Title: Azaindole tyrosine kinase inhibitors
Abstract: The present invention relates to novel 3-hetero-arylideneazaindolin-2-one compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
Patent Number: 6,849,641 Issued on 02/01/2005 to Tang, et al.
| Inventors:
|
Tang; Peng Cho (Moraga, CA);
Sun; Li (Foster City, CA);
McMahon; Gerald (Kenwood, CA)
|
| Assignee:
|
Sugen, Inc. (South San Francisco, CA)
|
| Appl. No.:
|
191199 |
| Filed:
|
November 12, 1998 |
| Current U.S. Class: |
514/300; 546/113 |
| Intern'l Class: |
C07D 471/02; A61K031/44; A61P035/00 |
| Field of Search: |
514/300
546/113
|
References Cited [Referenced By]
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| |
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|
Primary Examiner: Coleman; Brenda
Attorney, Agent or Firm: Foley & Lardner LLP, Burrous; Beth A.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No.
09/096,014 filed Jun. 10, 1998, which claims the benefit of U.S.
Provisional Application No. 60/049,324 filed Jun. 11, 1997, and U.S.
Provisional Application No. 60/059,381, filed Sep. 19, 1997, all of which
are incorporated by reference herein, in their entirety, including any
drawings, as if fully set forth herein.
Claims
What is claimed is:
1. An azaindole compound having the following chemical structure:
##STR4##
wherein,
A is selected from the group consisting of nitrogen, oxygen and sulfur and
it is understood that when A is oxygen or sulfur, R.sup.3 does not exist
and there is no bond;
B, D, E, F and G are independently selected from the group consisting of
carbon and nitrogen wherein only one of D, E, F and G is nitrogen and the
other of D, E, F, and G are carbon, and it is understood that when B, D,
E, F or G is nitrogen, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10,
respectively, do not exist and there is no bond;
Z is selected from the group consisting of oxygen, sulfur and NR.sup.11
wherein, R.sup.11 is selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, hydroxy, alkoxy, aryloxy, --C(.dbd.O)-R",
--C(.dbd.O)O--R", R"C(.dbd.O)O--, --S(.dbd.O).sub.2 R",
--C(.dbd.O)NR.sup.12 R.sup.13, R.sup.12 R.sup.13 NC(.dbd.NH)--, and
trihalomethanesulfonyl;
R.sup.1 is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
trihalomethanecarbonyl, trihalomethanesulfonyl, --C(.dbd.O)O--R",
R"C(.dbd.O)O--, --S(.dbd.O).sub.2 R", --C(.dbd.O)NR.sup.12 R.sup.13, and
R.sup.12 R.sup.13 NC(.dbd.NH)--;
R.sup.2 is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl and halogen;
when A is nitrogen, R.sup.3 is selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, hydroxy, alkoxy, aryloxy,
--C(.dbd.O)-R", --C(.dbd.O)O--R", trihalomethanesulfonyl, R"C(.dbd.O)O--,
--S(.dbd.O).sub.2 R", --C(.dbd.O)NR.sup.12 R.sup.13, and R.sup.12 R.sup.13
NC(.dbd.NH)--;
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are
independently selected from the group consisting of hydrogen, alkyl,
trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,
--R.sup.12 NC (.dbd.NH)NR.sup.13 R.sup.14, thioaryloxy, --S(.dbd.O)R",
--S(.dbd.O)NR.sup.12 R.sup.13, R.sup.12 S(.dbd.O).sub.2 NR.sup.13 --,
trihalomethanesulfonyl, --C(.dbd.O)-R", --C(.dbd.O)O--R", R"C(.dbd.O)O--,
--S(.dbd.O).sub.2 R", --C(.dbd.O) NR.sup.12 R.sup.13, cyano, nitro, halo,
amino --OC(.dbd.O)NR.sup.12 R.sup.13, R.sup.12 OC(.dbd.O)NR.sup.13 --,
--OC(.dbd.S)NR.sup.12 R.sup.13, R.sup.12 OC(.dbd.S)NR.sup.13 --, R.sup.12
R.sup.13 NC(.dbd.NH)--, --NR.sup.12 C(.dbd.O)NR.sup.13 R.sup.14, R.sup.12
C(.dbd.O)NR.sup.13 --, and --NR.sup.12 R.sup.13 ;
wherein R" is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring carbon);
and wherein R.sup.12, R.sup.13, and R.sup.14 are independently selected
from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,
--C(.dbd.O)--R", --S(.dbd.O).sub.2 R", and combined, a five or six
membered heteroalicyclic ring containing at least one nitrogen;
and the physiologically acceptable salts thereof.
