Indolinone derivatives as protein kinase/phosphatase inhibitors Number:7,071,332 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to certain 2-indolinone compounds which modulate the activity of protein kinases ("PKs") and phosphatases. The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.<H phosphatase, derivatives, Indolinone, deri, 7071332.html, Patent, pto, 7071332

Title: Indolinone derivatives as protein kinase/phosphatase inhibitors

Abstract: The present invention relates to certain 2-indolinone compounds which modulate the activity of protein kinases ("PKs") and phosphatases. The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

Patent Number: 7,071,332 Issued on 07/04/2006 to Tang, et al.

Inventors: Tang; Peng Cho (Moraga, CA); Harris; G. Davis (San Francisco, CA); Li; Xiaoyuan (Los Altos, CA)
Assignee: Sugen, Inc. (San Diego, CA)

Appl. No.: 725277

Filed: December 2, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
09871700	Jun., 2001	6706709
60209162	Jun., 2000

Current U.S. Class: 544/144 ; 544/131; 546/277.7; 548/455

Current International Class: C07D 413/14 (20060101); C07D 209/34 (20060101); C07D 401/14 (20060101)

Field of Search: 544/144,131 548/455 546/277.7

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Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Paviglianiti; Anthony J.
Attorney, Agent or Firm: Zielinski; Bryan C. Liptak; Vincent P.

Parent Case Text

CROSS-REFERENCE

This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Applications Ser. No. 60/209,162, filed Jun. 2, 2000, the disclosure of which is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound having a structure set forth in formula (I): ##STR00032## wherein: (a) R.sub.4 R.sub.6, and R.sub.8 R.sub.10 are hydrogen; (b) R.sub.1, R.sub.2, and R.sub.3 are each independently selected from the group consisting of hydrogen, halogen, carboxylic acid, optionally substituted ester, optionally substituted amide, optionally substituted alkyl, optionally substituted alkoxy, trihalomethyl, optionally substituted aryl, and optionally substituted heteroaryl; and (c) R.sub.7 is selected from the group consisting of lower alkyl substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino and lower alkoxy substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein: (a) R.sub.1 is selected from the group consisting of hydrogen and optionally substituted alkyl; (b) R.sub.2 and R.sub.3 are each independently selected from the group consisting of hydrogen, halogen, carboxylic acid, optionally substituted heteroaryl, and optionally substituted phenyl; and (c) R.sub.7 is selected from the group consisting of lower alkyl substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino and lower alkoxy substituted with a morpholinyl ring, a pyrrolidinyl ring or dialkylamino.

3. The compound of claim 2 wherein: (a) R.sub.1 is selected from the group consisting of hydrogen; (b) R.sub.2 is hydrogen, halogen, phenyl, or carboxylic acid; and (c) R.sub.3 is hydrogen, halogen, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halogen; and (d) R.sub.7 is lower alkyl substituted with a morpholinyl ring, a pyrrolidinyl ring a or dialkylamino.

4. The compound of claim 3 wherein R.sub.7 is selected from the group consisting of 3-diethylaminopropyl and 3-pyrrolidin-1-yl-propyl.

5. The compound of claim 3 wherein: (a) R.sub.1 is selected from the group consisting of hydrogen; (b) R.sub.2 is hydrogen, halogen, phenyl, or carboxylic acid; (c) R.sub.3 is hydrogen, halogen, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halogen; and (d) R.sub.7 is lower alkoxy substituted with a morpholinyl ring, a pyrrolidinyl ring a or dialkylamino.

6. The compound of claim 5, wherein R.sub.7 is selected from the group consisting of 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-pyrrolidin-1-yl-ethoxy, and 2-morpholin-4-yl-ethoxy.

