Pyridotriazines and pyridopyridazines

Details Pyridotriazines and pyridopyridazines Pyridotriazines and pyridopyridazines

2001-10-03

2004-01-27

Raymond, Richard L (Department: 1624)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S236000, C514S243000, C514S248000

Reexamination Certificate

active

06683183

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to bicyclic heterocycles that inhibit cyclin-dependent kinase or tyrosine kinase enzymes, or both, and as such are useful to treat cell proliferative disorders such as angiogenesis, atherosclerosis, restenosis, and cancer as well as immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals.
SUMMARY OF THE RELATED ART
Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. Tyrosine kinases are an integral part of growth factor receptors and are essential for the propagation of growth factor signal transduction leading to cellular proliferation, differentiation, and migration. Growth factor receptors are also known as receptor tyrosine kinases (RTKs). The aberrant regulation of growth factors or their cognate receptors plays a critical role in the progression of proliferative diseases. For example, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been implicated as important mediators of tumor promoted angiogenesis (Sun L. and McMahon G., “Inhibition of Tumor Angiogenesis by Synthetic Receptor Tyrosine Kinase Inhibitors,”
Drug Discovery Today,
2000;5(8):344-353). Solid tumors are dependent upon the formation of new blood vessels from preexisting vessels (angiogenesis) to nourish their growth and to provide a conduit for metastases. Accordingly, inhibitors of the FGF and VEGF RTKs, as well as other tyrosine kinases, are useful agents for the prevention and treatment of proliferative diseases dependent on these enzymes.
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., “Chemical Inhibitors of Cyclin-Dependent Kinases,”
Progress in Cell Cycle Research,
1995;1:351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1 (also known as cdc2), cdk2, cdk4, cdk5, cdk6, and wee-1 kinase. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of human tumors and other proliferative disorders such as restenosis (Fry D. and Garrett M., “Inhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for the Treatment of Cancer,”
Current Opinion in Oncologic, Endocrine, and Metabolic Investigational Drugs,
2000;2(1):40-59). Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated both preclinical and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur, et al.,
J. Natl. Cancer Inst.,
1992;84:1736-1740;
Int. J. Oncol.,
1996;9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-(hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely, et al.,
Eur. J. Biochem.,
1994;224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al.,
Biology of the Cell,
1995;83:105-120).
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration, and atherosclerosis and immunological disorders such as asthma, rheumatoid arthritis, autoimmune diabetes, and graft rejection associated with transplant surgery in mammals.
SUMMARY OF THE INVENTION
This invention provides bicyclic heterocycles that are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, restenosis, angiogenesis, diabetic retinopathy, psoriasis, and endometriosis and immunological disorders. These pyridotriazine and pyridopyridazine analogs are inhibitors of tyrosine kinases and cyclin-dependent kinases (cdks). The disclosed compounds are readily synthesized and can be administered by a variety of routes, including orally and parenterally.
The compounds of the invention are members of the class of compounds of Formula I:
and the pharmaceutically acceptable salts thereof, wherein:
W is NH, S, SO, or SO
2
;
X is N or CH;
Z is O, S, or NR
10
;
Each of R
1
, R
2
, and R
10
are independently selected from the group consisting of H, (CH
2
)
n
Ar, COR
4
, (CH
2
)
n
C
3
-C
5
heteroaryl, (CH
2
)
n
C
3
-C
5
heterocyclyl, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, C
2
-C
10
alkenyl, and C
2
-C
10
alkynyl, wherein n is 0, 1, 2, or 3, and the (CH
2
)
n
Ar, (CH
2
)
n
heteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR
5
R
6
, N(O)R
5
R
6
, NR
5
R
6
R
7
Y, C
1
-C
4
alkyl, phenyl, substituted phenyl, (CH
2
)
n
heteroaryl, hydroxy, C
1
-C
4
alkoxy, phenoxy, thiol, C
1
-C
4
thioalkyl, halo, COR
5
, CO
2
R
5
, CONR
5
R
6
, SO
2
NR
5
R
6
, SO
3
R
5
, PO
3
R
5
, C
1
-C
5
aldehyde, nitrile, nitro, C
3
-C
6
heteroaryloxy, T(CH
2
)
m
QR
4
,
C(O)T(CH
2
)
m
QR
5
, NHC(O)T(CH
2
)
m
QR
5
, T(CH
2
)
m
C(O)NR
5
NR
6
, and T(CH
2
)
m
CO
2
R
5
wherein each of m, m′, and m″ is independently 1-6, T is O, S, NR
7
, N(O)R
7
, NR
7
R
8
Y, or CR
7
R
11
, and Q is O, S, NR
11
, N(O)R
11
, or NR
11
R
8
Y;
R
3
and R
9
have the meanings of R
2
, wherein R
2
is as defined above, as well as OH, NR
12
R
13
, COOR
12
, OR
12
, CONR
12
R
13
, SO
2
NR
12
R
13
, SO
3
R
12
, PO
3
R
12
, T′(CH
2
)
m
Q′R
4
,
wherein T′ and Q′ are as defined above for T and Q, respectively;
R
4
, R
5
, R
6
, R
7
, R
11
, R
12
, R
13
, R
14
, and R
15
are each independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, N(C
1
-C
6
alkyl)
1 or 2
, (CH
2
)
n
Ar, C
3
-C
10
cycloalkyl, C
3
-C
6
heterocyclyl, and C
3
-C
6
heteroaryl, or R
5
and R
6
, or R
7
and R
8
, or R
12
and R
13
together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, sulfur, and substituted sulfur; or
when R
5
and R
6
, or R
7
and R
8
, or R
12
and R
13
together with the nitrogen to which they are attached form a ring, said ring is optionally substituted by 1 to 3 groups selected from OR
14
, NR
14
R
15
, (CH
2
)
m
OR
14
, (CH
2
)
m
NR
14
R
15
, T″—(CH
2
)
m
Q″R
14
, CO—T″—(CH
2
)
m
Q″R
14
, NH(CO)T″(CH
2
)
m
Q″R
14
, T″—(CH
2
)
m
CO
2
R
14
, or T″(CH
2
)
m
CONR
14
R
15
; wherein T″ and Q″ are as defined above for T and Q;
R
8
is C
1
-C
6
alkyl or C
3
-C
6
cycloallyl; and
Y is a halo counter-ion.
This invention also provides pharmaceutical formulations and pharmaceutical compositions comprising a compound of Formula I together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds within the scope of the present invention are inhibitors of a wide variety of kinases like the cyclin-dependent kinases such as cdk2, cdc2, and cdk4 and especially of growth factor mediated tyrosine kinases including those of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), as well as non-receptor tyrosine kinases such as a transforming gene of the Rous sarcoma retrovirus (Src) family, c-Src and Lck.
As inhibitors of cyclin-dependent, as well as growth factor-mediated and non-receptor tyrosine kinases

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