2. The compound or salt of claim 1 wherein R.sup.1 is selected from the
group consisting of hydrogen and alkyl.
3. The compund or salt of claim 2 wherein Z is oxygen.
4. The compound or salt of claim 3 wherein R.sup.2 is hydrogen.
5. The compound or salt of claim 4 wherein R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 are independently selected from the group consisting of hydrogen,
alkyl, alkoxy, thioalkoxy, nitro, amino and R.sup.12 C(.dbd.O)NR.sup.13
--.
6. The compound or salt of claim 5 wherein D is nitrogen.
7. The compound or salt of claim 5 wherein E is nitrogen.
8. The compound or salt of claim 5 wherein F is nitrogen.
9. The compound or salt of claim 5 wherein G is nitrogen.
10. The compound or salt of claim 1 wherein A is nitrogen.
11. The compound or salt of claim 10 wherein R.sup.3 is selected from the
group consisting of hydrogen and alkyl.
12. The compound or salt of claim 11 wherein R.sup.4, R.sup.5 and R.sup.6
are independently selected from the groups consisting of hydrogen, alkyl,
and --C(.dbd.O)O--R".
13. The compound or salt of claim 11 wherein R.sup.4 and R.sup.6 are alkyl
and R.sup.5 is hydrogen.
14. The compound or salt of claim 1 wherein A is sulfur.
15. The compound or salt of claim 14 wherein R.sup.4, R.sup.5 and R.sup.6
are heteroaryl, aryloxy, thioalkoxy, halo or nitro.
16. A compound selected from the group consisting of
3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-pyrrolo[2,3-b]pyridin
-2-one,
3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-
2-one,
3-(3H-imidazol-4-ylmethylene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one,
3-[4-methyl-5-(2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-1H
-pyrrol-3-yl]-propionic acid, and
3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl
)-1H-pyrrol-3-yl]-propionic acid.
17. A compound selected from the group consisting of:
3-(thien-2-methylidenyl)-4-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-4-aza-2-indolinone,
3-(2-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(pyrrol-2-methylidenyl)-4-aza-2-indolinone,
3-(4-methylthien-2-methylidenyl)-4-aza-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-4-aza-2-indoli
none,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-(2-methylmercaptothien-5-methylidenyl)-4-aza-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-4-aza-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-4-aza-2-indolinone,
3-(3-bromothien-2-methylidenyl)-4-aza-2-indolinone,
3-(2-carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-4-aza-2-indolinon
e,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-4-aza-
2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-4-aza-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-4-aza-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-4-aza-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-4-aza-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-4-aza-2-indolin
one,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-4-aza-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-4-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-methylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(pyrrol-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(4-methylthien-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2,4diethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indol
inone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-4-aza-5-methyl
-2-indolinone,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-methylmercaptothien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(3-bromothien-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indoli
none,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-
indolinone,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-4-aza-
5-methyl-2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-4-aza-5-methyl-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3(2,4-dimethylthien-5-methylidenyl)-4-aza-S5-methyl-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-4- aza-5-methyl-2-indolinone,
3(3-methyl-2-n-propylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-4-aza-5-methyl-
2-indolinone,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-4-aza-5-methyl-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-4-aza-
5-methyl-2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-4-aza-
5-methyl-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-4-aza-5-methyl-2-indol
inone,
3-(thien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(pyrrol-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(4methylthien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-indo
linone,
3-[4-(2-methoxycarbonylethyl)-3-methylprrol-2-methylidenyl]-7-aza-5-nitro-2
-indolinone,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-methlmercaptothien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-indolin
