Thieno[3,2-b] Pyridine-6-Carbonitriles and Thieno[2,3-b] Pyridine-5-Carbonitriles es-
Protein Kinase Inhibitors
Background of the invention
This invention relates to compounds that inhibit the activity of protein kinases.
Protein kinases are enzymes that catalyze the transfer of a phosphate group from
ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a
protein. Regulation of these protein kinases is essential for the control of a wide
variety of cellular events including proliferation and migration. Specific protein
kinases have been implicated in diverse conditions including cancer [Blume-Jensen,
P., Nature, 411, 355 (2001)) Traxler, P. M., Exp. Opin. Then Patents, 8, 1599 (1998);
Bridges, A. J., Emerging Drugs, 3, 279 (1998)]; restenosis [Mattsson, E., Trends
Cardiovascular Medicine 5, 200 (1995)]; atherosclerosis [Raines, E. W., Bioessays,
18, 271 (1996)]; angiogenesis [Shawver, L K., Drug Discovery Today, 2, 50 (1997);
Folkman, J., Nature Medicine, 1, 27 (1995)] stroke [Paul, R., Nature Medicine 7, 222
(2001)]; and osteoporosis [Boyce, J. Clin. Invest, 90,1622 (1992)].
Tyrosine kinases (TK) are a class of protein kinases. The major family of
cytoplasmic protein TKs is the Src family which consists of at least eight members
(Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) that participate in a variety of signaling
pathways [Schwartzberg, P. L, Oncogene, 17, 1463 (1998)]. The prototypical
member of this tyrosine kinase family is Src, which is involved in proliferation and
migration responses in many cell types [Sawyer, T., Expert Opin. Investig. Drugs, 10,
1327 (2001)]. Src activity has been shown to be elevated in breast, colon (-90%),
pancreatic (>90%) and liver (>90%) tumors. Greatly increased Src activity is also
associated with metastasis (>90%) and poor prognosis. Antisense Src message
impedes growth of colon tumor cells in nude mice [Staley, C. A., Cell Growth
Differentiation, 8, 269 (1997)], suggesting that Src inhibitors could slow tumor growth.
In addition to its role in cell proliferation, Src also acts in stress response pathways,
including the hypoxia response. Nude mice studies with colon tumor cells expressing
antisense Src message have reduced vascularization [Ellis, L. M., J. Biol. Chem.,
273, 1052 (1998)], which suggests that Src inhibitors could be anti-angiogenic as well
as anti-proliferative.
Src disrupts E-cadherin associated cell-cell interactions [E. Avezienyte,
Nature Cell Bio., 4, 632 (2002)]. A low molecular weight Src inhibitor prevents this
disruption thereby reducing cancer cell metastasis [Nam, J.S.,. Clinical Cancer Res.,
8,2340 (2002)].
Src inhibitors may prevent the secondary injury that results from a VEGF-
mediated increase in vascular permeability such as that seen following stroke
[Eliceiri, B. P., Mol. Cell., 4, 915 (1999); Paul, R., Nat. Med. 7, 222 (2001)].
Src also plays a role in osteoporosis. Mice genetically engineered to be
deficient in Src production were found to exhibit osteopetrosis, the failure to resorb
bone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin., Invest, 90, 1622
(1992)]. This defect was characterized by a lack of osteoclast activity. Since
osteoclasts normally express high levels of Src, inhibition of Src kinase activity may
be useful in the treatment of osteoporosis [Missbach, M., Bone, 24,437 (1999)].
Inhibitors of the NMDA (N-methyl-D-asparte) receptor could provide treatment
of chronic neuropathic pain [Urban, L Drug Dev. Res., 54, 159 (2002)]. The activity
of NMDA receptors is regulated by Src family kinases (SFKs) (Yu, X. M., Proc. Nat.
Acad. Sci., U.S.A., 96, 7697 (1999) and a low molecular weight SFK inhibitor, PP2,
decreases phosphorylation of the NMDA receptor NR2 subunit [Guo, W.J. Neuro.,
22(14), 6208 (2002)]. SFK inhibitors therefore have potential in the treatment of
neuropathic pain.
Tyrosine kinases (TKs) are divided into two classes: the non-transmembrane
TKs and transmembrane growth factor receptor TKs (RTKs) [Blume-Jensen, P.,
Nature, 411, 355 (2001)]. Growth factors, such as epidermal growth factor (EGF),
bind to the extracellular domain of their partner RTK on the cell surface which
activates the RTK, initiating a signal transduction cascade that controls a wide variety
of cellular responses including proliferation and migration. The overexpression of
EGF and also of members of the epidermal growth factor receptor (EGFr) family,
which includes EGF-r, erbB-2, erbB-3 and erbB-4, is implicated in the development
and progression of cancer [Rusch, V., Cytokine Growth Factor Rev., 7,133 (1996),
Davies, D. E., Biochem. Pharmacol., 51, 1101 (1996) and Modjtahedi, E., Int. J.
Oncol., 4,277 (1994)]. Specifically, over expression of the receptor kinase product of
the erbB-2 oncogene has been associated with human breast and ovarian cancers
[Slamon, D. J., Science, 244, 707 (1989) and Slamon, D. J., Science, 235, 177
(1987)]. Upregulation of EGFr kinase activity has been associated with epidermoid
tumors [Reiss, M., Cancer Res., 51, 6254 (1991)]; breast tumors [Macias, A.,
Anticancer Res., 7, 459 (1987)]; and tumors involving other major organs [Guliick,
W.J., Brit. Med Bull., 47,87 (1991)].
It is also known that deregulation of EGF receptors is a factor in the growth of
epithelial cysts in the disease described as polycystic kidney disease [Du, J., Amer.
J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J., Pediatric Res., 37(6), 755 (1995);
Gattone, V. H., Developmental Biology, 169(2), 504 (1995); Wilson, P. D., Eur. J.
Cell Biol., 61(1), 131, (1993)]. The compounds of this invention, which inhibit the
catalytic function of the EGF receptors, are consequently useful for the treatment of
this disease.
In addition to EGFr, there are several other RTKs including FGFr, the
receptor for fibroblast growth factor (FGF); flk-1, also known as KDR, and flt-1, the
receptors for vascular endothelial growth factor (VEGF); and PDGFr, the receptor for
platelet derived growth factor (PDGF). The formation of new blood vessels, a
process known as angiogenesis, is essential for tumor growth. Two natural
angiogenesis inhibitors, angiostatin and endostatin, dramatically inhibited the growth
of a variety of solid tumors. [O'Reilly, M. S., Cell, 79, 315 (1994); O'Reilly, M. S.,
Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell, 88, 277 (1997)]. Since FGF
and VEGF are known to stimulate angiogenesis, inhibition of the kinase activity of
their receptors should block the angiogenic effects of these growth factors. In
addition, the receptor tyrosine kinases tie-1 and tie-2 also play a key role in
angiogenesis [Sato, T. N., Nature, 376, 70 (1995)]. Compounds of the invention that
inhibit the kinase activity of FGFr, flk-1, flt-1, tie-1 or tie-2 may inhibit tumor growth by
their effect on angiogenesis.
PDGF is a potent growth factor and chemoattractant for smooth muscle cells
(SMCs). The renarrowing of coronary arteries following angioplasty is due in part to
the enhanced proliferation of SMCs in response to increased levels of PDGF.
Therefore, compounds that inhibit the kinase activity of PDGFr may be useful in the
treatment of restenosis. In addition, since PDGF and PDGFr are overexpressed in
several types of human gliomas, small molecules capable of suppressing PDGFr
activity, have potential utility as anticancer therapeutics [Nister, M., J. Biol. Chem.
266,16755 (1991); Strawn, L M., J. Biol. Chem. 269,21215 (1994)].
Other RTKs that could potentially be inhibited by compounds of this invention
include colony stimulating factor receptor, the nerve growth factor receptors (trka,
trkB and trkC), the insulin receptor, the insulin-like growth factor receptor, the
hepatocyte growth factor receptor and the erythropoietin-producing hepatic cell
receptor (EPH).
In addition to the RTKs there is another family of TKs termed the cytoplasmic
protein or non-receptor TKs. The cytoplasmic protein TKs have intrinsic kinase
activity, are present in the cytoplasm and nucleus, and participate in diverse
signaling pathways. There are a large number of non-receptor TKs including Abl,
Jak, Fak, Syk, Zap-70 and Csk. Inhibitors of Abl kinase are useful for the treatment
of chronic myeloid leukemia as evidenced by STI-571, marketed as Gleevec
[Kantarjian, H., N. Engl. J. Med., 346 (9), 645 (2110)].
Two members of the cytoplasmic protein TKs, Ick and ZAP-70 are
predominately expressed on T-cells and natural killer (NK) cells. Inhibitors of these
kinases can suppress the immune system and therefore have possible therapeutic
potential to treat autoimmune diseases such as rheumatoid arthritis, sepsis, and
transplant rejection [Kamens, J. S., Current Opin. Investig. Drugs, 2, 1213 (2001);
Myers, M., Current Pharm. Design, 3, 473 (1997)]. A low molecular weight Lck
inhibitor is effective in preventing allograft rejection [Waegell, W. Transplant.
Proceed. 34.1411 (2002).
Besides TKs, there are additional kinases including those that phosphorylate
serine and/or threonine residues on proteins. A major pathway in the cellular signal
transduction cascade is the mitogen-activated protein kinase (MAPK) pathway which
consists of the MAP kinase kinases (MAPKK), including mek, and their substrates,
the MAP kinases (MAPK), including erk [Seger, R., FASEB, 9, 726 (1995)]. When
activated by phosphorylation on two serine residues by upstream kinases, such as
members of the raf family, mek catalyzes the phosphorylation of threonine and
tyrosine residues on erk. The activated erk then phosphorylates and activates both
transcription factors in the nucleus and other cellular targets. Over-expression and/or
over-activation of mek or erk is associated with various human cancers [Sivaraman,
V. S., J. Clin. Invest, 99,1478 (1997)].
As mentioned above, members of the raf family of kinases phosphorylate
serine residues on mek. There are three serine/threonine kinase members of the raf
family known as a-raf, b-raf and c-raf. While mutations in the raf genes are rare in
human cancers, c-raf is activated by the ras oncogene which is mutated in a wide
number of human tumors. Therefore inhibition of the kinase activity of c-raf may
provide a way to prevent ras mediated tumor growth [Campbell, S. L, Oncogene, 17,
1395(1998)].
The cyclin-dependent kinases (cdks), including cdc2/cyclin B, cdk2/cyclin A,
cdk2/cyclin E and cdk4/cyclin D, and others, are serine/threonine kinases that
regulate mammalian cell division. Increased activity or activation of these kinases is
associated with the development of human tumors [Garrett, M. D., Current Opin.
Genetics Devel, 9, 104 (1999); Webster, K. R., Exp. Opin. Invest. Drugs, 7, 865
(1998)]. Additional serine/threonine kinases include the protein kinases A, B, and C.
These kinases are known as PKA or cyclic AMP-dependent protein kinase, PKB
(Akt), and PKC, and all three play key roles in signal transduction pathways
responsible for oncogenesis [Glazer, R. I., Current Pharm. Design, 4(3), 277 (1998)].
Compounds capable of inhibiting the kinase activity of mek, erk, raf, cdc2/cyclin B,
cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D, PKA, PKB (Akt) or PKC may be useful in
the treatment of diseases characterized by abnormal cellular proliferation, such as
cancer.
The serine/threonine kinase UL97 is a virion-associated protein kinase which
is required for the replication of human cytomegalovirus [Wolf, D.G., Arch. Virology
143(6), 1223 (1998) and He, Z., J. Virology, 71, 405(1997)]. Compounds capable of
inhibiting the kinase activity of UL97 may be useful antiviral therapeutics. Since
certain bacteria require the action of a histidine kinase for proliferation [Loomis, W.
F., J. Cell Sci., 110, 1141 (1997)], compounds capable of inhibiting such histidine
kinase activity may be useful antibacterial agents.
Thieno[3,2-b]pyridines, thieno[2,3-b]pyridines and certain pyridine and
pyrimidine derivatives have been noted as kinase inhibitors. These compounds differ
both in nature and placement of substituents at various positions when compared to
the compounds of this invention.
SUMMARY OF THE INVENTION
This invention relates to thieno[3,2-b]pyridine-6-carbonitrile and thieno[2,3-
b]pyridine-5-carbonitrile compounds as well as their pharmaceutical acceptable
salts of Formula la and Ib:
wherein:
X is -NH-, -NR4-, -O-, -S(O)m-, -NHCH2-;
m is an integer of 0-2;
n is an integer of 2-5;
q is an integer of 0-5;
R1 is a phenyl ring optionally substituted with one to four substituents selected from
the group consisting of -J, -NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4,
-NR4R4, -NR4S(O)mR4, -OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R4, -
NR4C(O)R4, -C(O+R4, -C(O)OR4, -C(O)NR4R4, -OC(O)R4, -OC(O)OR4, -OC(O)NR4R4,
NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, -R5NR4R4, -R5S(O)mR4, -
R5C(O)R4, -R5C(O)OR4, -R5C(O)NR4R4, -R5OC(O)R4, -R5OC(O)OR4,
R5OC(O)NR4R4,-R5NR4C(O)R4, -R5NR4C(O)OR4, -R5NR4C(O)NR4R4, or YR7;
R2 is -H, -R3, -J, -C(O)XR3, -CHO, wherein the R3 group may be substituted by one
or more groups selected from -C(O)XR8, -CHO, -C(O)Q, 1,3-dioxolane, -R8, -
(C(R9)2)qXR8, -(C(R9)2)qQ, -X^R^nXR", -X(C(R9)2)nQ, or - X(C(R9)2)q R8;
R3 is alkyl of 1 to 6 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl of 2-
6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R4 is H, alkyl of 1-6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, a trans- alkenyl of
2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;
R5 is a divalent group comprising alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, and alkynyl of 2-6 carbon atoms;
R6 is a divalent alkyl group of 2-6 carbon atoms;
R7 is a cycioalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, a aryl or heteroaryl
fused to one to three aryl or heteroaryl rings, wherein any of the aryl, cycioalkyl, or
heteroaryl rings may be optionally substituted with one to four substituents selected
from the group consisting of -H, -aryl, -CH2-aryl, -NH-aryl, -O-aryl, -S(O)m-aryl, -J, -
NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4, -NR4R4, -NR4S(O)mR4, -
OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R4, -NR4C(O)R4, -C(O)R4, -
C(O)OR4, -C(O)NR4R4, -OC(O)R4-, -OC(O)OR4, -OC(O)NR4R4, -NR4C(O)R4, -
NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, R5NR4R4, -R5SOmR4, -R5C(O)R4, -
R5C(O)OR4, -R5C(O)NR4R4, -R5C(O)R4, -RSC(O)OR4, -RSC(O)NR4R4, -R5OC(O)R4, -
R5C(O)OR4, -R5OC(O)NR4R4, -R5NR4C(O)R4, -R5NR4C(O)OR4, or -
R5NR4C(O)NR4R4;
R8 is -H, alkyl of 1 to 6 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R9 is-R4or-F;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2-, -SO2NH-, -C(OH)H-, -
X(C(R9)2)q-, -(C(R9)2)q-, -(C(R9)2)qX-, -C=C-, cis- and trans- -CH=CH- and cycloalkyl
of 3-10 carbon atoms;
Q is NZZ' wherein Z and Z' may be the same or different and may be H, alkyl of 1 to
6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or
heteroaryl, and
Z and Z taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally
substituted with -R4 on a carbon or a nitrogen, or on nitrogen by a group -
(C(R9)2)nXR3, -(C(R9)2)nNZ"T'", or on carbon by a group -(C(R9)2)qXR3, -
(C(R9)2)nNZ"Z'",
Z" and Z'" taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may contain an additional heteroatom selected from nitrogen,
oxygen and sulfur,
Z'" and Z" may be H, alkyl of 1 to 6 carbon atoms alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, aryl, or heteroaryl; and
J is fluoro, chloro, bromo, and iodo.
This invention also relates to compounds of Formulas Ic, Id, le, and If:
wherein:
X is -NH-, -NR4-, -O-, -S(O)m, -NHCH2-;
m is an integer of 0-2;
n is an integer of 2-5;
q is an integer of 0-5;
R1 is a phenyl ring optionally substituted with one to four substituents selected from
the group consisting of -J, -NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4,
-NR4R4, -NR4S(O)mR4, -OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R4, -
NR4C(O)R4, -C(O)R4, -C(O)OR4, -C(O)NR4R4, -OC(O)R4, -OC(O)OR4, -OC(O)NR4R4,
NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, -R5NR*R4, -R5S(O)mR4, -
R5C(O)R4, -R5C(O)OR4, -R5C(O)NR4R4, -R5OC(O)R4, -R5OC(O)OR4, -
R5OC(O)NR4R4,-R5NR4C(O)R4, -R5NR4C(O)OR4, -R5NR4C(O)NR4R4, or YR7;
R2 is -H, -R3, -J, -C(O)XR3, -CHO, wherein the R3 group may be substituted by one
or more groups selected from -C(O)XR8, -CHO, -C(O)O., 1,3-dioxolane, -R8, -
(C(R9)2)qXR8, -(C(R9)2)qQ, -X(C(R9)2)nXR8, -X(C(R9)2)nQ, or - X(C(R9)2)qR8;
R3 is alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl of 2-
6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R4 is H, alkyl of 1-6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, a trans- alkenyl of
2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;
R5 is a divalent group comprising alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, and alkynyl of 2-6 carbon atoms;
R6 is a divalent alkyl group of 2-6 carbon atoms;
R7 is a cycloalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, a aryl or heteroaryl
fused to one to three aryl or heteroaryl rings, wherein any of the aryl, cycloalkyl, or
heteroaryl rings may be optionally substituted with one to four substituents selected
from the group consisting of -H, -aryl, -CH^aryl, -NH-aryl, -O-aryl, -S(O)m-aryl, -J, -
NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4, -NR4R4, -NR4S(O)mR4, -
OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R\ -NR4C(O)R4, -C(O)R4, -
C(O)OR4, -C(O)NR4R4, -OC(O)R4-, -OC(O)OR4, -OC(O)NR4R4, -NR4C(O)R4, -
NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, R5NR4R4, -R5S(O)mR4, -R5C(O)R4, -
R5C(O)OR4, -R5C(O)NR4R4, -R5C(O)R4, -R5C(O)OR4, -RSC(O)NR4R4, -R5OC(O)R4, -
R5OC(O)OR4, -R5OC(O)NR4R4, -RsNR4C(0)R4, -R5NR4C(O)OR4, or -
R5NR4C(O)NR4R4;
R8 is -H, alkyl of 1 to 6 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R9 is-R4or-F;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2-, -SO2NH-, -C(OH)H-, -
X(C(R9)2)q-, -(C(R9)2)q-, -(C(R9)2)qX-, -C=C-, cis- and trans- -CH=CH- and cycloalkyl
of 3-10 carbon atoms;
Q is NZZ' wherein Z and T may be the same or different and may be H, alkyl of 1 to
6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or
heteroaryl, and
Z and Z' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally
substituted with -R4 on a carbon or a nitrogen, or on nitrogen by a group -
(C(R9)2)qR3, -(C(R9)2)qNZ''Z''', or on carbon by a group -(C(R9)2)qXR3, -
(C(R9)2)qNZ"Z",
Z" and Z'" taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may contain an additional heteroatom selected from nitrogen,
oxygen and sulfur; Z'" and Z" may be H, alkyl of 1 to 6 carbon atoms alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl; and
J is fluoro, chloro, bromo, and iodo.
R1 may be for example a phenyl ring optionally substituted with one to four
substituents selected from the group consisting of -J, -CF3, -OCF3, -R4, -OR4 and
YR7; and R7 is an aryl or heteroaryl ring, optionally substituted with one to four
substituents selected from the group consisting of -H, -J, -CF3, -OCF3, -R4 and OR4.
In particular R1 may be a phenyl ring optionally substituted with one to four
substituents selected from the group consisting of -CI, -R4 and -OR4.
An example of X is NH.
R4 may be for example alkyl of 1-6 carbon atoms.
An example of R2 is substituted aryl or heteroaryl, wherein the substituent
may be one or more groups selected from -(C(R9)2)qQ; e.g., wherein q is 1 to 3
and/or wherein R9 is H. Q may be for example NZZ' wherein Z and Z may be the
same or different and may be H, alkyl of 1 to 6 carbon atoms; or Z and Z taken
together with the nitrogen to which they are attached may form a heterocyclic ring
which may have an additional heteroatom selected from nitrogen and oxygen, said
ring may be substituted on nitrogen or carbon by R4 or on carbon by (CH2)2OH.
In some embodiments an example of R2 is R3 where R3 is alkynyl of 2-6
carbon atoms, aryl or heteroaryl; which groups may be substituted by one or more
groups selected from
-R8, -(CH2)qOR8, -(CH2)qNHR8, -(CH2)q NR4R8, -(CH2)qQ,
-O(CH2)nOR8, - NH(CH2)nOR8, - NR4(CH2)nOR8,
-O(CH2)nOR8, - NH(CH2)nNHR8, - NR4(CH2)nNHR8,
-O(CH2)nNR4R8, - NH(CH2)nCR8, - NR4(CH2)nNR4R8,
-O(CH2)nQ, -NH(CH2)nQ, - O(CH2)nQ,
- O(CH2)qR8; - NH(CH2)qR8; or - NR4(CH2)qR8;
R4 is H, alkyl of 1-6 carbon atoms;
Ra is -H, alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, frans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2-, -S-, -O-, -NR4-;
Q is NZZ' wherein Z and Z' may be the same or different and are selected from H,
alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, aryl, or heteroaryl, and
Z and Z" taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally
substituted with -R4on a carbon or a nitrogen, or on nitrogen by a group -(CH2)nOR3,
-(CH2)nNHR3, -(CH2)nNR4R3, -(CH2)nNZ'Z", or on carbon by a group -(CH2)qOR3, -
(CH2)qNHR3, -(CH2)q NR4R3, -(CH2)qNZ''Z'",
Z''' and Z" may be the same or different and are selected from H, alkyl of 1 to 6
carbon atoms
Z'' and Z'" taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may contain an additional heteroatom selected from nitrogen,
oxygen and sulfur.
