BACKGROUND OF THE INVENTION 0001 1. Field of the Invention 0002 The present invention relates to methods for treatment or prevention of neoplasia disorders using protein tyrosine kinase inhibitors in combination with cyclooxygenase inhibitors, in particular cyclooxygenase-2 selective inhibitors. 0003 2. State of the Art 0004 A neoplasm, or tumor, is an abnormal, unregulated, and disorganized proliferation of cell growth. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance. 0005 Cancer is now the second leading cause of death in the United States and over 8,000,000 persons in the United States have been diagnosed with cancer. In 1995, cancer accounted for 23.3% of all deaths in the United States. (See U.S. Dept. of Health and Human Services, National Center for Health Statistics, Health United States 1996-97 and Injury Chartbook 117 (1997)). 0006 Cancer is not fully understood on the molecular level. It is known that exposure of a cell to a carcinogen such as certain viruses, certain chemicals, or radiation, leads to DNA alteration that inactivates a suppressive gene or activates an oncogene. Suppressive genes are growth regulatory genes, which upon mutation, can no longer control cell growth. Oncogenes are initially normal genes (called prooncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely). 0007 Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia. 0008 Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of breast, lung, and testicular cancer. 0009 The adverse effects of systemic chemotherapy used in the treatment of neoplastic disease is most feared by patients undergoing treatment for cancer. Of these adverse effects nausea and vomiting are the most common and severe side effects. Other adverse side effects include cytopenia, infection, cachexia, mucositis in patients receiving high doses of chemotherapy with bone marrow rescue or radiation therapy; alopecia (hair loss); cutaneous complications (see M. D. Abeloff, et al: Alopecia and Cutaneous Complications. P. 755-56. In Abeloff, M. D., Armitage, J. O., Lichter, A. S., and Niederhuber, J. E. (eds) Clinical Oncology. Churchill Livingston, N.Y., 1992, for cutaneous reactions to chemotherapy agents), such as pruritis, urticaria, and angioedema; neurological complications; pulmonary and cardiac complications in patients receiving radiation or chemotherapy; and reproductive and endocrine complications. 0010 Chemotherapy-induced side effects significantly impact the quality of life of the patient and may dramatically influence patient compliance with treatment. 0011 Additionally, adverse side effects associated with chemotherapeutic agents are generally the major dose-limiting toxicity (DLT) in the administration of these drugs. For example, mucositis, is one of the major dose limiting toxicity for several anticancer agents, including the antimetabolite cytotoxic agents 5-FU, methotrexate, and antitumor antibiotics, such as doxorubicin. Many of these chemotherapy-induced side effects if severe, may lead to hospitalization, or require treatment with analgesics for the treatment of pain. 0012 The adverse side effects induced by chemotherapeutic agents and radiation therapy have become of major importance to the clinical management of cancer patients. 0013 Currently, scientists are looking at treating cancers via the use of antiangiogenic agents. Angiogenesis is believed to be the mechanism via which tumors get needed nutrients to grow and metastasize to other locations in the body. Antiangiogenic agents interfere with these processes and destroy or control tumors. 0014 For example, U.S. Pat. No. 5,854,205 describes an isolated endostatin protein that is an inhibitor of endothelial cell proliferation and angiogenesis; U.S. Pat. No. 5,843,925 describes a method for inhibiting angiogenesis and endothelial cell proliferation using a 7-substituted amino-9-(substituted glycyloamido-6-demethyl-6-deoxytetracycline; U.S. Pat. No. 5,861,372 describes the use of an aggregate endothelial inhibitor, angiostatin, and it use in inhibiting angiogenesis, PCT/GB97/00650 describes the use of cinnoline derivatives for use in the production of an antiangiogenic and/or vascular permeability reducing effect; Tai-Ping, D. describes potential anti-angiogenic therapies, see Trends Pharmacol. Sci. 16, No. 2, 57-66, 1995; Lode, H. et al. describes synergy between an antiangiogenic integrin alpha v antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastasis, see Proc. Nat. Acad. Sci. USA., 96 (4), 1591-1596, 1999; Giannis, A. et al describes Integrin antagonists and other low molecular weight compounds as inhibitors of angiogenesis, see New drugs in cancer therapy. Angew. Chem. Int. Ed. Engl. 36(6), 588-590, 1997; WO 97/41,844 describes a method of using combinations of angiostatic compounds for the prevention and/or treatment of neovascularization in human patients; WO 98/22,101 describes a method of using pyrozol-1-ylbenzenesulfonamides as anti-angiogenic agents; and U.S. Pat. No. 5,792,783 describes use of 3-heteroaryl-2-indolinone that are protein kinase inhibitors and antiangiogenic agents for the treatment of various cancers. 0015 Recently, it has been reported that treatment of colorectal cancer with a cyclooxygenase-2 selective inhibitor, specifically Celecoxib, in combination with an ART-2 inhibitor, specifically Herceptin, is more effective than when either agent is used alone. Accordingly, there is a need to discover new combinations of chemotherapeutic agents that when used together are more efficacious than when used alone. The present invention fulfills this need.

SUMMARY OF THE INVENTION 0016 In one aspect, this invention is directed to a method of treatment or prevention of cancers comprising administering to a mammal in need of such treatment a therapeutically effective amount of: 0017 a protein kinase inhibitor of the Formula (I): 1

0018 wherein: 0019 R is selected from the group consisting of hydrogen, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, piperidin-1-ylmethyl, 2-hydroxymethylpyrrolidin-1-ylmethyl, 2-carboxypyrrolidin-1-ylmethyl, and pyrrolidin-1-ylmethyl; 0020 R1 is selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl cycloalkyl, substituted cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, C(O)NR8R9, NR13R14, (CO)R15, and (CH2)rR16; 0021 R2 is selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, trihalomethyl, hydroxy, alkoxy, cyano, NR R4, NR13C(O)R4, C(O)R15, aryl, heteroaryl, and S(O)2NR13R14; 0022 R3 is selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, trihalomethyl, hydroxy, alkoxy, aryl, heteroaryl, NR13R14, NR13S(O)2R14, S(O)2NR13R14, NR13C(O)R14, NR13C(O)OR14, (CO)R15, and SO2R19; 0023 R4 is selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, hydroxy, alkoxy, and NR13R14; 0024 R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and C(O)R10; 0025 R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and C(O)R10; 0026 R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, C(O)R7, and C(O)R10 provided that when R is hydrogen then at least one of R5, R6 and R7 is C(O)R10; or 0027 R6 and R7 may combine to form a group selected from the group consisting of (CH2)4, (CH2)5 and (CH2)6; 0028 R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, subtituted alkyl, and aryl; 0029 R10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, N(R11)(alkylene)nR12 wherein the alkylene group is optionally substituted with a hydroxy group, and NR13R14; 0030 R11 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 0031 R12 is selected from the group consisting of NR13R14, hydroxy, C(O)R15, aryl, heteroaryl, N(O)R13R14, N(OH)R13, and NHC(O)R18 (wherein R18 is alkyl, substituted alkyl, haloalkyl, or aralkyl); 0032 R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, lower alkyl substituted with hydroxyalkylamino, cyanoalkyl, cycloalkyl, subtituted cycloalkyl, aryl and heteroaryl; or 0033 R13 and R14 may combine to form a heterocyclo group; 0034 R15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy; 0035 R16 is selected from the group consisting of hydroxy, NR13R14, C(O)R15, and C(O)NR13R14; 0036 R17 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl and heteroaryl; 0037 R19 is selected from the group consisting of alkyl, substituted alkyl, aryl, aralkyl, heteoaryl, or heteroaralkyl; and 0038 n and r are independently 1, 2, 3, or 4; 0039 in combination with a cyclooxygenase inhibitor; 0040 or a pharmaceutically acceptable salt thereof. 0041 Preferably, the protein kinase inhibitor of Formula (I) is used in combination with a cyclooxygenase-2 selective inhibitor selected from the group consisting of: 0042 (i) a compound of Formula (II): 2

0043 wherein: 0044 G is selected from the group consisting of O, S, and NRa wherein Ra is hydrogen or alkyl; 0045 R10a is selected from the group consisting of hydrogen and aryl; 0046 R11a is selected from the group consisting of carboxyl, alkyl, aralkyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarbonyl; 0047 R12a is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and 0048 R13a is one or more radicals independently selected from the group consisting of hydrogen, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; 0049 or R13a together with ring E forms a naphthyl ring; or 0050 (ii) a compound of Formula (III): 3

0051 wherein: 0052 A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; 0053 R1b is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R1b is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; 0054 R2b is selected from the group consisting of methyl and amino; and 0055 R3b is selected from the group consisting of a radical selected from hydrogen, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; 0056 or a pharmaceutically acceptable salt thereof. 0057 Preferably, the above compounds are administered as a pharmaceutical composition comprising one or more of the above compounds and a pharmaceutically acceptable excipient. Specifically, the therapeutic agents of this invention can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition. 0058 The methods of the present invention are useful for the treatment or prevention of neoplasia disorders including acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiatied carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor. 0059 The methods of the present invention provide one or more benefits. One of the benefits is that the compositions, agents and therapies of the present invention are administered in combination at a low dose, that is, at a dose lower than has been conventionally used in clinical situations for each of the individual components administered alone. 0060 A benefit of lowering the dose of the compounds, compositions, agents and therapies of the present invention administered to a mammal includes a decrease in the incidence of adverse effects associated with higher dosages. For example, by lowering the dosage of a chemotherapeutic agent such as methotrexate, a reduction in the frequency and the severity of nausea and vomiting will result when compared to that observed at higher dosages. Similar benefits are contemplated when a protein kinase inhibitor of the present invention is used in combination with a cyclooxygenase inhibitor, in particular a cyclooxygenase-2 selective inhibitor. 0061 By lowering the incidence of adverse effects, an improvement in the quality of life of a patient undergoing treatment for cancer is contemplated. Further benefits of lowering the incidence of adverse effects include an improvement in patient compliance, a reduction in the number of hospitalizations needed for the treatment of adverse effects, and a reduction in the administration of analgesic agents needed to treat pain associated with the adverse effects. 0062 Another benefit that is contemplated is that the inhibition of the tumors is greater when a protein kinase inhibitor is administered in combination with a cyclooxygenase inhibitor, preferably a cyclooxygenase-2 selective inhibitor than when either of these agents are administered alone. 0063 The present invention further includes kits comprising a COX-2 inhibitor and a protein kinase inhibitor of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Definitions 0064 Unless otherwise stated the following terms used in the specification and claims have the meanings discussed below: 0065 Alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms (whenever a numerical range; e.g. 1-20, is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). Alkyl groups containing from 1 to 4 carbon atoms are refered to as lower alkyl groups. When said lower alkyl groups lack substituents, they are referred to as lower alkyl groups. More preferably, an alkyl group is a medium size alkyl having 1 to 10 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, or tert-butyl, and the like. 0066 Substituted alkyl means the alkyl group as defined above is substituted with one or more, more preferably one to three, even more preferably one or two substituent(s) independently selected from the group consisting of halo, hydroxy, lower alkoxy, aryl optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, aryloxy optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and the nitrogen atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen (if present) atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, mercapto, (lower alkyl)thio, arylthio optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O), R18S(O)2, C(O)OR18, R18C(O)O, and NR18R19, wherein R18 and R19 are independently selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, (C3-C6)cycloalkyl, lower alkenyl, lower alkynyl and aryl optionally substituted with one or more, groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups. 0067 Preferably, the alkyl group is substituted with one or two substituents independently selected from the group consisting of hydroxy, 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen (if present) atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and the nitrogen atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, or NR18R19, wherein R18 and R19 are independently selected from the group consisting of hydrogen, lower alkyl. Even more preferably the alkyl group is substituted with one or two substituents which are independently of each other hydroxy, dimethylamino, ethylamino, diethylamino, dipropylamino, pyrrolidino, piperidino, morpholino, piperazino, 4-lower alkylpiperazino, phenyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl, triazinyl, and the like. 0068 Cycloalkyl refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring or a multicyclic fused ring (a fused ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. 0069 Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. 0070 Substituted cycloalkyl means a cycloalkyl group as defined above that is substituted with one or more, more preferably one or two substituents, independently selected from the group consisting of lower alkyl, trihaloalkyl, halo, hydroxy, lower alkoxy, aryl optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, aryloxy optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of the group being optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitogen (if present) atoms in the group being optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, mercapto,(lower alkyl)thio, arylthio optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, lower alkyl or lower alkoxy groups, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O), R18S(O)2, C(O)OR18, R18C(O)O, and NR18R19 are as defined above. 0071 Alkenyl refers to a lower alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. 0072 Alkynyl refers to a lower alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. 0073 Aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups of 1 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halo, hydroxy, lower alkoxy, mercapto,(lower alkyl)thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O), R18S(O)2, C(O)OR18, R18C(O)O, and NR18R19, with R18 and R19 as defined above. Preferably, the aryl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0074 Heteroaryl refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more, more preferably one, two, or three, even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halo, hydroxy, lower alkoxy, mercapto, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O), R18O)2, C(O)OR18, R18C(O)O, and NR18R19, with R18 and R19 as defined above. Preferably, the heteroaryl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0075 Heteroalicyclic refers to a monocyclic or fused ring group having in the ring(s) of 5 to 9 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heteroalicyclic groups are pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like. The heteroalicyclic ring may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halo, hydroxy, lower alkoxy, mercapto,(lower alkyl)thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O), R18S(O)2, C(O)OR18, R18C(O)O, and NR18R19, with R18 and R19 as defined above. Preferably, the heteroalicyclic group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0076 Preferably, the heteroalicyclic group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0077 Heterocycle means a saturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from optionally substituted lower alkyl (substituted with 1 or 2 substituents independently selected from carboxy or ester), haloalkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl, COR (where R is alkyl) or COOR where R is (hydrogen or alkyl). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-ethyloxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidone, 2-pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and the derivatives thereof. Preferably, the heterocycle group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, mono or dialkylamino. 0078 Hydroxy refers to an OH group. 0079 Alkoxy refers to both an O-(alkyl) and an O-(cycloalkyl) group. Representative examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. 0080 Aryloxy refers to both an O-aryl and an O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof. 0081 Mercapto refers to an SH group. 0082 Alkylthio refers to both an S-alkyl and an S-cycloalkyl group. Representative examples include, but are not limited to, e.g., methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. 0083 Arylthio refers to both an S-aryl and an S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thientylthio, pyrimidinylthio, and the like and derivatives thereof. 0084 Acyl refers to a C(O)R group, where R is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and NR18R19 groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and NR18R19 groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and NR8R19 groups. Representative acy groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like 0085 Aldehyde refers to an acyl group in which R is hydrogen. 0086 Thioacyl refers to a C(S)R group, with R as defined herein. 0087 Ester refers to a C(O)OR group with R as defined herein except that R cannot be hydrogen. 0088 Acetyl group refers to a C(O)CH3 group. 0089 Halo group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. 0090 Trihalomethyl group refers to a CX3 group wherein X is a halo group as defined herein. 0091 Trihalomethanesulfonyl group refers to a X3CS(O)2 groups with X as defined above. 0092 Cyano refers to a CN group. 0093 Methylenedioxy refers to a OCH2O group where the two oxygen atoms are bonded to adjacent carbon atoms. 0094 Ethylenedioxy group refers to a OCH2CH2O where the two oxygen atoms are bonded to adjacent carbon atoms. 0095 S-sulfonamido refers to a S(O)2NR18R19 group, with R18 and R19 as defined herein. 0096 N-sulfonamido refers to a NR18S(O)2R19 group, with R18 and R19 as defined herein. 0097 O-carbamyl group refers to a OC(O)NR18R19 group with R18 and R19 as defined herein. 0098 N-carbamyl refers to an R18OC(O)NR19 group, with R18 and R19 as defined herein. 0099 O-thiocarbamyl refers to a OC(S)NR18R19 group with R18 and R19 as defined herein. 0100 N-thiocarbamyl refers to a R18OC(S)NR19 group, with R18 and R19 as defined herein. 0101 Amino refers to an NR18R19 group, wherein R18 and R19 are both hydrogen. 0102 C-amido refers to a C(O)NR18R19 group with R18 and R19 as defined herein. 0103 N-amido refers to a R18C(O)NR19 group, with R18 and R19 as defined herein. 0104 Nitro refers to a NO2 group. 0105 Haloalkyl means an alkyl, preferably lower alkyl as defined above that is substituted with one or more same or different halo atoms, e.g., CH2Cl, CF3, CH2CF3, CH2CCl3, and the like. 0106 Aralkyl means alkyl, preferably lower alkyl as defined above which is substituted with an aryl group as defined above, e.g., CH2phenyl, (CH2)2phenyl, (CH2)3phenyl, CH3CH(CH3)CH2phenyl, and the like and derivatives thereof. 0107 Heteroaralkyl group means alkyl, preferably lower alkyl as defined above which is substituted with a heteroaryl group, e.g., CH2pyridinyl, (CH2)2pyrimidinyl, (CH2)3imidazolyl, and the like, and derivatives thereof. 0108 Monoalkylamino means a radical NHR where R is an unsubstitued alkyl or cycloalkyl group as defined above, e.g., methylamino, (1-methylethyl)amino, cyclohexylamino, and the like. 0109 Dialkylamino means a radical NRR where each R is independently an unsubstitued alkyl or cycloalkyl group as defined above, e.g., dimethylamino, diethylamino, (1-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like. 0110 Cyanoalkyl means alkyl, preferably lower alkyl as defined above, which is substituted with 1 or 2 cyano groups. 0111 Optional or optionally means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, heterocycle group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group. 0112 The terms 2-indolinone, indolin-2-one and 2-oxindole are used interchangeably herein to refer to a molecule having the chemical structure: 4