one,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-i
ndolinone,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-7-aza-
5-nitro-2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidcnyl)-7-aza-5-nitro-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-7-aza-5-nitro-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(3-bromothien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-7-aza-5-nitro-2
-indolinone,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-7-aza-5-nitro-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-7-aza-
5-nitro-2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-7-aza-
5-nitro-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-7-aza-5-nitro-2-indoli
none,
3-(thien-2-methylidenyl)-6-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-6-aza-2-indolinone,
3-(2-methylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(pyrrol-2-methylidenyl)-6-aza-2-indolinone,
3-(4-methylthien-2-methylidenyl)-6-aza-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-6-aza-2-indoli
none,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-(2-methylmercaptothien-5-methylidenyl)-6-aza-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-6-aza-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-6-aza-2-indolinone,
3-(3-bromothien-2-methylidenyl)-6-aza-2-indolinone,
3-(2carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-(3-ethoxycarbonyl-1,2,4trimethylpyrrol-5-methylidenyl)-6-aza-2-indolinone
,
3-(2-ethoxycarbonyl4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-6-aza-2
-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-6-aza-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-(4-methytmercaptothien-2-methylidenyl)-6-aza-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-6-aza-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-6-aza-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-cyclopropyl4-methylthien-5-methylidenyl)-6aza-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-6-aza-2-indolin
one,
3-(4-methoxycarbonyl-3-methoxycarbonylinethyl-2-methylpyrrol-5-methylidenyl
)-6-aza-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-6-aza-
2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-6-aza-
2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-6-aza-2-indolinone,
3-(thien-2-methylidenyl)-5-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-5-aza-2-indolinone,
3-(2-methylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(pyrrol-2-methylidenyl)-5-aza-2-indolinone,
3-(4-methylthien-2-methylidenyl)-5-aza-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-5-aza-2-indoli
none,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3-2-methylmercaptothien-5-methylidenyl)-5-aza-2-indolinone,
3-2,3-dimethylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-5-aza-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3(2-nitrothien-5-methylidenyl)-5-aza-2-indolinone,
3-(3-bromothien-2-methylidenyl)-5-aza-2-indolinone,
3-(2-carboxy4-ethyl-3-methylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3-(3-ethoxycarbonyl-1,2,4-trirnethylpyrrol-5-methylidenyl)-5-aza-2-indolino
ne,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-aza-
2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-5-aza-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-5-aza-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-5-aza-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-5-aza-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-5-aza-2-indolione,
3-(2-ethyl-3-methylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-aza-2-indolin
one,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-5-aza-2-indolinone,
3-[4-(1-methylpyrrol)-2-methylidenyl]-5-aza-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-5-aza-
2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-5-aza-
2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-5-aza-2-indolinone,
3-(thien-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinon
e,
3-(2-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone
,
3-(pyrrol-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(4-methylthien-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone
,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(py
rid-4-yl)-2-indolinone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-7-aza-6-methyl
-5-(pyrid-4-yl)-2-indolinone,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)
-2-indolinone
3-(2-methylmercaptothien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-in
dolinone
3-(2,3-dimethylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indoli
none,
3-(2-chlorothien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone
,
3-(2,4-dimethylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indol
inone,
