'N N
H
\ `I
N
98-7 N- -N 470.3 471.3 3.01
HN
S-N 0
H
ci
N \
98-8 NYl- N 440.2 441.2 2.39
HN~
/
S-N N
EtO
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
259
H
\ `I
~N \
98-9 N N 426.5 427.2 2.25
HN~ ~+
~~ /--~
S'N N
F
H
\ `I
N \
~
98-9 Ny N 440.2 441.2 2.35
HN~
S'N N
F
EXAMPLE 99
HO DPPA, Et3N, t-BuOH ~ ~
S BocHN
O O O
The substrate (500 mg) was suspended in t-BuOH (30 mL), and Et3N (0.45 mL) and
DPPA (0.73 mL) was added sequentially at room temperature. Then the mixture
was
heated at 85 C overnight. The reaction mixture was cooled to room
temperature, and
the solvent was evaporated under reduced pressure. The residue was taken up in
ethyl acetate (50 mL) and water (50 mL) was added. The biphasic mixture was
stirred
for 15 min. Then two layers were separated, and the aqueous layer was
extracted with
ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine
(50
mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give
the
crude product which was purified by column chromatography (SiO2). HPLC-MS tR =
1.70. Mass calculated for CjjH15N03S 241.08; observed MH+ (LCMS) 242.2 (m/z)
(UV254nm).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
260
EXAMPLE 100
HO ~~ OH ~TU' Et3N HO ~ NQ DPPA, Et3N
S Me(Me0)NH.HCI 'BuOH BOcHN S 11
O O O O O
Part A Part B
MgBr ~ ~ 30% TFA in CH2CI~
BocHN S TFA.HZN
THF-Et20 O
Part D s 0
Part C
N-NSEM N-NSEM N'NH
, DMF 1). Ti(OiPr)4, NaBH4, pip N
NaH
+ \~N \ N Part F
~ ~ N N
_`~
NY N Part E N Y N
I 2). HCI (PartG) HN
SOZMe HN
O 0
Part A: Diacid (3 g) was suspended in CH2CI2 (50 mL), and N,O-
dimethylhydroxylamine hydrochloride (1.69 g), HATU (6.6 g) and
diisopropylethylamine (12.12 mL) was added sequentially at room temperature.
The
reaction mixture was stirred overnight, and quenched by addition of water (100
mL).
The two layers were separated. The aqueous layer was acidified to pH 4.0, and
extracted with CHCI3 (5 x 100 mL). The organic layers were combined, and dried
(Na2SO4), filtered and evaporated under reduced pressure to give the product.
HPLC-
MS tR = 1.14. Mass calculated for C$H9NO4S 215.03; observed MH+ (LCMS) 216.1
(m/Z) (UV254nm).
Part B: The substrate from Part A (3.2 g) was suspended in t-BuOH (100 mL),
and
Et3N (2.27 mL) and DPPA (3.64 mL) was added sequentially at room temperature.
Then the mixture was heated at 85 C overnight. The reaction mixture was
cooled to
room temperature, and the solvent was evaporated under reduced pressure. The
residue was taken up in ethyl acetate (100 mL) and water (100 mL) was added.
The
biphasic mixture was stirred for 15 min. Then two layers were separated, and
the
aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined
organic
layer was washed with brine (150 mL), dried (Na2SO4), filtered and evaporated
under
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
261
reduced pressure to give the crude product which was purified by column
chromatography (Si02). HPLC-MS tR = 1.55. Mass calculated for C12H18N204S
286.1;
observed MH+ (LCMS) 287.2 (m/z) (UV254nm).
Part C: The substrate from Part B (191 mg) was dissolved in THF/Et20 (3mU6mL)
and cooled to 0 C. Then methylmagnesium bromide (0.83 mL, 2.0 M solution) was
added dropwise. The reaction mixture was warmed to room temperature, and
stirred
for 12 h and quenched by addition of saturated ammonium chloride (10 mL). The
two
layers were separated and the aqueous layer was extracted with ethyl acetate
(10
mL). The combined organic layer was washed with brine (30 mL), dried (Na2SO4),
filtered and evaporated under reduced pressure to give the crude product which
was
purified by column chromatography (Si02).
Part D: The substrate from Part C (10 mg) was dissolved in 30% TFA in CH2CI2
(2
mL), and the mixture was stirred for 30 min. Then the solvent was evaporated
under
reduced pressure and the residue was dried in vacuum. The crude product was
used
in the next step without further purification.