0113 The term pyrrole refers to a molecule having the chemical structure: 5

0114 The term pyrrole substituted 2-indolinone and 3-pyrrolidenyl-2-indolinone are used interchangeably herein to refer to a chemical compound having the general structure shown in Formula (I). 0115 Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed isomers. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. 0116 Stereoisomers that are not mirror images of one another are termed diastereomers and those that are non-superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as () or ()-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a racemic mixture. 0117 The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R6 substituent in a compound of formula (I) is 2-hydroxyethyl, then the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stercoisomers are well-known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 1992). 0118 The compounds of the present invention may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula (I) described herein may adopt an E or a Z configuration about the double bond connecting the 2-indolinone moiety to the pyrrole moiety or they may be a mixture of E and Z. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate RTK, CTK and/or STK activity and is not limited to any one tautomeric or structural isomeric form. 0119 A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. 0120 The compounds of the present invention may also act as a prodrug. A prodrug refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the prodrug) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. 0121 A further example of a prodrug might be a short polypeptide, for example, without limitation, a 2-10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound of this invention wherein the polypeptide is hydrolyzed or metabolized in vivo to release the active molecule. The prodrugs of a compound of Formula (I) are within the scope of this invention. 0122 Additionally, it is contemplated that a compound of Formula (I) would be metabolized by enzymes in the body of the organism such as human being to generate a metabolite that can modulate the activity of the protein kinases. Such metabolites are within the scope of the present invention. 0123 As used herein, a physiologically/pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. 0124 An pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. 0125 As used herein, the term pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include: 0126 (i) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perhcloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid such as the L-malate salt of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide; or 0127 (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion; or coordinates with an organic base. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic base include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. 0128 Method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts. 0129 Treat, treating and treatment refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease. This can be monitored by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. 0130 The term prevention includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia. 0131 The phrase therapeutically-effective is intended to qualify the amount of each agent that will achieve the goal of improvement in neoplastic disease severity and the frequency of neoplastic disease over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. 0132 A therapeutic effect or therapeutic effective amount is intended to qualify the amount of an anticancer agent required to relieve to some extent one or more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 3) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of tumor growth; 5) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 6) relieving or reducing the side effects associated with the administration of anticancer agents. 0133 The phrase combination therapy (or co-therapy) embraces the administration of a protein kinase inhibitor and a cyclooxygenase-2 inhibitor as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). Combination therapy generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, both the therapeutic agents may be administered orally or both therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. 0134 Adjunctive therapy encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.