7. A compound selected from the group consisting of: 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-- one, 5-bromo-3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihy- dro-indol-2-one, 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydr- o-indol-2-one, 5-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihy- dro-indol-2-one, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-- 2-one 5-bromo-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-d- ihydro-indol-2-one, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihyd- ro-indol-2-one, 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2- -one, 5-bromo-3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-di- hydro-indol-2-one, 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydr- o-indol-2-one, 3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol- -2-one, 5-bromo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,- 3-dihydro-indol-2-one, 6-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihy- dro-indol-2-one, 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-- one, 5-bromo-3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihy- dro-indol-2-one, 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-- one, 5-bromo-3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihy- dro-indol-2-one, 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-6-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihydro- -indol-2-one, 3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-indol- -2-one, 2-oxo-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-2,3-- dihydro-1H-indol-5-carboxylic acid, 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-dihydro- -1H-indole-5-carboxylic acid, 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-dihydro- -1H-indole-6-carboxylic acid, 4-(2-hydroxy-ethyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylen- e]-1,3-dihydro-indol-2-one, 6-pyridin-3-yl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,- 3-dihydro-indol-2-one, 6-(4-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethyle- ne]-1,3-dihydro-indol-2-one, 6-(3-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethyle- ne]-1,3-dihydro-indol-2-one, 6-(2-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethyle- ne]-1,3-dihydro-indol-2-one, 6-(4-fluoro-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylen- e]-1,3-dihydro-indol-2-one, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-dihydro-- 1H-indole-5-carboxylic acid, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-dihydro-- 1H-indole-6-carboxylic acid, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-dihyd- ro-indol-2-one, 4-(2-hydroxy-ethyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene- ]-1,3-dihydro-indol-2-one, 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-pyridin-3-yl-1,3- -dihydro-indol-2-one, 6-(4-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylen- e]-1,3-dihydro-indol-2-one, 6-(3-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylen- e]-1,3-dihydro-indol-2-one, 6-(2-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylen- e]-1,3-dihydro-indol-2-one, and 6-(4-fluoro-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene- ]-1,3-dihydro-indol-2-one; or a pharmaceutically acceptable salt thereof.

Description

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to certain 2-indolinone compounds which modulate the activity of protein kinases ("PKs") and phosphatases. The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

2. State of the Art

Cellular signal transduction is a fundamental mechanism whereby extracellular stimuli are relayed to the interior of cells and subsequently regulate diverse cellular processes. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. Phosphorylation of polypeptides regulates the activity of mature proteins by altering their structure and function. Phosphate most often resides on the hydroxyl moiety (--OH) of serine, threonine, or tyrosine amino acids in proteins.

Enzymes that mediate phosphorylation of cellular effectors generally fall into two classes. The first class consists of protein kinases which transfer a phosphate moiety from adenosine triphosphate to protein substrates. The second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl protein substrates. The converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.

Protein kinases and protein phosphatases are generally divided into two groups--receptor and non-receptor type proteins. Most receptor-type protein tyrosine phosphatases contain two conserved catalytic domains, each of which encompasses a segment of 240 amino acid residues. Saito et al., 1991, Cell Growth and Diff. 2:59 65. Receptor protein tyrosine phosphatases can be subclassified further based upon the amino acid sequence diversity of their extracellular domains. Saito et al., supra; Krueger et al., 1992, Proc. Natl. Acad. Sci. USA 89:7417 7421.

Protein kinases and protein phosphatases are also typically divided into three classes based upon the amino acids they act upon. Some catalyze the addition or hydrolysis of phosphate on serine or threonine only, some catalyze the addition or hydrolysis of phosphate on tyrosine only, and some catalyze the addition or hydrolysis of phosphate on serine, threonine, and tyrosine.

Tyrosine kinases can regulate the catalytic activity of other protein kinases involved in cell proliferation. Protein kinases with inappropriate activity are also involved in some types of cancer. Abnormally elevated levels of cell proliferation are associated with receptor and non-receptor protein kinases with unregulated activity.