Preferred compounds of the invention or a pharmaceutically acceptable salt
thereof include:
1-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-
carbonitrile;
2-Bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile;
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)thiolphenyl}amino]thieno[2,3-b]pyridine-5-
carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dlchlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorobenzyl)amino]thieno[3,2-bIpyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-DichIoro-5-methoxyphenyl)amino]-2-[4-(4-
morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-
yl]benzoic acid;
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-
yl]benzamide;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-
b]pyridine-6-carbonitrile;
2-(1-Benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-formylphenyl)thieno[2,3-b]pyridine-5-
carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-morpholin-4-
ylmethyl)phenyl]thieno[2,3-b]pyridine-5-carbonitrile;
4-[5-Cyano-4(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid
methyl ester;
2-(4-Hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonitrile;
2-[4-(4-Morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonitrile;
7-[(2,4-Dichloro-5-rnethoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-ethynylthienop[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2--yl)thien-3-yl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(5-forrnylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thienoI[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(morphorin--4-yl)methyl)thien-5-
yl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl]thieno[3,2-
b]pyridine-6-carbonitrile;
2-lodo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonltrile;
2-(4-Fonmylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-[4-(4-Methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-
6-carbonitrile;
2-[4-(Hydroxymethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile;
2-lodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-Bromo-7-[(4-phenoxypheny!)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(4-Phenoxyphenyl)amino]-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-
carbonitrile;
fert-Butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-
b]pyridin-2-yl}prop-2-enoate;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-
ynyl]thieno[2,3-b]pyridine-5-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-
5-carbonitrile;
(2E)-3-(6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-
yl)prop-2-enoate;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
2-(4-Formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyricline-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(1E)-3-(4-methylpiperazin-1-yl)-3-
oxoprop-1-enyl]thieno[3,2-b]pyridine-6-carbonitrile;
2-[3-(4-Methylpiperazin-1-yl)prop-1-ynyl]-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{1-methyl-2-[(4-methylpiperazin-1-
yl)methyl]-1H-imidazol-5-yl} thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichioro-5-methoxyphenyi)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]
thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2>4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-
[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2-Chloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2-Chloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}7-[(5-methoxy-2-methylphenyl)amino]-
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(5-Methoxy-2-methylphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl) phenyl]
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)amino]-2-(4[(-dimethylamino)methyl]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl) phenyl] thieno
[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[6-(4-methylpiperazin-1-ylmethyl)pyridin-
3-yl] thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethylamino)methyl]pyridin-3-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(4-methylpipera2in-1-ylmethyl)furan-3-
yl] thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]furan-3-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-
1-oxo-1H-thieno [3,2-b]pyridine-6-carbonitrite;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-
1,1 -dioxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}-1-oxo-
1 H-thieno[3,2-b]pyridine-6-carbonrtrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethyiamino)methyl]phenyl}-1,1-
dioxo-1 H-thienoI[3,2-b]pyridine-6-canbonitrile;
2-{4-[(Dimethylamino)methyl]phenyi}-1-oxo-7-[(3,4,5-trimethoxyphenyl)amino]-1H-
thieno[3,2-b]pyridine-6-carbonitrile; and
2-{4-[(Dimethylamino)methyl]phenyl}-1,1 -dioxo-7-[(3,4,5-trimethoxyphenyl)amino]-
1H-thieno[3,2-b]pyridine-6-carbonitrile.
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl)amino)-2-iodothieno[3,2-
b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-ylbut-
1-ynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[3-
(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-(4-
formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-[(4-
methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1 H-imidazo)-2-yl)thio]phenyl}amino)-2-[3-
(diethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-2-furyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)-2-furyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-
furyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-ethylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrite;
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-(4-({[2-
(dimethylamino)ethyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)aminol-]-2-[4-(dimethylamino)phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-
[(dimethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]-2-
furyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-2-yl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyIthien-2-yl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-dichloro-5-rnethoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-3-
yl)thieno[3,2-b]pyridine-6-carbonltrile;
7-[(2,4-dichloro-5-methoxyphenyl)arnino]-2-{5-[(4-rnethylpiperazin-1-yl)methyl]thien-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{2-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[3-
(dimethylamino)propyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichIoro-5-methoxyphenyl)amino]-2-({6-[(dirnethylamino)methyl]pyriclin-2-
yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-{5-[(dimethylamino)methyl]thien-2-
yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(pyridin-4-
ylmethyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrrol-3-yl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(2-
methoxyethyl)amino)methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-({[2-
(methylthio)ethyl]aminolmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(thiomorpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrite;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-morpholin-4-ylphenyl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-(4-
formylphenyl)thieno[3,2-b] pyridine-6-carbonitrile;
7-({3-chloro-4-[(1 -methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-
[(diethylamino]methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({5-[(dimethylamino)rnethyl]pyridin-2-
yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichlorophenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(butylamino)methyl]phenyl}-7-[(2>4-dichloro-5-methoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1-oxidothiomorpholin-4-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-
[(diethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-
hydroxypropyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonrtrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)pyridin-2-
l]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(6-morpholin-4-ylpyridin-3-yl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1,1-dioxidothiomorpholin-4-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyridin-2-ylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-phenylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4{[(2R,5S)-2,5-dimethylpiperazin-1-
l]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichlorphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4--dichloro-5-ethoxyphenyl)aminol-2-(4-formylphenyl}thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}thieno[3,2-b]pyricline-6-carbonitrile;
7-[(2,4-dichlorophenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)methyI]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-
methylbutyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(methylsulfonyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dich!oro-5-ethoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2>4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(pyridin-2-ylmethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{1-[2-(dimethylamino)ethyl]-1H-pyrrol-3-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichlorophenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(1-methyl-1H-imidazol-5-
yl)ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)arnino]-2-{6-[(dimethylarnino)rnethyl]pyridin-2-
yl}thieno[3,2-b]pyridine-6-carbonitriie;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-yl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)arnino]-2-{5-[(dimethylamino)methyl]pyridin-2-
yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(diethylamino)methyl]pyridin-2-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[2-
(dimethylamino)ethyr]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl]thieno[3,2-b]pyridine-6-carbonitrile;
4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}-N,N-
dimethylbenzamide;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-
furyl}thieno[3,2-b]pyridine-6-carbonitrile; and
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-3-furyl)thieno[3,2-b]pyridine-6-
carbonitrile.
For purposes of this invention a heteroaryl is an aromatic heterocyclic ring
system of one to three fused rings. The heteroaryl moieties are five or six membered
rings containing 1 to 4 heteroatoms selected from the group consisting of S, N, and
O; e.g., heteroaryl may have 5 to 14 ring members. One ring of the ring system may
be fully unsaturated, partially saturated, or fully saturated. The heteroaryl moieties
include, but are not limited to, thiophene, furan, pyrrole, pyrazole, imidazole, 1,2,3-
triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole, isothiazole, isoxazole, 1,3,4-
oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine, pyrazine,
pyridazine, 1,3,5-triazine, morpholine, thiomorpholine, thiomorpholine-5-oxide,
thiomorphdline-S,S-dioxide, piperidine, piperazine, pyrrolidine, aziridine, oxirane,
tetrahydrothiophene, tetrahydrofuran, 1,2-pyran, 1,4-pyran, dioxane, 1,3-dioxolane,
tetrahydropyran, naphthalene, 1,2,3,4-tetrahydronaphthalene, indan, indene,
isoindene, indole, 2,3-dihydroindole, 2-indazole, isoindazole, quinoline, isoquinoline,
tetrahydroquinoline, benzofuran, benzothiophene, benzimidazole, benzotriazole,
benzothiazole, benzoxazole, benzisoxazole, 1,2-benzopyran, cinnoline, phthalazine,
quinazoline, 1,8-naphthyridine, pyrido[3,2-b]pyridine, pyrido[3,4-b]pyridine,
pyrido[4,3-b]pyridine, pyrido[2,3-d]pyrimidine, purine, and pteridine. The heteroaryl
may be oxidized on a nitrogen atom to provide the corresponding N-oxide, such as
pyridine-N-oxide or quinoline -N-oxide. The heteroaryl may also be oxidized on a tri-
substitued nitrogen atom to provide the corresponding N-oxide, such as N-
ethylpiperazine-N-oxide. In another embodiment the heteroaryl may contain a
carbonyl group on one of the carbon atoms, such as pyrrolidinone, 1,3,4-oxadiazol-2-
one, or 2-indanone.
For purposes of this invention "alkyl" includes both straight and branched alkyl
moieties, preferably of of 1-6 carbon atoms and includes iso-propyi, n-butyl and the
like.
For purposes of this invention the term "cycloalkyl" refers to alicyclic
hydrocarbon groups of 3-7 carbon atoms and includes a simple carbocycle as well as
a carbocycle containing an alkyl substituent, for example, cyclopropyl, cyclohexyl,
adamantyl and the like.
For purposes of this invention the term "aryl" is defined as an aromatic
hydrocarbon moiety and may be substituted or unsubstituted and may contain for
example 6-14 carbon atoms and have one to three rings. An aryl may be selected
from but not limited to, the group: phenyl or biphenyl and may be optionally mono-,
di-, tri- or tetra-substituted with substituents selected from, but not limited to, the
group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy,
cyano, halogen, hydroxy, or nitro.
For purposes of this invention "alkenyl" is defined as a radical aliphatic
hydrocarbon that contains at least one carbon-carbon double bond and includes both
straight and branched carbon chains of 2-6 carbon atoms in all possible
configurational isomers, for example cis and trans, and includes ethenyl, 3-hexen-1-
yl and the like.
For purposes of this invention "alkynyl" includes both straight or branched
carbon chain of 2-6 carbon atoms that contains at least one carbon-carbon triple
bond and includes propenyl and the like.
In one embodiment of this invention the alkyl, alkenyl and alkynyl groups can
be substituted with such substituents as phenyl, substituted phenyl, hydroxy,
halogen, alkoxy, thioalkyl, carboxy, alkoxycarbonyl and acyl.
For purposes of this invention "alkoxy" comprises a group of 1-6 carbon
atoms having an alkyl group attached to an oxygen atom and includes methoxy, t-
butoxy and also includes polyethers such as -O-(CH2)2OCH3. A thioalkyl group of
1-6 carbon atoms is defined as an alkyl group attached to a sulfur atom and includes
methylthio and the like. A carboxy group is defined as -C(O)OH, and an
alkoxycarbonyl group is defined as -C(O)OR where R is a group of 1-6 carbon atoms
and includes methoxycarbonyl, allyloxycarbonyl and the like. An acyl group is
defined as a group -C(O)R where R is an aliphatic (e.g., alkyl) or aryl radical and
includes acetyl, trifluoroacetyl, benzoyl and the like.
The compounds of this invention may include a "divalent group" defined
herein as a linking group, for example, CH2CH2.
The compounds of this invention may contain one or more asymmetric carbon
atoms and may thus give rise to stereoisomers, such as enantiomers and
diastereomers. While shown without respect to stereochemistry in Formulas (la) -
(If), the present invention includes all the individual possible stereoisomers; as well
as the racemic mixtures and other mixtures of R and S stereoisomers (scalemic
mixtures which are mixtures of unequal amounts of enantiomers) and
pharmaceutically acceptable salts thereof. It should be noted that stereoisomers of
the invention having the same relative configuration at a chiral center may
nevertheless have different R and S designations depending on the substitution at
the indicated chiral center. Some of the compounds of this invention may contain
one or more double bonds; in such cases, the compounds of this invention include
each of the possible configurational isomers as well as mixtures of these isomers.
Pharmaceutically acceptable salts of the compounds of Formulas (la) - (If)
with an acidic moiety can be formed from organic and inorganic bases. For example
alkali metal salts: sodium, lithium, or potassium and N- tetraalkylammonium salts
such as N-tetrabutylammonium salts. Similarly, when a compound of this invention
contains a basic moiety, salts can be formed from organic and inorganic acids. For
example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic,
fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,
phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
This invention also provides a process for preparing a compound of formula
(1a) or (1b) as defined herein or a pharmaceutically acceptable salt thereof, which
comprises one of the following:
a) reacting a compound of formula:

or an S-oxide or S-dioxide thereof; wherein R2 is as defined herein with a compound
of formula R1XH where R1 and X are as defined herein to give a compound of
formula I(a) or (Ib);
or
b) reacting a compound of formula 1a or 1b or an S-oxide or S-
dioxide thereof in which R2 is a reactive substituent group to give a compound of
formula 1a or 1b in which R2 is a different substituent group as defined herein;
or
c) converting a compound of formula (1a) or (1b) to a
pharmaceutically acceptable salt thereof.
This invention also provides a process of producing a compound of Formula
(la) and Formula (Ib),

wherein R2 is iodine, comprising:
a. treating with a base, in an inert solvent at reduced temperature a
compound of Formula (a) or (a1);
b. adding iodine to the compound in step (a) to form a compound of
Formula (b) or (b'); and
c. adding a compound of formula R1XH to the compound in step (b) to
form a compound of Formula (la) or (Ib), wherein R2 is iodine.
This invention includes a compound of Formula (b) or (b')
This invention also provides a process of producing a compound of Formula
(la) or (Ib)
wherein R2 is bromine, comprising:
a. treating with a base, in an inert solvent at reduced temperature a
compound of Formula (a) or (a');
b. adding bromine or 1,1-dibromo-1,1,2,2-tetrafluoroethane to the
compound in step (a) to form a compound of Formula (z) or (z*); and
c. adding a compound of formula R1XH to the compound in step (b) to
form a compound of Formula (la) or (Ib), wherein R2 is bromine.
This invention includes a compound of Formula (z) or (z')
The above-identified processes are explained in greater detail under the
"Detailed Description of the Invention".
In a preferred embodiment of this invention an inert solvent is a compound
that does not react chemically with the compounds of this invention. A preferred inert
solvent includes for example tetrahydro furan (THF).
For purposes of this invention a reduced temperature is a temperature 300°C;
1H NMR (DMSO-d6) d7.43-7.55 (m, 3H), 7.63 (s, 1H), 7.83 (d, J = 7 Hz, 2H), 8.67 (s,
1H), 13.3 (s, 1H); MS 253.1 (M+H)+.
Analysis for C14H8N2OS-0.1 H2O:
Calcd: C, 66.17; H, 3.23; N, 11.02
Found: C, 66.14; H, 3.42; N, 11.00.
Reference Example 6
2-Bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile
A mixture of ethyl 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.3
g, 4.3 mmol) [Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14). 3295
(1987)] in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux
for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the
addition of acetic acid. The mixture is stirred at room temperature and the resulting
precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-
7-hydroxythieno[3,2-b]pyridine-6-carboxylic acid. A mixture of 2-bromo-7-
hydroxythieno[3,2-b]pyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-
carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,N'-dimethylformamide is
heated at 65°C for 2 hours. The mixture is poured into 50 mL of ice cold aqueous
ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by
filtration washing with water to provide 800 mg. of 2-bromo-7-hydroxythieno[3,2-
b]pyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-
carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at
reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice
water and treated with sodium bicarbonate. The resultant solids are collected by
filtration washing with water. The solids are purified by flash column chromatography
eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-
carbonitrile as yellow crystals, mp 198-199°C; 1H NMR (DMSO-d6) d8.12 (s, 1H),
9.11 (s,1H); MS 273.1,275.1,277.1 (M+H)+
Analysis for C8H2BrClN2S:
Calcd: C, 35.13; H, 0.74; N, 10.24
Found: C, 34.98; H, 0.80; N, 10.24.
Alternate Preparation of Reference Example 6
2-Bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03
mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL,
1.40 mmol, 2M in tetrahydrofuran) at -78°C over 5 minutes. After 30 minutes, 1,2-
dibromo-1,1,2,2,-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the
solution of the anion. The temperature is maintained at -78°C for 4 hours then
warmed to room temperature for 1 hour. The reaction mixture is poured into ice
water, extracted with dichloromethane, dried over sodium sulfate, and concentrated
in vacuo to afford a dark solid residue. The residue is purified by flash column
chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl
acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-
carbonitrile as an off white solid, mp 190-191°C; 1H NMR (DMSO-d6) d8.13 (s, 1H),
9.12 (s, 1H); MS 272.8,274.8,276.9 (M+H)+.
Analysis for C8H2BrCIN2S-0.3 H2O:
Calcd: C, 34.45; H, 0.94; N, 10.04
Found: C, 34.51; H, 1.01; N, 10.04.
Second Alternate Preparation of Reference Example 6
2-Bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03
mmol) in tetrahydrofuran (9.0 mL) at -78°C is slowly added lithium diisopropylamine
(0.62 mL, 1.24 mmol, 2M in tetrahydrofuran) over 10 minutes. After 40 minutes, a
solution of bromine (198 mg, 1.24 mmol) in 1.5 mL of tetrahydrofuran is added slowly
to the solution of the anion. The temperature is maintained at -78°C for 5 hours then
warmed to room temperature for 1 hour. The reaction mixture is poured into ice
water, extracted with dichloromethane, washed with brine, dried over sodium sulfate,
and concentrated in vacuo. The residue is purified by preparative thin layer
chromatography developing with 90% dichloromethane in hexane to provide 48 mg
of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carDonitrile as a pink solid, 1H NMR
(DMSO-d6) d8.13 (s, 1H), 9.12 (s, 1H); MS 272.8,274.8,276.8 (M+H)+.
Reference Example 7
7-Chlorothieno[3,2-b]pyridine-6-carboxylic acid
A mixture of ethyl 7-chlorothieno[3,2-b]pyridine-6-carboxylate (2.98 g, 12.3
mmol) [Thompson, M.; Forbes, I. F. EP 126970] in 40 mL of ethanol and 15 mL of 2.5
N sodium hydroxide is heated at reflux for 1 hour. The mixture is cooled to 0°C and
the pH is adjusted to 4 by the addition of 4 N hydrochloric acid. The mixture is stirred
at room temperature and the resulting precipitate is collected by filtration washing
with water to provide 2.47 g of 7-chlorothieno[3,2-b]pyridine-6-carboxylic acid as a
white solid, 1H NMR (DMSO-d6) d7.73 (d, J = 6 Hz, 1H), 8.44 (d, J = 6 Hz, 1H), 9.07
(S,1H).
Reference Example 8
7-Chlorothieno[3,2-b]pyridine-6-carboxamide
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carboxylic acid (13.8 g, 65 mmol)
and thionyl chloride (234 mL) is heated at reflux for 2 hours. After cooling the excess
thionyl chloride is removed by rotary evaporation. The residue is suspended in
acetone (350 mL) and the resulting suspension cooled in an ice-bath. Aqueous
ammonia (S.G. 0.880,62 mL) is added gradually, keeping the temperature below 10°
C. After concentration of the mixture, the resulting suspension is filtered off, washed
with water and air-dried to give 10.9 g of 7-chlorothieno[3,2-b]pyridine-6-carboxamide
as a beige solid, mp 180-182°C; 1H NMR (DMSO-d6) 87.71 (s, 1H), 7.89 (s, 1H),
8.14 (s, 1H), 8.35 (s, 1H), 8.73 (s, 1H); MS 213.0,215.0 (M+H)+.
Analysis for C8H5CIN2OS:
Calcd: C, 45.18; H, 2.37; N, 13.17.
Found: C, 45.38; H, 2.26; N, 13.11.
Found: C, 49.32; H, 1.50; N, 14.41.
Reference Example 9
7-Chloro-2-iodothieno[3,2-b]pyridine-6-carbonttrile
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (735 mg, 3.78
mmol) in 20 mL of tetrahydrofuran at -78°C is added dropwise 2.0 M lithium
diisopropylamide in heptaneAetrahydrofuran/ethylbenzene (2.2 mL, 4.40 mmol).
After stirring for 20 minutes, a solution of iodine (1.15 g, 4.53 mmol) in 4 mL of
tetrahydrofuran is added dropwise over 20 minutes. The reaction mixture is stirred at
-78°C for 5 hours, then 20 mL of chloroform and 10 mL of water are added. The
mixture is stirred at room temperature overnight, then partitioned between water and
chloroform. The organic layer is washed with a solution of sodium thiosulfate,
followed by water, then dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue is purified by flash column chromatography eluting with 5%
methanol in dichloromethane to provide 750 mg of 6-chloro-2-iodothieno[3,2-
b]pyridine-7-carbonitrile as yellow crystals, mp 209-211°C; 1H NMR (DMSO-d6)
58.17 (s, 1H),9.05(s, 1H).
Analysis for C8H2CIIN2S:
Calcd: C, 29.98; H, 0.63; N, 8.74
Found: C, 29.61; H, 0.87; N, 8.68.
Reference Example 10
4-Chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile
To a solution of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (1.2 g, 6.16 mmol)
[Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] in 72 mL of
tetrahydrofuran at -78°C is added dropwise 2.0 M lithium diisopropylamide in
heptane/tetrahydrofuran/ethylbenzene (3.7 mL, 7.40 mmol). After stirring for 35
minutes, a solution of iodine (1.9 g, 7.40 mmol) in 8 mL of tetrahydrofuran is added
dropwise over 20 minutes. The reaction mixture is stirred at -78°C for 4 hours, then
85 mL of dichioromethane and 20 mL of water are added. The mixture is allowed to
warm to room temperature. The reaction mixture is partitioned between water and
dichioromethane. The organic layer is washed with a solution of sodium thiosulfate,
dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is
purified by flash column chromatography editing with dichioromethane to provide 1.0
g of 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile as colorless crystals, mp 181-
182°C; 1H NMR (DMSO-d6) d 8.00 (s, 1H), 8.88 (s, 1H); MS 320.8 (M+H)+.
Analysis for C8H2CIIN2S:
Calcd: C, 29.98; H, 0.63; N, 8.74
Found: C, 30.12; H, 0.83; N, 8.35.
Reference Example 11
4-Chlorothieno[2,3-b]pyridine-5-carboxylic acid
A mixture of ethyl 4-chlorothieno[2,3-b]pyridine-5-carboxylate (800 mg, 3.31
mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14,807 (1977)] in 15 mL
of ethanol and 5 mL of 2.5 N sodium hydroxide is heated at reflux for 90 minutes.
The mixture is cooled to 0°C and the pH is adjusted to 4 by the addition of 2 N
hydrochloric acid. The mixture is stirred at room temperature and the resulting
precipitate is collected by filtration and washed with water to provide 250 mg of 4-
chlorothieno[2,3-b]pyridine-5-carboxylic acid as a white solid, mp 172-174°C; 1H
NMR (DMSO-d6) d7.62 (d, J = 6 Hz, 1H), 8.14 (d, J = 6 Hz, 1H), 8.94 (s, 1H); MS
212.0 (M-H)-.
Analysis for C8H4CINO2S:
Calcd: C, 44.98; H, 1.89; N, 6.56
Found: C, 44.99; H, 2.14; N, 6.43.
An additional 230 mg of 4-chlorothieno[2,3-b]pyridine-5-carboxylic acid is obtained
from the filtrate.
Reference Example 12
4-Chlorothieno[2,3-b]pyridine-5-carboxarnide
A mixture of 4-chlorothieno[2,3-b]pyridine-5-carboxylic acid (250 mg, 1.16
mmol) and 5 mL of thionyl chloride is heated at reflux for 2 hours. The mixture is
concentrated in vacuo and dried. Acetone is added to the residue and the solution is
cooled to 0°C. Aqueous ammonium hydroxide (15 mL) is slowly added and the
reaction mixture is stirred at 0°C for 2 hours. The reaction mixture is concentrated in
vacuo and water is added to the residue. The resultant solids are collected by
filtration washing with water to provide 175 mg of 4-chlorothieno[2,3-b]pyridine-5-
carboxamide as a white solid, mp 159-160°C; 1H NMR (DMSO-d6) d7.57 (d, J = 6
Hz, 1H), 7.84 (s, 1H), 8.11 (s, 1H), 8.12 (d, J = 6 Hz, 1H), 8.61 (s, 1H);
MS 213.0,214.9 (M+H)+.
Analysis for C8H5CIN2OS:
Calcd: C, 45.18; H, 2,37; N, 13.17
Found: C, 44.88; H, 2.35; N, 12.77.
Reference Example 13
4-Chlorothieno[2,3-b]pyridine-5-carbonitrile
A mixture of 4-chlorothieno[2,3-b]pyridine-5-carboxamide (145 mg, 0.68
mmol) and cyanuric chloride (200 mg, 1.08 mmol) in 5 mL of N,N-dimethylformamide
is stirred at room temperature for 30 minutes. Ice is added to the reaction mixture
and the resultant solids are collected by filtration washing with water to provide 84
mg of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 100-103°C; 1H
NMR (DMSO-d6) 57.66 (d, J = 6 Hz, 1H), 8.26 (d, J = 6 Hz, 1H), 9.03 (s, 1H); MS
195.0(M+H)+.