PREFERRED EMBODIMENTS 0135 While the broadest definition is set forth in the Summary of the Invention, certain compounds of Formula (I), (II) and (III) set forth below are preferred for carrying out the present invention. 0136 A. Protein Tyrosine Kinase InhibitorCompounds of Formula (I): 0137 (1) A preferred group of compounds of Formula (I) is that wherein R1, R3, and R4 are hydrogen. 0138 (2) Another preferred group of compounds of Formula (I) is that wherein R1, R2, and R4 are hydrogen. 0139 (3) Another preferred group of compounds of Formula (I) is that wherein R1, R2, and R3 are hydrogen. 0140 (4) Another preferred group of compounds of Formula (I) is that wherein R2, R3, and R4 are hydrogen. 0141 (5) Another preferred group of compounds of Formula (I) is that wherein R1, R2, R3 and R4 are hydrogen. 0142 (6) Yet another preferred group of compounds of Formula (I) is that wherein R5, R6 or R7, preferably R5 or R6, more preferably R6 is COR10 wherein R10 is NR11(CH2)nR12 wherein: 0143 R11 is hydrogen or lower alkyl, preferably hydrogen or methyl; 0144 n is 2, 3 or 4, preferably 2 or 3; and 0145 R12 is NR13R14 wherein R13 and R14 are independently alkyl, more preferably lower lower alkyl or R13 and R14 combine to form a group selected from (CH2)4, (CH2)5, (CH2)2O(CH2)2 or CH2)2N(CH3)(CH2)2, preferably R13 and R14 are independently hydrogen, methyl, ethyl, or combine to form morpholin-4-yl, pyrrolidin-1-yl, piperazin-1-yl, or 4-methylpiperazin-1-yl. 0146 More preferably, R5 or R6 in (6) above is N-(2-dimethylaminoethyl)aminocarbonyl, N-(2-ethylaminoethyl)-N-methylaminocarbonyl, N-(3-dimethylaminopropyl)-aminocarbonyl, N-(2-diethylaminoethyl)aminocarbonyl, N-(3-ethylaminopropyl)aminocarbonyl, N-(3-diethylaminopropyl)aminocarbonyl, 3-pyrrolidin-1-yl-propylaminocarbonyl, 3-morpholin-4-ylpropyl-aminocarbonyl, 2-pyrrolidin-1-ylethylaminocarbonyl, 2-morpholin-4-ylethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)ethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)propylaminocarbonyl, 2-(3,5-dimethylpiperazin-1-y)ethylaminocarbonyl or 2-(3,5-dimethylpiperazin-1-y)propylaminocarbonyl, even more preferably N-(2-diethylaminoethyl)aminocarbonyl or N-(2-ethylaminoethyl)amino-carbonyl. 0147 (7) Yet another preferred group of compounds of Formula (I) is that wherein R5, R6 or R7, preferably R5 or R6, more preferably R6 is COR10 wherein R10 is NR13R14 wherein R13 is hydrogen and R14 is alkyl, preferably lower alkyl substituted with hydroxy, aryl, heteroaryl, heteroalicyclic, or carboxy, more preferably methyl, ethyl, propyl or butyl substituted with hydroxy, aryl, heteroalicyclic such as piperidine, piperazine, morpholine and the like, heteroaryl, or carboxy. Even more preferably within this group (7), R5 or R6 is 2-ethoxycarbonylmethyl-aminocarbonyl, carboxymethylaminocarbonyl, 3-hydroxypropyl-aminocarbonyl, 2-hydroxyethylaminocarbonyl, 3-triazin-1-ylpropylamino-carbonyl, triazin-1-ylethylaminocarbonyl, 4-hydroxyphenylethylaminocarbonyl, 3-imidazol-1-ylpropyl-aminocarbonyl, pyridin-4-ylmethylaminocarbonyl, 2-pyridin-2-ylethylaminocarbonyl or 2-imidazol-1-ylethylaminocarbonyl. 0148 (8) Yet another preferred group of compounds of Formula (T) is that wherein R5, R6 or R7, preferably R5 or R6, more preferably R6 is COR10 wherein R10 is NR11(CH2)nR12 wherein: 0149 R11 is hydrogen or alkyl, preferably hydrogen or methyl; 0150 n is 2, 3 or 4, preferably 2 or 3; and 0151 R12 is NR13R14 wherein R13 and R14 together combine to form a heterocycle, preferably a 5, 6 or 7 membered heterocycle containing a carbonyl group and 1 or 2 nitrogen atoms. Preferably, R5 or R6 is 2-(3-ethoxycarbonylmethylpiperazin-1-yl)ethylaminocarbonyl, 2-(3-oxopiperazin-1-yl)ethylaminocarbonyl, 2-(imidazolidin-1-yl-2-one)ethylaminocarbonyl, 2-(tetrahydropyrimidin-1-yl-2-one)ethylaminocarbonyl, 2-(2-oxopyrrolidin-1-yl)-ethylaminocarbonyl, 3-(4-methylpiperazin-1-yl)propylaminocarbonyl, 3-(3-ethoxycarbonylmethylpiperazin-1-yl)propylaminocarbonyl, 3-(3-oxopiperazin-1-yl)propyl-aminocarbonyl, 3-(imidazolidin-1-yl-2-one)propyl-aminocarbonyl, 3-(tetrahydropyrimidin-1-yl-2-one)propylaminocarbonyl, 3-(2-oxopyrrolidin-1-yl)propyl-aminocarbonyl, 2-(2-oxohomopiperidin-1-yl)ethylamino-carbonyl or 3-(2-oxohomopiperidin-1-yl)propylaminocarbonyl. 0152 (9) Yet another preferred group of compounds of Formula (I) is that wherein R5, R6 or R7, preferably R5 or R6, more preferably R6 is COR10 wherein: 0153 (a) R10 is NR11(CH2)nR12 wherein: 0154 R11 is hydrogen or alkyl, preferably hydrogen or methyl; 0155 n is 2, 3 or 4, preferably 2 or 3; and 0156 R12 is NR13R14 wherein R13 is hydrogen and R14 is cyanoalkyl or NCORa where Ra is alkyl; or 0157 (b) R10 is NR13R14 wherein R13 and R14 together combine to form a heterocycle not containing a carbonyl group within the ring. Preferably, R5 or R6 is 2-(2-cyanoethylamino)ethylaminocarbonyl, 2-(acetylamino)-ethylaminocarbonyl, morpholinocarbonyl, piperidin-1-yl-carbonyl, 2-cyanomethylaminoethylaminocarbonyl or piperidin-1-ylcarbonyl. 0158 (10) Another preferred group of compouds of Formula (I) is that wherein R5 is COR10 wherein R10 is NR13R14 wherein R13 is hydrogen and R14 is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or NR18R19 wherein R18 and R19 are independently hydrogen or lower alkyl, more preferably R5 is 2-(diethylamino)-2-hydroxyethylaminocarbonyl, 2-(N-ethyl-N-2-hydroxyethylamino)ethylaminocarbonyl, carboxymethylamino-carbonyl, or 2-(2-hydroxyethylamino)ethylamino-carbonyl. 0159 (11) Yet another preferred group of compounds of Formula (I) is that wherein R6 is COR10 wherein R10 is NR13R14 wherein R13 is hydrogen and R14 is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or NR18R19 wherein R18 and R19 are independently hydrogen or lower alkyl; more preferably R6 is 2-(diethylamino)-2-hydroxyethylaminocarbonyl, 2-(N-ethyl-N-2-hydroxyethylamino)ethylaminocarbonyl, carboxymethylaminocarbonyl, or 2-(2-hydroxyethylamino)ethylamino-carbonyl. 0160 (12) Yet another preferred group of compounds of Formula (I) is that wherein R is COR10 wherein R10 is NR11(CH2)nR12 wherein R12 is N(O)NR13R14 or N(OH)R13 wherein R13 and R14 are independently selected from the group consisting of hydrogen and lower alkyl, preferably R5 is 2-(N-hydroxy-N-ethylamino)-ethylaminocarbonyl or 2-N(O)(C2H5)2ethyl-aminocarbonyl 0161 (13) Yet another preferred group of compounds of Formula (I) is that wherein R6 is COR10 wherein R10 is NR11(CH2)nR12 wherein R is N(O)NR13R14 or N(OH)R13 wherein R13 and R14 are independently selected from the group consisting of hydrogen and lower alkyl, preferably R6 is 2-(N-hydroxy-N-ethylamino)ethylaminocarbonyl or 2-N(O)(C2H5)2ethyl-aminocarbonyl. 0162 (14) In the above preferred groups (6)-(13) when R5 is COR10, then a more preferred group of compounds is that wherein: 0163 R6 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and 0164 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and C(O)R17 wherein R17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl. 0165 (15) In the above preferred groups (6)-(13) when R5 is COR10, then another more preferred group of compounds is that wherein R6 and R7 combine to form (CH2)4. 0166 (16) In the above preferred groups (6)-(13) when R6 is COR10, then a more preferred group of compounds is that wherein: 0167 R5 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and 0168 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and C(O)R17, wherein R17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl. 0169 (17) Within the above preferred and more preferred groups (6)-(16), an even more preferred group of compounds is that wherein: 0170 R1 is hydrogen, alkyl, C(O)NR8R9, cycloalkyl or aryl, preferably hydrogen, phenyl, 3,4-dimethoxyphenylaminocarbonyl, 4-methoxy-3-chlorophenylaminocarbonyl, even more preferably hydrogen or methyl, most preferably hydrogen; 0171 R2 is cyano, hydrogen, halo, lower alkoxy, aryl or S(O)2NR13R14 wherein R13 is hydrogen and R14 is hydrogen, aryl or alkyl, preferably R2 is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, dimethylaminosulfonyl, 3-chlorophenylaminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, isopropylamino-sulfonyl, more preferably hydrogen, fluoro, or bromo; 0172 R3 is selected from the group consisting of hydrogen, lower alkoxy, C(O)R15, NR13C(O)R14, aryl preferably aryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy, and heteroaryl, preferably heteroaryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy,; preferably hydrogen, methoxy, carboxy, phenyl, pyridin-3-yl, 3,4-dichlorophenyl, 2-methoxy-5-isopropylphenyl, 4-n-butylphenyl, 3-isopropylphenyl, more preferably hydrogen or phenyl; and 0173 R4 is hydrogen. 0174 (18) Another more preferred group of compounds of Formula (I) is that wherein: 0175 R1 is hydrogen, alkyl, C(O)NR8R9, cycloalkyl or aryl, preferably hydrogen, 3,4-dimethoxy-phenyl-aminocarbonyl, 4-methoxy-3-chlorophenylaminocarbonyl, even more preferably hydrogen or methyl, particularly hydrogen; 0176 R2 is cyano, hydrogen, halo, lower alkoxy, aryl or S(O)2NR13R14 wherein R13 is hydrogen and R14 is hydrogen, aryl or alkyl, preferably R2 is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, dimethylaminosulfonyl, 3-chlorophenylaminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, isopropylamino-sulfonyl, more preferably hydrogen, fluoro, or bromo; 0177 R3 is selected from the group consisting of hydrogen, lower alkoxy, C(O)R15, NR13C(O)R14, aryl preferably aryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy, and heteroaryl, preferably heteroaryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy,; preferably hydrogen, methoxy, carboxy, phenyl, pyridin-3-yl, 3,4-dichlorophenyl, 2-methoxy-5-isopropylphenyl, 4-n-butylphenyl, 3-isopropylphenyl, more preferably hydrogen or phenyl; and 0178 R4 is hydrogen. 0179 Within the above preferred group (18) a more preferred group of compounds is wherein: 0180 R5 is COR10 where R10 is as defined in the Summary of the Invention, preferably NR11(CH2)nR12 or NR13R14 as defined in the Summary of the Invention. 0181 R6 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and 0182 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and C(O)R17 wherein R17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl. 0183 In the above preferred group (18) another more preferred group of compounds is that wherein: 0184 R6 is COR10 where R10 is as defined in the Summary of the Invention, preferably NR11(CH2)nR12 or NR13R14 as defined in the Summary of the Invention. 0185 R5 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and 0186 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and C(O)R17 wherein R17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl. 0187 (19) Another more preferred group of compounds of Formula (I) is that wherein: 0188 R1 and R4 are hydrogen; 0189 R2 is selected from the group consisting of hydrogen, halo, lower alkoxy, C(O)R15 and S(O)2NR13R14; 0190 R3 is selected from the group consisting of hydrogen, lower alkoxy, C(O)R15, S(O)2NR13R14, aryl and heteroaryl; 0191 R5 is C(O)R10; 0192 R6 is selected from the group consisting of hydrogen and lower alkyl; and 0193 R7 is selected from the group consisting of hydrogen, lower alkyl and C(O)R17. 0194 It is another presently preferred embodiment of this invention that, in a compound having a structure as described in (15): 0195 R10 is selected from the group consisting of hydroxy, lower alkoxy and NR11(CH2)nR12, wherein 0196 n is 2 or 3; 0197 R11 is selected from the group consisting of hydrogen and lower alkyl; and, 0198 R12 is selected from the group consisting of aryl and NR13R14. 0199 It is a further presently preferred embodiment of this invention that, in a compound having a structure as described in the previous two paragraphs, R13 and R14 are independently selected from the group consisting of hydrogen, lower alkyl, and, combined, (CH2)4, (CH2)5, CH2)2O(CH2)2 or (CH2)2N(CH3)(CH2)2. 0200 (20) Another presently preferred embodiment of this invention is a compound in which: 0201 R1 is selected from the group consisting of hydrogen, lower alkyl, (CH2)rR16 and C(O)NR8R9; 0202 R2 is selected from the group consisting of hydrogen, halogen, aryl and S(O)2NR13R14; 0203 R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0204 R4 is hydrogen; 0205 R5 is selected from the group consisting of hydrogen and lower alkyl; 0206 R6 is C(O)R10; 0207 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0208 R16 is selected from the group consisting of hydroxy and C(O)R15; and, 0209 r is 2 or 3. 0210 A presently preferred embodiment of this invention is a compound having as structure described in the paragraph just above in which R3 is aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy and halo. 0211 (21) Likewise, it is a presently preferred embodiment of this invention that, in a compound in which: 0212 R1 is selected from the group consisting of hydrogen, lower alkyl, (CH2)rR16 and C(O)NR8R9; 0213 R2 is selected from the group consisting of hydrogen, halogen, aryl and S(O)2NR13R14; 0214 R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0215 R4 is hydrogen; 0216 R5 is selected from the group consisting of hydrogen and lower alkyl; 0217 R6 is C(O)R10; 0218 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0219 R16 is selected from the group consisting of hydroxy and C(O)R15; and, 0220 r is 2 or 3, 0221 R10 is selected from the group consisting of hydroxy, lower alkoxy, NR13R14 and NR11(CH2)nR12, wherein n is 1, 2 or 3, R11 is hydrogen and R12 is selected from the group consisting of hydroxy, lower alkoxy, C(O)R15, heteroaryl and NR13R14. 0222 (22) A further presently preferred embodiment of this invention is a compound having a structure as described in the paragraph immediately above in which R13 and R14 are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl and, combined, (CH2)4, (CH2)5, (CH2)2O(CH2)2, or (CH2)2N(CH3)(CH2)2. 0223 (23) Another presently preferred embodiment of this invention is a compound in which: 0224 R1 is C(O)NR8R9, wherein R8 is hydrogen and R9 is aryl optionally substituted with one or more groups selected from the group consisting of halo, hydroxy and lower alkoxy; 0225 R2 is selected from the group consisting of hydrogen, halogen, aryl and S(O)2NR13R14; 0226 R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0227 R4 is hydrogen; 0228 R5 is selected from the group consisting of hydrogen and lower alkyl; 0229 R6 is-C(O)R10; 0230 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0231 R16 is selected from the group consisting of hydroxy and C(O)R5; and, 0232 r is 2 or 3, 0233 (24) A still further presently preferred embodiment of this invention is a compound in which: 0234 R1 is selected from the group consisting of hydrogen and lower alkyl; 0235 R2 is selected from the group consisting of hydrogen, halo, lower alkoxy, aryl, C(O)R15 and S(O)2NR13R14; 0236 R3 is selected from the group consisting of hydrogen, halo, aryl, heteroaryl and C(O)R15; 0237 R4 is hydrogen; 0238 R5 is C(O)R10; and, 0239 R6 and R7 combine to form a (CH2)4 group. 0240 In a compound having a structure as described in the paragraph immediately above, it is a presently preferred embodiment that R10 is selected from the group consisting of hydroxy, alkoxy, NR13R14 and NH(CH2)nNR13R14 wherein n is 2 or 3. 0241 It is a presently preferred embodiment of this invention that, in a compound having a structure as described in the two paragraphs immediately above, R13 and R14 are independently selected from the group consisting of hydrogen, lower alkyl, and, combined, (CH2)4, (CH2)5, (CH2)2O(CH2)2 or (CH2)2N(CH3)(CH2)2. Representative compounds of Formula (I) are shown in Table I below. 1TABLE IExampleStructureName1

4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid 2

4-Methyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid 3

4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid methyl ester 4

5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2- carboxylic acid ethyl ester 5

5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2- carboxylic acid 6

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2- carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 7

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2- carboxylic acid (3-diethylaminopropyl)amide 8

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethylaminoethyl)amide 9

5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethylaminoethyl)amide 10

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethylaminoethyl)methylamide 11

5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethylaminoethyl)methylamide 12

3-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (3-diethylaminopropyl)amide 13

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2- carboxylic acid (3-diethylaminopropyl)amide 14

3-Methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (3-diethylaminopropyl)amide 15

5-(5-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole- 2-carboxylic acid (3-diethylaminopropyl)amide 16

5-(6-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole- 2-carboxylic acid (3-diethylaminopropyl)amide 17

3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H- isoindole-1-carboxylic acid (2-diethylaminoethyl)amide 18

3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H- isoindole-1-carboxylic acid (3-diethylaminopropyl)amide 19

3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H- isoindole-1-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 20

3-(2-Oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7- tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide 21

4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide 22

4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-morpholin-4-ylpropyl)amide 23

4-Benzoyl-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole- 2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 24

4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 25

4-Benzoyl-3-methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)- 1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 26

4-Benzoyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 27

4-Benzoyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 28

4-Benzoyl-5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 29

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide 30

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 31

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (3-morpholin-4-ylpropyl)amide 32

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (3-hydroxy-propyl)amide 33

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (2-hydroxy-ethyl)amide 34

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)amide 35

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 36

4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H- pyrrole-2-carboxylic acid 2-(4-hydroxy-phenyl)-ethylamide 37

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 38

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 39

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 40

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid 3-(4-methyl-piperazin-1-yl)-propylamide 41

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid 42

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 43

5-6-(2-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-methyl- 4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 44

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H- pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 45

5-6-(2-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-methyl- 4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 46

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H- pyrrole-3-carboxylic acid ethyl ester 47

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H- pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 48