In addition to their role in cellular proliferation, protein kinases are thought to be involved in cellular differentiation processes. Cell differentiation occurs in some cells upon nerve growth factor (NGF) or epidermal growth factor (EGF) stimulation. Cellular differentiation is characterized by rapid membrane ruffling, cell flattening, and increases in cell adhesion. Chao, 1992, Cell 68:995 997.

In an effort to discover novel treatments for cancer and other diseases, biomedical researchers and chemists have designed, synthesized, and tested molecules that inhibit the function of protein kinases. Some small organic molecules form a class of compounds that modulate the function of protein kinases. Examples of molecules that have been reported to inhibit the function of protein kinases are bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808), 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992), styryl compounds (by Levitzki, et al., U.S. Pat. No. 5,217,999, and entitled "Styryl Compounds which Inhibit EGF Receptor Protein Tyrosine Kinase), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495).

The compounds that can traverse cell membranes and are resistant to acid hydrolysis are potentially advantageous therapeutics as they can become highly bioavailable after being administered orally to patients. However, many of these protein kinase inhibitors only weakly inhibit the function of protein kinases. In addition, many inhibit a variety of protein kinases and will therefore cause multiple side-effects as therapeutics for diseases.

Despite the significant progress that has been made in developing compounds for the treatment of cancer, there remains a need in the art to identify the particular structures and substitution patterns that form the compounds capable of modulating the function of particular protein kinases.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides an indolinone compound having a structure set forth in formula (I):

##STR00001## wherein: (a) R.sub.4 R.sub.6, and R.sub.8 R.sub.10 are hydrogen; (b) R.sub.1, R.sub.2, and R.sub.3 are each independently selected from the group consisting of hydrogen, halogen, carboxylic acid, optionally substituted ester, optionally substituted amide, optionally substituted alkyl, optionally substituted alkoxy, trihalomethyl, optionally substituted aryl, and optionally substituted heteroaryl; and (c) R.sub.7 is selected from the group consisting of substituted alkyl, and substituted alkoxy; or a pharmaceutically acceptable salt thereof.

Preferably, (a) R.sub.1 is selected from the group consisting of hydrogen and optionally substituted alkyl, more preferably hydrogen; (b) R.sub.2 and R.sub.3 are each independently selected from the group consisting of hydrogen, halo, carboxylic acid, optionally substituted heteroaryl, and optionally substituted phenyl. Preferably R.sub.2 is hydrogen, halo, phenyl, or carboxylic acid, more preferably hydrogen, phenyl, --COOH, chloro, fluoro or bromo. Preferably, R.sub.3 is hydrogen, halo, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halo, more preferably phenyl, --COOH, pyridin-3-yl, 3-, or 4-methoxyphenyl or 4-fluorophenyl; and (c) R.sub.7 is selected from the group consisting of lower alkyl substituted with a heteroaliphatic ring or dialkylamino; or lower alkoxy substituted with a heteroaliphatic ring or dialkylamino, preferably R.sub.7 is lower alkyl substituted with a heteroaliphatic ring or dialkylamino; more preferably R.sup.7 is 3-diethylaminopropyl or 3-pyrrolidin-1-yl-propyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-pyrrolidin-1-yl-ethoxy, or 2-morpholin-4-yl-ethoxy.

In a second aspect, the invention provides for an indolinone compound having a structure set forth in formula (II):

##STR00002## wherein: (a) R.sub.11 R.sub.14 are hydrogen; (b) R.sub.15 and R.sub.16 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R.sub.15 and R.sub.16 taken together with the nitrogen atom to which they are attached form a ring structure selected from the group consisting of a five-membered or six-membered heteroaromatic ring, a five-membered or six-membered heteroaliphatic ring, a nine-membered fused bicyclic heteroaromatic ring, and a ten-membered fused bicyclic heteroaromatic ring; and (c) A is selected from the group consisting of formula (III), (IV), and (V):

##STR00003## wherein: (i) R.sub.19 R.sub.25 and R.sub.27 R.sub.31 are hydrogen; (ii) R.sub.17 and R.sub.18 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted alkoxy provided that both R.sub.17 and R.sub.18 are not hydrogen; and (iii) R.sub.26 is selected from the group consisting of optionally substituted alkyl; or a pharmaceutically acceptable salt thereof.