Analysis for CeH3CIN2S - 0.4 H2O:
Calcd: C, 47.60; H, 1.90; N, 13.88
Found: C, 47.65; H, 1.55; N, 13.90.
Reference Example 14
4-Chloro-2-methylthieno[2,3-b]pyridine-5-carbonitrile
To a solution of 4-chlorothienol2,3-b]pyridine-5-carbonitrile (0.3 g, 1.54 mmol)
in 15 mL of tetrahydrofuran at -78°C is added dropwise 2.0 M lithium
diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.93 mL, 1.85 mmol).
After stirring for 45 min, a solution of iodomethane (0.115 mL, 1.85 mmol) in 1 mL of
tetrahydrofuran is added dropwise. The reaction mixture is stirred at -78°C for 4
hours, then dichloromethane and water are added. The mixture is allowed to warm
to room temperature, then partitioned between water and dichloromethane. The
organic layer is washed with a solution of sodium thiosulfate, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with 1: 9 ethyl acetate: hexane to provide 0.1 g of 4-chloro-
2-methylthieno[2,3-b]pyridine-5-carbonitrile as colorless crystals, mp 101-102°C; 1H
NMR (DMSO-d6) d 2.68 (s, 3H), 7.39 (s, 1H), 8.92 (s, 1H); MS 209.0 (M+H)+.
Analysis for C9H5CIN2S:
Calcd: C, 51.80; H, 2.42; N, 13.42
Found: C, 52.11; H, 2.14; N, 13.08.
Reference Example 15
7-Chloro-2-methylthieno[3,2-b]pyridine-6-carbonitrile
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 2.57
mmol) in 15 mL of tetrahydrofuran at -78°C is added dropwise 2.0 M lithium
diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (1.6 mL, 3.21 mmol).
After stirring for 40 minutes, iodomethane (616 mg, 0.27 mL, 4.34 mmol) is added
dropwise over 7 minutes. The reaction mixture is stirred at -78°C for 5 hours, then
the mixture is partitioned between 20 mL of dichloromethane and 10 mL of water.
The organic layer is washed with a saturated aqueous ammonium chloride solution,
followed by saturated aqueous sodium chloride, then dried over sodium sulfate,
filtered and concentrated in vacuo. The residue is purified by flash column
chromatography editing with a gradient of 5% ethyl acetate in hexane to 20% ethyl
acetate in hexane to provide 274 mg of 7-chloro-2-methylthieno[3,2-b]pyridine-6-
carbonitrile as a white solid, mp 163-164°C; 1H NMR (DMSO-d6) d2.73 (s, 3H), 7.55
(s, 1H), 9.03 (s, 1H); MS 209.0,211.1 (M+H)+.
Analysis for C9H5CIN2S:
Calcd: C, 51.80; H, 2.42; N, 13.42
Found: C, 51.56; H, 2.25; N, 13.43.
Reference Example 16
4-Thiophen-2-yl-butyric acid methyl ester
A mixture of 4-(2-thienyl)butyric acid (4.25 g, 25.0 mmol) and 3 mL of
concentrated sulfuric acid in 25 mL of methanol is heated at reflux for 2 hours. The
reaction mixture is cooled to room temperature and partitioned between ethyl acetate
and saturated aqueous sodium carbonate solution. The organic layer is separated
and passed through a short pad of silica gel. The filtrate is concentrated and purified
by flash column chromatography eluting with 1: 5 ethyl acetate: hexane to provide
4.02 g of 4-thiophen-2-yl-butyric acid methyl ester as a yellow oil, 1H NMR (DMSO-
d6) d1.85 (quintet, J = 7 Hz, 2H), 2.35 (t J = 7 Hz, 2H ), 2.81 (t, J = 7 Hz, 2H), 3.59
(s, 3H), 6.84 (m, 1H), 6.95 (m, 1H), 7.32 (dd, J = 5,1 Hz, 1H); MS 185.0 (M+H)+
Analysis for C9H12O2S:
Calcd: C, 58.67; H, 6.56; N, 0.00
Found: C, 58.87; H, 6.57; N, 0.02.
Reference Example 17
4-(5-Nitro-thiophen-2-yl)-butyric acid methyl ester
To 8 mL of acetic anhydride at -20°C is added 1.2 mL of nitric acid (d = 1.5).
The mixture is kept at -20°C, and a solution of 4-thiophen-2-yl-butyric acid methyl
ester (1.84 g, 10.0 mmo!) in 12 mL of acetic anhydride is added dropwise. The
reaction mixture is stirred for 10 minutes after completion of addition, and poured into
an ice-water mixture. The product is extracted with ethyl acetate and the organic
layer is washed with 10 N aqueous sodium hydroxide solution, dried and
concentrated. The residue is purified by flash column chromatography eluting with 1:
4 ethyl acetate : hexane to provide 1.32 g of 4-(5-nitro-thiophen-2-yl)-butyric acid
methyl ester as a yellow oil; 1H NMR (DMSO-d6) d1.93 (quintet, J = 7 Hz, 2H), 2.41
(t, J = 7 Hz, 2H), 2.88 (t, J = 7 Hz, 2H), 3.59 (s, 3H), 7.04 (d, J = 5 Hz, 1H), 8.01 (d, J
= 5Hz,1H);MS 229.0(M)+
Analysis for C9H11NO4S:
Calcd: C, 47.15; H, 4.84; N, 6.11
Found: C, 47.17; H, 4.91; N, 6.36.
Reference Example 18
4-(5-Amino-thiophen-2-yl)-butyric acid methyl ester
A mixture of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester (2.29 g, 10.0
mmol) and palladium hydroxide (500 mg, 20% on carbon) in 30 mL of ethyl acetate
and 30 mL of methanol is hydrogenated at 50 psi for 48 hours. The reaction mixture
is filtered and concentrated. The residue is purified by flash column chromatography
eluting with 1:3 ethyl acetate: hexane to provide 1.32 g of 4-(5-amino-thiophen-2-yl)-
butyric acid methyl ester as a dark oil; 1H NMR (DMSO-d6) d1.74 (m, 2H), 2.38 (m,
2H ), 2.54 (m, 2H), 3.59 (s, 3H), 5.66 (d, J = 3 Hz, 1H), 6.24 (d, J = 3 Hz, 1H); MS
200.2 (M+H)+.
Reference Example 19
4-(4-Chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester
A mixture of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester (1.00 g, 5.0
mmol) and ethyl (ethoxymethylene)cyanoacetate (930 mg, 5.5 mmol) in 50 mL of
Coluene is heated at reflux for 1 hour. The reaction mixture is concentrated and 50
mL of Dowtherm-A is added. The mixture is heated at reflux for 3 hours and cooled
to room temperature. The crude reaction mixture is passed through a short pad of
silica gel, eluting with dichloromethane followed by 10% methanol in
dichloromethane. The crude product is further purified by flash column
chromatography eluting with 10% methanol in dichloromethane followed by another
flash column chromatography eluting with 10% methanol in ethyl acetate to provide
136 mg of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yI)butanoate as
a tan solid.
A mixture of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-
yl)butanoate (136 mg) and 2 drops of N,N-dimethylformamide in 5 mL of
phosphorous oxychloride is heated at reflux for 10 minutes and concentrated. To the
residue is added dichloromethane and the solution is washed with 1% aqueous
sodium bicarbonate solution. The organic layer is dried and concentrated. The
residue is purified by flash column chromatography eluting with dichloromethane to
provide 126 mg of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl
ester as a tan solid, mp 55-57°C; 1H NMR (DMSO-d6) d1.98 (quintet, J = 7 Hz, 2H),
2.42 (t, J = 7 Hz, 2H), 3.04 (t, J = 7 Hz, 2H), 3.59 (s, 3H), 7.42 (s, 1H), 8.94 (s, 1H);
MS 295.1 (M+H)+
Analysis for C13H11CIN2O2S:
Calcd: C, 52.97; H, 3.76; N, 9.50
Found: C, 52.80; H, 3.90; N, 9.25.
Reference Example 20
7-Chloro-2-formy!thieno[3,2-b]pyridine-6-carbonitrile
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03
mmol) in 6 mL of tetrahydrofuran at -78°C is added dropwise 2.0 M lithium
diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.645 mL, 1.29 mmol).
After stirring for 40 minutes, N,N-dimethylformamide (99 mg, 1.35 mmol) is added
dropwise over 5 minutes. The reaction mixture is stirred at -78°C for 4 hours, then
dichloromethane is added and the reaction mixture is allowed to warm to room
temperature. Water is added and the organic phase is separated and the aqueous
phase is extracted with dichloromethane. The organic phases are combined and
washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered
and concentrated in vacuo. The residue is purified by preparative thin layer
chromatography developing with 30% ethyl acetate in hexane to provide 62 mg of
7-chloro-2-formylthieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 188-189°C;
1H NMR (DMSO-d6) d 8.72 (s, 1H), 9.26 (s, 1H), 10.28 (s, 1H); MS 221.9,223.9 (M-
H)-
Analysis for C9H3CIN2OS:
Calcd: C, 48.55; H, 1.36; N, 12.58
Found: C, 48.69; H, 1.48; N, 12.30.
Reference Example 21
tert-Butyl(2E)-3-(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-2-enoate
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (100 mg, 0.45
mmol) in 5 mL of dichloromethane is added, in portions, (tert-
butoxycarbonylmethylene)triphenylphosphorane (0.645 mL, 1.29 mmol). After
stirring for 2.5 hours, the reaction mixture is allowed to stand at room temperature
overnight. The mixture is concentrated to ½ its volume and is purified by flash column
chromatography eluting with dichloromethane to provide 126 mg of tert-butyl (2E)-3-
(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-2-enoate as a white solid, mp 193-
194°C; 1H NMR (CDCI3) d1.55 (s, 9H), 6.46 (d, J = 16 Hz, 1H), 7.26 (s, 1H), 7.70 (s,
1H), 7.77 (d, J = 16 Hz, 1H), 8.84 (s, 1H); MS 321.1,323.2 (M+H)+
Analysis for C15H13CIN2O2S:
Calcd: C, 56.16; H, 4.08; N, 8.73
Found: C, 55.76; H, 3.76; N, 8.50.
Reference Example 22
7-Chloro-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.0
mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of
tetrakis(triphenylphosphine)palladium (0) in 13 mL of ethylene glycol dimethyl ether
and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours.
4-(dimethylamino)phenylboronic acid (105 mg) and
tetrakis(triphenylphosphine)palladium (0) (29 mg) are added and the reaction mixture
is heated at reflux for 6 hours. The mixture is treated with water and extracted into
dichloromethane and the organic phase is washed with brine and dried over sodium
sulfate, filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in
dichloromethane to provide 187 mg (60%) of 7-chloro-2-[4-
(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as an orange solid, mp
270-272°C; 1H NMR (CDCI3) d 3.07 (s, 6H), 6.73 (d, J = 5 Hz, 2H), 7.58 (s, 1H), 7.63
(d, J = 5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.
Reference Example 23
7-Chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chloro-2-iodo-thieno[3,2-b]pyridine-6-carbonitrile (1.00 g, 3.12
mmol), 4-formylphenylboronic acid (936 mg, 6.24 mmol) and 108 mgs of
tetrakis(triphenylphosphine)palladium (0) in 30 mL of ethylene glycol dimethyl ether
and 25 mL of aqueous saturated sodium bicarbonate is heated at reflux for 4 hours.
The mixture is cooled and the precipitate is collected by filtration washing with ethyl
acetate and diethyl ether to provide 818 mg of 7-chloro-2-(4-formylphenyl)thieno[3,2-
b]pyridine-6-carbonitrile as a yellow solid, mp 300-305°C; 1H NMR (CDCI3) d 7.93 (d,
J = 8 Hz, 2H), 7.96 (s, 1H), 8.03 (d, J = 8 Hz, 2H), 8.87 (s, 1H), 10.1 (s, 1H), MS
298.0, 300.0 (M-H)-H.
Reference Example 24
7-Chloro-2-{4-[(dimethylamino)methyl]phenyl}thleno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile
(700 mg, 2.34 mmol) and 6.0 mL of 2.0 M dimethylamine in tetrahydrofuran in 30 mL
of dichloromethane and 5 mL of dimethylformamide is cooled to 0-5°C. Sodium
triacetoxyborohydride (2.5 g, 11.7 mmol) is added in portions and after 5 minutes
0.10 mL of acetic acid is added. The mixture is stirred at room temperature for 2
hours then quenched by the addition of ice water and partitioned between
dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is
dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified
by flash column chromatography eluting with a gradient of dichloromethane to 10%
methanol in dichloromethane to provide 496 mg (65%) of 7-chloro-2-{4-
[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonrtrile as a yellow solid,
mp 166-168°C; 1H NMR (DMSO-d6) d 2.21 (s, 6H), 3.52 (s, 2H), 7.48 (d, J = 8 Hz,
2H), 7.95 (d, J = 8 Hz, 2H), 8.28 (s, 1H), 9.11 (s, 1H); MS 328.1, 330.1 (M+H)+;
HRMS found: 328.06622
Analysis for C17H14CIN3S-0.3 H2O:
Calcd: C, 61.27; H, 4.42; N, 12.61
Found: C, 61.22; H, 4.13; N, 12.50.
Example 1
7-[(2,4-Dichloro-5-methoxyanilino)]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60%
sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for
30 minutes. The solution is cooled and 7-chlorothieno[3,2-b]pyridine-6-carbonitrile
(200 mg, 1.02 mmol) is added. The reaction mixture is heated at reflux for 3.5 hours
then allowed to stir at room temperature overnight. The resultant black solution is
partitioned between ethyl acetate and water. The organic layer is washed with water,
dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is
purified by flash column chromatography eluting with 1:1 ethyl acetateihexane. The
fractions containing product are combined and concentrated. Diethyl ether is added
and the insoluble material collected by filtration to provide 131 mg of 7-[(2,4-dichloro-
5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 216-
220°C; 1H NMR (DMSO-d6) d3.85 (s, 3H), 7.40 (3,1H), 7.46 (d, J = 5 Hz, 1H), 7.76
(s, 1H), 8.11 (d, J = 5 Hz, 1H), 8.61 (s, 1H), 9.71 (s, 1H); MS 350.2 (M+H)+.
Analysis for C15H9Cl2N3OS - 0.25 H2O:
Calcd: C, 50.79; H, 2.70; N, 11.85.
Found: C, 50.79; H, 2.48; N, 11.56.
Example 2
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-oxo-2-phenyl-4,7-dihydrothieno[3,2-b]pyridine-6-carbonitrile
(878 mg, 3.48 mmol) and 10 mL of phosphorous oxychloride is heated at reflux for 1
hour. The reaction mixture is cooled to room temperature and hexane is added. The
solids are collected by filtration and stirred with saturated aqueous sodium
bicarbonate. The solids are collected by filtration washing with water, ethyl acetate
and methanol to provide 751 mg of 7-chloro-2-phenylthieno[3,2-b]pyridine-6-
carbonitrile that is not purified.
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60%
sodium hydride (69 mg, 1.73 mmol) in 10 mL of tetrahydrofuran is heated at reflux for
40 minutes. The solution is cooled and 7-chloro-2-phenylthieno[3,2-b]pyridine-6-
carbonitrile (270 mg, 1.0 mmol) is added. The reaction mixture is heated at reflux for
5.5 hours then allowed to stir at room temperature overnight. The resultant black
solution is partitioned between ethyl acetate and water. The aqueous layer is
acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic
ayer is dried over magnesium sulfate, filtered and concentrated in vacuo. The
esidue is treated with ethyl acetate and hexane and the insoluble material is
collected by filtration. The solid is suspended in hot methanol and ethyl acetate and
be mixture is filtered while warm to provide 50 mg of 7-[(2,4-dichloro-5-
Tiethoxyphenyl)amino]-2-phenylthieno[3,2-b]pyrtdine-6-carbonitrile as a light brown
solid, mp 274-276°C; 1H NMR (DMSO-d6) d3.86 (s, 3H), 7.40 (s, 1H), 7.44-7.53 (m,
3H), 7.73 (d, J = 7 Hz, 2H), 7.78 (s, 1H), 7.94 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS
426.1 (M+H)+.
Analysis for C21H13CI2N3OS - 0.25 H2O:
Cated: C, 58.54; H, 3.16; N, 9.75.
Found: C, 58.50; H, 3.07; N, 9.49.
Example 3
2-Bromo-7-[(2,4-dichlorc-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (221.8 mg, 1.16 mmol) and 60%
sodium hydride (46.2 mg, 1.16 mmol) in 6 mL of tetrahydrofuran is heated at reflux
for 1 hour. The solution is cooled and 2-bromo-7-chlorothieno[3,2-b]pyridine-6-
carbonitrile (150 mg, 0.55 mmol) is added. The resulting reaction mixture is heated at
reflux for 5 hours, cooled to room temperature, and then partitioned between
dichloromethane and water. The organic layer is washed with saturated aqueous
sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The
residue is purified by preparative thin layer chromatography developing with 40 %
ethyl acetate in hexane to provide 114.6 mg of 2-bromo-7-[(2,4-dichloro-5-
methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 228-
229°C; 1H NMR (DMSO-d6) d3.86 (s, 3H), 7.40 (s, 1H), 7.71 (s, 1H), 7.80 (s, 1H),
8.61 (s, 1H), 9.80 (s, 1H); MS 426.0,428.0 (M-H)-.
Analysis for C15H8BrCl2N3OS:
Calcd: C, 41.98; H, 1.88; N, 9.79.
Found: C, 42.08; H, 2.09; N, 9.62.
Example 4
7-[(2,4-Dichloro-5-methoxyphenyl)aminol]-2-iodothieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60%
sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for
1 hour. The solution is cooled and 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile
(320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight.
The reaction mixture is cooled to room temperature and partitioned between ethyl
acetate and water. The organic layer is washed with water, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-[(2,4-
dichloro-5-methoxyphenyl)aminol]-2-iodothieno[3,2-b]pyridine-6-carbonitrile as yellow
crystals, mp 233-234°C; 1H NMR (DMSO-d6) d3.85 (s, 3H), 7.38 (s, 1H), 7.77 (s,
1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (M+H)+.
Analysis for C15H8CI2N3OS:
Calcd: C, 37.84; H, 1.69; N, 8.83.
Found: C, 37.44; H, 1.75; N, 8.80.
Example 5
4-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitri!e
A mixture of 2,4-dichloro-5-methoxyaniline (300 mg, 1.57 mmol) and 60%
sodium hydride (70 rng, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for
30 minutes The solution is cooled and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile
[150 mg, 0.8 mmol) [Khan, M. A.; Guarconl, A. E., J. Heterocyclic Chem., 14, 807
(1977)] is added. The reaction mixture is heated at reflux for 3.5 hours. The resultant
alack solution is partitioned between ethyl acetate and water. The organic layer is
washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue is purified by flash column chromatography eluting with 2:3 ethyl
acetate:hexane. The fractions containing product are combined and concentrated.
Diethyl ether is added and the insoluble material is collected by filtration to provide 60
mg of 4-[(2,4-dichloro-5-methoxyphenyl)arnino]thieno[2,3-b]pyridine-5-carbonitrile as
a tan solid, mp 197-199°C; 1H NMR (DMSO-d6) d 3.85 (s, 3H), 7.38 (s, 1H), 7.68 (d,
J = 5.7 Hz, 1H), 7.76 (s, 1H), 7.81 (d, j= 5.7 Hz, 1H), 8.43 (s, 1H), 9.80 (s, 1H); MS
348.2 (M-H)-.
Analysis for C15H9Cl2lN3OS:
Calcd: C, 51.44; H, 2.59; N, 12.00.
Found: C, 51.57; H, 2.99; N, 11.60.
Example 6
4-[(3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl)amino]thien[2,3-b]pyridine-5-
carbonitrile
A mixture of (3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline (135 mg,
0.57 mmol), pyridine hydrochloride (66 mg, 0.57 mmol) and 4-chlorothieno[2,3-
b]pyridine-5-carbonitrile (0.1 g, 0.52 mmol) in 4 mL of 2-ethoxyethanol is heated at
reflux for 24 hours. The solution is cooled and the solvent is evaporated. The
resultant residue is treated with a minimum amount of methanol and the product is
purified by flash column chromatography eluting with 3% methanol in
dichloromethane. The fractions containing product are combined and concentrated.
Ethyl acetate is added and the insoluble material collected by filtration to provide 55
mg of 4-[(3-chloro-4-[(1-methyl-1 H-imidazol-2-yl)thio]phenyl)amino]thieno[2,3-
b]pyridine-5-carbonitrile as a tan solid, mp >240°C; 1H NMR (DMSO-d6) d 3.61 (s,
3H), 6.53 (d, J = 9 Hz, 1H), 7.15 (m, 1H), 7.17 (s, 1H), 7.44 (m, 1H), 7.52 (s, 1H),
7.54 (s, 1H), 7.81 (d, J = 6 Hz, 1H), 8.53 (s, 1H), 9.76 (s, 1H); MS 396.2 (M-H)-.
Analysis for C18H12CIN5S2 - 0.05 H2O:
Calcd: C, 54.33; H, 3.04; N, 17.60.
Found: C, 54.21; H, 3.06; N, 17.56.
Example 7
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (1.1 g, 5.7 mmol) and 60% sodium
hydride (285 mg, 9.9 mmol) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour.
The solution is cooled and 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile (1.0 g,
3.12 mmol) is added. The reaction mixture is heated at reflux for 5 hours then
allowed to stir at room temperature overnight. The resultant dark solution is
partitioned between ethyl acetate and water. The organic layer is washed with water,
dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is
purified by flash column chromatography eluting with 0.5: 9.5 methanol :
dichloromethane to provide 0.28 g of 4-[(2,4-dichloro-5-methoxyphenyl)aminoJ-2-
iodothieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 231-233°C. An
additional 0.09 g is obtained by chromatography of a mixture of unreacted starting
material and product using a gradient of 9 :1 to 1 :1 hexane: ethyl acetate. 1H NMR
(DMSO-d6) d 3.87 (s, 3H), 7.36 (s, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.39 (s, 1H), 9.76
(s, 1H); MS 473.8 (M-H)-.
Analysis for C15H8Cl2lN3OS - 0.05 H2O:
Calcd: C, 37.84; H, 1.69; N, 8.83.
Found: C, 37.77; H, 1.71; N, 8.81.
Example 8
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-rnethylthieno[2,3-b]pyridine-5-carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (0.15 g, 0.73 mmol) and 60%
sodium hydride (50 mg, 1.25 mmol) in 15 mL of tetrahydrofuran is heated at reflux for
1 hour. The solution is cooled and 4-chloro-2-methylthieno[2,3-b]pyridine-5-
carbonitrile (0.06 g, 0.29 mmol) is added. The reaction mixture is heated at reflux for
3 hours then allowed to stir at room temperature overnight The resultant black
solution is partitioned between ethyl acetate and water. The organic layer is washed
with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The
residue is purified by flash column chromatography eluting with 3: 7 ethyl acetate :
hexane. The fractions containing product are combined and concentrated. Diethyl
ether is added and the insoluble material collected by filtration to provide 79 mg of 4-
[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-carbonitrile
as a tan solid, mp 179-181 °C; 1H NMR (DMSO-d6) d2.57 (s, 3H), 3.85 (s, 3H), 7.32
(s, 1H), 7.39 (s, 1H), 7.74 (s, 1H), 8.35 (s, 1H), 9.61 (s, 1H); MS 362.1 (M-H)-
Analysis for C16H11Cl2N3OS
Calcd: C, 52.76; H, 3.04; N, 11.54.
Found: C, 52.46; H, 3.22; N, 11.14.