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 49

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 50

5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 51

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 52

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 53

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide 54

5-6-(2-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 55

5-6-(3-Methoxy-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 56

2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 57

2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 58

2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide 59

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 60

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 61

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide 62

5-6-(3,5-Dichloro-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 63

2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 64

2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 65

2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-dimethylamino-propyl)amide 66

2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-dimethylamino-propyl)amide 67

2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 68

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 69

3-4-(3-Diethylamino-propylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2- ylmethylene-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4- methoxy-phenyl)amide 70

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 71

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 72

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H- pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 73

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H- pyrrole-3-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide 74

5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (pyridin-4-ylmethyl)amide 75

5-6-(4-Butyl-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 76

5-6-(5-Isopropyl-2-methoxy-phenyl)-2-oxo-1,2-dihydroindol-3- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl- ethyl)amide 77

5-6-(4-Ethyl-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 78

5-6-(2,4-Dimethoxy-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 79

5-6-(3-Isopropyl-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 80

5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 81

3-4-(2-diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene- 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 82

5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 83

5-5-(3-Chloro-phenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 84

2,4-Dimethyl-5-2-oxo-5-(pyridin-3-ylsulfamoyl)-1,2-dihydroindol-3- ylidenemethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 85

3-3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2- ylmethylene-4-(2-hydroxy-ethyl)-1,3-dihydroindol-2-one 86

3-3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2- ylmethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide 87

5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 88

5-5-(3-Chloro-phenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 89

3-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid (2-dimethylamino-ethyl)-amide 90

3-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H- isoindole-1-carboxylic acid ethyl ester 91

3-(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 92

3-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 93

3-(3-Ethoxycarbonyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2-oxo- 2,3-dihydro-1H-indole-5-carboxylic acid 94

3-(5-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 95

100

3-(2-Oxo-5-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 96

101

3-(2-Oxo-5-sulfamoyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 97

102

3-(5-Methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7- tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester 98

103

3-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7- tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester 99

104

3-(2-Oxo-5-phenylsulfamoyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7- tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester 100

105

3-(6-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 101

106

3-(2-Oxo-6-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 102

107

3-(3-Ethoxycarbonyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2-oxo- 2,3-dihydro-1H-indole-6-carboxylic acid 103

108

3-(6-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid ethyl ester 104

109

3-(5-Isopropylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7- tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester 105

110

3-(3-Methylcarbamoyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2- oxo-2,3-dihydro-1H-indole-5-carboxylic acid 106

111

3-(3-Dimethylcarbamoyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2- oxo-2,3-dihydro-1H-indole-5-carboxylic acid 107

112

2-Oxo-3-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- ylmethylene-2,3-dihydro-1H-indole-5-carboxylic acid 108

113

3-3-(Morpholine-4-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- ylmethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid 109

114

3-3-(Morpholine-4-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- ylmethylene-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 110

115

3-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid methylamide 111

116

3-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro- 2H-isoindole-1-carboxylic acid dimethylamide 112

117

5-Bromo-3-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- ylmethylene-1,3-dihydro-indol-2-one 113

118

5-Bromo-3-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1- ylmethylene-1,3-dihydro-indol-2-one 114

119

3-(3-Dimethylcarbamoyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2- oxo-2,3-dihydro-1H-indole-6-carboxylic acid 115

120

4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)- 1H-pyrrole-3-carboxylic acid 116

121

4-Methyl-5-(4-methyl-5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3- ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic acid ethyl ester 117

122

4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)- 1H-pyrrole-3-carbonyl-amino-acetic acid ethyl ester 118

123

4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)- 1H-pyrrole-3-carbonyl-amino-acetic acid 119

124

3-3-Methyl-4-(piperidine-1-carbonyl)-1H-pyrrol-2-ylmethylene-2-oxo-2,3- dihydro-1H-indole-5-sulfonic acid methylamide 120

125

5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3- carboxylic acid 121

126

5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3- carboxylic acid ethyl ester 122

127

2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-methyl-1H-pyrrole- 3-carboxylic acid ethyl ester 123

128

2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-methyl-1H-pyrrole- 3-carboxylic acid 124

129

2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-methyl-1H-pyrrole- 3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 125

130

2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-methyl-1H-pyrrole- 3-carboxylic acid (2-diethylamino-ethyl)-amide 133

131

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid (2-acetylamino-ethyl)- amide399 M 1 134

132

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid (2-acetylamino-ethyl)- amide383 M 1 135

133

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-1H-pyrrole-3- carboxylic acid (2-acetylamino-ethyl)- amide365 M 1 136

134

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid 3-(2-oxo-tetrahydro- pyrimidin-1-yl)-propyl-amide500 M 1502 M 1 137

135

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid 3-(2-oxo-tetrahydro- pyrimidin-1-yl)-propyl-amide454 M 1 138

136

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid 3-(2-oxo-tetrahydro- pyrimidin-1-yl)-propyl-amide438 M 1 139

137

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-tetrahydro- pyrimidin-1-yl)-propyl-amide422 M 1 140

138

5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid 3-(2-oxo-tetrahydro- pyrimidin-1-yl)-propyl-amide447 M 1 141

139

Trifluoro-acetate4-2-(5-5-bromo-2-oxo- 1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carbonyl-amino)- ethyl-2-oxo-piperazin-1-ium;486 M 1488 M 1 126

140

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid (2- diethylaminoethyl)-amide381 M 1 127

141

5-5-Chloro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide415 M 1 128

142

2,4-Dimethhyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-pyrrolidin-1- ylethyl)-amide379 M 1 129

143

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)-amide397 M 1 130

144

5-5-Chloro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-1H- pyrrole-3-carboxylic acid (2- pyrrolidin-1-ylethyl)-amide413 M 1 131

145

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2- dimethylaminoethyl)-amide353 M 1 132

146

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)- amide371 M 1 142

147

5-5-Cyano-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 3-(2-oxo- pyrrolidin-1-yl)-propyl-amide430 M 1 143

148

5-5-Bromo-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-oxo- imidazolidin-1-yl)-ethyl-amide470 M 1472 M 1 144

149

5-5-Chloro-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-oxo- imidazolidin-1-yl)-ethyl-amide428 M 1 145

150

5-5-Fluoro-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-oxo- imidazolidin-1-yl)-ethyl-amide412 M 1 146

151

2,4-Dimethyl-5-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-1H-pyrrole- 3-carboxylic acid 2-(2-oxo- imidazolidin-1-yl)-ethyl-amide392 M 1 147

152

5-5-Cyano-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-oxo- imidazolidin-1-yl)-ethyl-amide419 M 1 148

153

4-2-(5-5-Bromo-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3-carbonyl- amino)-ethyl-piperazin-1-yl-acetic acid ethyl ester558 M 1560 M 1 149

154

4-2-(5-5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3-carbonyl- amino)-ethyl-piperazin-1-yl-acetic acid ethyl ester514 M 1 150

155

4-2-(5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carbonyl- amino)-ethyl-piperazin-1-yl-acetic acid ethyl ester498 M 1 153

156

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-1H-pyrrole-3- carboxylic acid 2-(cyanomethyl-amino)- ethyl-amide362 M 1 154

157

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide511 M 1513 M 1 155

158

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide469 M 1 156

159

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide453 M 1 157

160

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide435 M 1 158

161

5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide460 M 1 159

162

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-acetylamino-ethyl)- amide443 M 1445 M 1 160

163

Trifluoro-acetate4-2-(5-5-fluoro-2- oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carbonyl-amino)-ethyl-2- oxo-piperazin-1-ium;426 M 1 161

164

Trifluoro-acetate4-2-(2,4-dimethyl-5- 2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carbonyl- amino)-ethyl-2-oxo-piperazin-1-ium;408 M 1 162

165

Trifluoro-acetate4-2-(5-5-cyano-2- oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carbonyl-amino)-ethyl-2- oxo-piperazin-1-ium;433 M 1 163

166

5-5-Bromo-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-cyano- ethylamino)-ethyl-amide454 M 1456 M 1 164

167

5-5-Chloro-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-cyano- ethylamino)-ethyl-amide410 M 1 165

168

5-5-Fluoro-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-cyano- ethylamino)-ethyl-amide394 M 1 166

169

2,4-Dimethyl-5-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-1H-pyrrole-3- carboxylic acid 2-(2-cyano- ethylamino)-ethyl-amide376 M 1 167

170

5-5-Cyano-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid 2-(2-cyano- ethylamino)-ethyl-amide401 M 1 168

171

Trifluoro-acetate4-2-(5-5-chloro-2- oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H- pyrrole-3-carbonyl-amino)-ethyl-2- oxo-piperazin-1-ium;440 M 1 168

172

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(4-methyl-piperazin-1-yl)- ethyl-amide424 M 1 169

173

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(4-methyl-piperazin-1-yl)- ethyl-amide440 M 1 170

174

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(4-methyl-piperazin-1-yl)- ethyl-amide484 M 1486 M 1 171

175

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid 2-(4-methyl-piperazin-1-yl)-ethyl- amide406 M 1 172

176

2,4-Dimethyl-5-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid 2-(3,5-dimethyl-piperazin-1-yl)-ethyl- amide422 M 1 173

177

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(3,5-dimethyl-piperazin-1- yl)-ethyl-amide438 M 1 174

178

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(3,5-dimethyl-piperazin-1- yl)-ethyl-amide456 M 1 175

179

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-(3,5-dimethyl-piperazin-1- yl)-ethyl-amide498 M 1500 M 1 176

180

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid 3- (4-methyl-piperazin-1-yl)-propyl- amide422 M 1 177

181

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 3-(4-methyl-piperazin-1-yl)- propyl-amide438 M 1 178

182

5-5-Chloro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 3-(4-methyl-piperazin-1-yl)- propyl-amide454 M 1 179

183

5-5-Bromo-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 3-(4-methyl-piperazin-1-yl)- propyl-amide498 M 1500 M 1 180

184

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid 2- (4-benzyl-piperazin-1-yl)-ethyl- amide482 M 1 181

185

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(4-benzyl-piperazin-1-yl)- ethyl-amide500 M 1 182

186

5-5-Chloro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(4-benzyl-piperazin-1-yl)- ethyl-amide517 M 1 183

187

5-5-Bromo-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(4-benzyl-piperazin-1-yl)- ethyl-amide560 M 1562 M 1 184

188

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3-pyrrolidin-1yl-2-one)- amide480 M 1 185

189

Trifluoroacetate 4-2-(5-5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carbonylamino)-ethyl- 2-oxo-piperazin-1-ium440 M 1 186

190

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3-pyrrolidin-1yl-2-one)- amide 187

191

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3-pyrrolidin-1yl-2-one)- amide 188

192

5-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3-pyrrolidin-1yl-2-one)- amide 189

193

5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-pyridin-2-ylethyl)-amide 190

194

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-pyridin-2-ylethyl)-amide trifluroracetate salt 191

195

5-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-pyridin-2-ylethyl)-amide hydrochloride salt 192

196

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-pyridin-2-ylethyl)-amide trifluroracetate salt 193

197

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-ethylaminoethyl)-amide 194

198

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-aminoethyl)-amide 195

199

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-diethyl-N- oxoaminoethyl)-amide 196

200

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-ethyl-N-hydroxy- aminoethyl)-amide 197

201

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-2-hydroxyethyl)- amide 198

202

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-ethyl-2-(2- hydroxyethyl)aminoethyl-amide 199

203

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid 2-ethyl-2-(1- hydroxyethyl)aminoethyl-amide 200

204

5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-N-acetylaminoethyl)- amide 201

205

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (carboxymethyl)-amide 202

206

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid 2-(2-hydroxethylamino)ethyl-amide 203

207

5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid (2-pyridin-2-ylethyl)-amide trifluoroacetate 204

208

5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-2-onepropyl)-amide trifluoroacetate 205

209

3-(3,5-dimethylpyrrol-2-ylmethylidene)-1-(4- methylpiperazin-1-ylmethyl)-2-indolinone 206