Part E: The sulfone (574.19 mg) and amine trifluoroacetic acid salt (514 mg)
was
dissolved in DMF (15 mL) under argon and treated with NaH (432 mg, 60%
dispersion
in oil). After LCMS indicated complete conversion of starting material to
product, the
reaction mixture was quenched with saturated ammonium chloride solution (15
mL).
Then ethyl acetate (25 mL) was added. The two layers were separated, and the
aqueous layer was extracted with ethyl acetate (25 mL). The combined organic
layer
was washed with brine (30 ml), dried (Na2SO4), filtered and evaporated under
reduced
pressure to give the crude product which was purified by column chromatography
(Si02). HPLC-MS tR = 2.31. Mass calculated for C22H28N6O2SSi 468.2; observed
MH+
(LCMS) 469.1 (m/z) (UV254nm).
Part F: Ketone (25 mg) was suspended in Ti(O-i-Pr)4 (1 mL) and treated with
piperidine (0.2 mL) under argon. The mixture was stirred at room temperature
overnight. Then methanol (2 mL) was added followed by NaBH4 (10 mg). The
reaction
mixture was stirred for additional 30 min. and quenched by addition of 2M
aqueous
NaOH (5 mL). It was filtered, and ethyl acetate (5 ml) was added to the
filtrate. The
two layers were separated, and the aqueous layer was extracted with ethyl
acetate (5
ml). The combined organic layer was dried (Na2SO4), filtered and evaporated
under
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
262
reduced pressure to give the crude product which was taken to the next step
without
further purification.
Part G: The substrate was dissolved in 4N HCI in dioxane and stirred for 30
min.
LCMS indicated complete conversion of starting material to the product. Then
solvent
was evaporated under reduced pressure, and the crude material was purified by
reverse phase HPLC. HPLC-MS tR = 1.28. Mass calculated for C21H25N7S 407.2;
observed (M-84)+ (LCMS) 323 (m/z) (UV254nm)=
The compounds in Table 28 were prepared following similar procedure.
TABLE 28
LCMS
Example Column 2 MW (M- HPLC
84)+ MS tR
m/z
N-NH
N
NY lN
100-1 HN 407.2 323 1.28
~
N-NH
N
NY N
100-2 H INs 421.2 337.1 1.34
~
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
263
EXAMPLE 101
TFAA / Et2O; H
H2N,_,-\OEt K2C03 (36%) F3CyN ~~OEt LAH / EtZO (36%) F3Cv N
Step A O Step B ,,~ OEt
Step A: To a solution of 2-ethoxyethylamine (2.0 g, 22.4 mmol) in diethyl
ether (40
mL) at 0 C was added trifluoroacetic anhydride (4.7 g, 22.4 mmol) dropwise.
The
reaction was stirred at room temperature for 1 hr. Potassium carbonate (10 g)
was
added to the reaction solution. The reaction was stirred at room temperature
for 1 hr.
The mixture was filtered through Celite and the organic filtrate was
concentrated to
give 1.5 g (36% yield) of the title compound.
Step B: A solution of the (trifluoromethyl)acetamide from Step A (1.5 g, 8.1
mmol) in
Et20 (20 mL) was added to a flask charged with lithium aluminum hydride (0.92
g,
24.3 mmol) in Et20 (20 mL). The reaction was stirred at room temperature for
30 min,
then at reflux for 12 hr. The reaction was cooled to room temperature and
quenched
with MeOH until the bubbling ceased. The reaction was diluted with Et20 (30
mL) and
filtered through a pad of Celite. The filtrate was concentrated by
distillation to give 0.5
g (36% yield) of title compound as a colorless liquid. The amine was used
without
further purification.
EXAMPLE 102
F F F
F
F O F+ F~N~\OEt pYr/CHppy(55%) F~N'-'-\OEt LAH/Et20(83%) _
O 0 StepA O Step B F OEt
Step A: To a solution of 2-ethoxyethylamine (1.0 g, 11.2 mmol) in
dichloromethane
(50 mL) at 0 C was added pyridine (2.2 g, 28.1 mmol). Difluoroacetic anhydride
(2.3
g, 13.5 mmol) was then slowly added to the reaction solution. The reaction was
further stirred at 0 C for 15 min, then at room temperature for 2.5 hr. The
reaction
was diluted with dichloromethane (50 mL) and H20 (20 mL). The reaction was
sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The
organic
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
264
phase was dried over NaSO4 and concentrated in vacuo to give 1.03 g (55%
yield) of
the (difluoromethyl)acetamide as a colorless liquid.