Example 9
7-[(2,4-Dichloro-5-methoxyphenyl}amino]-2-methylthieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 2,4-dichloro-5-methoxyaniline (507 mg, 2.64 mmol) and 60%
sodium hydride (105.6 mg, 2.64 mmol) in 15 mL of tetrahydrofuran is heated at reflux
for 1 hour. The solution is cooled and 7-chloro-2-methylthieno[3,2-b]pyridine-6-
carbonitrile (275.3 mg, 1.32 mmol) is added. The reaction mixture is heated at reflux
for 6 hours, cooled to room temperature and partitioned between dichloromethane
and water. The organic layer is washed with saturated aqueous sodium chloride,
dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified
by flash column chromatography eluting with a gradient of 5% ethyl acetate in
hexane to 20% ethyl acetate in hexane followed by preparative thin layer
chromatography developing with 20% ethyl acetate in dichloromethane, to provide
108 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-
carbonitrile as an off white solid, mp 213-214°C; 1H NMR (DMSO-d6) 62.51 (s, 3H),
3.85 (s, 3H), 7.20 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H); MS
362.1, 364.3 (M+H)+.
Analysis for C16H11Cl2N3OS:
Calcd: C, 52.76; H, 3.04; N, 11.54.
Found: C, 52.86; H, 2.95; N, 11.56.
Example 10
7-[(2,4-Dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride
(82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The
solution is cooled and 7-chlorothieno[3.2-b]pyridine-6-carbonitrile (200 mg, 1.03
mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled
to room temperature, and concentrated in vacuo. The residue is treated with water
for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant
solid is purified by flash column chromatography eluting with a gradient of 1% ethyl
acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-[(2,4-
dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 198-
200°C;1H NMR (DMSO-d6) 57.47 (d, J = 4 Hz, 1H), 7.54 (dd, J = 6, 2 Hz, 1H), 7.59
(d, J = 6 Hz, 1H), 7.81 (d, J = 2 Hz, 1H), 8.12 (d, J = 4 Hz, 1H), 8.61 (s, 1H), 9.67 (s,
1H); MS 318.1, 320.2 (M+H)+.
Analysis for C14H7CI2N3S-0.3 H2O:
Calcd: C, 51.64; H, 2.35; N, 12.91.
Found: C, 51.64; H, 2.08; N, 12.86.
Example 11
7-[(2,4-Dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol),
potassium carbonate (194.9 mg,1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34
mmol) in 3 mL of N,N-dimethylforrnamide is stirred at 110° C for 4 hours and allowed
to cool to ambient temperature. The reaction mixture is treated with water and stirred
at ambient temperature for 10 minutes. The crude solid is collected by filtration
washing with water, dried in vacuo, then purified by flash column chromatography
eluting with a gradient of 5 % ethyl acetate in hexane to 20% ethyl acetate in hexane
to provide 244 mg of 7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile as
a white solid, mp 158-160°C; 1H NMR (DMSO-d6) d7.63 (dd, J = 6, 2 Hz, 1H), 7.68
(d, J = 4 Hz, 1H), 7.74 (d, J = 6 Hz, 1H), 7.80 (d, J = 2 Hz, 1H), 8.33 (d, J = 4 Hz,
1H), 9.03 (s, 1H); MS 320.9,322.9 (M+H)+.
Analysis for C14H6CI2N2OS:
Calcd: C, 52.35; H, 1.88; N, 8.72.
Found: C, 52.28; H, 1.69; N, 8.49.
Example 12
7-[(2,4-Dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol)
and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide
is stirred at room temperature for 1 hour, and then concentrated in vacuo. The
resulting residue is treated with water and stirred for 1 hour. The precipitate is
filtered, washed with water, air dried, and then purified by flash column
chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl
acetate in hexane to provide 249.0 mg of 7-[(2,4-dichlorophenyl)thio]thieno[3,2-
b]pyridine-6-carbonitriIe as a white solid, mp 126-128°C; 1H NMR (DMSO-d6) d7.47
(dd, J = 6,2 Hz, 1H), 7.54 (d, J = 6 Hz, 1H), 7.73 (d, J = 4 Hz, 1H), 7.88 (d, J = 2 Hz,
1H), 8.43 (d, J = 4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (M+H)+.
Analysis for C14H6CI2N2S2:
Calcd: C, 49.86; H, 1.79; N, 8.31.
Found: C, 49.87; H, 1.67; N, 8.18.
Example 13
7-[(2,4-Dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol),
2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine
in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is
concentrated in vacuo and the residue is treated with a saturated aqueous sodium
bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with
water, dried in vacuo, and then purified by flash column chromatography eluting with
a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to
provide 261.2 mg of 7-[(2,4-dichlorobenzyl)amino]thieno[3)2-b]pyridine-6-carbonitrile
as a white solid, mp 215-216°C; 1H NMR (DMSO-dfe) 84.95 (d, J = 5 Hz, 2H), 7.28 (d,
J = 6 Hz, 1H), 7.40 (dd, J = 6,2 Hz, 1H), 7.46 (dd, J = 4,2 Hz, 1H), 7.69 (d, J = 2 Hz,
1H), 8.12 (d, J = 5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J = 6 Hz, 1H); MS 334.0, 335.8
(M+H)+.
Analysis for C15H9CI2N3S:
Caicd: C, 53.90; H, 2.71; N, 12.57.
Found: C, 53.58; H, 2.43; N, 12.49.
Example 14
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (240 mg, 0.50 mmol), 4-formylphenylboronic acid (150 mg,
1.0 mmol) and 4 mg of tetrakis(triphenylphosphine)palladium(0) in 20 mL of ethylene
glycol dimethyl ether and 16 mL of saturated aqueous sodium bicarbonate is heated
at reflux for 2 hours. The reaction mixture is cooled to room temperature and
partitioned between water and ethyl acetate. The organic layer is dried over sodium
sulfate, filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with chloroform to provide 160 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)aminol-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as
yellow crystals, mp 261-262°C; 1H NMR (DMSO-d6) d3.87 (s, 3H), 7.41 (s, 1H), 7.63
(s, 1H), 7.90-8.03 (m, 4H), 8.15 {s, 1H), 8.65 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H);
MS 454.0 (M+H)+.
Analysis for C22H13CI2N3O2S -1.0 H2O:
Calcd: C, 55.94; H, 3.20; N, 8.90,
Found: C, 56.24; H, 2.87; N, 9.02.
Example 15
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-
morpholinylmethyl)phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Morpholine (16 mg, 0.18 mmol) is added to a suspension of 7-[(2,4-dichloro-
5-mettioxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (66
mg, 0.15 mmol) in 5 mL of dichloromethane and 0.5 mL of N,N-dimethylformamide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (85 mg, 0.40
mmol) is added. After stirring at 0°C for 1.5 hours, acetic acid (0.02 mL) is added
and the reaction mixture is allowed to warm to room temperature and stirred
overnight. The reaction is quenched by the addition of water and then partitioned
between water and dichloromethane. The organic layer is dried over sodium sulfate,
filtered and concentrated in vacuo. The residue is purified by flash column
chromatography to provide 48 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-
(4-morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals,
mp 244-245°C; 1H NMR (DMSO-d6) d2.36 (m, 4H), 3.50 (s, 2H), 3.57 (m, 4H), 3.85
(s, 3H), 7.31 (s, 1H), 7.42 (d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 7.89
(s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 525.2 (M+H)+.
Example 16
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
N-methylpiperazlne (177 µL, 1.6 mmol) is added to a suspension of 7-[(2,4-
dichloro-5-methoxyphenyl}amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile (560 mg, 1.23 mmoi) in 12 mL of dichloromethane and 3 mL of N,N-
dimethylformamide. The reaction mixture is cooled to 0°C and sodium
triacetoxyborohydride (1.3 g, 6.13 mmol) is added. After stirring at 0°C for 10
minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to
warm to room temperature and stirred for 5.5 hours. The reaction is quenched by the
addition of water and then partitioned between saturated aqueous sodium
bicarbonate and dichloromethane. The organic layer is washed with water, dried
over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by
flash column chromatography eluting with 5% methanol in dichloromethane. The
fractions containing product are combined and concentrated in vacuo. The residue is
washed with diethyl ether to provide 215 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-
b]pyridine-6-carbonitrile as white crystals, mp 226-228°C; 1H NMR (DMSO-d6) d2.17
(s, 3H), 2.37 (br s, 8H), 3.49 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.40 (d, J = 8 Hz, 2H),
7.67(d, J = 8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 538.2
(M+H)+.
Analysis for C27H25Cl2N5OS- 0.25 H2O:
Calcd: C, 59.72; H, 4.73; N, 12.90.
Found: C, 59.60; H, 4.51; N, 12.88.
Example 17
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
4-(2-Hydroxyethyl)piperazine (104 mg, 0.80 mmol) is added to a suspension
of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-
6-carbonitrile (227 mg, 0.50 mmol) in 15 mL of dichloromethane and 1 mL of N,N-
dimethylformamide. The reaction mixture is cooled to 0°C and sodium
triacetoxyborohydride (800 mg, 3.8 mmol) is added. After stirring at 0°C for 1.5
hours, 2 drops of acetic acid are added and the reaction mixture is allowed to warm
to room temperature and stirred overnight. The reaction is quenched by the addition
of water and then partitioned between aqueous sodium bicarbonate and
dichloromethane. The organic layer is dried over sodium sulfate, filtered and
concentrated in vacuo. The residue is purified by flash column chromatography
eluting with 10% methanol in dichloromethane to provide 100 mg of 7-[(2,4-
dichloro-5-methoxyphenyl)amino]-2-(4-[(4-hydroxyethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 189-190°C;
1H NMR (DMSO-d6) d2.27-2.44 (m, 10H), 3.41-3.50 (m, 4H), 3.85 (s, 3H), 4.36 (s,
1H), 7.37 (s, 1H), 7.40 (d, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 7.89 (s,
1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 566.3 (M-H)-.
Example 18
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
Piperidine (50 mg, 0.59 mmoi) is added to a suspension of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (200
mg, 0.44 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformarnide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (500 mg, 2.4
mmol) is added. After stirring at 0°C for 1.5 hours, a few drops of acetic acid are
added and the reaction mixture is allowed to warm to room temperature and stirred
overnight. The reaction is quenched by the addition of water and then partitioned
between aqueous sodium bicarbonate and dichloromethane. The organic layer is
dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified
by flash column chromatography eluting with a gradient of 1 : 1 hexane : ethyl
acetate to 5% methanol in ethyl acetate to provide 41 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-6-
carbonitrile as yellow crystals, mp 218-220°C; 1H NMR (DMSO-d6) d1.38 (m, 2H),
1.50 (m, 4H), 2.33 (m, 4H), 3.46 (m, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.40 (d, J = 8 Hz,
2H), 7.67 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.72 (s, 1H); MS
521.3 (M-H)-.
Example 19
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl}amino]thieno[3,2-b]pyridine-2-
yl]benzoic acid
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg,
2.12 mmol) and 100 mg of tetrakis(triphenylphosphine)palladium(0) in 50 mL of
ethylene glycol dimethyl ether and 35 mL of saturated aqueous sodium bicarbonate
is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature
and partitioned between water and ethyl acetate. The organic layer is washed with
saturated aqueous sodium chloride, dried over sodium sulfate, filtered and
concentrated in vacuo. The residue is purified by flash column chromatography
eluting with a gradient of chloroform to 10% methanol in chloroform to provide 4-{6-
cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl]benzoic
acid as yellow crystals, mp >300°C; 1H NMR (DMSO-d6) d3.86 (s, 3H), 7.40 (s, 1H),
7.78 (S, 1H), 7.86 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 8.03 (s, 1H), 8.08 (s,
1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s, 1H); MS 470.2 (M+H)+.
Example 20
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-
yl}benzamide
1,1'-Carbonyldiimidazole (100 mg, 0.61 mmol) is added to a suspension of 4-
{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl]benzoic
acid (130 mg, 0.28 mmol) in 10 mL of N,N-dimethylforrnamide. After stirring at 60°C
for 2 hours the reaction mixture is allowed to cool to room temperature and ammonia
gas is bubbled through the mixture for 15 minutes. The mixture is stirred at room
temperature for an additional 60 minutes and poured into 50 g of ice and stirred for
30 minutes. The mixture is adjusted to pH 4 with concentrated hydrochloric acid and
stirred for 60 minutes. The resulting precipitate is collected by filtration washing with
water and dried under reduced pressure. The resulting solid is purified by flash
column chromatography eiuting with a gradient of ethyl acetate to 20% methanol in
ethyl acetate to provide 12.3 mg of 4-{6-cyano-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yI}benzamide as a gray solid, mp
>300°C; 1H NMR (DMSO-d6) d3.86 (s, 3H), 7.40 (s, 1H), 7.48 (s, 1H), 7.78 (s, 1H),
7.82 (d, J = 8Hz, 2H), 7.97 (d, J = 8 Hz, 2H), 8.06 (s, 2H), 8.08 (s, 1H), 8.63 (s,
1H), 9.78 (s, 1H); MS 468.9,471.1 (M+H)+.
Example 21
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethyny)]thieno[3,2-
b]pyridine-6-carbonrtrile
A mixture of 7-[(2,4-dich)oro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (134 mg, 0.28 mmol), 1-ethynyl-4-methoxybenzene (50 µLt
0.39 mmol), 3 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(l)
iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 24 hours.
An additional 1 mL of triethylamine and 4 mL of benzene are added and the reaction
is heated at reflux for 6 hours. The mixture is cooled to room temperature and 2 mL
of methanol are added. The solvents are removed in vacuo and the residue is treated
with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing
with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water,
and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue is purified by flash column chromatography
editing with 4 : 1 hexane : ethyl acetate to provide 92 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-
carbonitrile as yellow crystals, mp 249-250°C; 1H NMR (DMSO-d6) d3.81 (s, 3H),
3.86 (s, 3H), 7.01 (d, J = 7 Hz, 2H), 7.40 (s, 1H), 7.55 (d, J = 7 Hz, 2H), 7.70 (s, 1H),
7.79 (s, 1H), 8.65 (s, 1H), 9.81 (s, 1H); MS 477.9,479.9 (M-H)-.
Analysis for C24H15Cl2N3O2S -0.1 (C2H4)2O- 0.2 C6H14:
Calcd: C, 60.71; H, 3.70; N, 8.30.
Found: C, 60.60; H, 3.45; N, 8.08.
Example 22
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 2-ethynylpyridine (90 µL, 0.82 mmol),
7.3 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(l) iodide in 2
mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture
is cooled to room temperature and 5 mL of methanol are added. The solvents are
removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The
insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is
washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium
chloride. The combined aqueous layers are extracted with dichloromethane. The
organic layer is washed with saturated aqueous sodium chloride, dried over
magnesium sulfate, filtered and concentrated in vacuo. The aqueous layer is
adjusted to pH 6 and extracted with chloroform. The organic layer is washed with
water, dried over magnesium sulfate, filtered and concentrated in vacuo. The
residues are combined and purified by flash column chromatography eluting with 5%
methanol in dichloromethane. The fractions containing product are combined and
concentrated. The resultant solid is recrystallized from ethyl acetate and hexane to
provide 92 mg of 7-[(2,4-dichIoro-5-methoxyphenyl)amino]-2-(pyridin-2-
ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as light brown crystals, mp 237-239°C;
1H NMR (DMSO-d6) d3.86 (s, 3H), 7.35-7.52 (m, 2H), 7.73 (d, J = 8 Hz, 1H), 7.80 (s,
1H), 7.83-7.92 (m, 2H), 8.60-8.72 (m, 2H), 9.89 (s, 1H); MS 449.1,450.9 (M-H)-.
Example 23
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-
b]pyridine-6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 1-dimethylamino-2-propyne (90 µL,
0.84 mmol), 7.5 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(l)
iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight
The mixture is cooled to room temperature and 2 mL of methanol are added. The
solvents are removed in vacuo and the residue is treated with 10 mL of chloroform.
The insoluble material is removed by filtration, washing with chloroform. The filtrate is
washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium
chloride. The combined aqueous layers are brought to pH 8 by adding 2 N sodium
hydroxide. The aqueous layer is extracted with chloroform, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with 5% methanol in dichloromethane to provide 225 mg of
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-
b]pyridine-6-carbonitrile as red crystals, mp 164-166°C; 1H NMR (DMSO-d6) d2.21
(s, 6H), 3.53 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s,
1H), 9.77 (s, 1H); MS 429.3, 431.2 (M-H)-.
Example 24
2-(1-Beruofuran-2-yl)-7-[(2Adichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-
6-carbonitrile
A mixture of 7-[(2,4-dich)oro-5-methoxyphenyl)amino]-2-lodothieno[3,2-
b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 2-benzofuranboronic acid (340 mg,
2.10 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of
ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate
is heated at reflux for 2.5 hours. An additional 50 mg of
tetrakis(triphenylphosphine)palladium(0) is added and the reaction is heated at reflux
for 1 hour. The reaction mixture is cooled to room temperature and partitioned
between water and ethyl acetate. The organic layer is washed with water, dried over
sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash
column chromatography eluting with 2 : 1 hexane : ethyl acetate. The fractions
containing product are combined and concentrated in vacuo. The residue is washed
with diethyl ether to provide 160 mg of 2-(1-benzofuran-2-yl)-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 281 -
282°C; 1H NMR (DMSO-d6) d3.87 (s, 3H), 7.29-7.45 (m, 3H), 7.61 (s, 1H), 7.69-7.73
(m, 2H), 7.81 (s, 1H), 8.02 (s, 1H), 8.65 (s, 1H), 9.82 (s, 1H); MS 464.2, 465.9 (M-
H)..
Analysis for C23H13CI2N3O2S- 0.25 H2O:
Calcd: C, 58.67; H, 2.89; N, 8.92.
Found: C, 58.56; H, 2.82; N, 8.69.
Example 25
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 3-formylphenylboronic acid (330 mg,
2.2 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of
ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate
is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature
and partitioned between water and ethyl acetate. The organic layer is washed with
water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is
purified by flash column chromatography eluting with 1 : 1 hexane : ethyl acetate.
The fractions containing product are combined and concentrated in vacuo. The
residue is recrystallized from ethyl acetate to provide 62 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as
yellow crystals, mp 262-263°C; 1H NMR (DMSO-d6) d3.86 (s, 3H), 7.39 (s, 1H), 7.69-
7.82 (m, 2H), 7.98 (s, 1H), 8.03-8.14 (m, 2H), 8.23 (s, 1H), 8.64 (s, 1H), 9.80 (s,
1H), 10.08 (s, 1H); MS 452.0,453.9 (M-H)-.
Analysis for C22H13Cl2N3O2S:
Calcd: C, 58.16; H, 2.88; N, 9.25.
Found: C, 57.80; H, 2.85; N, 9.16.
Example 26
7-[(2,4-Dichloro-5-methoxyphenyl)aminol-2-[3-(morpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
Morpholine (100µL, 1.15 mmol) is added to a suspension of 7-[(2,4-dichloro-
5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (400
mg, 0.88 mrnol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (1.0 g, 4.73
mmol) is added. After stirring at 0°C for 1 hour, 2 drops of acetic acid are added and
the reaction mixture is allowed to warm to room temperature and stirred for 2 hours.
The reaction is quenched by the addition of water and then partitioned between
saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is
washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue is purified by flash column chromatography eluting with a gradient of 1 :
1 hexane : ethyl acetate to 5% methanol in ethyl acetate to provide 154 mg of 7-
[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-
b]pyridine-6-carbonitrile as yellow crystals, mp 205-207°C; 1H NMR (DMSO-d6)
d2.38 (m, 4H), 3.51 (s, 2H), 3.59 (m, 4H), 3.86 (s, 3H), 7.32-7.48 (m, 3H), 7.64-7.70
(m, 2H), 7.77 (s, 1H), 7.91 (s, 1H), 8.61 (s, 1H), 9.74 (s, 1H); MS 523.1, 525.0 (M-
H)-.
Analysis for C26H22Cl2NO2S- 0.50 H2O:
Calcd: C, 58.43; H, 4.34; N, 10.48.
Found: C, 58.49; H, 4.10; N, 10.39.
Example 27
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-
carbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-
b]pyridine-5-carbonitrile (0.25 g, 0.52 mmol), 4-formylphenylboronic acid (0.16 mg,
1.05 mmol), and 30 mg of tetrakis(triphenylphosphine)palladium(0) in 45 mL of
ethylene glycol dimethyl ether is prepared. To the mixture is added 20 mL of a
saturated sodium carbonate solution and the reaction mixture is heated at reflux for 1
hour. The mixture is allowed to warm to room temperature and partitioned between
water and dichloromethane. The organic layer is dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue is triturated with ethyl acetate and
the resulting solid is filtered and washed with diethyl ether to provide 0.16 g of 4-
[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-
carbonitrile as an off white solid, mp >240°C; 1H NMR (DMSO-d6) d 3.87 (s, 3H), 7.42
(s, 1H), 7.79 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 8.46 (s, 1H),
8.47 (s, 1H), 9.92 (s, 1H), 10.06 (s, 1H); MS 452.0 (M-H)-.
Analysis for C22H13Cl2N3O2S:
Calcd: C, 58.16; H, 2.88; N, 9.25.
Found: C, 58.09; H, 2.53; N, 9.00.
Example 28
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-
ylmethyl)phenyl)thieno[2,3-b]pyridine-5-carbonitrile
A suspension of 4-[(2,4-dichloro-5-methoxypbeny))amino]-2-(4-
formylphenyl)thieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.24 mmol) in 1 mL of N,N-
dimethylformamide and 4 mL of dichloromethane is prepared. To the mixture is
added morpholine (0.03 mL, 0.32 mmol). The reaction mixture is cooled to 0°C and
sodium triacetoxyborohydride (0.26 g, 1.2 mmol) is added. After stirring at 0°C for 30
minutes a drop of acetic acid is added and the mixture is stirred at 0°C for an
additional 4 hours. Additional morpholine (0.01 mL, 0.1 mmol) and sodium
triacetoxyborohydride are added and the reaction mixture is allowed to warm to room
temperature and stirred overnight. The resultant light brown solution is partitioned
between dichloromethane and water. The organic layer is washed with saturated
aqueous sodium chloride and water, dried over magnesium sulfate, filtered and
concentrated in vacuo. The resulting residue is triturated with acetone and water to
provide 86 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-
ylmethyl)phenyl]thieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 106-108°C;
1H NMR (DMSO-d6) d 2.38 (br s, 4H), 3.51 (br s, 2H), 3.59 (br s, 4H), 3.86 (s, 3H),
7.40 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 8.19 (s,
1H), 8.42 (s, 1H), 9.80 (s, 1H); MS 525.0 (M+H)+.
Analysis for C26H22Cl2O2S
Calcd: C, 59.43; H, 4.22; N, 10.66.
Found: C, 59.34; H, 4.02; N, 10.26.
Example 29
4-[5-Cyano-4-(3,4,5-trimethoxyphenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid
methyl ester
A mixture of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl
ester (60 mg, 0.20 mmol), 3,4,5-trimethoxyaniline (92 mg, 0.50 mmol), and pyridine
hydrochloride (10 mg, 0.09 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for
24 hours. The solution is cooled and the solvent is evaporated. The residue is
purified by flash column chromatography eluting with 1:1 ethyl acetate : hexane to
provide 62 mg of 4-[5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-
yl]-butyric acid methyl ester as a tan solid, mp 101-103°C; 1H NMR (DMSO-d6) d1.94
(quintet, J = 7 Hz, 2H), 2.41 (t, J = 7 Hz, 2H), 2.88 (t, J = 7 Hz, 2H), 3.60 (s, 3H), 3.67
(s, 3H), 3.75 (s, 6H), 6.60 (s, 2H), 7.28 (s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS 442.1
(M+H)+.