210

3-(3,5-dimethylpyrrol-2-ylmethylidene)-1- (pyrrolidin-1-ylmethyl)-2-indolinone

0242 The compound numbers correspond to the Example numbers in the Examples section. That is, the synthesis of Compound 1 in Table 1 is described in Example 1. The compounds presented in Table 1 are exemplary only and are not to be construed as limiting the scope of this invention in any manner. Additional protein kinase inhibitors that can be used in this method include 3-(3,5-dimethylpyrrol-2-ylmethylidene)-2-indolinone (su 5416); 3-3,5-dimethyl-4-(2-carboxyethyl)pyrrol-2-ylmethylidene-2-indolinone (su 6668), and 3-3-(2-carboxyethyl)-5-methylpyrrol-2-ylmethylidene)-2-indolinone. 0243 B. Cyclooxygenase-2 Selective IhbibitorsCompounds of Formulae (II) and (III): 0244 Nonlimiting examples of COX-2 inhibitors that may be used in the present invention are identified in Tables II and III below. 2TABLE IITrade/CompoundResearch NameReferenceDosage1,5-Diphenyl-3-substitutedWO 97/13755pyrazolesradicicolWO 96/25928. Kwon et al(Cancer Res(1992) 52 6296)GB-02283745TP-72Cancer Res 1998 58 4717-7231-(4-chlorobenzoyl)-3-4-(4-A-183827.0fluoro-phenyl)thiazol-2-ylmethyl-5-methoxy-2-methylindoleGR-2530354-(4-cyclohexyl-2-methyloxazol-JTE-522JP 90528825-yl)-2-fluorobenzenesulfonamide5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(methyl-5-pyridinyl)-pyridine2-(3,5-difluoro-phenyl)-3,4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-oneL-768277L-783003MK-966; VIOXXUS 596897412.5-100 mgpoIndomethacin-derivedWO 96/374679200 mg/kg/dayindolalkanoic acid1-Methylsulfonyl-4-1,1-WO 95/30656. WO 95/30652.dimethyl-4-(4-fluoro-WO 96/38418. WO 96/38442.phenyl)cyclopenta-2,4-dien-3-ylbenzene4,4-dimethyl-2-phenyl-3-4-(methylsulfonyl)phenylcyclo-butenone2-(4-methoxyphenyl)-4-methyl-EP 7998231-(4-sulfamoylphenyl)-pyrroleN-5-(4-RWJ-63556fluorophenoxythiophene-2-methanesulfon-amide5(E)-(3,5-di-tert-butyl-4-S-2474EP 595546hydroxy)benzylidene-2-ethyl-1,2-isothiazolidine-1,1-dioxide3-formylamino-7-T-614DE 38/34204methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-oneBenzenesulfonamide; 4-(5-4-celecoxibUS 5466823methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-CS 502(Sankyo)2-(2-chloro-6-lumiracoxibWO 99/11605fluorophenyl)amino-5-(Cox-189)methylbenzeneacetic acid5-chloro-6-methyl-3-4-etoricoxib (MK 663)WO 98/03484(methylsulfonyl)phenyl-2,3-bipyridineBMS 34070US 6180651meloxicamUS 423329915-30 mg/daynimesulideUS 3840597

0245

3TABLE IIIWO 99/30721WO 99/30729US 5760068WO 98/15528WO 99/25695WO 99/24404WO 99/23087FR 27/71005EP 921119FR 27/70131WO 99/18960WO 99/15505WO 99/15503WO 99/14205WO 99/14195WO 99/14194WO 99/13799GB 23/30833US 5859036WO 99/12930WO 99/11605WO 99/10332WO 99/10331WO 99/09988US 5869524WO 99/05104US 5859257WO 98/47890WO 98/47871US 5830911US 5824699WO 98/45294WO 98/43966WO 98/41511WO 98/41864WO 98/41516WO 98/37235EP 86/3134JP 10/175861US 5776967WO 98/29382WO 98/25896ZA 97/04806EP 84/6,689WO 98/21195GB 23/19772WO 98/11080WO 98/06715WO 98/06708WO 98/07425WO 98/04527WO 98/03484FR 27/51966WO 97/38986WO 97/46524WO 97/44027WO 97/34882US 5681842WO 97/37984US 5686460WO 97/36863WO 97/40012WO 97/36497WO 97/29776WO 97/29775WO 97/29774WO 97/28121WO 97/28120WO 97/27181WO 95/11883WO 97/14691WO 97/13755WO 97/13755CA 21/80624WO 97/11701WO 96/41645WO 96/41626WO 96/41625WO 96/38418WO 96/37467WO 96/37469WO 96/36623WO 96/36617WO 96/31509WO 96/25405WO 96/24584WO 96/23786WO 96/19469WO 96/16934WO 96/13483WO 96/03385US 5510368WO 96/09304WO 96/06840WO 96/06840WO 96/03387WO 95/21817GB 22/83745WO 94/27980WO 94/26731WO 94/20480WO 94/13635FR 27/70,131US 5859036WO 99/01131WO 99/01455WO 99/01452WO 99/01130WO 98/57966WO 98/53814WO 98/53818WO 98/53817WO 98/47890US 5830911US 5776967WO 98/22101DE 19/753463WO 98/21195WO 98/16227US 5733909WO 98/05639WO 97/44028WO 97/44027WO 97/40012WO 97/38986US 5677318WO 97/34882WO 97/16435WO 97/03678WO 97/03667WO 96/36623WO 96/31509WO 96/25928WO 96/06840WO 96/21667WO 96/19469US 5510368WO 96/09304GB 22/83745WO 96/03392WO 94/25431WO 94/20480WO 94/13635JP 09052882GB 22/94879WO 95/15316WO 95/15315WO 96/03388WO 96/24585US 5344991WO 95/00501US 5968974US 5945539US 5994381US 6180651

0246 Pyrazoles can be prepared by methods described in WO 95/15316. Pyrazoles can further be prepared by methods described in WO 95/15315. Pyrazoles can also be prepared by methods described in WO 96/03385. Thiophene analogs can be prepared by methods described in WO 95/00501. Preparation of thiophene analogs is also described in WO 94/15932. Oxazoles can be prepared by the methods described in WO 95/00501. Preparation of oxazoles is also described in WO 94/27980. Isoxazoles can be prepared by the methods described in WO 96/25405. Imidazoles can be prepared by the methods described in WO 96/03388. Preparation of imidazoles is also described in WO 96/03387. Cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Pat. No. 5,344,991. Preparation of cyclopentane Cox-2 inhibitors is also described in WO 95/00501. Terphenyl compounds can be prepared by the methods described in WO 96/16934. Thiazole compounds can be prepared by the methods described in WO 96/03,392. Pyridine compounds can be prepared by the methods described in WO 96/03392. Preparation of pyridine compounds is also described in WO 96/24585. 0247 The celecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,466,823. 0248 The valdecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,633,272. 0249 The parecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,932,598. 0250 The rofecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,968,974. 0251 The Japan Tobacco JTE-522 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in JP90/52,882. 0252 The lumiracoxib (Cox-189) used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 99/11605. 0253 The etoricoxib (MK 663) used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 98/03484. 0254 Bristol Meyers Squibb's BMS 34070 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 6,180,651. 0255 The above references listed in Tables II and III above describe various COX-2 inhibitors suitable for use in the present invention described herein, and processes for their manufacture, are hereby individually incorporated by reference. 0256 Preferred COX-2 inhibitors that may be used in the present invention include, but are not limited to: 211

0257 JTE-522, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; 0258 C2) 0259 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(methyl-5-pyridinyl)pyridine, 0260 C3) 0261 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one; 212

0262 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-benzenesulfonamide; 213

0263 rofecoxib, 4-(4-(methylsulfonyl)phenyl-3-phenyl-2(5H)-furanone; 214

0264 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 0265 C7) 0266 N-4-(5-methyl-3-phenylisoxazol-4ylphenylsulfonylpropanamide; 215

0267 4-5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-ylbenzenesulfonamide; 216

0268 6-5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl-3(2H)-pyridazinone; 217

0269 N-(4-nitro-2-phenoxyphenyl)methanesulfonamide; 218

0270 3-(3,4-difluorophenoxy)-5,5-dimethyl-4-4-(methylsulfonyl)phenyl-2(5H)-furanone; 219

0271 N-6-(2,4-difluorophenyl)thio-2,3-dihydro-1-oxo-1H-inden-5-ylmethanesulfonamide; 220

0272 3-(4-chlorophenyl)-4-4-(methylsulfonyl)phenyl-2(3H)-oxazolone; 221

0273 4-3-(4-fluorophenyl)-2,3-dihydro-2-oxo-4-oxazolylbenzenesulfonamide; 222

0274 3-4-(methylsulfonyl)phenyl-2-phenyl-2-cyclopenten-1-one; 223

0275 4-(2-methyl-4-phenyl-5-oxazolyl)benzenesulfonamide; 224

0276 3-(4-fluorophenyl)-4-4-(methylsulfonyl)phenyl-2(3H)-oxazolone. 225

0277 5-(4-fluorophenyl)-1-4-(methylsulfonyl)phenyl-3-(trifluoromethyl)-1H-pyrazole; 226

0278 4-5-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 227

0279 4-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylbenzenesulfonamide; 228

0280 4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-ylbenzenesulfonamide; 229

0281 N-2-(cyclohexyloxy)-4-nitrophenylmethanesulfonamide; 230

0282 N-6-(2,4-difluorophenoxy)-2,3-dihydro-1-oxo-1H-inden-5-ylmethanesulfonamide; 231

0283 3-(4-chlorophenoxy)-4-(methylsulfonyl)aminobenzenesulfonamide; 232

0284 3-(4-fluorophenoxy)-4-(methylsulfonyl)aminobenzenesulfonamide; 233

0285 3-(1-methyl-1H-imidazol-2-yl)thio-4 (methylsulfonyl) aminobenzenesulfonamide; 234

0286 5,5-dimethyl-4-4-(methylsulfonyl)phenyl-3-phenoxy-2(5H)-furanone; 235

0287 N-6-(4-ethyl-2-thiazolyl)thio-1,3-dihydro-1-oxo-5-isobenzofuranylmethanesulfonamide; 236

0288 3-(2,4-dichlorophenyl)thio-4-(methylsulfonyl)aminobenzenesulfonamide; 237

0289 1-fluoro-4-2-4-(methylsulfonyl)phenylcyclopenten-1-ylbenzene; 238

0290 4-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-ylbenzenesulfonamide; 239

0291 3-1-4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-ylpyridine; 240

0292 4-2-(3-pyridinyll)-4-(trifluoromethyl)-1H-imidazol-1-ylbenzenesulfonamide; 241

0293 4-5-(hydroxymethyl)-3-phenylisoxazol-4-ylbenzenesulfonamide; 242

0294 4-3-(4-chlorophenyl)-2,3-dihydro-2-oxo-4-oxazolylbenzenesulfonamide; 243

0295 4-5-(difluoromethyl)-3-phenylisoxazol-4-ylbenzenesulfonamide; 244

0296 1,1:2,1-terphenyl-4-sulfonamide; 245

0297 4-(methylsulfonyl)-1,1,2,1-terphenyl; 246

0298 4-(2-phenyl-3-pyridinyl)benzenesulfonamide; 247

0299 N-(2,3-dihydro-1,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-yl)methanesulfonamide; and 248

0300 N-3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-ylmethanesulfonamide; 249

250

0301 2-(2-chloro-6-fluorophenyl)amino-5-methylbenzeneacetic acid 251

0302 5-chloro-6-methyl-3-4-(methylsulfonyl)phenyl-2,3-bipyridine 252

0303 More preferred COX-2 inhibitors that may be used in the present invention are selected from the group consisting of: 253

0304 JTE-522, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; 0305 II) 0306 5-chloro-3-(4-methylsulfonyl)phenyl)-2-(methyl-5-pyridinyl)pyridine; 0307 III) 0308 2(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one; 254

0309 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-benzenesulfonamide; 255

0310 rofecoxib, 4-(4-(methylsulfonyl)phenyl-3-phenyl-2(5H)-furanone; 256

0311 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 0312 VII) 0313 N-4-(5-methyl-3-phenylisoxazol-4ylphenylsulfonylpropanamide; 257

0314 4-5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-ylbenzenesulfonamide; and 258

0315 2-(2-chloro-6-fluorophenyl)amino-5-methylbenzeneacetic acid 0316 Still more preferably, the COX-2 inhibitors that may be used in the present invention include, but are not limited to celecoxib, valdecoxib, parecoxib, rofecoxib, lumiracoxib and Japan Tobacco JTE-522. 0317 Also included in the combination of the invention are the isomeric forms, prodrugs and tautomers of the described compounds and the pharmaceutically-acceptable salts thereof. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.

