Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-29
2003-10-21
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S201000, C546S187000, C546S197000, C546S113000, C546S194000, C514S323000, C514S316000, C514S321000, C514S300000, C514S253090, C514S318000, C544S130000, C544S364000
Reexamination Certificate
active
06635640
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to certain 4-heteroaryl-3-heteroarylidenyl-2-indolinones compounds and their physiologically acceptable salts which modulate the activity of protein kinases (“PKs”). The compounds of the present invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical composition containing these compounds and methods of preparing these compounds are also described.
2. State of the Art
The following is offered as background information only and is not admitted to be prior art to the present invention.
PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer) (see U.S. Pat. No. 5,792,783 which is incorporated herein by reference in its entirety).
In view of the apparent link between PK-related cellular activities and wide variety of human disorders, a great deal of effort is being expended in an attempt to identify ways to modulate PK activity. Some of this effort has involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (Published PCT Appl. WO 94/10202, Kendall and Thomas,
Proc. Nat'l Acad. Sci.,
90:10705-09 (1994), Kim, et al.,
Nature,
362:841-844 (1993)); RNA ligands (Jelinek, et al.,
Biochemistry,
33:10450-56); Takano, et al.,
Mol. Bio. Cell
4:358A (1993); Kinsella, et al.,
Exp. Cell Res.
199:56-62 (1992); Wright, et al.,
J. Cellular Phys.,
152:448-57) and tyrosine kinase inhibitors (Published PCT Appls. WO 94/03427; 1 WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al.,
Proc. Am. Assoc. Cancer Res.,
35:2268 (1994)).
In addition to the above, attempts have been made to identify small molecules which act as PK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (Published PCT Appl. WO 92/20642), vinyleneazaindole derivatives (Published PCT Appl. WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have been described as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), quinazoline derivatives (EP App. No.0 566 266 A1), selenaindoles and selenides (Published PCT Appl. WO 94/03427), tricyclic polyhydroxylic compounds (Published PCT Appl. WO 92/21660), benzylphosphonic acid compounds (Published PCT Appl. WO 91/15495) and indolinone compounds (U.S. Pat. No. 5,792,783) have all been described as PTK inhibitors useful in the treatment of cancer. However these compounds have limited utility because of toxicity or poor bioavailability. Accordingly, there is a need for compounds that overcome these limitations. The compounds of the present invention fulfil this need.
SUMMARY OF THE INVENTION
In one aspect, this invention is directed to a compound of formula (I):
wherein:
R
1
and R
2
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, —CX
3
, hydroxy, alkoxy, nitro, cyano, —C(O)R
26
, —C(O)OR
26
, R
26
C(O)O—, —C(O)NR
28
R
29
, R
26
C(O)NR
28
—, —NR
28
R
29
,
—S(O)
2
R
26
, —S(O)
2
OR
26
, —S(O)
2
NR
28
R
29
, R
26
S(O)
2
NR
28
, X
3
CS(O)
2
— and X
3
CS(O)
2
NR
28
— where X is F, Cl, Br, or I;
Het is selected from the group consisting of:
wherein:
A
1
, A
2
, A
3
, A
4
, and A
5
are selected from the group consisting of carbon and nitrogen with the proviso that at least one and no more than two of A
1
, A
2
, A
3
, A
4
, and A
5
are nitrogen;
R
3
, R
4
, R
5
, R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, halo, hydroxy, alkoxy, X
3
C—, nitro, cyano, —NR
28
R
29
, —C(O)OR and —C(O)NR
28
R
29
