Indolyl-urea derivatives of thienopyridines useful as...

Details Indolyl-urea derivatives of thienopyridines useful as... Indolyl-urea derivatives of thienopyridines useful as...

2003-02-21

2004-12-21

Desai, Rita (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S301000

Reexamination Certificate

active

06833456

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel thienopyridine and thienopyridine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
Compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following patents and applications: PCT international patent application publication number WO 00/38665 (published Jul. 6, 2001), PCT international patent application publication number WO 97/49688 (published Dec. 31, 1997), PCT international patent application publication number WO 98/23613 (published Jun. 4, 1998), U.S. patent application Ser. No. 60/299,879 (filed Jun. 21, 2001), U.S. patent application Ser. No. 09/502,129 (filed Feb. 10, 2000), U.S. patent application No. 60/209,686 (filed Jun. 6, 2000), U.S. patent application No. 60/214,373 (filed Jun. 28, 2000), U.S. patent application Ser. No. 08/953,078 (filed Oct. 17, 1997), U.S. Pat. No. 6,071,935 issued Jun. 6, 2000, PCT international patent application publication number WO 96/30347 (published Oct. 3, 1996), PCT international patent application publication number WO 96/40142 (published Dec. 19, 1996), PCT international patent application publication number WO 97/13771 (published Apr. 17, 1997), and PCT international patent application publication number WO 95/23141 (published Aug. 31, 1995). The foregoing patent and applications are incorporated herein by reference in their entirety.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and hence to influence cell proliferation. The foregoing tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. It is known that such kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. It has also been shown that epidermal growth factor receptor (EGFR) is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It has also been shown that EGFR inhibitors may be useful in the treatment of pancreatitis and kidney disease (such as proliferative glomerulonephritis and diabetes-induced renal disease), and may reduce successful blastocyte implantation and therefore may be useful as a contraceptive. See PCT international application publication number WO 95/19970 (published Jul. 27, 1995), hereby incorporated by reference in its entirety.
It is known that polypeptide growth factors such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995), hereby incorporated by reference in its entirety. Agents, such as the compounds of the present invention, that are capable of binding to or modulating the KDR/FLK-1 receptor may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, age related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
SUMMARY OF THE INVENTION
A compound represented by the formula I
wherein
X is —CH— or —N—;
Y is —NH—, —O—, —S—, or —CH
2
—;
R
1
is H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, —C(O)(C
1
-C
6
alkyl), C
6
-C
10
aryl or a 5 to 13 membered heterocyclic, wherein said C
6
-C
10
aryl and 5 to 13 membered heterocyclic groups are unsubstituted or substituted with 1 to 5 R
5
substituents;
each R
5
is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R
8
, —C(O)OR
8
, —OC(O)R
8
, —OC(O)OR
8
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, —OR
9
, —SO
2
NR
6
R
7
, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, C
1
-C
6
alkylamino, —(CH
2
)
j
O(CH
2
)
q
NR
6
R
7
, —(CH
2
)
t
O(CH
2
)
9
OR
9
, —(CH
2
)
t
OR
9
, —S(O)
j
(C
1
-C
6
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5 to 10 membered heterocyclic), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
j
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
q
(5 to 10 membered heterocyclic), —C(O)(CH
2
)
t
(5 to 10 membered heterocyclic), —(CH
2
)
j
NR
7
(CH
2
)
q
NR
6
R
7
, —(CH
2
)
j
NR
7
CH
2
C(O)NR
6
R
7
, —(CH
2
)
j
NR
7
(CH
2
)
q
NR
9
C(O)R
8
, (CH
2
)
j
NR
7
(CH
2
)
t
O(CH
2
)
q
OR
9
, —(CH
2
)
j
NR
7
(CH
2
)
q
S(O)
j
(C
1
-C
6
alkyl), —(CH
2
)
j
NR
7
(CH
2
)
t
R
6
, —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), and —SO
2
(CH
2
)
t
(5 to 10 membered heterocyclic), wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH
2
)
q
— and —(CH
2
)
t
— moieties of the said R
5
groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 6, and the alkyl, aryl and heterocyclic moieties of the said R
5
groups are unsubstituted or substituted with one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R
8
, —C(O)OR
8
, —OC(O)R
8
, —OC(O)OR
8
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —(CH
2
)
t
NR
6
R
7
, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5 to 10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, and —(CH
2
)
t
OR
9
, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R
6
and R
7
is independently selected from H, OH, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5 to 10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, —(CH
2
)
t
CN(CH
2
)
t
OR
9
, —(CH
2
)
t
CN(CH
2
)
t
R
9
and —(CH
2
)
t
OR
9
, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the said R
6
and R
7
groups are unsubstituted or substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
8
, —C(O)OR
8
, —CO(O)R
8
, —OC(O)OR
8
, —NR
9
C(O)R
10
, —C(O)NR
9
R
10
, —NR
9
R
10
, C
1
-C
6
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5 to 10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, and —(CH
2
)
t
OR
9
, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, where when R
6
and R
7
are both attached to the same nitrogen, then R
6
and R
7
are not both bonded to the nitrogen directly through an oxygen;
each R
8
is independently selected from H, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
)
t
(5 to 10 membered heterocycli

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