Utility 0318 The compounds of the present invention are inhibitor of protein kinases (PKs) and cyclooxygenase enzyme, in particular cyclooxygenase-2 enzyme, and are therefore useful in the treatment of cancer. 0319 The PKs whose catalytic activity is modulated by the compounds of Formula (I) of this invention include protein tyrosine kinases such as receptor tyrosine kinases (RTKs), cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment, etc.). See, Schlessinger and Ullrich, 1992, Neuron 9:303-391. 0320 It has been shown that tyrosine phosphorylation sites on growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl et al., 1992, Cell 69:413-423, Songyang et al., 1994, Mol. Cell. Biol. 14:2777-2785), Songyang et al., 1993, Cell 72:767-778, and Koch et al., 1991, Science 252:668-678. Several intracellular substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups: (1) substrates that have a catalytic domain, and (2) substrates which lack such domain but which serve as adapters and associate with catalytically active molecules. Songyang et al., 1993, Cell 72:767-778. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. 0321 STKs, being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-line response to a PTK event. STKs have been implicated in the signaling process which initiates DNA synthesis and subsequent mitosis leading to cell proliferation. 0322 Thus, PK signal transduction results in, among other responses, cell proliferation, differentiation, growth and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis. 0323 A precise understanding of the mechanism by which the compounds of this invention inhibit PKs is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds of Formula (I) interact with the amino acids in the catalytic region of PKs. PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs. Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs. More specifically, it is thought that the 2-indolinone component of the compounds of Formula (I) binds in the general space normally occupied by the adenine ring of ATP. Specificity of a particular molecule for a particular PK may then arise as the result of additional interactions between the various substituents on the 2-indolinone core and the amino acid domains specific to particular PKs. Thus, different indolinone substituents may contribute to preferential binding to particular PKs. The ability to select compounds active at different ATP (or other nucleotide) binding sites makes the compounds of Formula (I) useful for targeting any protein with such a site. The compounds of Formula (I) disclosed herein thus have utility in in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins. 0324 Additionally, the compounds of Formula (I) provide a therapeutic approach to the treatment of many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers. 0325 Further examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds of present invention may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders. 0326 Cell proliferative disorders, which may be prevented, treated or further studied by the present invention include cancer, blood vessel proliferative disorders and mesangial cell proliferative disorders. 0327 Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and angiogenesis (spreading of blood vessels). While vasculogenesis and angiogenesis play important roles in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a pivotal role in cancer development where they result in the formation of new capillaries needed to keep a tumor alive. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness. 0328 Two structurally related RTKs have been identified to bind VEGF with high affinity: the fms-like tyrosine I (fit-1) receptor (Shibuya et al., 1990, Oncogene,5:519-524; De Vries et al., 1992, Science, 255:989-991) and the KDR/FLK-1 receptor, also known as VEGF-R2. Vascular endothelial growth factor (VEGF) has been reported to be an endothelial cell specific mitogen with in vitro endothelial cell growth promoting activity. Ferrara & Henzel, 1989, Biochein. Biophys. Res. Comm., 161:851-858; Vaisman et al., 1990, J. Biol. Chem., 265:19461-19566. Information set forth in U.S. application Ser. Nos. 08/193,829, 08/038,596 and 07/975,750, strongly suggest that VEGF is not only responsible for endothelial cell proliferation, but also is the prime regulator of normal and pathological angiogenesis. See generally, Klagsburn & Soker, 1993, Current Biology, 3(10)699-702; Houck, et al., 1992, J. Biol. Chem., 267:26031-26037. 0329 Normal vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and female reproductive processes such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy. Folkman & Shing, 1992, J. Biological Chem., 267(16):10931-34. Uncontrolled vasculogenesis and/or angiogenesis has been associated with diseases such as diabetes as well as with malignant solid tumors that rely on vascularization for growth. Klagsburn & Soker, 1993, Current Biology, 3(10):699-702; Folkham, 1991, J. Natl. Cancer Inst., 82:4-6; Weidner, et al., 1991, New Engl. J. Med., 324:1-5. 0330 The surmised role of VEGF in endothelial cell proliferation and migration during angiogenesis and vasculogenesis indicates an important role for the KDR/FLK-1 receptor in these processes. Diseases such as diabetes mellitus (Folkman, 198, in XIth Congress of Thrombosis and Haemostasis (Verstraeta, et al., eds.), pp. 583-596, Leuven University Press, Leuven) and arthritis, as well as malignant tumor growth may result from uncontrolled angiogenesis. See e.g., Folkman, 1971, N. Engl. J. Med., 285:1182-1186. The receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and/or angiogenesis and a variety of severe diseases which involve abnormal cellular growth caused by such processes. Plowman, et al., 1994, DN&P, 7(6):334-339. More particularly, the KDR/FLK-1 receptor's highly specific role in neovascularization make it a choice target for therapeutic approaches to the treatment of cancer and other diseases which involve the uncontrolled formation of blood-vessels. 0331 Thus, the present invention provides compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-1 when activated by ligands such as VEGF. Although it is believed that the compounds of the present invention act on a receptor or other component along the tyrosine kinase signal transduction pathway, they may also act directly on the tumor cells that result from uncontrolled angiogenesis. 0332 Although the nomenclature of the human and murine counterparts of the generic flk-I receptor differ, they are, in many respects, interchangeable. The murine receptor, Flk-1, and its human counterpart, KDR, share a sequence homology of 93.4% within the intracellular domain. Likewise, murine FLK-I binds human VEGF with the same affinity as mouse VEGF, and accordingly, is activated by the ligand derived from either species. Millauer et al., 1993, Cell, 72:835-846; Quinn et al., 1993, Proc. Natl. Acad. Sci. USA, 90:7533-7537. FLK-1 also associates with and subsequently tyrosine phosphorylates human RTK substrates (e.g., PLC- or p85) when co-expressed in 293 cells (human embryonal kidney fibroblasts). 0333 Models which rely upon the FLK-1 receptor therefore are directly applicable to understanding the KDR receptor. For example, use of the murine FLK-1 receptor in methods which identify compounds that regulate the murine signal transduction pathway are directly applicable to the identification of compounds which may be used to regulate the human signal transduction pathway, that is, which regulate activity related to the KDR receptor. Thus, chemical compounds identified as inhibitors of KDR/FLK-1 in vitro, can be confirmed in suitable in vivo models. Both in vivo mouse and rat animal models have been demonstrated to be of excellent value for the examination of the clinical potential of agents acting on the KDR/FLK-1 induced signal transduction pathway. 0334 Thus, the present invention provides compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-1 receptor and interfering with the signal transduced by KDR/FLK-1. Thus the present invention provides a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi's sarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon and epidermoid carcinoma. In addition, data suggests the administration of compounds which inhibit the KDR/Flk-1 mediated signal transduction pathway may also be used in the treatment of hemangioma, restenois and diabetic retinopathy. 0335 Furthermore, this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 receptor. 0336 Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and autophosphorylation. Binding sites are thereby created for intracellular signal transduction molecules which leads to the formation of complexes with a spectrum of cytoplasmic signalling molecules that facilitate the appropriate cellular response, e.g., cell division and metabolic effects to the extracellular microenvironment. See, Schlessinger and Ullrich, 1992, Neuron, 9:1-20. 0337 The close homology of the intracellular regions of KDR/FLK-1 with that of the PDGF- receptor (50.3% homology) and/or the related flt-1 receptor indicates the induction of overlapping signal transduction pathways. For example, for the PDGF- receptor, members of the src family (Twamley et al., 1993, Proc. Natl. Acad. Sci. USA, 90:7696-7700), phosphatidylinositol-3-kinase (Hu et al., 1992, Mol. Cell. Biol., 12:981-990), phospholipase c (Kashishian & Cooper, 1993, Mol. Cell. Biol., 4:49-51), ras-GTPase-activating protein, (Kashishian et al., 1992, EMBO J., 11:1373-1382), PTP-ID/syp (Kazlauskas et al., 1993, Proc. Natl. Acad. Sci. USA, 10 90:6939-6943), Grb2 (Arvidsson et al., 1994, Mol. Cell. Biol., 14:6715-6726), and the adapter molecules Shc and Nck (Nishimura et al., 1993, Mol. Cell. Biol., 13:6889-6896), have been shown to bind to regions involving different autophosphorylation sites. See generally, Claesson-Welsh, 1994, Prog. Growth Factor Res., 5:37-54. Thus, it is likely that signal transduction pathways activated by KDR/FLK-1 include the ras pathway (Rozakis et at, 1992, Nature, 360:689-692), the PI-3-kinase, the src-mediated and the plcy-mediated pathways. Each of these pathways may play a critical role in the angiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells. Consequently, a still further aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis as such processes are controlled by these pathways. 0338 Conversely, disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis, are also implicated and may be treated or prevented by the methods of this invention. 0339 Fibrotic disorders refer to the abnormal formation of extracellular matrices. Examples of fibrotic disorders include hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. An increased extracellular matrix resulting in a hepatic scar can also be caused by a viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis. Other fibrotic disorders implicated include atherosclerosis. 0340 Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as such disorders as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. The RTK PDGFR has been implicated in the maintenance of mesangial cell proliferation. Floege et al., 1993, Kidney International 43:47S-54S. 0341 Many cancers are cell proliferative disorders and, as noted previously, PKs have been associated with cell proliferative disorders. Thus, it is not surprising that PKs such as, for example, members of the RTK family have been associated with the development of cancer. Some of these receptors, like EGFR (Tuzi et al., 1991, Br. J. Cancer 63:227-233, Torp et al., 1992, APMIS 100:713-719) HER2/neu (Slamon et al., 1989, Science 244:707-712) and PDGF-R (Kumabe et al., 1992, Oncogene, 7:627-633) are over-expressed in many tumors and/or persistently activated by autocrine loops. In fact, in the most common and severe cancers these receptor over-expressions (Akbasak and Suner-Akbasak et al., 1992, J. Neurol. Sci., 111:119-133, Dickson et al., 1992, Cancer Treatment Res. 61:249-273, Korc et al., 1992, J. Clin. Invest. 90:1352-1360) and autocrine loops (Lee and Donoghue, 1992, J. Cell. Biol., 118:1057-1070, Korc et al., supra, Akbasak and Suner-Akbasak et al., supra) have been demonstrated. For example, EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer. PDGFR has been associated with glioblastoma and melanoma as well as lung, ovarian and prostate cancer. The RTK c-met has also been associated with malignant tumor formation. For example, c-met has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas. Additionally c-met has been linked to leukemia. Over-expression of the c-met gene has also been detected in patients with Hodgkins disease and Burkitts disease. 0342 IGF-IR, in addition to being implicated in nutritional support and in type-II diabetes, has also been associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al., 1989, J. Clin. Invest. 84:1418-1423) and small lung tumor cells (Macauley et al., 1990, Cancer Res., 50:2511-2517). In addition, IGF-I, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist et al., 1993, Cancer Res. 53:2475-2478. The importance of IGF-IR and its ligands in cell proliferation is further supported by the fact that many cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) are stimulated to grow by IGF-I. Goldring and Goldring, 1991, Eukaryotic Gene Expression,1 :301-326. Baserga and Coppola suggest that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, 1995, Cancer Res., 55:249-252, Baserga, 1994, Cell 79:927-930, Coppola et al., 1994, Mol. Cell. Biol., 14:4588-4595. 0343 STKs have been implicated in many types of cancer including, notably, breast cancer (Cance, et al, Int. J. Cancer, 54:571-77 (1993)). 0344 The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, restenosis, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated in corneal and dermal wound healing. Defects in Insulin-R and IGF-1R are indicated in type-II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman et al., 1994, DN&P 7:334-339. 0345 As noted previously, not only RTKs but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, bik, hck, fgr and yrk (reviewed by Bolen et al., 1992, FASEB J., 6:3403-3409) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in many PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp60v-src) in chicken. Moreover, its cellular homolog, the proto-oncogene pp60c-src transmits oncogenic signals of many receptors. Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp60c src, which is characteristic of malignant cells but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders. 0346 Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders. 0347 STKs have been associated with inflamation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis. 0348 PKs have also been implicated in embryo implantation. Thus, the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents. Additional disorders which may be treated or prevented using the compounds of this invention are immunological disorders such as autoimmune disease, AIDS and cardiovasular disorders such as atherosclerosis. 0349 Finally, both RTKs and CTKs are currently suspected as being involved in hyperimmune disorders. 0350 Examples of the effect of a number of exemplary compounds of this invention on several PTKs are shown in Table 2 below. The compounds and data presented are not to be construed as limiting the scope of this invention in any manner whatsoever. 0351 B. Cyclooxygenase-2 inhibitor or COX-2 inhibitor or cyclooxygenase-2 inhibitor includes agents that specifically inhibit a class of enzymes, cyclooxygenase-2, with less significant inhibition of cyclooxygenase-1. Preferably, it includes compounds which have a cyclooxygenase-2 IC50 of less than about 0.2 M, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC50 of greater than about 1 M, and more preferably of greater than 10 M. 0352 Studies indicate that prostaglandins synthesized by cyclooxygenases play a critical role in the initiation and promotion of cancer. Moreover, COX-2 is overexpressed in neoplastic lesions of the colon, breast, lung, prostate, esophagus, pancreas, intestine, cervix, ovaries, urinary bladder, and head & neck. In several in vitro and animal models, COX-2 inhibitors have inhibited tumor growth and metastasis. 0353 In addition to cancers per se, COX-2 is also expressed in the angiogenic vasculature within and adjacent to hyperplastic and neoplastic lesions indicating that COX-2 plays a role in angiogenesis. In both the mouse and rat, COX-2 inhibitors markedly inhibited bFGF-induced neovascularization. The utility of COX-2 inhibitors as chemopreventive, antiangiogenic and chemotherapeutic agents is described in the literature (Koki et al., Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy. Exp. Opin. Invest. Drugs (1999) 8(10) pp. 1623-1638, hereby incorporated by reference). Amplification and/or overexpression of HER-2/nue (ErbB2) occurs in 20-30% of human breast and ovarian cancers as well as in 5-15% of gastric and esophageal cancers and is associated with poor prognosis. Additionally, it has been recently discovered in vitro that COX-2 expression is upregulated in cells overexpressing the HER-2/neu oncogene. (Subbaramaiah et al., Increased expression of cyclooxygenase-2 in HER-2/neu-overexpressing breast cancer. Cancer Research (submitted 1999), hereby incorporated by reference). In this study, markedly increased levels of PGE2 production, COX-2 protein and mRNA were detected in HER-2/neu transformed mammary epithelial cells compared to a non-transformed partner cell line. Products of COX-2 activity, i.e., prostaglandins, stimulate proliferation, increase invasiveness of malignant cells, and enhance the production of vascular endothelial growth factor, which promotes angiogenesis. Further, HER-2/neu induces the production of angiogenic factors such as vascular endothelial growth factor. 0354 Consequently, the administration of a COX-2 inhibitor in combination with an anti HER-2/neu antibodies such as trastuzumab (Herceptin) and other therapies directed at inhibiting HER-2/neu is contemplated to treat cancers in which HER-2/neu is overexpressed. 0355 Also, it is contemplated that COX-2 levels are elevated in tumors with amplification and/or overexpression of other oncogenes including but not limited to c-myc, N-myc, L-myc, K-ras, H-ras, N-ras. Products of COX-2 activity stimulate cell proliferation, inhibit immune surveillance, increase invasiveness of malignant cells, and promote angiogenesis. Consequently, the administration of a protein kinase inhibitor in combination with a COX-2 inhibitor of the present invention is useful to prevent or treat cancers in which oncogenes are overexpressed. 0356 Specific COX-2 inhibitors are useful for the treatment of cancer (WO98/16227) and in several animal models reduce angiogenesis driven by various growth factors (WO98/22101). Anti-angiogenesis was achieved with a COX-2 inhibitor in rats implanted with bFGF, vascular endothelium growth factor (VEGF) or carrageenan, proteins with well-known angiogenic properties. (Masferrer, et al., 89th Annual Meeting of the American Association for Cancer Research, March 1998.)