In one preferred embodiment: (i) R.sub.15 is hydrogen or alkyl, more preferably hydrogen or methyl; (ii) R.sub.16 is hydrogen, alkyl, phenyl optionally substituted with one or two substituents selected from halo or unsubstituted lower alkyl or 5 or 6 membered heteroaryl; more preferably hydrogen, methyl, isopropyl, phenyl, pyridin-3-yl, 3-chlorophenyl, or 4-chloro-2-fluorophenyl; or (iii) R.sub.15 and R.sub.16 together with the nitrogen to which they are attached form 2,3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoisoquinolin-2-yl ring wherein said rings are optionally substituted with halo or alkyl, preferably R.sub.15 and R.sub.16 together with the nitrogen atom to which they are attached form 2,3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, 5-bromo-2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoisoquinolin-2-yl; (iv) A is group of formula III where: R.sub.17 is hydrogen, methyl, or methoxy, preferably hydrogen; and R.sub.18 is selected from the group consisting of lower alkoxy substitued with heteroalicyclic, preferably 2-pyrrolidin-1-yl-ethoxy and 2-morpholin-4-yl-ethoxy.

Another preferred group of compound is that wherein: (i) R.sub.15 is hydrogen or alkyl, preferably hydrogen or methyl; (ii) R.sub.16 is hydrogen, alkyl, phenyl optionally substituted with one or two substituents selected from halo or unsubstituted lower alkyl, or 5 or 6 membered heteroaryl; preferably hydrogen, methyl, isopropyl, phenyl, pyridin-3-yl, 3-chlorophenyl, or 4-chloro-2-fluorophenyl; or R.sub.15 and R.sub.16 together with the nitrogen to which they are attached form 2,3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoisoquinolin-2-yl ring wherein said rings are optionally substituted with halo or alkyl, preferably 3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, 5-bromo-2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoisoquinolin-2-yl; and (iii) A is group of formula IV where R.sub.26 is selected from the group consisting of optionally substituted alkyl, preferably hydrogen or methyl.

Another preferred group of compounds is that wherein: (i) R.sub.15 is hydrogen or alkyl, preferably hydrogen or methyl; (iii) R.sub.16 is hydrogen, alkyl, phenyl optionally substituted with one or two substituents selected from halo or unsubstituted lower alkyl or 5 or 6 membered heteroaryl; more preferably hydrogen, methyl, isopropyl, phenyl, pyridin-3-yl, 3-chlorophenyl, or 4-chloro-2-fluorophenyl; or R.sub.15 and R.sub.16 together with the nitrogen to which they are attached form 2,3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoquinolin-2-yl ring wherein said rings are optionally substituted with halo or alkyl, preferably R.sub.15 and R.sub.16 together with the nitrogen atom to which they are attached form 2,3-dihydroindol-1-yl, 2,3-dihydro-2H-quinolin-1-yl, 5-bromo-2,3-dihydro-2H-quinolin-1-yl, or 2,3-dihydro-2H-isoisoquinolin-2-yl; (ii) A is group of formula V.

As used herein, the term "optionally substituted alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, non-branched, or cyclic. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group is optionally substituted with one, two, or three substituents individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, or halo. The term "substituted alkyl" means that the alkyl group as defined above carries at least one of the substituents listed above.

The term "optionally substituted aryl" refer to an aromatic carbocyclic group of 6 to 12 ring atoms which has at least one ring having a conjugated .pi. electron system (e.g., phenyl, napthyl, tetrahydronaphthyl, and the like) which is optionally substituted with one, two, or three substituents independently selected from optionally susbstituted alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxyl amino, amido, nitro, and ester.

"Optionally substituted phenyl" refers to a phenyl group that is optionally substituted with one, two, or three substituents independently selected from optionally susbstituted alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxyl amino, amido, nitro, and ester.