Analysis for C22H23N3O5S:
Calcd: C, 59.85; H, 5.25; N, 9.52.
Found: C, 59.72; H, 5.41; N, 9.40.
Example 30
2-(4-Hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonhrile
To a solution of 4-[5-cyano-4-(3,4,5-trimethoxyphenylamino)-thieno[2,3-
b]pyridin-2-yl]-butyric acid methyl ester (1.10 g, 2.5 mmol) in 15 mL of
tetrahydrofuran at room temperature is added dropwise lithium borohydride in
tetrahydrofuran (10 mL, 2.0 M, 20 mmol).. The mixture is heated at reflux for 1 hour,
and cooled to room temperature. Methanol (20 mL) is added, and stirring is
continued at room temperature overnight. The reaction mixture is partitioned
between saturated aqueous sodium chloride and ethyl acetate. The organic layer is
dried, and concentrated. The residue is purified by flash column chromatography
eluting with with 2:1 ethyl acetate : hexane to provide 563 mg of 2-(4-hydroxybutyl)-
4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a white
solid, mp 125-127°C; 1H NMR (DMSO-d6) d1.50 (m, 2H), 1.72 (m, 2H), 2.91 (t, J = 7
Hz, 2H), 3.42 (m, 2H), 3.68 (s, 3H), 3.76 (s, 6H), 4.42 (t, J = 5 Hz, 1H), 6.75 (s, 2H),
7.44 (s, 1H), 8.45 (s, 1H), 10.23 (s, 1H); MS 414.4 (M+H)+.
Example 31
2-[4-(4-Morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonitrile
To a solution of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-
thieno[2,3-b]pyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464
mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine
(314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at
room temperature for 2 hours and concentrated. The residue is purified by flash
column chromatography eluting with a gradient of 9 :1 hexane : ethyl acetate to 1 :
2 hexane : ethyl acetate to provide crude 2-(4-bromobutyl)-4-[(3,4,5-
trimethoxyphenyl}amino]-thieno[2,3-b]pyridine-5-carbonitrile. The crude 2-(4-
bromobutyl)-4-[(3,4,5-trirnethoxyphenyl}amino]--thieno[2,3-b]pyridine-5-carbonitrile is
heated 70°C in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67
mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash
column chromatography eluting with a gradient of ethyl acetate to 10% methanol in
ethyl acetate to provide 2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyi)amino]-
thieno[2I3-b)pyridine-5-carbonrtrile as a yellow oil; 1H NMR (DMSO-d6) d1.49
(quintet, J = 7 Hz, 2H), 1.68 (quintet, J = 7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J = 7 Hz,
2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H),
9.46 (s, 1H); MS 483.5 (M+H)+.
Example 32
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-
b]pyridine-6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), (trimethylsilyl)acetylene (237 µL, 1.67
mmol), 12.5 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(i)
iodide in 3.5 mL of triethylamine and 12 mL of benzene is heated at reflux for 20
hours. The mixture is cooled to room temperature and 50 mL of chloroform are
added. The mixture is washed with saturated aqueous sodium chloride, dried over
sodium sulfate, filtered through a celite pad and concentrated in vacuo. The resulting
brown solid is suspended in diethyl ether. The solids are collected by filtration and
washed with diethyl ether to yield 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-
[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 169-
171°C; 1H NMR (CDCI3) d0.26 (s, 9H), 3.88 (s, 3H), 6.79 (s, 1H), 6.89 (s, 1H), 7.51
(s, 1H), 7.56 (s, 1H), 8.65 (s, 1H); MS 444.1,446.1 (M-H)-.
Analysis for C20H17Cl2N3OSSi- 0.15 CHCI3:
Calcd: C, 52.12; H, 3.72; N, 9.05.
Found: C, 52.23; H, 3.41; N, 9.12.
Example 33
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile
To the suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-
[(trimethylsilyl)ethynyl] thieno[3,2-b]pyridine-6-carbonitrile (97 mg, 0.22 mmol) in 10
mL of methanol is added potassium carbonate (46 mg, 0.33 mmol) The mixture is
stirred at room temperature for 30 minutes, concentrated in vacuo and then
partitioned between water and ethyl acetate. The organic layer is dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by
flash column chromatography eluting with 1: 1 ethyl acetate: hexane to provide 38
mg of 7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-ethynylthieno[3,2-b]pyridine-6-
carbonitrile as white crystals, mp 198-200°C; 1H NMR (DMSO-d6) d 3.85 (s, 3H),
5.01 (s, 1H), 7.38 (s, 1H), 7.72 (s, 1H), 7.79 (s, 1H), 8.63 (s, 1H), 9.85 (s, 1H); MS
372.0 (M-H)-.
Analysis for C17H9Cl2N3OS- 0.60 C4H10O:
Calcd: C, 55.64; H, 3.61; N, 10.03.
Found: C, 55.34; H, 3.45; N, 9.64.
Example 34
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-
[(trimethylsilyl)ethynyll thieno[3,2-b]pyridine-6-carbonitrile (365 mg, 0.82 mmol), 4-
iodopyridine (252 mg, 1.23 mmol), potassium carbonate (565 mg, 4.09 mmol), 30 mg
of bis(triphenylphosphine)palladium(ll) chloride, 43 mg of triphenylphosphine and 8
mg of copper(l) iodide in 10 mL of tetrahydrofuran and 2 mL of methanol is heated at
reflux overnight The mixture is cooled to room temperature and 50 mL of chloroform
are added. The mixture is washed with water and saturated aqueous sodium
chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The
residue is purified by two flash column chromatographies, first eluting with 5%
methanol in dichloromethane and then eluting with 1: 1 ethyl acetate : hexane to
provide 174 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-
ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as orange crystals, mp 221-223°C; 1H
NMR (CDCI3) d 3.86 (s, 3H), 7.43 (s, 1H), 7.59 (d, J = 5 Hz, 2H), 7.81 (s, 1H), 7.89
(s, 1H), 8.61-8.71 (m, 3H), 9.89 (s, 1H); MS 451.2 (M-H)+.
Analysis for C22N12Cl2OS- 0.11 CHCI3:
Calcd: C, 57.17; H, 2.62; N, 12.06.
Found: C, 57.42; H, 2.65; N, 11.68.
Example 35
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (160 mg, 0.33 mmol), 3-ethynylpyridine (45 mg, 0.43 mmol),
5 mg of tetrakis(triphenylphosphine)palladium(0) and 20 mg of copper(l) iodide in 2
mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture
is cooled to room temperature and 5 mL of methanol is added. The solvents are
removed in vacuo and the residue is treated with 50 mL of chloroform. The insoluble
material is removed by filtration, washing with chloroform. The filtrate is washed with
water. The residue is suspended in acetone, combined with the chloroform phase
and concentrated in vacuo. The residue is purified by flash column chromatography
eluting with a gradient of 5% methanol in dichloromethane to 10% methanol and 1%
ammonium hydroxide in dichloromethane. The fractions containing product are
combined and concentrated to provide 99 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as
light brown crystals, mp 249-250°C; MS 451.0(M+H)+.
Analysis for C22H12CI2N4OS:
Calcd: C, 58.55; H, 2.68; N, 12.41.
Found: C, 58.49; H, 2.65; N, 12.11.
Example 36
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-3-yl]thieno[3,2-
b]pyridine-6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (564 mg, 1.18 mmol), tributyl-(5-[1,3]dioxolan-2-yl-thiophen-
3-yl)-stannane (680 mg, 1.52 mmol) and a pinch of
bis(triphenylphosphine)palladium(ll) chloride in 15 mL of dioxane is heated at reflux
for 5 hours. Additional bis(triphenylphosphine)palladium(ll) chloride is added and the
reaction is heated at reflux overnight. Additional bis(triphenylphosphine)palladium(ll)
chloride and 10 mL of dioxane are added and the reaction is heated at reflux for 5
hours. The reaction mixture is concentrated in vacuo and partitioned between water
and chloroform. The organic layer is dried over sodium sulfate, filtered and
concentrated in vacuo. The residue is purified by flash column chromatography
eluting with 1 : 1 hexane : ethyl acetate. The fractions containing product are
combined and concentrated in vacuo to provide 447 mg of 7-[(2,4-dichloro-5-
methoxyphenyl}amino]-2-[5-(1,3-dioxolan-2-yl)thien-5-yl}thieno[3,2-b]pyridine-6-
carbonitrile as white crystals, mp 219-221 °C; 1H NMR (DMSO-d6) d3.85 (s, 3H),
3.92-4.10 (m, 4H), 6.08 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H), 7.75 (s, 1H), 7.80 (s, 1H),
7.97 (S, 1H), 8.60 (s, 1H), 9.69 (s, 1H); MS 502.1 (M-H)-.
Analysis for C22H15CI2N3O3S2:
Calcd: C, 52.39; H, 3.00; N, 8.33.
Found: C, 52.58; H, 3.21; N, 7.93.
Example 37
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile
To the suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-
dioxolan-2-yl)thien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile (337 mg, 0.67 mmol) in 10
mL of tetrahydrofuran is added 5 mL of 2N hydrochloric acid. The mixture is stirred at
room temperature, overnight The mixture is slowly poured into 30 mL of saturated
aqueous sodium bicarbonate and extracted with chloroform. The organic layer is
washed with saturated aqueous sodium chloride, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with 5% methanol in dichloromethane to provide 271 mg of
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile as yellow crystals, mp 259-261 °C; 1H NMR (DMSO-d6) d 3.85 (s, 3H),
7.38 (s, 1H), 7.76 (s, 1H), 7.93 (s, 1H), 8.42 (s, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 9.76
(s, 1H), 9.98 (s, 1H); MS 458.1 (M-H)-.
Analysis for C20H11Cl2N3O2S2+ 0.05 CH2CI2+ 0.10 CHCI3:
Calcd: C, 50.78; H, 2.37; N, 8.82.
Found: C, 50.59; H, 2.21; N, 8.74.
Example 38
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile
1-Methylpiperazine (70 µL, 0.63 mmol) is added to a suspension of 7-[(2,4-
dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-5-yl}thieno[3,2-b]pyridine-6-
carbonitrile (225 mg, 0.49 mmol) in 4 mL of dichloromethane and 1 mL of N,N-
dimethylformamide. The reaction mixture is cooled to 0°C and sodium
triacetoxyborohydride (520 mg, 2.45 mmol) is added. After stirring at 0°C for 10
minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to
warm to room temperature and stirred for 4 hours. The reaction is quenched by the
addition of water and then partitioned between saturated aqueous sodium
bicarbonate and dichloromethane. The organic layer is washed with water, dried
over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by
flash column chromatography eluting with 5% methanol in dichloromethane. The
fractions containing product are combined and concentrated in vacuo. The residue is
washed with diethyl ether to provide 133 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2{5-[(4-methylpiperazin-1-yl)methyl]thien-3-y}thieno[3,2-
b]pyridine-6-carbonitrile as white crystals, mp 224-226°C; 1H NMR (DMSO-d6) d2.18
(s, 3H), 2.25-2.55 (m, 8H), 3.68 (s, 2H), 3.85 (s, 3H), 7.35 (s, 1H), 7.37 (s, 1H), 7.74
(s, 1H), 7.75 (s, 1H), 7.82 (s, 1H), 8.58 (s, 1H), 9.68 (s, 1H); MS 523.1, 544.2
(M+H)+.
Analysis for C25H23CI2N5OS2- 0.50 H2O:
Calcd: C, 54.24; H, 4.37; N, 12.65.
Found: C, 54.57; H, 4.34; N, 12.30.
Example 39
7-[(2,4-Dlchloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-
yl]thieno[3,2-b]pyridine-6-carbonitrile
Morpholine (50 µL, 0.57 mmol) is added to a suspension of 7-[(2,4-dichioro-5-
methoxyphenyl)amino]-2-(5-formylthien-5-yl}thieno[3,2-b]pyridine-6-carbonitrile (200
mg, 0.43 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (460 mg,
2.17 mmol) is added. After stirring at 0°C for 10 minutes, 2 drops of acetic acid are
added and the reaction mixture is allowed to warm to room temperature and stirred
for 4 hours. The reaction is quenched by the addition of water and then partitioned
between saturated aqueous sodium bicarbonate and dichloromethane. The organic
layer is washed with water, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude residue is purified by flash column chromatography eluting with 5%
methanol in dichloromethane to provide 169 mg of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]thieno[3,2-b]pyridine-6-
carbonitrile as a white solid, mp 209-212°C; MS 531.0(M+H)+.
Analysis for C24H20CI2N4O2S2:
Calcd: C, 54.24; H, 3.79; N, 10.54.
Found: C, 54.16; H, 3.43; N, 10.40.
Examples 40 & 41
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile and
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl]thieno[3,2-
b]pyridine-6-carbonitrile
4-Hydroxypiperidine (100 mg, 0.99 mmol) is added to a suspension of 7-[(2,4-
dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile (165 mg, 0.36 mmol) in 5 mL of dichloromethane and 2 mL of N,N-
dimethylformamide. The reaction mixture is cooled to 0°C and sodium
triacetoxyborohydride (0.55 g, 2.60 mmoi) is added. After stirring at 0°C for 4 hours,
3 drops of acetic acid are added and the reaction mixture is allowed to warm to room
temperature and stirred for 1.5 hours. The reaction is quenched by the addition of
water and then partitioned between saturated aqueous sodium bicarbonate and
dichloromethane. The organic layer is washed with water, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue is purified by flash column
chromatography eluting with a gradient of ethyl acetate to 5% methanol in ethyl
acetate to provide 98 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-
hydroxypiperidin-1-yl)methyl)phenyl}thieno[3,2-b]pyridine-6-carbonitrile as yellow
crystals, mp 149-150°C; 1H NMR (DMSO-d6) d1.35-1.45 (m, 2H), 1.65-1.75 (m, 2H),
2.00-2.10 (m, 2H), 2.62-2.70 (m, 2H), 3.47 (s, 3H), 3.85 (s, 3H), 4.54 (d, J = 4 Hz,
1H), 7.37 (s, 1H), 7.40 (d, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 7.89 (s,
1H), 8.59 (s, 1H), 9.72 (s, 1H); MS 536.9 (M-H)-.
Analysis for C27H24CI2N4O2S- 2.00 H2O+ 0.1 C4HeO2+ 0.15 C6H14:
Calcd: C, 56.90; H, 5.21; N, 9.38.
Found: C, 56.61; H, 4.85; N, 8.99.
From the above flash column chromatography is also isolated 61 mg of 7-[(2,4-
dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl]thieno[3,2-b]pyridine-
6-carbonitrile as yellow crystals, mp 239-240°C; 1H NMR (DMSO-d6) d3.86 (s, 3H),
4.54 (d, J = 6 Hz, 2H), 5.29 (t, J = 6 Hz, 1H), 7.38 (s, 1H), 7.43 (d, J = 8 Hz, 2H),
7.69(d, J = 8 Hz, 2H), 7.77 (s, 1H), 7.90 (s, 1H), 8.61 (s, 1H), 9.72 (s, 1H); MS 456.1
(M+H)+.
Analysis for C22H15Cl2N3O2S- 0.70 H2O:
Calcd: C, 56.34; H, 3.52; N, 8.96.
Found: C, 56.73; H, 3.65; N, 8.55.
Example 42
2-lodo-7-[(4-phenoxyphenyI)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 4-phenoxyaniline (1.05 g, 5.67 mmol), pyridine hydrochloride
(100 mg, 0.76 mmol) and 4-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (1 g,
3.12 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux for 1.5 hours. The
solution is poured into saturated aqueous sodium bicarbonate and the resulting solid
is collected by filtration, washed with water and dried under reduced pressure. The

solid is purified by flash column chromatography eluting with chloroform. The
fractions containing product are combined and concentrated. Diethyl ether is added
and the insoluble material collected by filtration to provide 1.38 g of 2-iodo-7-[(4-
phenoxyphenyl)amino]thieno[2,3-b]pyridine-6-carbonitrile as white crystals, mp 260-
262°C;1H NMR (DMSO-d6) d 7.09 (t, J = 8 Hz, 4H), 7.17 (t, J = 8 Hz, 1H), 7.36 (d, J
= 8 Hz, 2H), 7.43 (t, J = 8 Hz, 2H), 7.73 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.0
(M-H)-.
Analysis for C20H12IN3OS - 0.10 CHCI3:
Calcd: C, 50.16; H, 2.54; N, 8.73.
Found: C, 50.15; H, 2.31; N, 8.55.
Example 43
2-(4-Formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2-iodo-7-[(4-phenoxyphenyl)amino]thieno[2,3-b]pyridine-5-
carbonitrile (600 mg, 1.28 mmol), 4-formylphenylboronic acid (380 mg, 2.53 mmol)
and 75 mg of tetrakis(triphenylphosphine)palladium(0) in 53 mL of ethylene glycol
dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at
reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned
between water and ethyl acetate. The organic layer is washed with water, dried over
sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash
column chromatography eluting with 2 : 1 hexane : ethyl acetate to provide 2-(4-
formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as
yellow crystals, mp 230-232°C; 1H NMR (DMSO-d6) d 7.06-7.20 (m, 5H), 7.36-7.45
(m, 4H), 7.92-8.05 (m, 4H), 8.11 (s, 1H), 8.63 (s, 1H), 9.67 (s, 1H), 10.05 (s, 1H); MS
446.2 (M-H)-.
Analysis for C27H17N3O2S- 0.40 H2O:
Calcd: C, 71.31; H, 3.95; N, 9.24.
Found: C, 70.97; H, 3.48; N, 9.16.
Example 44
2-[4-(4-Methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile
1-Methylpiperazine (65 µL, 0.59 mmol) is added to a suspension of 2-(4-
formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (200
mg, 0.45 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (474 mg,
2.24 mmol) is added. After stirring at 0°C for 10 minutes, 3 drops of acetic acid are
added and the reaction mixture is allowed to warm to room temperature and stirred
for 4 hours. The reaction is quenched by the addition of water and then partitioned
between saturated aqueous sodium bicarbonate and dichloromethane. The organic
layer is washed with water, dried over sodium sulfate, filtered and concentrated in
vacuo. The residue is purified by flash column chromatography eluting with 5%
methanol in dichloromethane to provide 138 mg of 2-[4-(4-methylpiperazin-1-
ylmethyl)phenyr]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as
white crystals, mp 199-201 °C; 1H NMR (DMSO-d6) d2.17 (s, 3H), 2.37 (br s, 8H),
3.50 (s, 2H), 7.05-7.18 (m, 5H), 7.35-7.44 (m, 6H), 7.66 (d, J = 8 Hz, 2H), 7.86 (s,
1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 532.3 (M+H)+.
Analysis for C32H29N5OS:
Calcd: C, 72.29; H, 5.50; N, 13.17.
Found: C, 72.14; H, 5.61; N. 13.11.
Examples 45 & 46
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-
6-carbonitrile
2-[4-(Hydroxymethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile
Morpholine (51 µL, 0.58 mmol) is added to a suspension of 2-(4-
formylphenyl)-7-[(4-phenoxyphenyl}amino]thieno[3,2-b]pyridine-6-carbonitrile (200
mg, 0.45 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dirnethylforrnamide.
The reaction mixture is cooled to 0°C and sodium triacetoxyborohydride (474 mg,
2.24 mmol) is added. After stirring at 0°C for 10 minutes, 2 drops of acetic acid are
added and the reaction mixture is allowed to warm to room temperature and stirred
for 4 hours. The reaction is quenched by the addition of water and then partitioned
between saturated aqueous sodium bicarbonate and dichloromethane. The organic
layer is washed with water, dried over sodium sulfate, filtered and concentrated in
vacuo. The residue is purified by flash column chromatography eluting with ethyl
acetate to provide 79 mg of 2-[4-(morpholin-4-ylmethyl)phenyl]-7-[(4-
phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-
256°C; 1H NMR (DMSO-d6) d2.36 (s, 4H), 3.51 (s, 2H), 3.58 (s, 4H), 7.04-7.18 (m,
5H), 7.34-7.45 (m, 6H), 7.67 (d, J =8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H);
MS 519.2 (M+H)+.
Analysis for C31H26N4O2S:
Calcd: C, 71.79; H, 5.05; N, 10.80.
Found: C, 71.96; H, 4.97; N, 10.60.
From the above flash column chromatography, is also isolated 37 mg of 2-[4-
(hydroxymethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile as yellow crystals, mp 225-228°C; 1H NMR (DMSO-d6) d4.54 (d, J = 6
Hz, 2H), 5.31 (t, J = 6 Hz, 1H), 7.06-7.19 (m, 5H), 7.35-7.43 (m, 6H), 7.67 (d, J = 8
Hz, 2H), 7.86 (S, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 450.3 (M+H)+.
Analysis for C27H19N3O2S- 0.50 H2O:
Calcd: C, 70.71; H, 4.39; N, 9.16.
Found: C, 70.53; H, 4.02; N, 9.03.
Example 47
2-lodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyricline-6-carbonitrile
A mixture of 3,4,5-trimethoxyaniline (964 mg, 5.26 mmol), pyridine
hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno[3,2-b]pyridine-6-
carbonitrile (937 mg, 2.92 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux
overnight. The solution is poured into saturated aqueous sodium bicarbonate and
the resulting solid is collected by filtration, washed with water and dried under
reduced pressure. The resultant solid is purified by flash column chromatography
eluting with 2% methanol in dichloromethane. The fractions containing product are
combined and concentrated to provide 1.17 g of 2-iodo-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp
254-256°C; 1H NMR (DMSO-d6) d 3.70-3.78 (m, 9H), 6.66 (s, 2H), 7.72 (s, 1H), 8.53
(s, 1H), 9.56 (s, 1H); MS 468.1 (M+H)+.
Analysis for C17H14IN3O3S:
Calcd: C, 43.70; H, 3.02; N, 8.99.
Found: C, 43.96; H, 2.91; N, 8.98.
Example 48
2-Bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 4-phenoxyaniline (430 mg, 2.32 mmol), pyridine hydrochloride
(244 mg, 2.11 mmol) and 2-bromo-4-chlorothieno[3,2-b]pyridine-6-carbonitrile (578
mg, 2.11 mmol) in 10 mL of 2-ethoxyethanol is heated at 125°C for 4 hours. The
mixture is poured into diethyl ether and the solids are collected by filtration. The
solids are stirred with saturated aqueous sodium bicarbonate for 1 hour. The solids
are collected by filtration, washed with water and diethyl ether to give 717 mg of 2-
bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid,
mp 248-250°C; 1H NMR (DMSO-d6) d7.01-7.19 (m, 5H), 7.23-7.47 (m, 4H), 7.66 (s,
1H), 8.57 (s, 1H), 9.62 (s, 1H); MS 422.1, 424.1 (M+H)+.
Analysis for C20H12BrN3OS-0.2 H2O:
Calcd: C, 56.40; H, 2.93; N, 9.87.
Found: C, 56.34; H, 2.66; N, 9.91.
Example 49
7-[(4-Phenoxyphenyl)amino]-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 2-bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile (200 mg, 0.47 mmol), 4-vinylpyridine (79.7 mg, 0.75 mmol), palladium
acetate (21.1 mg, 0.094 mmol) and tri-o-tolylphosphine (7.2 mg, 0.024 mmol) in 4 mL
of N,N-dimethylforrnamide and 2.3 mL of triethylamine is heated at 125°C for 4 hours.