Step B: A solution of the (difluoromethyl)acetamide from Step A (1.04 g, 6.20
mmol)
in Et20 (21 mL) was added to a flask charged with lithium aluminum hydride
(0.47 g,
12.39 mmol) in Et20 (25 mL) at 0 C while under a N2 atmosphere. The reaction
was
stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was
quenched by the sequential addition of 0.47 mL of H20; 0.47 mL of 15 % NaOH
(aq)
solution; 1.4 mL H20. The reaction was stirred at room temperature for 15 min
then
filtered through a pad of Celite. The filtrate was concentrated by
distillation to give
0.79 g (83% yield) of the title compound as a colorless liquid. The amine was
used
without further purification.
EXAMPLE 103
H2N OH TFAA / pyr / CH2q2 (60%) F3Cy N
H OH LAH / Et20 (65%0) F3 ~N OH
A 0~ Step B 5
Step A: To a solution of 1-amino-l-cyclopentane methanol (1.0 g, 8.68 mmol) in
dichloromethane (35 mL) at 0 C was added pyridine (2.4 g, 30.4 mmol).
Trifluoroacetic anhydride (4.6 g, 21.7 mmol) was then slowly added to the
reaction
solution. The reaction was further stirred at 0 C for 15 min, then at room
temperature
for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated
NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in
vacuo to give 1.07 g (60% yield) of the title compound as a light brown
liquid. The title
compound was used directly in the next reaction (Step B) without further
purification.
Step B: A solution of the (trifluoromethyl)acetamide from Step A (0.64 g, 3.06
mmol) in
Et20 (10 mL) was added to a flask charged with lithium aluminum hydride (0.35
g, 9.1
mmol) in Et20 (30 mL) at 0 C while under a N2 atmosphere. The reaction was
stirred
under a N2 atmosphere at 0 C for 30 min, then at room temperature for 19 hr.
The
reaction was cooled to room temperature and stirred for 3 days. The reaction
was
then cooled to 0 C and quenched by the sequential addition of 0.35 mL of H20;
0.35
mL of 15 % NaOH (aq) solution; 1.05 mL H20. The reaction was stirred at room
temperature for 20 min then filtered through a pad of Celite. The filtercake
was
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
265
washed with Et20 and concentrated in vacuo to give 0.39 g (65% yield) of the
title
compound as a white solid. The amine was used without further purification.
EXAMPLE 104
~OH TFAA / pyr / CHpCIp (38%) ~ u OH LAH / Et20 (92%) F C^N "OH
H2N Step A F3C H' ~/ Step B 3 H
Step A: To a solution of 2-amino-2-methyl-l-propanol (1.0 g, 11.2 mmol) in
dichloromethane (100 mL) at 0 C was added pyridine (3.1 g, 39.6 mmol).
Trifluoroacetic anhydride (5.9 g, 28.1 mmol) was then slowly added to the
reaction
solution. The reaction was further stirred at 0 C for 15 min, then at room
temperature
for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated
NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in
vacuo to give 0.79 g (38% yield) of the title compound as a white solid.
Step B: A solution of the (trifluoromethyl)acetamide from Step A (0.79 g, 4.29
mmol) in
Et20 (43 mL) was added to a flask charged with lithium aluminum hydride (0.49
g,
12.91 mmol) in Et20 (13 mL) at 0 C while under a N2 atmosphere. The reaction
was
stirred under a N2 atmosphere at 0 C for 30 min, then at reflux for 4 hr. The
reaction
was cooled to room temperature and stirred for 3 days. The reaction was then
cooled
to 0 C and quenched by the sequential addition of 0.49 mL of H20; 0.49 mL of
15 %
NaOH (aq) solution; 1.47 mL H20. The reaction was stirred at room temperature
for
20 min, then filtered through a pad of Celite. The filtercake was washed with
Et20 and
concentrated in vacuo to give 0.67 g (92% yield) of the title compound as a
white
solid. The amine was used without further purification.
EXAMPLE105
O F ~
F~ ~F ~OH pyr/CHZCIp(74%) F` ~O~ LAH/Et20(97%) F~N OH
0 0 +HN Step A 7F H O Step B F H
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
266
Step A: To a solution of 2-amino-2-methyl-l-propanol (1.0 g, 11.2 mmol) in
dichloromethane (50 mL) at 0 C was added pyridine (2.7 g, 33.7 mmol).