The term "cycloalkyl" refers to a saturated, cyclic group of 3 to 6 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) which is optionally substituted with one, two, or three substituents independently selected from optionally susbstituted alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxyl amino, amido, nitro, and ester.

The term "optionally susbtituted heteroaryl or heteroaromatic ring" refers to a ring system of 5 to 10 ring atoms in which one, two, three, or four of the atoms forming the backbone is a heteroatom selected from nitrogen, oxygen, or sulfur, the remaining being carbon e.g., pyridine, furan, pyrrole, indole, pyrazine, pyrimidine, tetrazole, imidazole, and the like. The heteroaromatic/heteroaryl ring may be single or fused bicyclic ring and wherein one of the rings may be partially or fully saturated e.g., 2,3-dihydroindole, 2,3-dihydroquinoline, 2,3-dihydroisoquinoline, and the like. The heteroaryl/heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from optionally susbstituted alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxyl amino, amido, nitro, and ester.

The term "optionally susbtituted heteroaliphatic or heteroalicyclic" refers to a saturated ring system of 5 to 9 ring atoms in which in which one, two, three, or four of the atoms forming the backbone is a heteroatom selected from nitrogen, oxygen, or sulfur, the remaining being carbon e.g., piperazine, piperidine, pyrrolidine, morpholine, tetrahydrofuran and the like. The heteroaliphatic ring is optionally substituted with one, two, or three substituents independently selected from optionally susbstituted alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxyl amino, amido, nitro, and ester.

The term "halogen" refers to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.

The term "trihalomethyl" refers to the --C(X).sub.3 group, where X is a halogen group as defined above e.g., trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

The term "optionally substituted alkoxy" is a group of formula --O-alkyl wherein alkyl is as defined above. The term "substituted alkoxy" means that the alkyl group as defined above carries at least one of the substituents listed above. The term "alkoxy" means that the alkyl chain in the alkoxy group as defined above is not substituted.

When X is hydrogen, then the alkoxy group becomes a "hydroxy" group, i.e., --OH.

A "nitro" is a substituent of formula --NO.sub.2.

The term "alkylthio" refers to --SR group where R is unsubstituted alkyl as defined above e.g., methylthio, ethylthio, and the like.

The term "aryloxy" refers to --OR group where R is aryl group as defined above, e.g., phenoxy, and the like.

The term "arylthio" refers to --SR group where R is aryl group as defined above e.g., phenylthio, and the like.

The term "dialkylamino" means --NRR where each R is an unsubstituted alkyl group of 1 6 carbon atoms e.g., dimethylamino, diethylamino, and the like.

The term "optionally substituted ester" refers to --COOR where R is an alkyl group as defined above.

The term "optionally substituted amide" refers to --CONR.sup.aR.sup.b where R.sup.a and R.sup.b are hydrogen or unsubstituted lower alkyl.

"Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, citric acid, maleic acid, succinic acid, tartaric acid, and the like.

Some of the preferred compounds of the invention that have the generic structure of formula I are listed in Table 1.