Pharmaceutical Composition and Administration 0357 A compound of the present invention or a pharmaceutically acceptable salt thereof, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). Techniques for formulation and administration of drugs may be found in Remington's Pharmacological Sciences, Mack Publishing Co., Easton, Pa., latest edition. 0358 As used herein, administer or administration refers to the delivery of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof of this invention to an organism for the purpose of prevention or treatment of a PK-related disorder. 0359 Suitable routes of administration may include, without limitation, oral, rectal, topical, transmucosal or intestinal administration or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular injections. The preferred routes of administration are oral and parenteral. 0360 Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation. 0361 Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will be targeted to and taken up selectively by the tumor. 0362 Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. 0363 Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. 0364 For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. 0365 For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores. Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used. 0366 Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. 0367 Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers may be added in these formulations, also. 0368 The capsules may be packaged into brown glass or plastic bottles to protect the active compound from light. The containers containing the active compound capsule formulation must be stored at controlled room temperature (15-30 C.). 0369 For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. 0370 The compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents. 0371 Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. 0372 Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. 0373 The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. 0374 In addition to the fomulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharamcologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt. 0375 A non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer and an aqueous phase such as the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of such a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80, the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars or polysaccharides may substitute for dextrose. 0376 Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addtion, certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity. 0377 Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. 0378 The pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. 0379 Many of the PK modulating compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species. Examples of salts in which the compound forms the positively charged moiety include, without limitation, quaternary ammonium (defined elsewhere herein), salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, malate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH)2), etc.). 0380 Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, e.g., the modulation of PK activity or the treatment or prevention of a PK-related disorder. 0381 More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. 0382 Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. 0383 For any compound used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the PK activity). Such information can then be used to more accurately determine useful doses in humans. 0384 Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC50 and the LD50 (both of which are discussed elsewhere herein) for a subject compound. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in The Pharmacological Basis of Therapeutics, Ch. 1 p.1). 0385 Dosage amount and interval may be adjusted individually to provide plasma levels of the active species which are sufficient to maintain the kinase modulating effects. These plasma levels are referred to as minimal effective concentrations (MECs). The MEC will vary for each compound but can be estimated from in vitro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations. 0386 Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. 0387 At present, the therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.25 mg/m2 to 1500 mg/m2 per day; preferably about 3 mg/m2/day. Even more preferably 50 mg/qm qd till 400 mg/qd. 0388 Therapeutically effective amounts of cyclooxygenase inhibitor is from about 0.1 mg to about 10,000 mg for the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1,000 mg. 0389 The amount of active ingredient that may be combined with other anticancer agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. 0390 In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration and other procedures known in the art may be employed to determine the correct dosage amount and interval. 0391 The amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. 0392 The compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration. Such notice, for example, may be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like. 0393 It is also an aspect of this invention that a compound described herein, or its salt or prodrug, might be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above. For instance, a compound, salt or prodrug of this invention might be combined with alkylating agents such as fluorouracil (5-FU) alone or in further combination with leukovorin; or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); and triazines, e.g., dacarbazine (used in the treatment of soft tissue sarcoma). 0394 A compound, salt or prodrug of this invention can also be used in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias. 0395 It is contemplated that a compound, salt or prodrug of this invention can also be used in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer), vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer); and the enzymatic chemotherapeutic agents such as L-asparaginase. 0396 In addition to the above, a compound, salt or prodrug of this invention could also be used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate); estrogens (e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens, e.g., testosterone propionate; and aromatase inhibitors such as anastrozole. Other antineoplastic agents known in the art can be used along with the combination therapy of the present invention. Examples of these antineoplastic agents and other are give in Applicants' U.S. patent application Ser. No. 60/113,786, filed Dec. 23, 1998, and PCT Application Publication No. WO 00/38716 the disclosure of which is incorporated herein by reference. 0397 Finally, it is also contemplated that the combination of a compound of this invention will be effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.

