Heteroaromatic bicyclic derivatives useful as anticancer agents

Details Heteroaromatic bicyclic derivatives useful as anticancer agents Heteroaromatic bicyclic derivatives useful as anticancer agents

2000-01-20

2002-10-15

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S266100, C514S266200, C544S293000, C544S284000

Reexamination Certificate

active

06465449

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel bicyclic derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
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 which, on 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 enzymes which 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 which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, VEGF and TGF-&bgr;. It is known that such kinases are frequently 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. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals.
Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently, five European patent publications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published Nov. 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO 97130034 (published Aug. 21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula 1
and to pharmaceutically acceptable salts and solvates thereof, wherein: X is N or CH;
A represents a fused 5, 6 or 7-membered ring optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from —N(R
1
)—, O, and S(O)
j
, wherein j is an integer from 0 to 2, the fused ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused wherein the R
1
group attached to the nitrogen is absent if a double bond includes the foregoing optional nitrogen moiety —N(R
1
)—, with the proviso that the fused ring does not form part of a purine and that the fused ring does not contain two adjacent O or S(O)
j
atoms, and wherein the carbon atoms of the A moiety are optionally substituted with 1 to 3 R
5
groups;
each R
1
and R
2
is independently H or C
1
-C
6
alkyl;
R
3
is —(CR
1
R
2
)
m
-R
8
wherein m is 0 or 1;
or R
1
and R
3
are taken together to form a group of the formula
wherein said group is optionally substituted with 1 to 3 R
5
groups;
R
4
is —(CR
1
R
2
)
t
(C
6
-C
10
aryl) or —(CR
1
R
2
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, wherein said R
4
groups are substituted with 1 to 3 groups independently selected from —(CR
1
R
2
)
q
NR
1
R
9
, —(CR
1
R
2
)
q
NR
9
(C
1
-C
6
alkanoyl), —(CR
1
R
2
)
q
O(CR
1
R
2
)
r
R
9
, and —(CR
1
R
2
)
q
R
9
wherein q and r are each independently an integer from 0 to 5, and wherein the heterocyclic, aryl and alkyl moieties of the foregoing groups are optionally substituted with 1 to 3 R
10
groups;
each R
5
is independently selected from halo, hydroxy, —NR
1
R
2
, C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, and trifluoromethoxy;
each R
6
and R
7
is independently selected from H, C
1
-C
6
alkyl, —(CR
1
R
2
)
t
(C
6
-C
10
aryl), and —(CR
1
R
2
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R
6
and R
7
groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR
1
R
2
, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, hydroxy, and C
1
-C
6
alkoxy;
each R
8
is independently selected from —(CR
1
R
2
)
t
(C
6
-C
10
aryl) and —(CR
1
R
2
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and each of the foregoing R
8
groups is optionally substituted with 1 to 5 R
10
groups;
R
9
is a fused or bridged bicyclic ring or a spirocyclic ring, wherein said ring contains from 5 to 12 carbon atoms in which up to 2 carbon atoms are optionally replaced with a hetero moiety selected from O, S(O)
j
wherein j is an integer from 0 to 2, and —NR
11
—, provided that two O atoms, two S(O)
j
moieties, an O atom and a S(O)
j
moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other, and wherein said ring is saturated or partially unsaturated with up to two carbon-carbon double bonds, and the carbon atoms of said ring are optionally substituted with 1 to 4 R
10
groups;
or where R
9
is as —NR
1
R
9
then R
9
optionally can be taken together with R
1
and the nitrogen to which R
1
and R
9
are attached to form a fused or bridged bicyclic ring or a spirocyclic ring, wherein said ring is saturated and contains from 5 to 12 carbon atoms in which up to 2 carbon atoms are optionally replaced with a hetero moiety selected from O, S(O)
j
wherein j is an integer from 0 to 2, and —NR
1
—, provided that two O atoms, two S(O)
j
moieties, or an O atom and a S(O)
j
moiety are not attached directly to each other, and wherein the carbon atoms of said rings are optionally substituted with 1 to 4 R
10
groups;
each R
10
is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C
1
-C
6
alkoxy, C
1
-C
10
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, —C(O)R
5
, —C(O)OR
6
, —OC(O)R
6
, —NR
8
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, —NR
6
OR
7
, —SO
2
NR
6
R
7
, —S(O)
j
(C
1
-C
6
alkyl) wherein j is an integer from 0 to 2, —(CR
1
R
2
)
t
(C
6
-C

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