TABLE-US-00001 TABLE 1 Compound Number Compound Name IN-001 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro-in- dol-2-one IN-002 5-bromo-3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-1,3-di- hydro-indol-2- one IN-003 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-6-phenyl-1,3-d- ihydro-indol-2- one IN-004 3-[5-(3-diethylamino-propyl)-1H-indol-2-ylmethylene]-5-phenyl-1,3-d- ihydro-indol-2- one IN-005 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-- dihydro-indol-2- one IN-006 5-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,- 3-dihydro-indol-2- one IN-007 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-- indol-2-one IN-008 5-bromo-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-- dihydro-indol-2- one IN-009 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3- -dihydro-indol- 2-one IN-010 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-i- ndol-2-one IN-011 5-bromo-3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-d- ihydro-indol-2- one IN-012 3-[5-(2-dimethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-- dihydro-indol-2- one IN-013 3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro- -indol-2-one IN-014 5-bromo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3- -dihydro-indol-2- one IN-015 6-phenyl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,- 3-dihydro-indol-2- one IN-016 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-in- dol-2-one IN-017 5-bromo-3-[5-(2-diethylamino-etthoxy)-1H-indol-2-ylmethylene]-1,3-d- ihydro-indol-2- one IN-018 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-6-phenyl-1,3-d- ihydro-indol-2- one IN-019 3-[5-(2-diethylamino-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3-d- ihydro-indol-2- one IN-020 3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-1,3-dihydro- -indol-2-one IN-021 2-oxo-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indol- 5-carboxylic acid IN-022 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-carboxylic acid IN-023 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 6-carboxylic acid IN-024 4-(2-hydroxy-ethyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylme- thylene]-1,3- dihydro-indol-2-one IN-025 6-pyridin-3-yl-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethyle- ne]-1,3-dihydro- indol-2-one IN-026 6-(4-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylm- ethylene]-1,3- dihydro-indol-2-one IN-027 6-(3-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylm- ethylene]-1,3- dihydro-indol-2-one IN-028 6-(2-methoxy-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylm- ethylene]-1,3- dihydro-indol-2-one IN-029 6-(4-fluoro-phenyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylme- thylene]-1,3- dihydro-indol-2-one IN-030 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-carboxylic acid IN-031 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-6-carboxylic acid IN-032 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-5-phenyl-1,3- -dihydro-indol- 2-one IN-033 4-(2-hydroxy-ethyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmet- hylene]-1,3- dihydro-indol-2-one IN-034 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-6-pyridin-3-- yl-1,3-dihydro- indol-2-one IN-035 6-(4-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylme- thylene]-1,3- dihydro-indol-2-one IN-036 6-(3-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylme- thylene]-1,3- dihydro-indol-2-one IN-037 6-(2-methoxy-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylme- thylene]-1,3- dihydro-indol-2-one IN-038 6-(4-fluoro-phenyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmet- hylene]-1,3- dihydro-indol-2-one

The above compounds have the structure of formula X, with the R.sub.101, R.sub.102, R.sub.103, and R.sub.112 substituents as defined in Table 2.

TABLE-US-00002 TABLE 2 (X) ##STR00004## Com- pound Number R.sub.101 R.sub.102 R.sub.103 R.sub.112 IN-001 H H 3-diethylamino-propyl H IN-002 Br H 3-diethylamino-propyl H IN-003 H Phenyl 3-diethylamino-propyl H IN-004 Phenyl H 3-diethylamino-propyl H IN-005 Phenyl H 2-dimethyl- H amino-ethoxy IN-006 Phenyl H 2-pyrroli- H din-1-yl-ethoxy IN-007 H H 2-morpho- H lin-4-yl-ethoxy IN-008 Br H 2-morpho- H lin-4-yl-ethoxy IN-009 H Phenyl 2-morpho- H lin-4-yl-ethoxy IN-010 H H 2-dimethyl- H amino-ethoxy IN-011 Br H 2-dimethyl- H amino-ethoxy IN-012 H Phenyl 2-dimethyl- H amino-ethoxy IN-013 H H 2-pyrroli- H din-1-yl-ethoxy IN-014 Br H 2-pyrroli- H din-1-yl-ethoxy IN-015 H Phenyl 2-pyrroli- H din-1-yl-ethoxy IN-016 H H 2-diethylamino-ethoxy H IN-017 Br H 2-diethylamino-ethoxy H IN-018 H Phenyl 2-diethylamino-ethoxy H IN-019 Phenyl H 2-diethylamino-ethoxy H IN-020 H H 3-pyrroli- H din-1-yl-propyl IN-021 --COOH H 3-pyrroli- H din-1-yl-propyl IN-022 --COOH H 2-pyrroli- H din-1-yl-ethoxy IN-023 H --COOH 2-pyrroli- H din-1-yl-ethoxy IN-024 H H 2-pyrroli- 2-hy- din-1-yl-ethoxy droxy-ethyl IN-025 H Py- 2-pyrroli- H ridin-3-yl din-1-yl-ethoxy IN-026 H 4-Meth- 2-pyrroli- H oxy din-1-yl-ethoxy Phenyl IN-027 H 3-Meth- 2-pyrroli- H oxy din-1-yl-ethoxy Phenyl IN-028 H 2-Meth- 2-pyrroli- H oxy din-1-yl-ethoxy Phenyl IN-029 H 4-Fluoro 2-pyrroli- H Phenyl din-1-yl-ethoxy IN-030 --COOH H 2-morpho- H lin-4-yl-ethoxy IN-031 H --COOH 2-morpho- H lin-4-yl-ethoxy IN-032 Phenyl H 2-morpho- H lin-4-yl-ethoxy IN-033 H H 2-morpho- 2-hy- lin-4-yl-ethoxy droxy-ethyl IN-034 H Py- 2-morpho- H ridin-3-yl lin-4-yl-ethoxy IN-035 H 4-Meth- 2-morpho- H oxy lin-4-yl-ethoxy Phenyl IN-036 H 3-Meth- 2-morpho- H oxy lin-4-yl-ethoxy Phenyl IN-037 H 2-Meth- 2-morpho- H oxy lin-4-yl-ethoxy Phenyl IN-038 H 4-Fluoro 2-morpho- H Phenyl lin-4-yl-ethoxy