After cooling to room temperature the reaction mixture is concentrated in vacuo and
the residue is diluted with dichloromethane. The organic phase is washed with water
and saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and
concentrated in vacuo.
The reaction is repeated a second time with the modification that the reaction
mixture is now heated at 125°C for only 60 minutes. The crude products are
combined and purified by thin layer preparative chromatography developing with 7%
methanol in dichloromethane. A second thin layer preparative chromatography
developing with 5% methanol in dichloromethane gives 16 mg of 7-[(4-
phenoxyphenyl)aminol-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-carbonitrile
as a yellow solid, mp 240-241 °C; 1H NMR (DMSO-d6) d 7.02-7.21 (m, 6H), 7.32-7.47
(m, 4H), 7.57-7.62 (m, 2H), 7.67 (s, 1H), 7.83 (d, J = 16 Hz, 1H), 8.56-8.62 (m, 3H),
9.60 (s, 1H); MS 446.9 (M+H)+.
Analysis for C27H18N4OS-0.5 H2O:
Calcd: C, 71.19; H, 4.20; N, 12.30.
Found: C, 71.06; H, 3.85; N, 12.09.
Example 50
tert-Butyl(2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-
b]pyridin-2-yl}prop-2-enoate
A mixture of tert-butyl (2E)-3-(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-
2-enoate (1.29 g , 3.74 mmol), 2,4-dichloro-5-methoxyaniline (862 mg, 4.49 mmol),
Tris(dibenzylideneacetone)-dipalladium(0) (343 mg, 0.37 mmol), potassium
phosphate (1.29 g, 5.61 mmol) and 2-dicyclohexylphosphino-2'-(N,N-
dimethylamino)biphenyl (456 mg, 1.16 mmol) in 36 mL of ethylene glycol dimethyl
ether is heated at 90°C for 3 hours. The reaction mixture is cooled to room
temperature and partitioned between water and ethyl acetate. The aqueous layer is
extracted with additional ethyl acetate and the organic layers are combined, dried
over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by
flash column chromatography eluting with a gradient of hexane to 40% ethyl acetate
in hexane to provide 974 mg of tert-butyl (2E)-3-[6-cyano-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}prop-2-enoate as a light tan solid, mp
224°C dec; 1H NMR (DMSO-d6) d 1.48 (s, 9H), 3.85 (s, 3H), 6.26 (d, J = 16 Hz, 1H),
7.37 (S, 1H), 7.75 (d, J = 16 Hz, 1H), 7.78 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H), 9.80 (s,
1H); MS 476.0,478.0 (M+H)+.
Analysis for C22H19Cl2N3O3S-0.4 H2O:
Calcd: C, 54.64; H, 4.13; N, 8.69.
Found: C, 54.51; H, 3.96; N, 8.50.
Example 51
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-
ynyl}thieno[2,3-b]pyridine-5-carbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-
b]pyridine-5-carbonitrile (160 mg, 0.34 mmol), 1-methyl-4-prop-2-ynyl-piperazine (70
mg, 0.5 mmol), 15 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide
(8 mg, 0.016 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux
for 7 hours. The reaction mixture is cooled to room temperature and partitioned
between water and dichloromethane. The organic layer is dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue is triturated with ether and
hexanes to provide 110 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-
methylpiperazin-1-yl)prop-1-ynyl]thieno[2,3-b]pyridine-5-carbonitrile as an off white
solid, mp 175°C (decomposition); 1H NMR (DMSO-d6) d2.17 (s, 3H), 2.37 (bs, 4H),
2.54 (bs, 4H), 3.62 (s, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.91 (s, 1H), 8.47
(bs, 1H), 9.83 (bs, 1H); MS 486.2 (M+H)+.
Analysis for C23H21Cl2N5OS:
Calcd: C, 56.79; H, 4.35; N, 14.40.
Found: C, 56.39; H, 4.33; N, 14.06.
Example 52
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-
5-carbonitrile
A mixture of 4-[(2,4-dichloro5-methoxyphenyl)amino]-2-iodothieno[2,3-
b]pyridine-5-carbonitrile (220 mg, 0.50 mmol), 3-ethynylpyridine (72 mg, 0.7 mmol),
20 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide (6 mg, 0.22
mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 5 hours.
The reaction mixture is cooled to room temperature and a solid appears. The solid is
triturated with hot ethyl acetate, filtered, washed with hexanes and dried under
vacuum to provide 100 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-
ylemynyl)thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 191°C
(decomposition); 1H NMR (DMSO-d6 + TFA) d3.88 (s, 3H), 7.37 (s, 1H), 7.43 (s, 1H),
7.78 (s, 1H), 7.85 (bs, 1H), 8.16 (s, 1H), 8.39 (bs, 1H), 8.54 (s, 1H), 10.02 (bs, 1H);
MS 451.0 (M+H)+.
Analysis for C22H12Cl2N4OS - 0.1 H2O:
Calcd: C, 58.55; H, 2.68; N, 12.41.
Found: C, 58.31; H, 2.71; N, 12.36.
Example 53
(2E)-3-(6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-
yl)prop-2-enoate
A solution of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridine-2yl)prop-2-enoate (910.8 mg, 1.91
mmol), trifluoroacetic acid (2.18 g, 19.1 mmol) in 27 mL of dichloromethane is stirred
at room temparature for 3 days, then concentrated in vacuo. The residue is triturated
with ether to provide 741 mg of (2E)-3-(6-cyano-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)prop-2-enoic acid as a beige solid, mp
>250°C; 1H NMR (DMSO-d6) d 3.84 (s, 3H), 6.28 (d, J = 16 Hz, 1H), 7.38 (s, 1H),
7.70 - 7.88 (m, 2H), 7.90 (s, 1H), 8.62 (s, 1H), 9.81 (s, 1H), 12.50 (s, 1H); MS 420.1,
422.0 (M+H)+.
Analysis for C18H11Cl2N3O3S:
Calcd: C, 51.44; H, 2.64; N, 10.00
Found: C, 51.52; H, 2.81; N, 9,68.
Example 54
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imiclazol-5-
yl)thieno[3,2-b]pyridine-6-carbonitiile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-6-carbonitrile (443.2 mg, 0.93 mmol), 1-methyl-5-(tributyIstannyl)-1H-
midazole-2-carbaldehyde (743.1 mg, 1.86 mmol),
dichlorobis(triphenylphosphine)palladium(ll) (33.0 mg, 0.047 mmol) and triethylamine
(103.2 mg, 1.02 mmol) in 8.0 mL of 1,4-dioxane is heated at 110°C for 3 hours. After
cooling, the mixture is treated with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The organic phases are washed with brine, dried over
sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash
column chromatography eluting with a gradient of 5% ethyl acetate in
dichloromethane to 50% ethyl acetate in dichloromethane to provide 222.7 mg of 7-
[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-
yl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 225-227°C; 1H NMR
(DMSO-d6) d 3.86 (s, 3H), 4.08 (d, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.77 (s, 1H), 7.90
(s, 1H), 8.67 (s, 1H), 9.77 (s, 1H), 9.87 (s, 1H); MS 458.1,460.1 (M+H)+.
Analysis for C20H13Cl2N5O2S - 0.5 H2O:
Calcd: C, 51.40; H, 3.02; N, 14.98
Found: C, 51.43; H, 2.88; N, 14.60.
Example 55
2-(4-Formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 2-iodo-7-[(3,4I5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile (500 mg, 1.07 mmol), 4-formylphenylboronic acid (240.7 mg, 1.61 mmol),
etrakis(triphenylphosphine)palladium(0) (61.8 mg, 0.054 mmol) in 16 mL of
saturated aqueous sodium bicarbonate and 20 mL of ethylene glycol dimethyl ether
is heated at reflux for 3 h. After cooling, the mixture is treated with water. The
recipitate is filtered, washed with water, ethyl acetate, and ether, then dried in vacuo
o provide 447.2 mg of 2-(4-formylphenyl)-7-[(3,4,5-
rimethoxyphenyl)amino]thfeno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp
268-270°C; 1H NMR (DMSO-d6) d 3.73 (s, 3H), 3.75 (s, 6H), 6.69 (s, 2H), 7.94 (d, J =
8 Hz, 2H), 8.00 (d, J = 8 Hz, 2H), 8.10 (s, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.00 (s,
1H); HRMS 446.11691 (M+H)+.
Example 56
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(1E)-3-(4-methylpiperazin-1-yl)-3-
oxoprop-1-enyl)thieno[3,2-b]pyridine-6-carbonitrile
A mixture of (2E)-3-{6-cyano-7-[2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}prop-2-enoic acid (68.8 mg, 0.16
mmol), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (109.3
mg, 0.21 mmol), diisopropylethylamine (103.4 mg, 0.80 mmol), 1-methylpiperazine
(16 mg, 0.1 mmol) in 2.5 mL of dichloromethane is stirred at room temperature under
nitrogen for 18 hours, and then quenched with saturated aqueous sodium
bicarbonate. The organic phase is separated and the aqueous phase is extracted
with dichloromethane. The organic phases are combined and washed with brine,
dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified
by preparative thin layer chromatography developing with 7% methanol in
dichloromethane to provide 43.8 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-
[(1 E)-3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enyl]thieno[3,2-b]pyridine-6-carbonitrile
as an off white solid, mp 218-220°C; 1H NMR (DMSO-d6) d2.19. s, 3H), 2.31 (s, 4H),
3.55 (s, 2H), 3.62 (s, 2H), 3.84 (s, 3H), 7.16 (d, j= 15 Hz, 1H), 7.31 (s, 1H),7.62 (d,
J= 15 Hz, 1H), 7.73 (s, 1H), 7.92 (s, 1H), 8.58 (s, 1H), 9.77 (s, 1H); MS 502.2, 504.2
(M+H)+.
Analysis for C23H21Cl2N5O2S:
Calcd: C, 54.98; H, 4.21; N, 13.94.
Found: C, 54.67; H, 4.28; N, 13.55.
Example 57
2-[3-(4-Methylpiperazin-1-yl)prop-1-ynyl]-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 2-iodo-7-[(3,4,5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile (200 mg, 0.43 mmol), 1-methyl-4-prop-2-ynyl-piperazine (89.1 mg, 0.65
mmol), 9.9 mg of tetrakis(triphenylphosphine)palladium(0) and 2.1 mg of copper(l)

iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 7 hours.
The mixture is cooled to room temperature and 2 mL of methanol are added. The
solvents are removed in vacuo and the residue is treated with 10 mL of chloroform.
The insoluble material is removed by filtration, washing with chloroform. The filtrate is
concentrated in vacuo and the residue is purified by preparative thin layer
chromatography developing with 10% methanol in dichloromethane to provide 112.1
mg of 2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a beige solid, mp 180-
182°C; 1H NMR (DMSO-d6) d2.35 (s, 3H), 2.50 (s, 2H), 2.56 (s, 6H), 3.62 (s, 2H),
3.71 (s, 3H), 3.74 (s, 6H), 6.68 (s, 2H), 7.59 (s, 1H), 8.61 (s, 1H), 9.62 (s, 1H); MS
478.2, (M+H)+.
Analysis for C25H27N5O3S - 0.5H2O:
Calcd: C, 61.71; H, 5.80; N, 14.39.
Found: C, 61.84; H, 5.58; N, 14.53.
Example 58
2-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
1-Methylpiperazine (135.2 mg, 1.35 mmol) is added to a suspension of 2-(4-
formylphenyl)-7-[3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile
(200 mg, 0.45 mmol) in 8 mL of dichloromethane and 1.1 mL of N,N-
dimethylformamide The reaction mixture is cooled to 0°C and sodium
triacetoxyborohydride (572.2 mg, 2.70 mmol) is added. After stirring at 0°C for 10
minutes, 0.13 mL of acetic acid are added and the reaction mixture is allowed to
warm to room temperature and stirred for 2 hours. The reaction is quenched by the
addition of water and then partitioned between saturated aqueous sodium
bicarbonate and dichloromethane. The organic layer is washed with brine, dried over
sodium sulfate, filtered and concentrated in vacuo. The residue is purified by
preparative thin layer chromatography developing with 12% methanol in
dichloromethane to give a solid which is triturated with ether and ethyl acetate (1:1),
to provide 125.2 mg of 2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7-[(3,4,5-
trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a beige solid, mp 189-
191°C; 1H NMR (DMSO-d6) d2.15 (s, 3H), 2.35 (s, 8H), 3.47 (s, 2H), 3.72 (s, 3H),
3.75 (s, 6H), 6.67 (s, 2H), 7.39 (d, J= 8 Hz, 2H), 7.66 (d, j= 8 Hz, 2H), 7.86 (s, 1H),
8.60 (s, 1H), 9.55 (s, 1H); MS 530.2 (M+H)+.
Analysis for C29H31N5O3S -1.0 H2O:
Calcd: C, 63.60; H, 6.07; N, 12.79.
Example 59
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{1-methyl-2-[(4-methylpiperazin-1-
yl)methyl]-1 H-imidazol-5-yl} thieno[3,2-b]pyridine-6-carbonitrile
To a solution of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-
methyl-1H-imidazole-5-yl)thieno[3,2-b]pyridine-6-carbonitrile (200.6 mg, 0.44 mmol)
1-methylpiperazine (132.2 mg, 1.32 mmol) in 4.3 mL of dichloromethane and 1.1 mL
of N,N-dimethylformamide is added sodium triacetoxyborohydride (559.5 mg, 2.64
mmol) in portions at 0-5°C followed by 0.13 mL of acetic acid. The resulting reaction
mixture is stirred for 30 minutes, allowed to warm to room temperature and stirred for
5 hours. The reaction is quenched by the addition of water and then partitioned
between saturated aqueous sodium bicarbonate and dichloromethane. The organic
layer is washed with brine, dried over sodium sulfate, filtered and concentrated in
vacuo. The residue is purified by flash column chromatography eluting with a
gradient of 5% methanol in dichloromethane to 20% methanol in dichloromethane to
provide 145.2 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{1-methyl-2-[(4-
methylpiperazine-1-yl)methyl]-1H-imidazole-5-yl}thieno[3,2-b]pyridine-6-carbonitrile
as an off white solid, mp 234-235°C; 1H NMR (DMSO-d6) d2.18 (s, 3H), 2.41 (s, 8H),
3.59 (S, 2H), 3.77 (s, 3H), 3.85 (s, 3H), 7.14 (s,1H), 7.37 (s, 1H), 7.63 (s, 1H), 7.75 (s,
1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 542.2, 544.1 (M+H)+.
Analysis for C25H25CI2N7OS - 0.9 H2O:
Calcd: C, 53.74; H, 4.83; N, 17.55.
Found: C, 53.39; H, 4.61; N, 17.45.
Example 60
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]
thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-iodothieno(3,2-
b]pyridine-6-carbonitrile (200 mg, 0.42 mmol), 1-methyl-4-prop-2-ynyl-piperazine
(87.0 mg, 0.65 mmol), 9.7 mg of tetrakis(triphenylphosphine)palladium(0) and 2.0 mg
of copper(l) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux
for 5 hours. The mixture is cooled to room temperature and 2 mL of methanol are
added. The solvents are removed in vacuo and the residue is purified by preparative
thin layer chromatography developing with 12% methanol in dichloromethane to give
a solid which is triturated with ether containing several drops of dichloromethane, to
provide 89.6 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-
1-yl)prop-1-ynyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 172-173°C;
1H NMR (DMSO-d6) d2.18 (s, 3H), 2.37 (s, 4H), 2.49 (s, 4H), 3.59 (s, 2H), 3.85 (s,
3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.82 (s 1H); MS 486.1,
488.1 (M+H)+.
Analysis for C23H21CI2N5OS:
Calcd: C, 56.79; H, 4.35; N, 14.40.
Found: C, 56.39; H, 4.28; N, 14.19.
Example 61
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile
A suspension of 2 M dimethylamine in tetrahydrofuran (1.13 mL, 2.25 mmol)
and 2-(4-formylphenyl)-7-[3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile (200 mg, 0.45 mmol) in 4.5 mL of dichloromethane and 1.1 mL of N,N-
dimethylformamide is cooled to 0°C and sodium triacetoxyborohydride (572.2 mg,
2.70 mmol) is added. After stirring at 0°C for 5 minutes, 0.13 mL of acetic acid are
added and the reaction mixture is allowed to warm to room temperature and stirred
for 17 hours. The reaction is quenched by the addition of water and then partitioned
between saturated aqueous sodium bicarbonate and dichloromethane. The organic
layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is
purified by flash column chromatography eluting with a gradient of 1% methanol in
ichloromethane to 10% methanol in dichloromethane to provide 147.2 mg 2-{4-
dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
pyridine-6-carbonitrile as a yellow solid, mp 199-201 °C; 1H NMR (DMSO-d6) d2.15
3, 6H), 3.41 (s, 2H), 3.72 (s, 3H), 3.75 (s, 6H), 6.67 (s, 2H), 7.39 (d, J = 8 Hz, 2H),
.66 (d, J = 8 Hz, 2H), 7.87 (s, 1H), 8.60 (s, 1H), 9.54 (s, 1H); MS 475.2 (M+H)+.
dialysis for C26H26N4O3S - 0.6 H2O:
Calcd: C, 64.34; H, 5.65; N, 11.54.
Found: C, 64.19; H, 5.68; N, 11.49.
Example 62
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-
[(dimethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile
To a suspension of 2-(4-formylphenyl)-7-[2,4-dichloro-5-
lethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (312 mg, 0.69 mmql) and
.73 mL of 2 M dimethylamine in tetrahydrofuran (3.45 mmol) in 6.9 mL of
ichloromethane and 1.7 mL of N,N-dimethylformamide at 0°C is added sodium
acetoxyborohydride (877 mg, 4.14 mmol). After stirring at 0°C for 5 minutes, 0.20
mL of acetic acid are added and the reaction mixture is allowed to warm to room
temperature and stirred for 17 hours. The reaction is quenched by the addition of
water and then partitioned between saturated aqueous sodium bicarbonate and
dichloromethane. The organic layer is dried over sodium sulfate, filtered and
oncentrated in vacuo. The residue is purified by flash column chromatography
eveloping with a gradient of from 1% to 10% methanol in dichloromethane to give a
solid which is washed with hexane to provide 222 mg of 7-[(2,4-dichloro-5-
hethoxyphenyJ)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6
carbonitrile as a tan solid, mp 224-225°C; 1H NMR (DMSO-d6) d2.17 (s, 6H), 3.44 (s,
H), 3.86 (s, 3H), 7.37 (s, 1H), 7.40 (d, J= 8 Hz, 2H), 7.68 (d, j= 8 Hz, 2H), 7.76 (s,
H), 7.90 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 483.1,485.1 (M+H)+.
dialysis for C24H20CI2N4OS - 0.5 H2O:
Calcd: C, 58.54; H, 4.30; N, 11.38.
Found: C, 58.45; H, 4.20; N, 11.27.
Evaluation of representative compounds of this invention in several standard
harmacological test procedures indicated that the compounds of this invention
possess significant antiproliferative activity and are inhibitors of protein tyrosine
kinases. Based on the activity shown in the standard pharmacological test
procedures, the compounds of this invention are therefore useful as antineoplastic
agents. In particular, these compounds are useful in treating, inhibiting the growth of,
or eradicating neoplasms such as those of the breast, kidney, bladder, mouth, larynx,
esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate and skin.
In addition to having antineoplastic properties, the compounds of the present
invention are expected to be useful in treating a variety of protein tyrosine kinase
associated disorders including, but not limited to, osteoarthritis, restenosis,
atherosclerosis, fibroplasia, angiofibromas, hemangiomas, diabetes, acute and
chronic nephropathies, Kaposi's sarcoma, atheroma, neovascular glaucoma,
neovascularization associated with macular degeneration, rheumatoid arthritis,
psoriatic arthritis, transplant rejection, T-cell mediated hypersensitivity diseases,
including gluten-sensitive enteropathy (Celiac disease), contact and delayed-type
hypersensitivity, psoriasis, contact dermatitis, protection from ischemic or reperfusion
injury such as that incurred during organ transplantation, stroke or myl)cardial
infarction, transplantation tolerance induction, lupus, graft versus host disease,
glomerulonephritis, serum sickness, respiratory and skin allergies, autoimmune
alopecia, pernicious anemia, Hashimoto's thyroiditis, autoimmune hyperthyroidism,
Addison's disease, multiple sclerosis, inflammatory bowel disease, acute
inflammatory responses (for example acute respiratory distress syndrome), Behcet's
disease, atopic dermatitis, systemic sclerosis and eczema.
Example 63
N-(6-Cyanothieno[3,2-b]pyridin-7-yl)-N-(2,4-dichloro-5-methoxyphenyl)acetamide
A mixture of 7-[(2,4-dichloro-5-methoxyanilino)amino]thieno[3,2-b]pyridine-6-
carbonrtrile (332 mg, 0.95 mmol), acetic anhydride (976 mg, 9.5 mmol), and 4-
(dimethylamino)pyridine (140 mg, 1.14 mmol) in 3 mL of pyridine are heated at
reflux for 2 hours. The mixture is cooled to room temperature and concentrated in
vacuo. Dichloromethane and water are added and the organic layer is extracted,
dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo and
the residue is purified by chromatography eluting with 2% methanol in
dichloromethane to provide 280 mg of N-(6-cyanothieno[3,2-b]pyridin-7-yl)-N-(2,4-
dichloro-5-methoxyphenyl)acetamide as a white solid, mp 202-204°C; 1H NMR
DMSO-d6) d 2.23 (s, 3H), 3.95 (s, 3H), 7.69 (d, J = 6 Hz, 1H), 7.84 (s, 2H). 8.35 (d,
= 6 Hz, 1H), 9.11 (s, 1H); MS 392.0 (M+H)+.
Analysis for C17H11CI2N3O2S:
Calcd: C, 52.05; H, 2.83; N, 10.71.
Round: C, 52.44; H, 2.93; N, 10.45.
Example 64
7-[(2,4-Dichloro-5-methoxyphenyl}amino]-2-[(E)-2-phenylvinyl}thieno[3,2-b]pyridine-6-
carbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-
b]pyridine-5-carbonitrile (250 mg, 0.53 mmol), E-styrylboronic acid (90 mg, 0.60
mmol), 20 mg of tetrakis(triphenylphosphine)palladium(0), 390 mg of potassium
phosphate, and 0.1 mL of water in 3 mL of toluene is heated at 110°C overnight.
The mixture is cooled to room temperature and ethyl acetate and water are added.
The solid is collected by filtration, dissolved in a hot mixture of methanol and
dichloromethane and passed through celite. The filtrate is concentrated in vacuo and
dried to give 48 mg of 7-{(2,4-dichloro-5-methoxyphenyl)amino]-2-[(E)-2-
phenylvinyl]thieno[3,2-b]pyridine-6-carbonitrile as a light yellow solid. The ethyl
acetate layer is separated, dried over magnesium sulfate and filtered. The filtrate is
concentrated in vacuo and the residue is purified by chromatography eluting with a
gradient of 0 to 5% methanol in dtchloromethane. The fractions are concentrated
and the solid is triturated with hot ether, filtered and dried to provide an additional 49
mg of product, mp 236-238°C; 1H NMR (DMSO-d6) d 3.85 (s, 3H), 7.15 (d, J = 16
Hz, 1H), 7.31-7.42 (m, 4H), 7.54 (d, J = 16 Hz, 1H), 7.56-7.65 (m, 3H), 7.77 (s, 1H),
8.58 (s, 1H), 9.66 (s, 1H); HRMS 452.0.3872 (M+H)+.