Difluoroacetic anhydride (3.9 g, 22.4 mmol) was then slowly added to the
reaction
solution. The reaction was further stirred at 0 C for 15 min, then at room
temperature
for 2 hr. The reaction was diluted with dichloromethane (50 mL) and H20 (20
mL).
The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq);
brine. The organic phase was dried over NaSO4 and concentrated in vacuo to
give
2.04 g (74% yield) of the title compound as a colorless liquid.
Step B: A solution of the (difluoromethyl)acetamide from Step A (2.04 g, 8.31
mmol)
in Et20 (17 mL) was added to a flask charged with lithium aluminum hydride
(0.95 g,
24.92 mmol) in Et20 (50 mL) at 0 C while under a N2 atmosphere. The reaction
was
stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was
quenched by the sequential addition of 0.95 mL of H20; 0.95 mL of 15 % NaOH
(aq)
solution; 2.85 mL H20. The reaction was stirred at room temperature for 15 min
then
filtered through a pad of Celite. The filtercake was washed with Et20 and
concentrated
in vacuo to give 1.23 g (97% yield) of the title compound as white needles.
The amine
was used without further purification.
EXAMPLE 106
N SteP A N Step 6 N
N~ N Me3SI / NaH N
N 1 N
~ N Dess-Martin 1
SEMN Oxidation SEMN DMSO / RT SEMN
~ ~-CHO
/
S-N OH S-N S-N
Step C N N
NaOMe / CH3OH N~N 4) MsCI / Et3N (Step D) N - \
N
SEMN, OCH3 5) 4-F-Piperidine (Step E) SEMN OCH3
DMF / 60 C
N
/l \
S-N OH 6) 4N-HCI-Dioxane (Step F) S-N
F
Step A: Dess-Martin periodinane reagent (1.3 g; 3.1 mmol) was added to a
solution of
the isothiazole-alcohol (450 mg; 1 mmol) in 30 mL of THF containing 0.06 mL of
water
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
267
and the reaction mixture was stirred at room temperature for 45 min. The
reaction was
diluted with ether and filtered and washed with more ether. The filtrate was
washed
with saturated NaHCO3 solution, brine and dried. Concentration in vacuo gave
the
isothiazole aldehyde (418 mg; 93%). 1H-NMR (CDCI3): 10 (s, 1H); 7.68 (s, 1H);
7.65
(s, 1 H); 7.4 (s, 1 H); 7.3 (s, 1 H); 6.65 (s, 2H); 3.7 (t, J = 6 Hz, 2H); 2.6
(s, 3H); 1.95
(m,1 H); 1.1 (q, J = 2, 6 Hz, 2H); 1.0 (t, J = 6 Hz, 2H); 0.8 (q, J = 2, 6 Hz,
2H); -0.05 (s,
9H).
Step B: To a solution of sodium hydride (60% in mineral oil; 169 mg; 4.2 mmol)
in a
mixture of 3.6 mL of DMSO and 3.6 mL of THF cooled to -10 C, was added a
solution
of trimethyl sulfonium iodide (863 mg; 4.2 mmol) in 3.6 mL of DMSO drop wise.
This
was followed by the addition of a solution of the aldyhyde (363 mg; 0.84 mmol)
in 5.6
mL of anhydrous THF, added in one portion. After stirring at room temperature
for one
hour, the reaction mixture was quenched with ice water. The organic products
were
extracted with EtOAc. The combined aqueous layers were back extracted with
ethyl
acetate. All the organic extracts were pooled and washed with water, brine and
dried
over Na2SO4 and concentrated to obtain the crude product. Elution of the major
spot
from Flash silica gel using 25% EtOAc in hexanes gave the desired isothiazole
epoxide (316 mg; 85%). 1 H-NMR (CDCI3): 7.7 (s, 1 H); 7.35 (s, 1 H); 7.05 (s,
1 H); 6.8
(d,J=4Hz, 1 H); 6.5 (d, J = 4 Hz, 1 H); 4.05 (t, J = 2 Hz, 1 H); 3.7 (t, J = 6
Hz, 2 H); 3.2
(t, J 4 Hz, 1 H); 3.05 (t, J = 2 Hz, 1 H); 2.6 (s, 3H); 1.95 (m,1 H); 1.1 (q,
J = 2, 6 Hz,
2H); 0.95 (t, J = 6 Hz, 2H); 0.8 (q, J = 2, 6 Hz, 2H); -0.05 (s, 9H).