Some of the compounds of the invention that have the generic structure of formula II are listed in Table 3.

TABLE-US-00003 TABLE 3 Compound Number Compound Name IN-039 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid amide IN-040 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid amide IN-041 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid methylamide IN-042 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid dimethylamide IN-043 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid isopropylamide IN-044 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid phenylamide IN-045 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid pyridin-3-ylamide IN-046 5-(2,3-dihydro-indole-1-sulfonyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1- H-indol-2- ylmethylene]-1,3-dihydro-indol-2-one IN-047 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid (3-chloro-phenyl)-amide IN-048 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid (3-chloro-phenyl)-methyl-amide IN-049 2-oxo-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-2,3-d- ihydro-1H-indole- 5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide IN-050 5-(3,4-dihydro-2H-quinoline-1-sulfonyl)-3-[5-(2-pyrrolidin-1-yl-eth- oxy)-1H-indol-2- ylmethylene]-1,3-dihydro-indol-2-one IN-051 5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-3-[5-(2-pyrrolidin-1-yl-- ethoxy)-1H-indol- 2-ylmethylene]-1,3-dihydro-indol-2-one IN-052 5-(5-bromo-2,3-dihydro-indole-1-sulfonyl)-3-[5-(2-pyrrolidin-1-yl-e- thoxy)-1H-indol-2- ylmethylene]-1,3-dihydro-indol-2-one IN-053 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid methylamide IN-054 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid dimethylamide IN-055 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid isopropylamide IN-056 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid phenylamide IN-057 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid pyridin-3-ylamide IN-058 5-(2,3-dihydro-indole-1-sulfonyl)-3-[5-(2-morpholin-4-yl-ethoxy)-1H- -indol-2- ylmethylene]-1,3-dihydro-indol-2-one IN-059 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid (3-chloro-phenyl)-amide IN-060 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid (3-chloro-phenyl)-methyl-amide IN-061 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-di- hydro-1H- indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide IN-062 5-(3,4-dihydro-2H-quinoline-1-sulfonyl)-3-[5-(2-morpholin-4-yl-etho- xy)-1H-indol-2- ylmethylene]-1,3-dihydro-indol-2-one IN-063 5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-3-[5-(2-morpholin-4-yl-e- thoxy)-1H-indol- 2-ylmethylene]-1,3-dihydro-indol-2-one IN-064 5-(5-bromo-2,3-dihydro-indole-1-sulfonyl)-3-[5-(2-morpholin-4-yl-et- hoxy)