Example 65
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-
yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-
ylethynyl)thieno[3,2-b]pyridine-6-carbonltrile (57 mg, 0.13 mmol), 4-(2-
chloroethyl)morpholine hydrochloride (24 mg, 0.13 mmol), and cesium carbonate (42
mg, 0.13 mmol) in 1 mL of dimethylformamide is heated at 50°C overnight. The
mixture is cooled to room temperature and then added to water. The resulting
precipitate is collected by filtration. The collected solid is purified by flash column
chromatography, eluting with 1:7 methanol: ethyl acetate to provide 50 mg of 7-[(2,4-
dichloro-5-methoxyphenyl)amino]-2-{[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-
yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp greater than
200°C; 1H NMR (DMSO-d6) d 2.44 (br s, 4H), 2.62 (t, 2H), 3.53 (br s, 4H), 3.81 (s,
3H), 4.23 (br s, 2H), 6.77 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.80 (br, 1H), 8.24 (br,
1H), 8.37 (s, 1H), 13.36 (br s, 1H); MS 553.1 (M+H)+.
Example 66
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(E)-2-
(2H-1,2,3-triazol-2-yl)vinyl]thieno[3,2-b]pyridine-6-carbonitrile
To a mixture of 1,2,3-triazole (50 DL, 0.81 mmol) and cesium hydroxide
monohydrate (18 mg, 0.11 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is added slowly
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile
(200 mg, 0.54 mmol). The mixture is heated to 120°C for 12 hours, cooled to room
temperature and partitioned between water and ethyl acetate. The organic layer is
washed with water, dried over sodium sulfate, and concentrated in vacuo. The
residue is purified by flash column chromatography eluting with a gradient of
methanol in dichloromethane (0-2%) to provide 90 mg (38%) of 7-[(2,4-dichloro-5-
methoxyphenyl)amino]-2-[(E)-2-(2H-1,2,3-triazol-2-yl)vinyl]thieno[3,2-b]pyridine-6-
carbonitrile as a yelllow solid, mp 315-316°C; 1H NMR (DMSO-d6-TFA) d 3.88 (s,
3H), 7.50 (s, 1H), 7.65 (d, J = 14 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.15 (s, 2H),
8.32 (d, J = 14 Hz, 1H), 9.01 (s, 1H); MS 443.0 (M+H)+.
Analysis tor C19H12CI2N6OS - 0.1 CH2CI2:
Calcd: C, 50.77; H, 2.72; N, 18.60
Found: C, 50.54; H, 2.32; N, 18.25.
Example 67
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-2-furyl)thieno[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 37, MS 441.1,446.1 (M+H)+, mp > 250.
Example 68
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)-2-furyl]thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for ecample 36, MS 488.1,490.1, mp 187-189.
Example 69
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-
furyl}thleno [3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 527.9,529.9 (M+H)+, mp 215-217.
Example 70
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-ethylpiperazin-1-
yl)methyrjphenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepare as for example 15, MS 552.0 (M+H)+, mp 198-200.
Example 71
7-[(2,4-dichloro-5-methoxyphenyl)aminol-2-{4-[(4pyrrolldin-1-ylpiperidin-1-
yl)methyphenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, HRMS 452.0387, mp 230 decomposition.
Example 72
7-[(2,4-dichloro-5-methoxyphenyl)amlno]-2-(4-{[[2-
(dlmethylamino)ethyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyrldlne-6-
carbonitrile
Prepared as for example 15, MS 540 (M+H)+, mp > 245.
Example 73
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(dimethylamino)phenyl]thleno[3,2-
b]pyridine-6-carbonltrile
Prepared as for example 14, MS 469.0,471.1 (M+H)+, mp 255-258.
Example 74
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 538.0, 540.0 (M+H)+, mp 178-180.
Example 75
7-[(2,4-dichloro-5-melhoxyphenyl)amino]-2-{3-
[(dimethylamino)methyl]phenyl)thieno[3,2-b]pyridlne-6-carbonitrile
Prepared as for example 15, MS 483.0,485.0 (M+H)+, mp 204-206.
Example 76
7-[(2,4-dichloro-5-methoxyphenyl)amlno]-2-{5-[(dlmethylamino)methyl]-2-
furyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 473.0,475.0 (M+H)+, mp 200-202.
Example 77
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-clioxo!an-2-yl)thien-2-yl]thieno[3,2-
b]pyridine-6-carbonitriie
Prepared as for example 36, MS 503.8, 505.8 (M+H)+, mp 213-217.
Example 78
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile
Prepared as for example 14, MS 459.9 (M+H)+, mp 128-130.
Example 79
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-2-yl)thieno[3,2-b]pyridine-
6-carbonitrile
Prepared as for example 37, MS 459.9,461.8 (M+H)+, mp > 245.
Example 80
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-3-
yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 488.9,490.9 {M+H)+, mp 184-186.
Example 81
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 544.0, 546.0 (M+H)+, softens 182, mp 200-202.
Example 82
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-iodothieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 47. MS 523.8(M+H)+, mp 290-291.
Example 83
7-({3-chloro-4-[(1-methyl-1H-lmidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 14, MS 573.3(M+H)+, mp 150-152.
Example 84
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{2-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 544.2 (M+H)+, mp 218-219.
Example 85
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[3-
(dlmethylamino)propyl](methyl)amlno]methyl}phenyl)thieno[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 15, MS 554.3 (M+H)+, mp 205 decomp.
Example 86
7-({3-chloro-4-[(1-methyl-1H-lmidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-ylbut-
1-ynyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 535.3,537.2 (M+H)+, mp 195-200.
Example 87
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({6-[(dlmethylamlno)methyl]pyridin-2-
yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 508.2,510.2 (M+H)+, mp 190-191.
Example 88
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-2-
yl)thieno[3,2-b]pyrldine-6-carbonitrile
Prepared as for example 15, MS 486.8,488.8 (M+H)+, mp 210-212.
Example 89
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(pyridin-4-
ylmethyl)amino]methyl}phenyl)thieno[3,2-b]pyrldine-6-carbonitrile
Prepared as for example 15, MS 546.1 (M+H)+, mp 128-130.
Example 90
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrrol-3-yl)theino[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 14, MS 415.0 (M+H)+, mp > 245.
Example 91
7-({3-chloro-4-[(1-methyl-1H-lmidazol-2-yl)thio]phenyl}amino)-2-[3-
(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 479.0,481.1 (M+H)+, mp 204-207.
Example 92
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(2-
methoxyethyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 513.0 (M+H)+, mp 162-164.
Example 93
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-({[2-
(methylthio)ethyl]amino}methyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 527.0 (M-H)-, mp 154-156.
Example 94
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(thiomorpholin-4-
ylmethyl)phenyl]thleno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 541.0 (M+H)+, mp 198-201.
Example 95
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperazin-1-
ylmethyl)phenyl)thieno[3,2-b]pyrldine-6-carbonitrile
Prepared as for example 15, MS 524.1 (M+H)+, mp 218-220.
Example 96
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-morpholin-4-ylphenyl)thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 36, MS 511.0, 513.0 (M+H)+, mp > 250.
Example 97
7-({3-chloro-4-[(1-methyl-1H-lmidazol-2-yl)thio]phenyl}amino)-2-(4-
formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 14, MS 502.0 (M+H)+, mp 279-281.
Example 98
7-({3-chloro-4-l(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-
[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonnitrile
Prepared as for example 15, MS 559.0 (M+H)+, mp 200-203.
Example 99
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-[(4-
methylpiperazln-1-yl)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 585.0 (M+H)+, mp 221-224.
Example 100
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({5-[(dimethylamino)methyl]pyridin-2-
yl]ethynyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 508.0 (M+H)+, mp 215-217.
Example 101
7-[(2,4-dichloro-5-methoxyphenyl}aminol-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 34, MS 440.0 (M+H)+, mp +200 decomposition.
Example 102
7-[(2,4-dichlorophenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 1, MS 445.8,447.8 (M+H)+, mp 230-233.
Example 103
7-[(2f4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-mehylpiperazin-1-yl)methyl]pyridin-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 36, MS 539.0 (M+H)+, mp 229-232.
Example 104
2-{4-t(butylamino)methylphenyl}-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 15, MS 511.0 (M+H)+, mp 167-169.
Example 105
7-t(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-((1-oxidothiomorpholin-4-
yl)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 557.0 (M+H)+, mp 242-245.
Example 106
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-
[(diethylamino)methyl}phenyl)thieno[3,2-b]pyridine-6-carbornitrile
Prepared as for example 15, MS 511.0 (M+H)+, mp 160-162.
Example 107
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-
hydroxypropyl)amino)methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 513.1 (M+H)+, mp 141-143.
Example 108
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-(1H-pyrazol-4-ylethynyl)pyridin-2-
l]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 36, MS 526.0, 528.0 (M+H)+, mp 227-229.
Example 109
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-(6-morpholin-4-ylpyridin-3-thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 36, MS 512.1, 514.1 (M+H)+, mp 225-227.
Example 110
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 1, MS 489.9,491.9 (M+H)+, mp 232-233.
Example 111
7-[(2,4-dlchloro-5-methoxyphenyl)amino]-2-{4-[(1,1-dloxidothiomorpholin-4-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 573.1 (M+H)+, mp > 245.
Example 112
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyridin-2-ylplperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 601.2 (M+H)+, mp 245-247.
Example 113
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-phenylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 600.2 (M+H)+, mp 238-240.
Example 114
7-[(2,4-dlchloro-5-methoxyphenyl)amino]-2-(4{[(2R,5S)-2,5-dimethylpiperazin-1-
l]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonltrile
Prepared as for example 15, MS 552.2 (M+H)+, mp 165-168.
Example 115
7-[(2,4-dichloiphenyl)amino]-2-(4-fomylphenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 14, MS 424.0,426.1 (M+H)+, mp 170-171.
Example 116
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-(4-forrnylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 14, MS 468.1,470.1 (M+H)+, mp > 245.
Example 117
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}thleno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 20, MS 552.1,554.1 (M+H)+, mp 240-243 dec.
Example 118
7-({3-chloro-4-[(1-methyl-1H-lmida2ol-2-yl)thio]phenyl}amino)-2-[3-
(diethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 507.1,509.2(M+H)+, mp 190-194.
Example 119
7-[(2,4-dichlorophenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile
Prepared as for example 15, MS 508.1, 510.1 (M+H)+, mp 245-247.
Example 120
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 630.1 (M+H)+, mp 176-179.
Example 121
7-[(2,4-dlchloro-5-methoxyphenyl)amino]-2-(4-{[(3-
methylbutyl)amino]methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrite
Prepared as for example 15, MS 525.1 (M+H)+, mp 195-197.
Example 122
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-([4-methylsulfony)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 602.1 (M+H)+, mp 211-213.
Example 123
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 552.2,554.2 (M+H)+, mp 227-229.
Example 124
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(pyrldin-2-ylmethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 615.1 (M+H)+, mp 105-107.
Example 125
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{1-[2-(dimethylamlno)ethyl}-1H-pyrrol-3-
yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 65, MS 486.2 (M+H)+, mp 230 decomposition.
Example 126
7-[(2,4-dichlorophenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 50, MS 439.2,441.1 (M+H)+, mp 239-241.
Example 127
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(1-methyl-1H-imidazol-5-
yl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 21, MS 454.1 (M+H)+, mp >260.
Example 128
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-{6-[(dimethylamino)methyl]pyridin-2-
yl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 36, MS 484.1,486.1 (M+H)+, mp 221-223.
Example 129
7-[(2,4-dichloro-5-methoxyphenyl}amino]-2-(1H-pyrazol-4-yl)thieno)methyl]pyridine-6-
carbonitrile
Prepared as for example 14, MS 416.0 (M+H)+, mp +250 decomposition.
Example 130
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl)ethynyl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 65, MS 484.0 (M+H)+, mp 172.5.
Example 131
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-
yl]thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 65, MS 529.1 (M+H)+, mp 155.2.
Example 132
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]pyridin-2-
yl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 36, MS 484.0,486.0 (M+H)+, mp 229-231.
Example 133
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-[(diethylamino)methyr|pyridin-2-
yl}thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 36, MS 512.0,514.0 (M+H)+, mp 192-193.
Example 134
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[2-
(dimethylamino)ethyl]phenyl}thleno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 14, MS 497.0,499.0 (M+H)+, mp 196-197.
Example 135
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 60, MS 460.0 (M+H)+, mp +250 decomposition.
Example 136
4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}-N,N-
dimethylbenzamide
Prepared as for example 14, MS 497.1,499.0 (M+H)+, mp 246-249.
Example 137
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-
furyl)thieno[3,2-b]pyridine-6-carbonitrile
Prepared as for example 15, MS 528.1,530.1 (M+H)+, mp 189-192.
Example 138
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-3-furyl)thieno[3,2-b]pyridine-6-
carbonitrile
Prepared as for example 14, MS 444.0,446.0 (M+H)+, mp 223-224.
The test procedures used and results obtained are shown below.
Anchorage Independent Src-transformed Fibroblast Proliferation Assay
Rat2 fibroblasts stably transformed with a plasmid containing a CMV
promoter controlled v-Src/Hu c-Src fusion gene in which the catalytic domain of
human c-Src was inserted in place of the v-Src catalytic domain in the v-Src gene are
used for the measurement of src dependent suspension growth. Ultra-low cluster
plates (Costar # 3474) are seeded with 10,000 cells per well on Day 1. Compound is
added in serial two-fold dilutions from 10 micromolar to 0.009 micromolar on Day 2
and MTS reagent (Promega) is added on Day 5 (100 microliters of MTS/medium mix
+ 100 microliters of medium already on the cells and the absorbance is measured at
490nm. The results are analyzed as follows to yield an IC50 for proliferation
(micromolar units) as follows: %inhibition = (Abs490 nm sample - blank)/(Abs490
nm no cmpd control - blank) X 100%. The results obtained for representative
compounds of this invention are listed in Table 1. Multiple entries for a given
compound indicate that it was tested multiple times.
Anchorage Independent Lck-transformed Fibroblast Proliferation Assay
Rat2 fibroblasts stably transformed with a plasmid containing a CMV
promotor controlled v-Src/Hu Lck fusion gene in which the catalytic domain of human
Lck was inserted in place of the v-Src catalytic domain in the v-Src gene are used for
the measurement of src dependent suspension growth. Ultra-low cluster plates
(Costar # 3474) are seeded with 10,000 cells per well on Day 1. Compound is added
in serial two-fold dilutions from 10 micromolar to 0.009 micromolar on Day 2 and
MTS reagent (Promega) is added on Day 5 (100 microliters of MTS/medium mix +
100 microliters of medium already on the cells and the absorbance is measured at
490nm. The results are analyzed as follows to yield an IC50 for proliferation
(micromolar units) as follows: %inhibition = (Abs490 nm sample - blank)/(Abs490
nm no cmpd control - blank) X 100%. The results obtained for representative
compounds of this invention are listed in Table 2. Multiple entries for a given
compound indicate that it was tested multiple times.
Src Kinase Assay
Recombinant human Src enzyme was obtained from Pan Vera (P3044). Biotinylated
peptide corresponding to residues 6 - 20 of Cdk1 was used as a substrate (Biotin-
KVEKIGEGTYGWYK-COOH). Homogeneous fluorescence resonance energy
transfer kinase assays were performed using the europium/APC detection format
(LANCE, Perkin Elmer). Src enzyme (10 ng) was mixed with biotinylated peptide
(final concentration 2 µM), 50 mM Hepes (pH 7.5), 10 mM MgCI2, 20 ug/ml BSA,
0.001% Brij-35 (Sigma), 100 µM ATP, 1% DMSO. The kinase reaction was incubated
for 70 min at 37°C. The reaction was stopped with EDTA at a final concentration of
30mM EDTA/25mM Hepes (pH 7.5)/10 µg/ml BSA. The mixture was combined with
Eu-labeled anti-phosphotyrosine antibody PT66 (Perkin Elmer, AD0068) and
Streptavidin Surelight-APC (Perkin Elmer, CR130-100) in 50 mM Hepes (pH 7.5)/ 20
µg/ml BSA, and incubated for 30 min according to manufacturer's specifications.
Fluorescence intensity at 665 nm was used to monitor the extent of the kinase
reaction. Multiple entries for a given compound indicate that it was tested multiple
times. The results obtained for representative compounds of this invention are listed
in Table 3.
Table 3
Raf/Mek Kinase Cascade Assay
Raf-1 (c-Raf) is used to phosphorylate and activate inactive GST-MEK1 which
then can phosphorylate and activate inactive p42 GST-MAPK, which subsequently is
measured for phosphorylation of the TEY sequence (aa's 202-204) by a phospho-
specific antibody from Sigma (cat. # 77439219041) Reagents: Sf9 insect cell lysate
containing full length 6his-tagged recombinant human c-Raf. (Specific Activity:
~200U/ml). Human Non-active Mek-1-GST and human GST-MAP kinase
(recombinant proteins produced in E. coli).
Stock Solutions Raf/Mek cascade Assay:
1. Assay Dilution Buffer (ADB): 20mM MOPS, pH 7.2, 25mM ß-glycerol phosphate,
5mM EGTA, 1mM sodium orthovanadate, 1mM dithiothreitol.
2. Magnesium/ATP Cocktail: 500µM cold ATP and 75 mM magnesium chloride in
ADB.
4. Active Kinase: Human Active c-Raf: Use at 0.4U per assay point.
5. Non-active GST-MEK1: Use at 0.1µg per assay point.
6. Non-active GST-p42 MAP Kinase: Use at 1.0µg per assay point.
Stock Solutions ELISA:
1. TBST - Tris (50 mM, pH 7.5), NaCI (150 mM), Tween-20 (0.05 %)
2. Superblock (Pierce)
3. Anti-GST Ab (Pharmacia)
4. Anti-Phospho MAPK (Sigma)
5. Anti-Mouse Ab / Europium conjugate (Wallac)
Assay Procedure:
First Stage: c-Raf Dependent Activation of GST-MEK and GST-MAPK
1. Add 20 ml of ADB per assay (i.e. per well of a 96 well plate)
2. Add 10 ml of 0.5 mM cold ATP and 75 mM magnesium chloride in ADB.
3. Add 2 ml of c-Raf (0.4U/assay), in conjunction with 1.6ml non-active MEK1 (0.4
mg/assay).
4. Add 4 ml of non-active GST-p42 MAP Kinase (1.0 mg/assay).
5. Incubate for 60 minutes at 30°C in a shaking incubator.
6. Transfer this mixture to an anti-GST Ab coated 96 well plate (Nunc Immunosorb
plates coated o/n with a-GST, then blocked with Pierce Superblock).
7. Incubate for 60 minutes at 30°C in a shaking incubator
Wash 3X with TBST, add Anti-Phospho MAPK (Sigma) (1:3000)
6. Incubate for 60 minutes at 30°C in a shaking incubator
7. Wash 3X with TBST, add Anti-Mouse Ab / Europium conjugate (Wallac) (1:500)
8. Incubate for 60 minutes at 30°C in a shaking incubator
9. Wash 3X with TBST, Read plates in Wallac Victor model Plate Reader.
10. Collect data analyze in Excel for single point and IC50 determinations.
Single point assay - % inhibition at 10 mg/ml (% Inhibition = 1 - cpd.treated
sample/untreated control). IC50 determinations - done on compounds from single
point assays with >80% inhibition. Typically, the Raf/Mek assay is run at compound
concentrations from 10 DM to 1 nM in half log dilutions. (% inhibition is determined
for each compound concentration). . Multiple entries for a given compound indicate
that it was tested multiple times. The results obtained measure Raf and/or Mek
kinase I nhibition, and for representative compounds of this invention are listed in
Table 4.
Cell Based Screen for Inhibitors of Raf and/or Mek Kinase.
Materials
Cell Lines: Human tumor cell lines LoVo which are known to be growth inhibited
by low nM concentrations of a reference standard inhibitor of Ras and human
adenocarcinoma cell line CaCo-2, which is known to be growth resistant to the
same reference compound.
Cell Media : RPMI 1640 with 10% Fetal Bovine Serum supplemented with L-
glutamine and Pennicilin/Streptomycin.
Compounds: Supplied usually as a 10 mM stock in 100% DMSO.
Normal Saline: 150 mM NaCI+V
Trichloroacetic Acid (TCA): 50% (w/v) in water
Sulforhodamine B (SRB): 0.4% (w/v) in 1% Acetic Acid
Tris Base: 10 mM in water
Methods
Cells are plated at 2000 cells per well for cell line LoVo, 1,750 cells for cell line
BXPC3, 1,000 cells for cell line WM266-4 and 1500 cells for cell line CaCo-2 in
96 well plates. Cells are plated in media (200 µl) and allowed to adhere
overnight at 37°C. At 24 hours post plating, compounds are added directly at a
volume of 0.5 µl. For the qualitative screen (compounds screened at 25 µM)
compound is added directly to cells. For the quantitative screen, compound is
first diluted in DMSO to generate concentrations of compound or reference
standard of: 1, 5, 10 and 25 µM. It is advisable to make the dilutions in an
identical 96 well plate so that compounds can be added using a multichannel
micropipettor set at 0.5 µI. The cells are then incubated for four days after
which the media is removed using a 12 well manifold by first tipping the plate
forward at a 45 degree angle and then inserting the manifold in an upright
orientation to prevent the tips of the manifold from disturbing cells at the bottom
of the plate. 200 µl of normal saline is then added to each well using an 8 well
multichannel pipettor, followed by the careful addition of 50µI of 50% TCA. The
plates are then incubated for 2 hours at 4°C, after which the supernatant is
removed using the same technique as above and the plated washed twice with
200 µl water. The plates are then air dried and 50 µl of SRB stock solution is
carefully added so that the entire bottom of each well is covered. This again
can be used using an 8 well multichannel pipettor. The SRB is incubated with
fixed cells for 15 minutes at room temperature after which the SRB is removed
with the manifold as described above and the plates washed twice with 350 µl
of 1% acetic acid per well each time. The plates are then air dried after which
the bound SRB is released from protein by the addition of 200 µl of Tris base.
Resolubilizing the SRB is aided by placing the plates on a rotator for 15-30
minutes. The absorbance of each well is determined at 550 or 562 nm using a
microtiter plate reader.
Each compound or dilution thereof is performed in triplicate. Outliers are
identified by visual inspection of the data. Each plate should have a "0" control
(vehicle only).
Qualitative screen: To calculate % inhibition of a compound at 25 µM, the
following formula is used: 1- (experimental absorbance @ 25 µM compound/
"0" control absorbance) x 100= % inhibition at 25 µM. Compounds having >50%
inhibition at 25µM are placed in the quantitative assay.
Quantitative Assay: A standard curve is constructed by plotting the concentration of
compound against the average absorbance calculated at that concentration. A curve
is plotted and the concentration at which the curve passes through the 50% the
absorbance mark seen in the "0" control well is the IC20 calculated for that compound.
Multiple entries for a given compound indicate that it was tested multiple times. The
results obtained for representative compounds of this invention are listed in Table 4.
