Kinase inhibitors

Details Kinase inhibitors Kinase inhibitors

2002-12-12

2004-12-14

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S193000, C546S194000, C546S199000, C546S275700, C514S316000, C514S319000, C514S321000

Reexamination Certificate

active

06831175

ABSTRACT:

TECHNICAL FIELD
The present invention relates to compounds which are useful for inhibiting protein kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Protein kinases have been clearly shown to be important in the progression of many disease states that are induced by the inappropriate proliferation of cells. These kinases are often found to be up-regulated in many hyperproliferative states such as cancer. These kinases may be important in cell signaling, where their inappropriate activation induces cells to proliferate (e.g. EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF-1R, RET, TIE2). Alternatively, they may be involved in signal transduction within cells (e.g. c-Src, PKC, Akt, PKA, c-Ab1, PDK-1). Often these signal transduction genes are recognized proto-oncogenes. Many of these kinases control cell cycle progression near the G1-S transition (e.g. Cdk2, Cdk4), at the G2-M transition (e.g. Wee1, Myt1, Chk1, Cdc2) or at the spindle checkpoint (Plk, Aurora1 or 2, Bub1 or 3). Furthermore, kinases are intimately linked to the DNA damage response (e.g. ATM, ATR, Chk1, Chk2). Disregulation of these cellular functions; cell signaling, signal transduction, cell cycle control, and DNA repair, are all hallmarks of hyperproliferative diseases, particularly cancer. It is therefore likely that pharmacological modulation of one or more kinases would be useful in slowing or stopping disease progression in these diseases.
SUMMARY OF THE INVENTION
In its principle embodiment the present invention provides a compound of formula (I)
or a therapeutically acceptable salt thereof, wherein
X is selected from the group consisting of C(R
8
) and N; wherein R
8
is selected from the group consisting of hydrogen, alkyl, amino, carboxy, cyano, halo, hydroxy, and amido;
X′ is selected from the group consisting of C and N;
Y is selected from the group consisting of C and N;
Y′ is selected from the group consisting of C(R
9
) and N; wherein R
9
is selected from the group consisting of hydrogen and -L
2
-L
3
(R
3
)(R
6
);
Z is selected from the group consisting of C and N;
provided that 0, 1, or 2 of X, X′, Y, Y′, and Z are N;
L
1
is selected from the group consisting of a bond, —O—, —NR
5
—, alkenyl, alkynyl, —C(O)—, —S—, —S(O)—, —S(O)
2
—, —S(O)
2
N(R
5
)—, —N(R
5
)S(O)
2
—, —C(R
12
)
2
—, —C(R
12
)
2
N(R
5
)—, —N(R
5
)C(O)—, and —C(O)N(R
5
)—; wherein each group is drawn with its left end attached to R
1
and its right end attached to the aromatic ring;
L
2
is selected from the group consisting of a bond, —O—, —C(R
12
)
2
—, —S—, —N(R
5
)—, —N(R
5
)C(O)—, and —C(O)N(R
5
)—;
L
3
is selected from the group consisting of a bond, alkylidene and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, amino, cyano, and hydroxy;
R
1
is selected from the group consisting of aryl, heteroaryl, and heterocycle;
R
2
and R
4
are independently absent or selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, arylalkynyl, cyano, cyanoalkenyl, halo, heteroaryl, heterocycle, hydroxyalkyl, and nitro; or
R
2
and L
1
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; or
R
4
and L
2
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle;
provided that when L
3
is alkylidene, R
4
and L
2
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle;
R
3
is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
R
6
is selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylamino, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
provided that when L
1
and L
2
are bonds, at least one of R
3
and R
6
is other than hydrogen;
R
5
is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl;
R
7
is absent or selected from the group consisting of hydrogen, alkyl, cyanoalkenyl, and -L
2
-L
3
(R
3
)(R
6
); or
R
7
and L
1
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, and heterocycle; and
each R
12
is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, amino, aryl, cyano, halo, heteroaryl, heterocycle, and nitro.
In another embodiment the present invention provides a compound of formula (II)
or a therapeutically acceptable salt thereof, wherein
L
1
is selected from the group consisting of a bond, —O—, —N(R
5
)—, alkenyl, alkynyl, —N(R
5
)C(O)—, and —C(O)N(R
5
)—;
L
2
is selected from the group consisting of a bond, —O—, —N(R
5
)—, —N(R
5
)C(O)—, and —C(O)N(R
5
)—;
L
3
is selected from the group consisting of a bond, alkylidene, and alkylene, wherein the alkylidene and the alkylene are optionally substituted with one or two substituents independently selected from the group consisting of amino, cyano, and hydroxy;
R
1
is selected from the group consisting of aryl, heteroaryl, and heterocycle;
R
2
and R
4
are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, arylalkynyl, amino, cyano, cyanoalkenyl, halo, hydroxyalkyl, and heteroaryl; wherein the heteroaryl is selected from the group consisting of furyl, pyrazinyl, thiazolyl, and thienyl; or
R
2
and L
1
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, pyrazolyl, and phenyl; or
R
4
and L
2
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo; provided that when L
3
is alkylidene, R
4
and L
2
, together with the carbon atoms to which they are attached, form a ring selected from the group consisting of dihydropyrrolyl, phenyl, pyridinyl, and pyrrolyl; wherein the ring can be optionally substituted with oxo;
R
3
is absent or selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, and heterocycle;
R
6
are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, arylalkylthio, aryloxy, arylthio, cycloalkyl, heteroaryl, and heteroarylalkoxy, heteroaryloxy, and heterocycle;
provided that when L
1
and L
2
are bonds, at least one of R
3
and R
6
is other than hydrogen;
R
5
is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, and heteroarylsulfonyl; and
X is selected from the group consisting of C(R
8
) and N; wherein R
8
is selected from the group consisting of hydrogen, amino, carboxy, cyano, and halo.
In another embodiment the present invention provides a compound of formula (III)
or a therapeutically acceptable salt thereof, wherein
L
1
is selected from the group consisting of a bond, —O—, —N(R
5
)—, alkenyl, alkynyl, and —N(R
5
)C(O)—;
L
2
is selected from the group consisting of a bond, —O—, —N(R
5
)—, —N(R
5
)C(O)—, and —C(O)N(R
5
)—;
L
3
is alkylene, wherein the alkylene is substituted with one or two substituents independently selected from the group consisting of amino and hydroxy;
R
1
is selected from the group consisting of aryl, heteroaryl, and heterocycle;
R
2
and R
4
are independently selected from the group consisting of hydrogen and halo;
R
3
and R
6
are independently selected from the group consisting of hydrogen, aryl, arylalkoxy, and heteroaryl; provided that wh

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