3-(2-nitrothien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(3-bromothien-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(2-carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(pyrid
-4-yl)-2-indolinone,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-
(pyrid-4-yl)-2-indolinone,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol
-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indol
inone,
3-(2-ethylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indoli
none,
3-(4-methylmercaptothien-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-in
dolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-7-aza-6-methyl-5-(pyrid-4-yl)-2-
indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-in
dolinone,
3-(2,4-dimethylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indoli
none,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl
)-2-indolinone
3-(2-ethyl-3-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-in
dolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-
2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2
-indolinone
3-(2-n-butylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinon
e,
3-(2-n-propylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolino
ne,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-7-aza-6-methyl-
5-(pyrid-4-yl)-2-indolinone,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-7-aza-6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-7-aza-
6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-7-aza-
6-methyl-5-(pyrid-4-yl)-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-7-aza-6-methyl-5-(pyri
d-4-yl)-2-indolinone,
3-(thien-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(pyrrol-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(4-methylthien-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indo
linone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-5-amino-7-aza-
2-indolinone,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-methylmercaptothien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(3-bromothien-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-carboxy-4-ethyl-3-methylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indolin
one,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-5-amino-7-aza-2-i
ndolinone,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-amin
o-7-aza-2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3- [2-trifluoro-1-(thien-2-yl)-ethylidenyl]-5-amino-7-aza-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-5-amnino-7-aza-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-amino-7-aza-2
-indolinone,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-5-aiino-7-aza-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-5-amin
o-7-aza-2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-5-amin
o-7-aza-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-5-amino-7-aza-2-indoli
none,
3-(thien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(1-methylpyrrol-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-methylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(pyrrol-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(4-methylthien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-methylidenyl)-5-acetamido-7-aza-2-
indolinone,
3-[4-(2-methoxycarbonylethyl)-3-methylpyrrol-2-methylidenyl]-5-acetamido-7-
aza-2-indolinone,
3-(2,4-dimethyl-3-ethylpyrrol-5-methylidenyl)-5-acetamido-7-aza-2-indolinon
e,
3-(2-methylmercaptothien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2,3-dimethylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-chlorothien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2,4-dimethylpyrrol-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-nitrothien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(3-bromothien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-carboxy4-ethyl-3-methylpyrrol-5-methylidenyl)-5-acetamdo-7-aza-2-indol
inone,
3-(3-ethoxycarbonyl-1,2,4-trimethylpyrrol-5-methylidenyl)-5-acetamido-7-aza
-2-indolinone,
3-(2-ethoxycarbonyl-4-methoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-acet
amido-7-aza-2-indolinone,
3-(3,4-dimethylpyrrol-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-ethylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2,4-diethylpyrrol-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(4-methylmercaptothien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-[2-trifluoro-1-(thien-2-yl)-ethylidenyl]-5-acetamido-7-aza-2-indolinone,
3-(2,4-diisopropylpyrrol-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2,4-dimethylthien-5-methylidenyl)-5-acetarnido-7-aza-2-indolinone,
3-(2-ethyl-3-methylthien-5-methylidenyl)-5-acetarnido-7-aza-2-indolinone,
3-(2-isopropyl-3-methylthien-5-methylidenyl)-5-acetainido-7-aza-2-indolinon
e,