where X is as defined above; it being understood that when A
1
, A
2
, A
3
, A
4
or A
5
is nitrogen, R
3
, R
4
, R
5
, R
6
or R
7
, respectively, does not exist;
D is carbon or nitrogen;
R
8
, R
9
, R
11
and R
12
are independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, nitro, cyano and —NR
28
R
29
;
Z is selected from the group consisting of oxygen, sulfur, and —NR
10
;
R
10
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, —C(O)R
26
, —C(S)R
26
, —C(O)OR
26
, —C(O)NR
28
R
29
, —C(S)NR
28
R
29
, —C(NH)NR
28
R
29
and —S(O)
2
R
26
;
E
1
, E
2
, E
3
and E
4
are selected from the group consisting of carbon, nitrogen, oxygen and sulfur with the proviso that when D is carbon then at least one of E
1
, E
2
, E
3
and E
4
is other than carbon and that no more than one of E
1
, E
2
, E
3
or E
4
is oxygen or sulfur;
the dotted circle inside the five-member ring contain D, E
1
, E
2
, E
3
and E
4
ring means that the ring system is aromatic;
R
13
, R
14
, R
15
and R
16
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, mercapto, thioalkoxy, halo, nitro, cyano, —C(O)R
26
, —C(O)OR
26
, —C(O)NR
28
R
29
and —NR
28
R
29
, it being understood that, when one of E
1
, E
2
, E
3
or E
4
is sulfur or oxygen and any of the others is nitrogen, there is no R group bonded to any of those nitrogens, it also being understood that, when two or three of E
1
, E
2
, E
3
or E
4
are nitrogen, there is an R group bonded to one of the nitrogens and that R group is selected from the group consisting of hydrogen and alkyl, there being no R group bonded to any of the other nitrogens;
Q is selected from the group consisting of:
where:
G
1
, G
2
, G
3
, G
4
and G
5
are selected from the group consisting of carbon and nitrogen with the proviso that no more than two of G
1
, G
2
, G
3
, G
4
and G
5
are nitrogen;
R
17
, R
18
, R
19
, R
20
and R
21
are independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo,
—NR
28
R
29
, —(CH
2
)
n
C(O)R
26
, —(CH
2
)
n
C(O)OR
26
and —(CH
2
)
n
C(O)NR
28
R
29
,
—(CH
2
)
n
NR
28
R
29
, —(CH
2
)
n
S(O)
2
R
26
and —(CH
2
)
n
S(O)
2
NR
28
R
29
;
J
1
is selected from the group consisting of nitrogen, oxygen and sulfur such that when J
1
is nitrogen, R
22
is selected from the group consisting of hydrogen, alkyl and —C(O)R
26
; and
when J
1
is oxygen or sulfur, R
22
does not exist;
J
2
, J
3
and J
4
are selected from the group consisting of carbon and nitrogen;
R
23
, R
24
and R
25
are independently selected from the group consisting of hydrogen, alkyl, aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, unsubstituted lower alkoxy and halo, halo,
—(CH
2
)
n
C(O)R
26
, —(CH
2
)
n
C(O)OR
26
and —(CH
2
)
n
C(O)NR
28
R
29
, —(CH
2
)
n
NR
28
R
29
,
—(CH
2
)
n
S(O)
2
R
26
, —(CH
2
)
n
S(O)
2
NR
28
R
29
, —(CH
2
)
n
OR
26
, —O(CH
2
)
n
NR
28
R
29
and —C(O)NH (CH
2
)
n
NR
28
R
29
;
n is 0, 1, 2, or 3;
R
23
and R
24
or R
24
and R
25
may combine to form a group selected from the group consisting of —CH
2
CH
2
CH
2
CH
2
—, —CH═CR
33
—CR
34
═CH— and
—C(O)Y(CH
2
)
2
— and group wherein Y is selected from the group consisting of oxygen, sulfur and —N(R
27
)— and R
33
and R
34
are selected from the group consisting of hydrogen, —(CH
2
)
n
NR
28
R
29
and —O(CH
2
)
n
NR
28
R
29
where, when one of R
33
or R
34
is —(CH
2
)
n
NR
28
R
29
or
—O(CH
2
)
n
NR
28
R
29
, the other is hydrogen;
it being understood that, when J
2
, J
3
or J
4
is nitrogen, R
23
, R
24
or R
25,
respectively, does not exist;
R
26
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
R
27
is se
Cui Jingrong
Huang Ping
Tang Peng Cho
Wei Chung Chen
Burrous Beth A.
Foley & Lardner
Liu Hong
Shah Mukund J.
Sugen Inc.
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