WE CLAIM :
1. Thieno [3,2-b] pyridine-6-carbonitriles and thieno[2,3-b] pyridine-5-
carbonitriles of formula (1a) or formula (1b)
or an S-oxide or S-dioxide thereof
wherein:
X is -NH-, -NR4-, -O-, -S(O)m-, -NHCH2-;
m is an integer of 0-2;
n is an integer of 2-5;
q is an integer of 0-5;
R1 is a phenyl ring optionally substituted with one to four substituents selected from
the group consisting of -J, -NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4,
-NR4R4, -NR4S(O)mR4, -OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R4, -
NR4C(O)R4, -C(O)R4, -C(O)0R4, -C(O)NR4R4, -OC(O)R4, -OC(O)OR4, -OC(O)NR4R4,
NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, -R5NR4R4, -R5S(O)mR4, -
R5C(O)R4, -R5C(O)OR4, -R5C(O)NR4R4, -R5OC(0)R4, -R5OC(O)OR4, -
R5OC(O)NR4R4,-R5NR4C(O)R4, -R5NR4C(O)OR4, -RSNR4C(O)NR4R4, or YR7;
R2 is -H, -R3, -J, -C(O)XR3, -CHO, wherein the R3 group may be substituted by one
or more groups selected from -C(O)XRB, -CHO, -C(O)Q, 1,3-dioxolane, -R8, -
(C(R9)2)qXR8, -(C(R9)2)qQ, -X(C(R9)2)nXR8, -X(C(R9)2)nQ, or - X(C(R9)2)q R8;
R3 is alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, frans-alkenyl of 2-
6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R4 is H, alkyl of 1-6 carbon atoms, os-alkenyl of 2-6 carbon atoms, a trans- alkenyl of
2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;
R5 is a divalent group comprising alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, and alkynyl of 2-6 carbon atoms;
R6 is a divalent alkyl group of 2-6 carbon atoms;
R7 is a cycloalkyl ring of 3-7 carbons, an aryl or heteroaryl ring, a aryl or heteroaryl
fused to one to three aryl or heteroaryl rings, wherein any of the aryl, cycloalkyl, or
heteroaryl rings may be optionally substituted with one to four substituents selected
from the group consisting of -H, -aryl, -CH2-aryl, -NH-aryl, -O-aryl, -S(O)m-aryl, -J, -
NO2, -CN, -N3, -CHO, -CF3, -OCF3, -R4, -OR4, -S(O)mR4, -NR4R4, -NR4S(O)mR4, -
OR6OR4, -OR6NR4R4, -N(R4)R6OR4, -N(R4)R6NR4R4, -NR4C(O)R4, -C(O)R4, -
C(O)OR4, -C(O)NR4R4, -OC(O)R4-, -OC(O)OR4, -OC(O)NR4R4, -NR4C(O)R4, -
NR4C(O)OR4, -NR4C(O)NR4R4, -R5OR4, R5NR4R4, -R5S(O)mR4, -R5C(O)R4, -
R5C(O)OR4, -R5C(O)NR4R4, -R5C(O)R4, -R5C(O)0R4, -R5C(O)NR4R4, -R5OC(O)R4, -
R5OC(O)OR4, -R5OC(O)NR4R4, -R5NR4C(O)R4, -R5NR4C(O)OR4, or -
R5NR4C(O)NR4R4;
R8 is -H, alkyl of 1 to 6 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, trans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
R9 is-R4 or-F;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2-, -SO2NH-, -C(OH)H-, -
X(C(R9)2)q-, -(C(R9)2)q-, -(C(R9)2)qX-, -C=C-, cis- and trans- -CH=CH- and cycloalkyl
of 3-10 carbon atoms;
Q is NZZ' wherein Z and 71 may be the same or different and and may be H, alkyl of
1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl,
or heteroaryl;
Z and Z' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, optionally substituted with -R4 on a carbon or a nitrogen, or on
nitrogen by a group -(C(R9)2)nXR3, -C(R9)2)nNZ''Z''', or on carbon by a group
(C(R9)2)qXR3, -(C(R9)2)qNZ"Z''',
Z' and Z''' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur;
Z" and Z''' may each be selected from H, alkyl of 1 to 6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, aryl, or heteroaryl, and
J is fluoro, chloro, bromo, and iodo; or
a pharmaceutical ly acceptable salt thereof.
2. A compound of formula 1a or 1b as claimed in claim 1 wherein X is NH.
3. A compound of formula la or lb as claimed in claim 1 or claim 2 wherein R1
is a phenyl ring optionally substituted with one to four substituents selected from the
group consisting of -J, -CF3, -OCF3, -R4, -OR4 and YR7; and R7 is an aryl or
heteroaryl ring, optionally substituted with one to four substituents selected from the
group consisting of -H, -J, -CF3, -OCF3, -R4 and OR4.
4. A compound of formula la or lb as claimed in claim 1 or claim 2 wherein R1
is a phenyl ring optionally substituted with one to four substituents selected from the
group consisting of -CI, -R4 and -OR4.
5. A compound of formula 1a or 1b as claimed in claim 4 wherein R4 is alkyl of
1-6 carbon atoms.
6. A compound of formula 1a or 1b as claimed in claim 1 wherein R2 is
substituted aryl or heteroaryl, wherein the substituent may be one or more groups
selected from -(C(R9)2)qQ.
7. A compound of formula 1a or 1b as claimed in claim 6 wherein q is 1 to 3.
8. A compound of formula 1a or 1b as claimed in claim 6 or claim 7 wherein R9
is H.
9. A compound of formula 1a or 1b as claimed in any one of claims 6 to 8
wherein Q is NZZ' wherein Z and 71 may be the same or different and may be H,
alkyl of 1 to 6 carbon atoms; or Z and Z' taken together with the nitrogen to which
they are attached may form a heterocyclic ring which may have an additional
heteroatom selected from nitrogen and oxygen, said ring may be substituted on
nitrogen or carbon by R4 or on carbon by (CH2)2OH.
10. A compound of formula 1a or 1b as claimed in claim 1 or claim 2 wherein
R2 is R3 where R3 is alkynyl of 2-6 carbon atoms, aryl or heteroaryl; which groups
may be substituted by one or more groups selected from
-RB, -(CH2)qOR8, -(CH2)qNHR8, -(CH2)q NR4R8, -(CH2)qQ,
-O(CH2)nOR8, - NH(CH2)nOR8, - NR4(CH2)nOR8,
-O(CH2)nNHR8, - NH(CH2)nNHR8, - NR4(CH2)nNHR8,
-O(CH2)nNR4R8, - NH(CH2)nCR8, - NR4(CH2)nNR4R8,
-O(CH2)nQ, -NH(CH2)nQ, - NR4(CH2)nQ,
- O(CH2)qR8; - NH(CH2)qR8; or - NR4(CH2)qR8;
R4 is H, alkyl of 1-6 carbon atoms;
R8 is -H, alkyl of 1 to 6 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, trans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2-, -S-, :O-, -MR4-;
Q is NZZ' wherein Z and Z' may be the same or different and are selected from H,
alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, aryl, or heteroaryl, and
Z and Z' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally
substituted with -R4 on a carbon or a nitrogen, or on nitrogen by a group -(CH2)nOR3,
-(CH2)nNHR3, -(CH2)nNR4R3, -(CH2)nNZ"Z"', or on carbon by a group -(CH2)qOR3, -
(CH2)qNHR3, -(CH2)qNR4R3, -(CH2)qNZ'Z"',
Z" and Z'" may be the same or different and are selected from H, alkyl of 1 to 6
carbon atoms
Z" and Z"' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may contain an additional heteroatom selected from nitrogen,
oxygen and sulfur.
11. A compound as claimed in claim 1 which is one of the following :
7-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6carbonitrile;
2-Bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile;
4-[(3-Chloro-4-[(1-methyl-1H-imida2ol-2-yl)thio]phenyl)amino]thieno[2,3-b]pyridine-5-
carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-methylthieno[2I3-b]pyridine-5-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-morpholinylmethyl)phenyl] thieno
[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
yl]methyl} phenyl) thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]
thieno [3,2-b] pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl] thieno
[3,2-b]pyridine-6-carbonitrile;
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}
benzoic acid;
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}
benzamide;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]
pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]
pyridine-6-carbonitrile;
7-[(2,4-Dich!oro-5-methoxypheny!)amino]-2-[3-(dimethyIamino)prop-1-ynyl] thieno
[3,2-b]pyridine-6-carbonitrile;
2-(1-Benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b] pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(3-formyIphenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-ylmethyl) phenyl] thieno
[3,2-b]pyridine-6-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-bJpyridine-5-
carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-ylmethyl) phenyl] thieno
[2,3-b]pyridine-5-carbonitrile;
4-[5-Cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid
methyl ester;
2-(4-Hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonitrile;
2-[4-(4-Morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(trimethy!si!yl)ethynyl]thieno[3,2-b]
pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]
pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]
pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl}thien-5-yl}thieno
[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dich!oro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyI)amino]-2-{4-[(4-hydroxypiperidin-1-yl) methyl]
phenyl} thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl]thieno[3,2-b]
pyridine-6-carbonitrile;
2-lodo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-(4-Formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-[4-(4-Methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]
pyridine-6-carbonitrile;
2-[4-(Morpholin-4-ylmethy[)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b] pyridine-
6-carbonitrile;
2-[4-(Hydroxymethyl)phenyl]-7-[(4-phenoxypheny!)amino]thieno[3,2-b]pyridine-6-
carbonitrile;
2-lodo7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-Bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(4-Phenoxyphenyl)amino]-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-
carbonitrile;
tert-Butyl(2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]
pyridin-2-yl}prop-2-enoate;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]
thieno [2,3-b]pyridine-5-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]
pyridine-5-carbonitrile;
(2E)-3-(6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)
prop-2-enoate;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-yl)
thieno [3,2-b]pyridine-5-carbonitrile;
2-(4-Formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(1E)-3-(4-methylpiperazin-1-yl)-3-
oxoprop-1-enyl)thieno[3,2-b]pyridine-6-carbonitrile;
2-[3-(4-Methylpiperazin-1-yl)prop-1-ynyl]-7-[(3,4,5-trimethoxyphenyl)amino] thieno
[3,2-b]pyridine]-6-carbonitrile;
2-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]
thieno[3,2-b]pyridinel-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{1 -methyl-2-[(4-methylpiperazin-1 -
yl)methyl]-1 H-imidazol-5-yl} thieno[3,2-b]pyridinej-6-carbonitrile; and
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]
thieno[3,2-b]pyrldineJ-5-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-
[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-
[(diethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-ethylp!perazin-1-ylmethyl)phenyl]
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2-Chloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-
b]pyridine-5-carbonitrile;
7-[(2-Chloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-
ylmethyl)phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}7-[(5-methoxy-2-methylphenyl)amino]-
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(5-methoxy-2-methylphenyl)amino]-2-[4-(4-methylpiperazin-1-yImethyl) phenyl]
thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)amino]-2-{4-[(dimethyIamino)methyl]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichlorophenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl] thieno [3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[6-(4-methy!piperazin-1-ylmethyI)pyridin-
3-yl] thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethylamino)methyl]pyridin-3-
yl}thieno[3,2-b]pyridine-5-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(4-methylpiperazin-1-ylmethyl)furan-5-
yl] thieno [3,2-b]pyridine-6-carbonitrile; or
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]furan-3-
yl)thieno[3,2-b]pyridine-6-carbonitrile.
12. A compound as claimed in claim 1 which is one of the following :
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]
thieno [3,2-b]pyridine-5-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-rnethoxyphenyl)amino]-2-{4-
[(dimethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-
morpholinylmethyl)phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-DichIoro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-
yl]thieno[3,2-b]pyridine-6-carbonitrile; or
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile.
13. A compound as claimed in claim 1 of Formula (1a) or Formula (1b)
wherein:
X is -NH-
n = 2-5
q = 1-3
R1 is a phenyl ring optionally substituted with one to four substituents selected from
the group consisting of -CI, -R4, -OR4;
R2 is substituted aryl or heteroaryl, wherein the substituent may be one or more
groups selected from -(C(R9)2)qQ;
R4 is alkyl of 1-6 carbon atoms;
R9 is H;
Q is NZZ' wherein Z and Z' may be the same or different and may be H, alkyl of 1 to
6 carbon atoms;
Z and Z' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen
and oxygen, said ring may be substituted on nitrogen or carbon by R4 or on carbon
by (CH2)2OH; or
a pharmaceutically acceptable salt thereof.
14. A compound as claimed in claim 13 which is one of the following :
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl) phenyl]
thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphehyl)amino]-2-{4-
[(dimethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-
morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-
ylmethyl)phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-
yl}thieno[3,2-b]pyridine-6-carbonitrile; or
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile.
15. A compound as claimed in claim 1 of formula (1a) or formula (1b)
wherein:
Xis-NH-,
n is an integer of 2-5;
q is an integer of 0-5;
R1 is a phenyl ring optionally substituted with one to four substituents selected from
the group consisting of -J, -CF3, -OCF3, -R4, -OR4, or YR7;
R2 is alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
and may be substituted by one or more groups selected from
-R8, -(CH2)qOR8, -(CH2)qNHR8, -(CH2)q NR4R8, -(CH2)qQ,
-O(CH2)nOR8, - NH(CH2)nOR8, - NR4(CH2)nOR8,
-O(CH2)nNHR8, - NH(CH2)nNHR8, - NR4(CH2)nNHR8,
-O(CH2)nNR4R8, - NH(CH2)nCR8, - NR4(CH2)nNR4R8,
-O(CH2)nQ, -NH(CH2)nQ, - NR4(CH2)nQ,
- O(CH2)qR8; - NH(CH2)qR8; or - NR4(CH2)qR8;
R3 is alkyl of 1 to 6 carbon atoms;
R4 is H, alkyl of 1-6 carbon atoms;
R7 is an aryl or heteroaryl ring, optionally substituted with one to four substituents
selected from the group consisting of -H, -J, -CF3, -OCF3, -R4, -OR4;

R8 is -H, alkyl of 1 to 6 carbon atoms, cis-alkenyl of 2-6 carbon atoms, trans-alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl or heteroaryl;
Y is -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHSO2,-, -S-, -O-, -NR4-;
Q is NZZ' wherein Z and Z' may be the same or different and are selected from H,
alkyl of 1 to 6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, aryl, or heteroaryl, and
Z and Z' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may have an additional heteroatom selected from nitrogen,
oxygen, and sulfur, and may comprise morpholine, piperazine, piperidine, optionally
substituted with -R4 on a carbon or a nitrogen, or on nitrogen by a group -(CH2)nOR3,
-(CH2)nNHR3, -(CH2)nNR4R3, -(CH2)nNZ''Z"', or on carbon by a group -(CH2)qOR3, -
(CH2)qNHR3, -(CH2)q NR4R3, -(CH2)qN''Z'",
Z"' and Z" may be the same or different and are selected from H, alkyl of 1 to 6
carbon atoms
Z" and Z''' taken together with the nitrogen to which they are attached may form a
heterocyclic ring which may contain an additional heteroatom selected from nitrogen,
oxygen and sulfur;
and J is fluoro, chloro, bromo and iodo
16. A compound as claimed in claim 15 which is one of the following
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-
morpholinylmethyl)phenyl}thieno[3,2-b]pyridine-6-carbonrtrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-
ylmethyl)phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-
yI]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)arnino]-2-[4-(piperidin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-
bjpyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyI)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyI)amino]-2-[3-(morpholin-4-
ylmethyl)phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(morphoiin-4-
ylmethyl)phenyl}thieno[2,3-b]pyridine-5-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-4-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}thieno[3,2-b]pyridine-5-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-
yl]thieno[3,2-b]pyridine-5-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(hydroxymethyl)phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
2-[4-(4-Methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-
6-carbonitrile;
2-[4-(Hydroxymethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(4-Phenoxyphenyl)amino]-2-[(E)-2-pyridin-4-ylethenyl]thieno[3,2-b]pyridine-6-
carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpipera2in-1-yl)prop-1-
ynyl]thieno[3,2-b]pyridine-5-carbonitrile;
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-
5-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
2-[3-(4-Methylpiperazin-1-yl)prop-1-ynyI]-7-[(3,4,5-trimethoxyphenyl)-
amino]thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)-
amino]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{1-nnethyl-2-[(4-methylpiperazin-1-
yl)methyl]-1H-imidazol-5-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]
thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonrtrile; or
7-[(2,4-DichIoro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]-
pheny[}thieno[3,2-b]pyridine-6-carbonitrile.
17. A compound as claimed in claim 1 which is an S-oxide or S-dioxide of
Formula (1c), Formula (1d), (1e) or (1f):
wherein: X, R1 and R2are as defined in claim 1.
18. A compound as claimed in claim 17 which is one of the following :
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-
1 -oxo-1H-thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-yImethyl)phenyl]-
1,1 -dioxo-1H-thieno [3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}-1-oxo-
1H-thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(dimethylamino)methyl]phenyl}-1,1 -
dioxo-1H-thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(Dimethylamino)methyl]phenyl}-1-oxo-7-[(3,4,5-trimethoxyphenyl)amino]-1H-
thieno[3,2-b]pyridine-6-carbonitrile; or
2-{4-[(Dimethylamino)methyl]phenyl}-1,1 -dioxo-7-[(3,4,5-trimethoxyphenyl)amino]-
1H-thieno[3,2-b]pyridine-6-carbonitrile.
19. A pharmaceutical composition comprising a compound of Formula (1a)
and (Ib) or an S-oxide or S-dioxide thereof as claimed in any one of claims 1 to 18 or
a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition as claimed in claim 19 for treating or
inhibiting a pathological condition or disorder in a mammal.
21. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder is cancer.
22. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder is stroke.
23. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder is osteoporosis.
24. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder is polycystic kidney disease.
25. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder comprises autoimmune disease, rheumatoid
arthritis, and transplant rejection.
26. A pharmaceutical composition as claimed in claim 19 wherein the
pathological condition or disorder is neuropathic pain.
27. A process for preparing a compound of formula (1a) or (1b) as claimed in
claim 1 or a pharmaceutical^ acceptable salt thereof, which comprises one of the
following:
a) reacting a compound of formula:
or an S-oxide or S-dioxide thereof; wherein R2 is as defined in Claim 1 with a
compound of formula R1XH where R1 and X are as defined in Claim 1 to give a
compound of formula 1(a) or (1b);
or
b) reacting a compound of formula 1a or 1b or an S-oxide or S-
dioxide thereof in which R2 is a reactive substituent group to give a compound of
formula 1a or 1b in which R2 is a different substituent group as defined in claim 1;
or
c) converting a comppund of formula (1 a) or (1 b) to a
pharmaceutically acceptable salt thereof.
28. A process of producing a compound of Formula (1a) or (1b) as claimed in
claim 1, wherein R2 is iodine, comprising:
a) treating with a base, in an inert solvent at reduced temperature
compound of Formula (a) or (a');a
b) adding iodine to the compound in step (a) to form a compound
of Formula (b) or (b'); and
c) adding a compound of formula R1XH to the compound in step
(b) to form a compound of Formula (1a) or (Ib), wherein R2 is iodine.
29. A process of producing a compound of Formula (1a) or (1b) as claimed in
claim 1, wherein R2 is bromine, comprising:
a) treating with a base, in an inert solvent at reduced temperature a
compound of Formula (a) or (a');
b) adding 1,1-dibromo-1,1,2,2-tetrafluoroethane to the compound in step
(a) to form a compound of Formula (z) or (z'); and
c) adding a compound of formula R1XH to the compound in step (b) to
form a compound of Formula (1a) or (1b), wherein R2 is bromine.
30. A compound as claimed in claim 1 which is one of the following.:
7-({3-chloro-4-[(1-methyl- 1H-imidazol-2-yl)thio]phenyI}amino)-2-iodothieno[3,2-
b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-
ylmethyl)pheny]thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[4-(morpholin-4-ylbut-
1-ynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[3-
(dimethylamino)prop-1-ynyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-(4-
formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-[(4-
methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[3-
(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[{2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formyl-2-furyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1I3-dioxolan-2-y!)-2-furyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-
furyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-ethylpiperazin-1-
yl)methyl]phenyI}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[2-
(dimethylamino)ethyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{3-
[(dimethylamino)methyl]phenyl}triieno[3,2-b]pyridine-6-carbonitrile;

7-[(2,4-dichloro-5-methoxyphenyl)aminol-2-{5-[(dimethylamino)methyl]-2-
furyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-2-y!]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formylthien-3-yl)thieno[3,2-b]pyridine-
6-carbonitrile,-
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-2-yl)thieno[3,2-b]pyridine-
6-carbonitrile;
7-[(2,4ndichloro-5-rnethoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-3-
yl)thieno[3,2-b]jpyridine-6-carbonitrile;
7-[(2,4-dichloro5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]thien-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)aminoJ-2-{2-[(4-methylpiperazin-1-yl)methyl]thien-
3-yl}trieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[[3-
(dimethylamino)propyl](methyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({6-[(dlmethylamino)methyl]pyridin-2-
yl}ethynyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]thien-2-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(pyridin-4-
ylmethyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro5-methoxyphenyl)amino]-2-(iH-pyrrol-3-yl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(2-
methoxyethyl)amino]methyI}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)aminb]-2-[4-({[2-
(methylthio)ethyl]amino)methyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(thiomorpholin-4-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperazin-1-
ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-morpholin-4-ylphenyl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-(4-
formylphenyl)thieno[3,2-b] pyridine-6-carbonitrile;
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-{4-
[(diethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-({5-[(dimethylamino)methyl]pyridin-2-
yl}ethynyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichlorophenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;,
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-
2-yl}thieno[3,2-b]pyridine-6-carbonitrile;
2-{4-[(butylamino)methyl]phenyl}-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1-oxidothiomorpholin-4-
yl)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-
[(diethylamino)methyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-
hydroxypropyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)pyridin-2-
l]thieno[3,2-b]pyridine-5-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(6-morpholin-4-ylpyriclin-3-yl)thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile;
7-[(2',4-dichloro-5-methoxyphenyl)amino]-2-{4-[(1,1 -dioxidothiomorpholin-4-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-pyridin-2-ylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyi)amino]-2-{4-[(4-phenylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4{[(2R,5S)-2,5-dimethylpiperazin-1-
l]methyl)phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichlorphenyl)amino]-2-(4-foimylphenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dich!orophenyl)amino]-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thieno[3,2-
b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxypheny!)amino]-2-(4-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl)phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[(3-
methylbutyl)amino]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(methylsulfonyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-ethoxyphenyl)amino]-2-{4-[(4-methylpiperazin-1-
yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(pyridin-2-ylmethyl)piperazin-1-
yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-nnethoxyphenyl)amino]-2-{1-[2-(dimethylamino)ethyl]-1H-pyrrol-3-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichlorophenyl)amino]-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4'dichloro-5-methoxyphenyl)amino]-2-[(1 -methyl-1 H-imidazol-5-
yl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{6-[(dimethy!amino)methyl]pyridin-2-
yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-yl)thieno[3,2-b]pyridine-6-
carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-morpholin-4-ylethyl)-1H-pyrazoI-4-
yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(dimethylamino)methyl]pyridin-2-
yl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(diethylamino)methyl]pyridin-2-
yl}thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[2-
(dimethylamino)ethyl]phenyl)thieno[3,2-b]pyridine-6-carbonitrile;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[1-(2-hydroxyethyl)-1H-pyrazol-4-
yl)thieno[3,2-b]pyridjne-6-carbonitrile;
4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}-N,N-
dimethylbenzamide;
7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-
furyl}thieno[3,2-b]pyridine-6-carbonitrile; and
7-[(2,4-dichloro-5-methoxyphenyl)amino3-2-(5-formyl-3-furyl)thieno[3,2-b]pyridine-6-
carbonitrile.
This invention provides compounds of Formula (1a) - (1f) wherein: X, R1 and
R2 are defined hereinbefore in the specification, which are useful in the treatment of
cancer, stroke, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid
arthritis, and transplant rejection and process for producing said compounds.