3-(3-methyl-2-n-propylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-n-butylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-n-propylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(4-acetyl-2-ethoxycarbonyl-3-methylpyrrol-5-methylidenyl)-5-acetamido-7-a
za-2-indolinone,
3-(4-methoxycarbonyl-3-methoxycarbonylmethyl-2-methylpyrrol-5-methylidenyl)
-5-acetamido-7-aza-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-5-acet
amido-7-aza-2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-acetar
ido-7-aza-2-indolinone,
3-[2-(2-carboxyethyl)-3-methylpyrrol-2-methylidenyl]-5-acetamido-7-aza-2-in
dolinone
3-(2-phenylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-phenylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-phenylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-phenylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-phenylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yi)-2-indolinone
,
3-(2-phenylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-phenylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-6-aza-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-5-aza-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-7-aza-6-mnethyl-5-(pyrid-4-yl)-2-indolino
ne,
3-(3-phenoxythien-2-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-4aza-2-indolinone,
3-(3-phenoxythien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-[2-[1-methyl-5-(trifluoromethyl)-pyrrol-3-yl]thien-5-methylidenyl]-4-aza-
2-indolinone,
3-[2-[1-methyl-3-(trifluoromethyl)-pyrrol-5-yl]thien-5-methylidenyl]-4-aza-
2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-cyclopropyl-4-methylthien-5-methylidenyl)-5-acetarnido-7-aza-2-indolin
one,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)
-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-cyclohexyl-3-methylthien-5-methylidenyl)-5-acetamnido7-aza-2-indolinon
e,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-4-aza-2-indolinone,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-7-aza-6-methyl-5-(pyr
id-4-yl)-2-indolione,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-5-amino-7-aza-2-indol
inone,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-5-acetamido-7-aza-2-i
ndolinone,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-7-aza-5-nitro-2-indol
inone,
3-[4-(4-chlorobenzoyl)-1-methylpyrrol-2-methylidenyl]-6-aza-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-5-amino-7-aza-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidcnyl)-5-acetamido-7-aza-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-6-aza-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-i
ndolinon
3-(2-benzyl-4-methylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(2-benzyl-4-methylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-4-aza-5-methyl-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-ind
olinone,
3-(4-phenylethynylthien-2-methylidenyl)-4-aza-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-5-amino-7-aza-2-indolione,
3-(4-phenylethynylthien-2-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-6-aza-2-indolinone,
3-(4-phenylethynylthien-2-methylidenyl)-5-aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-6aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-5-aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-7-aza-6-methyl-5-(pyrid-4-yl)-2-ind
olinone,
3-(2-phenylethynylthien-5-methylidenyl)-5-amnino-7-aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-5-acetamido-7-aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-7-aza-5-nitro-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-4-aza-2-indolinone,
3-(2-phenylethynylthien-5-methylidenyl)-4-aza-5-methyl-2-indolinone, and
3-(2-phenylthien-5-methylidenyl)-4-aza-2-indolinone.
18. A pharmacological composition of said compound or salt of claim 1.
19. A method for synthesizing a compound of claim 1 comprising the step of
reacting a first reactant with a second reactant in a solvent and in the
presence of a base at elevated temperatures, wherein said first reactant
has the structure set forth in formula
##STR5##
wherein
D, E, F and G are independently selected from the group consisting of
carbon and nitrogen wherein only one of D, E, F and G is nitrogen and the
other of D, E, F, and G are carbon, and it is understood that when D, E, F
or G is nitrogen, R.sup.7, R.sup.8, R.sup.9 and R.sup.10, respectively, do
not exist and there is no bond;
R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently selected from the
group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
thiohydroxy, thioalkoxy, thioaryloxy, --S(.dbd.O)R", --S(.dbd.O).sub.2
NR.sup.12 R.sup.13, R.sup.12 S(.dbd.O).sub.2 NR.sup.13 --,
trihalomethanesulfonyl, --C(.dbd.O)--R", R.sup.12 C(.dbd.O)NR.sup.13 --,
--C(.dbd.O)O--R", R"C(.dbd.O)O--, --S(.dbd.O).sub.2 R",
--C(.dbd.O)NR.sup.12 R.sup.13, cyano, nitro, halo, --OC(.dbd.O)NR.sup.12
R.sup.13, R.sup.12 OC(.dbd.O)NR.sup.13 --, --OC(.dbd.S)NR.sup.12 R.sup.13,