Step C: A solution of sodium methoxide in methanol (25% by wt; 4.5 mmol; 1 mL)
was
added to a solution of the epoxide (201 mg; 0.45 mmol) in a 1:1 mixture of DMF-
methanol (4 mL). The resulting solution was heated at 60 C for 3.5 hr, then
cooled to
room temperature and quenched with water. Extracted the organic product with
EtOAc, washed the organic extract with water and brine and dried over Na2SO4.
Concentration gave the crude product. Purification by flash silica gel
chromatography
using 1:1 mixture of CH2CI2 and EtOAc provided the desired methoxymethyl
carbinol
(180 mg; 84%) as colorless oil. 'H-NMR (CDCI3): 7.7 (s, 1 H); 7.35 (s, 1 H);
7.2 (s, 1 H);
6.7 (d, J = 4 Hz, 1 H); 6.58 (d, J = 4 Hz, 1 H); 5.0 (d, J = 2 Hz, 1 H); 3.7
(m, 3H); 3.5 (s,
3H); 2.95 (d, J = 14 Hz, 1 H); 2.6 (s, 3H); 1.95 (m,1 H); 1.05 (d, J = 4 Hz,
2H); 0.95 (t, J
= 6 Hz, 2H); 0.8 (d, J = 4 Hz, 2H), -0.05 (s, 9H).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
268
Step D-F: This sequence of steps was carried out as described for Example 76
in 64%
overall yield for the 3 step sequence. HPLC. HPLC-MS tR = 2.85. Mass
calculated for
C21H27FN60S = 430.2; observed (M-H)+ (LCMS) 431.2 (m/z) (UV25anm)=
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
269
ASSAYS:
Aurora Enzyme Assay
An in vitro assay was developed that utilizes recombinant Aurora A or Aurora B
as an enzyme source and a peptide based on PKA as the substrate.
Aurora A Assay:
Aurora A kinase assays were performed in low protein binding 384-well plates
(Coming Inc). All reagents were thawed on ice. Compounds were diluted in 100%
DMSO to desirable concentrations. Each reaction consisted of 8 nM enzyme
(Aurora
A, Upstate cat#14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-
GRTGRRNSICOOH ), 25 M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10
mM Tris, 10 mM MgCI2, 0.01 % Tween 20). For each reaction, 14 l containing
TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 pl diluted
compound. The kinase reaction was started by the addition of 5 l diluted
enzyme.
The reaction was allowed to run for 2 hours at room temperature. The reaction
was
stopped by adding 60 l IMAP beads (1:400 beads in progressive (94.7% buffer
A:
5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours,
fluorescent
polarization was measured using an Analyst AD (Molecular devices).
Aurora B Assay:
Aurora B kinase assays were performed in low protein binding 384-well plates
(Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100%
DMSO to desirable concentrations. Each reaction consisted of 26 nM enzyme
(Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices,
5TAMRA-GRTGRRNSICOOH ), 50 M ATP (Roche), 1 mM DTT (Pierce), and kinase
buffer (10 mM Tris, 10 mM MgC12, 0.01 % Tween 20). For each reaction, 14 i
containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 l
diluted compound. The kinase reaction was started by the addition of 5 l
diluted
enzyme. The reaction was allowed to run for 2 hours at room temperature. The
reaction was stopped by adding 60 l IMAP beads (1:400 beads in progressive
(94.7% buffer A: 5.3% buffer B) 1 X buffer, 24 mM NaCI). After an additional 2
hours,
fluorescent polarization was measured using an Analyst AD (Molecular devices).
CA 02690557 2009-12-11
WO 2008/156614 PCT/US2008/007295
270
IC50 Determinations:
Dose-response curves were plotted from inhibition data generated each in
duplicate, from 8 point serial dilutions of inhibitory compounds.
Concentration of
compound was plotted against kinase activity, calculated by degree of
fluorescent
polarization. To generate IC50 values, the dose-response curves were then
fitted to a
standard sigmoidal curve and IC50 values were derived by nonlinear regression
analysis.
Compounds of the present invention exhibit Aurora A IC50 values of about 4 nm
to about 3000 nM, Aurora B IC50 values of about 13 nM to about 3000 nM, and p-
HH3
IC50 values of about 1 nM to about 10,000 nM.
While the present invention has been described in conjunction with the
specific
embodiments set forth above, many altematives, modifications and other
variations
thereof will be apparent to those of ordinary skill in the art. All such
alternatives,
modifications and variations are intended to fall within the spirit and scope
of the
present invention.