R.sup.12 OC(.dbd.S)NR.sup.13 --, R.sup.12 R.sup.13 NC(.dbd.NH)--,
--R.sup.12 NC(.dbd.NH)NR.sup.13 R.sup.14, --NR.sup.12 C(.dbd.O)NR.sup.13
R.sup.14, amino, and --NR.sup.12 R.sup.13 ;
Z is selected from the group consisting of oxygen, sulfur and NR.sup.11
wherein, R.sup.11 is selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, hydroxy, alkoxy, aryloxy, --C(.dbd.O)--R",
trihalomethanesulfonyl --C(.dbd.O)O--R", R"C(.dbd.O)O--, --S(.dbd.O).sub.2
R", --C(.dbd.O)NR.sup.12 R.sup.13, and R.sup.12 R.sup.13 NC(.dbd.NH)--;
R.sup.1 is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
trihalomethanecarbonyl, trihalomethanesulfonyl --C(.dbd.O)O--R",
R"C(.dbd.O)O--, --S(.dbd.O).sub.2 R", --C(.dbd.O)NR.sup.12 R.sup.13, and
R.sup.12 R.sup.13 NC(.dbd.NH)--; and wherein said second reactant is an
acyl compound having the structure set forth in formula 3
##STR6##
wherein
A is selected from the group consisting of nitrogen, oxygen and sulftir and
it is understood that when A is oxygen or sulfur, R.sup.3 does not exist
and there is no bond;
B is selected from the group consisting of carbon and nitrogen and it is
understood that when B is nitrogen, R.sup.6 does not exist and there is no
bond;
R.sup.2 is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl and halogen;
when A is nitrogen, R.sup.3 is selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, hydroxy, alkoxy, aryloxy,
--C(.dbd.O)--R", --C(.dbd.O)O--R", R"C(.dbd.O)O--, --S(.dbd.O).sub.2 R",
--C(.dbd.O)NR.sup.12 R.sup.13, R.sup.12 R.sup.13 NC(.dbd.NH)--, and
trihalomethanesulfonyl;
R.sup.4, R.sup.5, and R.sup.6 are independently selected from the group
consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl,
aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy,
thioalkoxy, thioaryloxy, --S(.dbd.O)R", --S(.dbd.O).sub.2 NR.sup.12
R.sup.13, R.sup.12 S(.dbd.O).sub.2 NR.sup.13 --, trihalomethanesulfonyl,
--C(.dbd.O)--R", --S(.dbd.O).sub.2 --R", R.sup.12 C(.dbd.O)NR.sup.13 --,
cyano, nitro, halo, --OC(.dbd.O)NR.sup.12 R.sup.13, R.sup.12
OC(.dbd.O)NR.sup.13 --, --OC(.dbd.S)NR.sup.12 R.sup.13,
R12OC(.dbd.S)NR.sup.13 --, --C(.dbd.O)O--R", R"C(.dbd.O)O--,
--C(.dbd.O)NR.sup.12 R.sup.13, R.sup.12 R.sup.13 NC(.dbd.NH)--, --R.sup.12
NC(.dbd.NH)NR.sup.13 R.sup.14, --NR.sup.12 C(.dbd.O)NR.sup.13 R.sup.14,
amino and --NR.sup.12 R.sup.13 ;
wherein R" is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring carbon);
and wherein R.sup.12, R.sup.13, and R.sup.14 are independently selected
from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,
--C(.dbd.O)--R", --S(.dbd.O).sub.2 R, and, combined, a five- or six-member
heteroalicyclic ring containing at least one nitrogen.
20. The method of claim 19, wherein said base is selected from the group
consisting of a nitrogen base and an inorganic base.
21. The method of claim 19, wherein said solvent is selected from the group
consisting of water, an alcohol, and dimethyformamide.
Description
INTRODUCTION
The present invention relates generally to organic chemistry, biochemistry,
pharmacology and medicine. More particularly, it relates to novel
heterocyclic compounds, and their physiologically acceptable salts and
prodrugs, which modulate the activity of protein tyrosine kinases ("PTKs")
and, therefore, are expected to exhibit a salutary effect against
disorders related to abnormal PTK activity.
BACKGROUND OF THE INVENTION
The following is offered as background information only and is not admitted
to be or describe prior art to the present invention.
Growth factor receptors are cell-surface proteins. When bound by a growth
factor ligand, growth factor receptors are converted to an active form
which interacts with proteins on the inner surface of a cell membrane.
This leads to phosphorylation on tyrosine residues of the receptor and
other proteins and to the formation inside the cell of complexes with a
variety of cytoplasmic signaling molecules that, in turn, effect numerous
cellular responses such as cell division (proliferation), cell
differentiation, cell growth, expression of metabolic effects to the
extracellular microenvironment, etc. For a more complete discussion, see
Schlessinger and Ullrich, Neuron, 9:303-391 (1992) which is incorporated
by reference, including any drawings, as if fully set forth herein.
Growth factor receptors with PTK activity, known as receptor tyrosine
kinases ("RTKs"), comprise a large family of transmembrane receptors with
diverse biological activity. At present, at least nineteen (19) distinct
subfamilies of RTKs have been identified. An example of these is the
subfamily designated the "HER" RTKs, which include EGFR (epithelial growth
factor receptor), HER2, HER3 and HER4. These RTKs consist of an
extracellular glycosylated ligand binding domain, a transmembrane domain
and an intracellular cytoplasmic catalytic domain that ca