EXAMPLES

Synthetic Examples 0398 The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. 0399 Synthesis of Protein Kinase Inhibitor of the Present InventionCompounds of Formula (I) 0400 General Synthetic Procedure: 0401 The following general methodology may be employed to prepare the compounds of this invention: 0402 The appropriately substituted 2-oxindole (1 equiv.), the appropriately substituted aldehyde (1.2 equiv.) and a base (0.1 equiv.) are mixed in a solvent (1-2 ml/mmol 2-oxindole) and the mixture is then heated for from about 2 to about 12 hours. After cooling, the precipitate that forms is filtered, washed with cold ethanol or ether and vacuum dried to give the solid product. If no precipitate forms, the reaction mixture is concentrated and the residue is triturated with dichloromethane/ether, the resulting solid is collected by filtration and then dried. The product may optionally be further purified by chromatography. 0403 The base may be an organic or an inorganic base. If an organic base is used, preferably it is a nitrogen base. Examples of organic nitrogen bases include, but are not limited to, diisopropylamine, trimethylamine, triethylamine, aniline, pyridine, 1,8-diazabicyclo5.4.1undec-7-ene, pyrrolidine and piperidine. 0404 Examples of inorganic bases are, without limitation, ammonia, alkali metal or alkaline earth hydroxides, phosphates, carbonates, bicarbonates, bisulfates and amides. The alkali metals include, lithium, sodium and potassium while the alkaline earths include calcium, magnesium and barium. 0405 In a presently preferred embodiment of this invention, when the solvent is a protic solvent, such as water or alcohol, the base is an alkali metal or an alkaline earth inorganic base, preferably, a alkali metal or an alkaline earth hydroxide. 0406 It will be clear to those skilled in the art, based both on known general principles of organic synthesis and on the disclosures herein which base would be most appropriate for the reaction contemplated. 0407 The solvent in which the reaction is carried out may be a protic or an aprotic solvent, preferably it is a protic solvent. A protic solvent is a solvent which has hydrogen atom(s) covalently bonded to oxygen or nitrogen atoms which renders the hydrogen atoms appreciably acidic and thus capable of being shared with a solute through hydrogen bonding. Examples of protic solvents include, without limitation, water and alcohols. 0408 An aprotic solvent may be polar or non-polar but, in either case, does not contain acidic hydrogens and therefore is not capable of hydrogen bonding with solutes. Examples, without limitation, of non-polar aprotic solvents, are pentane, hexane, benzene, toluene, methylene chloride and carbon tetrachloride. Examples of polar aprotic solvents are chloroform, tetrahydro-furan, dimethylsulfoxide and dimethylformamide. 0409 In a presently preferred embodiment of this invention, the solvent is a protic solvent, preferably water or an alcohol such as ethanol. 0410 The reaction is carried out at temperatures greater than room temperature. The temperature is generally from about 30 C. to about 150 C., preferably about 80 C. to about 100 C., most preferable about 75 C. to about 85 C., which is about the boiling point of ethanol. By about is meant that the temperature range is preferably within 10 degrees Celcius of the indicated temperature, more preferably within 5 degrees Celcius of the indicated temperature and, most preferably, within 2 degrees Celcius of the indicated temperature. Thus, for example, by about 75 C. is meant 75 C.10 C., preferably 75 C.5 C. and most preferably, 75 C.2 C. 0411 2-Oxindoles and aldehydes, may be readily synthesized using techniques well known in the chemical arts. It will be appreciated by those skilled in the art that other synthetic pathways for forming the compounds of the invention are available and that the following is offered by way of example and not limitation. 0412 Method A: Formylation of Pyrroles 0413 POCl3 (1.1 equiv.) is added dropwise to dimethylformamide (3 equiv.) at 10 C. followed by addition of the appropriate pyrrole dissolved in dimethylformamide. After stirring for two hours, the reaction mixture is diluted with H2O and basified to pH 11 with 10 N KOH. The precipitate which forms is collected by filtration, washed with H2O and dried in a vacuum oven to give the desired aldehyde. 0414 Method B: Saponification of Pyrrolecarboxylic Acid Esters 0415 A mixture of a pyrrolecarboxylic acid ester and KOH (2-4 equiv.) in EtOH is refluxed until reaction completion is indicated by thin layer chromatography (TLC). The cooled reaction mixtrue is acidified to pH 3 with 1 N HCl. The precipitate which forms is collected by filtration, washed with H2O and dried in a vacuum oven to give the desired pyrrolecarboxylic acid. 0416 Method C: Amidation 0417 To a stirred solution of a pyrrolecarboxylic acid dissolved in dimethylformamide (0.3M) is added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (1.2 equiv.), 1-hydroxybenzotriazole (1.2 equiv.), and triethylamine (2 equiv.). The appropriate amine is added (1 equiv.) and the reaction stirred until completion is indicated by TLC. Ethyl acetate is then added to the reaction mixture and the solution washed with saturated NaHCO3 and brine (with extra salt), dried over anhydrous MgSO4 and concentrated to afford the desired amide. 0418 Method D: Condensation of Aldehydes and Oxindoles Containing Carboxylic Acid Substituents 0419 A mixture of the oxindole (1 equivalent), 1 equivalent of the aldehyde and 13 equivalents of piperidine (or pyrrolidine) in ethanol (0.4 M) is stirred at 90-100 C. until reaction completion is indicated by TLC. The mixture is then concentrated and the residue acidified with 2N HCl. The precipitate that forms is washed with H2O and EtOH and then dried in a vacuum oven to give the product. 0420 Method E: Condensation of Aldehydes and Oxindoles not Containing Carboxylic Acid Substituents 0421 A mixture of the oxindole (1 equivalent), 1 equivalent of the aldehyde and 1-3 equivalents of piperidine (or pyrrolidine) in ethanol (0.4 M) is stirred at 90-100 C. until reaction completion is indicated by TLC. The mixture is cooled to room temperature and the solid which forms is collected by vacuum filtration, washed with ethanol and dried to give the product. If a precipitate does not form upon cooling of the reaction mixture, the mixture is concentrated and purified by column chromatography. 0422 C. Examples of Oxindole Syntheses 0423 The following examples of the synthesis of representative oxindoles is not to be construed as limiting the scope of this invention in any manner whatsoever. Alternate routes to the oxindoles shown as well as other oxindoles to be used to make the compounds of this invention will become apparent to those skilled in the art based on the following disclosures. Such syntheses and oxindoles are within the scope and spirit of this invention. 0424 5-Amino-2-oxindole 0425 5-Nitro-2-oxindole (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of the title compound as a white solid. 0426 5-Bromo-2-oxindole 0427 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to 10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at 10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. 0428 4-Methyl-2-oxindole 0429 Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid. 0430 7-Bromo-5-chloro-2-oxindole 0431 5-Chloro-2-oxindole (16.8 g) and 19.6 g of N-bromosuccinimide were suspended in 140 mL of acetonitrile and refluxed for 3 hours. Thin layer chromatography (silica, ethyl acetate) at 2 hours of reflux showed 5-chloro-2-oxindole or N-bromosuccinimide (Rf 0.8), product (Rf 0.85) and a second product (Rf 0.9) whose proportions did not change after another hour of reflux. The mixture was cooled to 10 C., the precipitate was collected by vacuum filtration, washed with 25 mL of ethanol and sucked dry for 20 minutes in the funnel to give 14.1 g of wet product (56% yield). The solid was suspended in 200 mL of denatured ethanol and slurry-washed by stirring and refluxing for 10 minutes. The mixture was cooled in an ice bath to 10 C. The solid product was collected by vacuum filtration, washed with 25 mL of ethanol and dried under vacuum at 40 C. to give 12.7 g (51% yield) of 7-bromo-5-chloro-2-oxindole. 0432 5-Fluoro-2-oxindole 0433 5-Fluoroisatin (8.2 g) was dissolved in 50 mL of hydrazine hydrate and refluxed for 1.0 hr. The reaction mixtures were then poured in ice water. The precipitate was then filtered, washed with water and dried in a vacuum oven to afford the title compound. 0434 5-Nitro-2-oxindole 0435 2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at 10 to 15 C. while 2.1 mL of fuming nitric acid was added dropwise. After the addition of the nitric acid the reaction mixture was stirred at 0 C. for 0.5 hr and poured into ice-water. The precipitate was collected by filtration, washed with water and crystallized from 50% acetic acid. The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70%) of 5-nitro-2-oxindole. 0436 5-Aminosulfonyl-2-oxindole 0437 To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30 C. during the addition. After the addition, the reaction mixture was stirred at room temperature for 1.5 hr, heated to 68 C. for 1 hr, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulfonyl-2-oxindole (50% yield) which was used without further purification. 0438 5-Chlorosulfonyl-2-oxindole (2.1 g) was added to 10 mL of ammonium hydroxide in 10 mL of ethanol and stirred at room temperature overnight. The mixture was concentrated and the solid collected by vacuum filtration to give 0.4 g (20% yield) of the title compound as an off-white solid. 0439 5-Isopropylaminosulfonyl-2-oxindole 0440 To a 100 mL flask charged with 27 mL chlorosulfonic acid was slowly added 13.3 g 2-oxindole. The reaction temperature was maintained below 30 C. during the addition. The reaction mixture was stirred at room temperature for 1.5 hour, heated to 68 C. for 1 hour, cooled, and poured into water. The precipitate which formed was filtered, washed with water and dried in a vacuum oven to give 11.0 g (50%) of 5-chlorosulfonyl-2-oxindole which was used without further purification. 0441 A suspension of 3 g 5-chlorosulfonyl-2-oxindole, 1.15 g isopropylamine and 1.2 mL of pyridine in 50 mL of dichloromethane was stirred at room temperature for 4 hours during which time a white solid formed. The solid was collected by vacuum filtration, slurry-washed with hot ethanol, cooled, collected by vacuum filtration and dried under vacuum at 40 C. overnight to give 1.5 g (45%) of 5-isopropylaminosulfonyl-2-oxindole. 0442 1HNMR (360 MHz, DMSO-d6) 10.69 (s, br, 1H, NH), 7.63 (dd, J2 and 8 Hz, 1H), 7.59 (d, J2 Hz, 1H), 7.32 (d, J7 Hz, 1H, NHSO2), 6.93 (d, J8 Hz, 1H), 3.57 (s, 2H), 3.14-3.23 (m, 1H, CH(CH3)2), 0.94 (d, J7 Hz, 6H, 2CH3). 0443 5-Phenylaminosulfonyl-2-oxindole 0444 A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), aniline (0.782 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 ml) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and acidified with 1N hydrochloric acid (16 mL). The organic layer was washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL) and then chromatographed on silica gel eluting with methanol/dichloromethane 1:9 to give of 5-phenylaminosulfonyl-2-oxindole. 0445 1HNMR (360 MHz, DMSO-d6) 10.71 (s, br, 1H, NH), 10.10 (s, br, 1H, NH), 7.57-7.61 (m, 2H), 7.17-7.22 (m, 2H), 7.06-7.09 (m, 2H), 6.97-7.0 (m, 1H), 6.88 (d, J8.4 Hz, 1H), 3.52 (s, 2H). 0446 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide 0447 A solution of 5-chlorosufonyl-2-oxindole (3 g) and 3-aminopyridine (1.46 g) in pyridine (15 mL) was stirred at room temperature overnight at which time a brown solid was present. The solid was filtered, washed with ethanol and dried under vacuum to yield 1.4 g (38%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide. 0448 1HNMR (360 MHz, DMSO-d6) 10.74 (s, 1H, NH), 10.39 (s, 1H, SO2NH), 8.27-8.28 (d, 1H), 8.21-8.23 (m, 1H), 7.59-7.62 (m, 2H), 7.44-7.68 (m, 1H), 7.24-7.28 (m, 1H), 6.69-6.71 (d, 1H), 3.54 (s, 2H). 0449 MS m/z (APCI) 290.2. 0450 5-Phenyloxindole 0451 5-Bromo-2-oxindole (5 g, 23.5 mmol) was dissolved in 110 mL toluene and 110 mL ethanol with stirring and a little heat. Tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.6 mmol) was added followed by 40 mL (80 mmol) 2M aqueous sodium carbonate. To this mixture was added benzene boronic acid (3.7 g, 30.6 mmol) and the mixture was heated in a 100 C. oil bath for 12 hours. The reaction was cooled, diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate (200 mL), water (200 mL), 1N HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated to afford a brown solid. Trituration with dichloromethane afforded 3.8 g (77%) of 5-phenyl-2-oxindole as a tan solid. 0452 1H NMR (360 MHz, DMSO-d6) 10.4 (br s, 1H, NH), 7.57 (dd, J1.8 and 7.2 Hz, 1H), 7.5 to 7.35 (m, 5H), 7.29 (m, 1H), 6.89 (d, J8.2 Hz, 1H), 3.51 (s, 2H, CH2CO). 0453 MS m/z 209 M. 0454 In similar fashion, the following oxindoles can be prepared: 0455 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one 0456 1H NMR (360 MHz, DMSO-d6) 10.46 (br, 1H, NH), 7.64 (d, J1.8 Hz, 2H), 7.57 (m, 1H), 7.27 (m, 2H), 7.05 (d, J1.1 Hz, 1H), 3.5 (s, 2H). 0457 MS-EI m/z 277/279 M. 0458 6-(4-Butylphenyl)-1,3-dihydroindol-2-one 0459 1H NMR (360 MHz, DMSO-d6) 10.39 (s, 1H, NH), 7.49 (d, J8.0 Hz, 2H), 7.25 (d, J8 Hz, 3H), 7.17 (dd, J1.5 and 7.8 Hz, 1H), 6.99 (d, J1.5 Hz, 1H), 3.48 (s, 2H, CH2CO), 2.60 (t, J7.5 Hz, 2 Hz, CH2CH3), 1.57 (m, 2H, CH2), 1.32 (m, 2H, CH2), 0.9 (t, J7.5 Hz, 3H, CH3). 0460 6-(5-Isopropyl-2-methoxyphenyl)-1,3-dihydroindol-2-one 0461 1H NMR (360 MHz, DMSO-d6) 10.29 (br s, 1H, NH), 7.16-7.21 (m, 2H), 7.08 (d, J2.4 Hz, 1H), 6.97-7.01 (m, 2H), 6.89 (d, J0.8 Hz, 1H), 3.71 (s, 3H, OCH3), 3.47 (s, 2H, CH2CO), 2.86 (m, 1H, CH(CH3)2), 1.19 (d, J6.8 Hz, 6H, CH(CH3)2). 0462 MS-EI m/z 281 M. 0463 6-(4-Ethylphenyl)-1,3-dihydroindol-2-one 0464 1H NMR (360 MHz, DMSO-d6) 10.39 (br s, 1H, NH), 7.50 (d, J8.2 Hz, 2H), 7.28 (d, J8.2 Hz, 2H), 7.25 (d, J7.5 Hz, 1H), 7.17 (dd, J1.6 & 7.5 Hz, 1H), 6.99 (d, J1.6 Hz, 1H), 3.48 (s, 2H, CH2CO), 2.63 (q, J7.6 Hz, 2H, CH2CH3), 1.20 (t, J7.6 Hz, 3H, CH2CH3). 0465 MS-EI m/z 237 M. 0466 6-(3-Isopropylphenyl)-1,3-dihydroindol-2-one 0467 1H NMR (360 MHz, DMSO-d6) 10.37 (br s, 1H, NR), 7.43 (m, 1H), 7.35-7.39 (m, 1H), 7.17-7.27 (m, 3H), 7.01 (d, J1.8 Hz, 1H), 3.49 (s, 2H, CH2CO), 2.95 (m, 1H, CH(CH3)2), 1.24 (d, J6.8 Hz, 6H, CH(CH3)2). 0468 MS-EI m/z 251 M. 0469 6-(2,4-Dimethoxyphenyl)-1,3-dihydroindol-2-one 0470 1H NMR (360 MHz, DMSO-d6) 10.28 (br s, 1H, NH), 7.17 (m, 2H), 6.93 (dd, J1.6 & 7.6 Hz, 1H), 6.86 (d, J1.6 Hz, 1H), 6.63 (d, J2.4 Hz, 1H), 6.58 (dd, J2.4 & 8.5 Hz, 1H), 3.79 (s, 3H, OCH3),3.74 (s, 3H, OCH3), 3.45 (s, 2H, CH2CO). 0471 MS-EI m/z 269 M. 0472 6-Pyridin-3-yl-1,3-dihydroindol-2-one 0473 1H NMR (360 MHz, DMSO-d6) 10.51 (s, 1H, NH), 8.81 (d, J2.5 Hz, 1H), 8.55 (dd, J1.8 and 5.7 Hz, 1H), 8 (m, 1H), 7.45 (dd, J5.7 and 9.3 Hz, 1H), 7.3 (m, 2H), 7.05 (s, 1H), 3.51 (s, 2H, CH2CO). 0474 MS m/z 210 M. 0475 2-Oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-ethoxyphenyl)-amide 0476 To a solution of 4-carboxy-2-oxindole (200 mg, 1.13 mmol) and 3-chloro-4-methoxyphenylamine (178 mg, 1.13 mmol) in dimethylformamide (15 mL) at room temperature was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 997 mg, 2.26 mmol) followed by 4-dimethylaminopyridine (206 mg, 1.69 mmol). The mixture was stirred at room temperature for 72 hours. The reaction was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (100 mL), water, 2N hydrochloric acid (100 mL), water (3200 mL) and brine. It was then dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate to give 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)-amide as a pink solid. 0477 1HNMR (360 MHz, DMSO-d6) 10.50 (s, br, 1H, NH), 10.12 (s, br, 1H, NH), 7.9 (s, J2.5 Hz, 1H), 7.62 (dd, J2.5 & 9 Hz, 1H), 7.38 (d, J7.6 Hz, 1H), 7.32 (t, J7.6 Hz, 1H), 7.13 (d, J9 Hz, 1H), 6.98 (d, J7.6 Hz, 1H), 3.83 (s, 3H, OCH3), 3.69 (s, 2H, CH2). 0478 MS-EI m/z 316 M. 0479 4-Carboxy-2-oxindole 0480 A solution of trimethylsilyldiazomethane in hexane (2 M) was added dropwise to a solution of 2.01 g 2-chloro-3-carboxy-nitrobenzene in 20 mL methanol at room temperature until no further gas evolution occurred. Acetic acid was then added to quench excess trimethylsilyldiazomethane. The reaction mixture was evaporated under vacuum and the residue was dried in an oven overnight. The 2-chloro-3-methoxycarbonylnitrobenzene obtained was pure enough for the following reaction. 0481 Dimethyl malonate (6.0 mL) was added to an ice-cold suspension of 2.1 g sodium hydride in 15 mL DMSO. The reaction mixture was stirred at 100 C. for 1 hour and then cooled to room temperature. 2-Chloro-3-methoxycarbonylnitrobenzene (2.15 g) was added in one portion and the mixture was heated to 100 C. for 1.5 hours. The reaction mixture was then cooled to room temperature, poured into ice water, acidified to pH 5 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3.0 g of the dimethyl 2-methoxycarbonyl-6-nitrophenyl-malonate. 0482 Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness, 20 mL ethanol and 1.1 g of tin(II) chloride were added and the mixture was refluxed for 2 hours. The mixture was filtered through Celite, concentrated and chromatographed on silica gel using ethyl acetate:hexane:acetic acid as eluent to give 0.65 g (37%) of 4-carboxy-2-oxindole as a white solid. 0483 1HNMR (360 MHz, DMSO-d6) 12.96 (s, br, 1H, COOH), 10.74 (s, br, 1H, NH), 7.53 (d, J8 Hz, 1H), 7.39 (t, J8 Hz, 1H), 7.12 (d, J8 Hz, 1H), 3.67 (s, 2H). 0484 D. Synthesis of Pyrrole Substituted 2-indolinones.

Example 1 0485 4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid 0486 4-Methyl-2-pyrrolecarboxylic acid ethyl ester (commercially available) was formylated using method A to give (73%) of 5-formyl-4-methyl-2-pyrrolecarboxylic acid ethyl ester. It was then hydrolysed using method B to give 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (58%). 0487 Oxindole (133 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 268 mg (100%) of the title compound as an orange-red solid. 0488 1HNMR (360 MHz, DMSO-d6) 13.84 (s, br, 1H, NH), 12.84 (s, br, 1H, COOH), 10.98 (s, br, 1H, NH), 7.82 (d, J7.5 Hz, 1H), 7.67 (s, 1H, H-vinyl), 7.18 (t, J7.5 Hz, 1H), 7.01 (t, J7.5 Hz, 1H), 6.88 (d, J7.5 Hz, 1H), 6.71 (d, J2.2 Hz, 1H), 2.32 (s, 3H, CH3). 0489 MS (negative mode) 266.8 M1.

Example 2 0490 4-Methyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid 0491 1-Methyl-1,3-dihydroindol-2-one (147 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 250 mg (86%) of the title compound. 0492 1HNMR (360 MHz, DMSO-d6) 13.82 (s, br, 1H, NH), 12.88 (s, br, 1H, 7.83 (d, J7.5 Hz, 1H), 7.65 (s, 1H, H-vinyl), 7.26 (t, J7.5 Hz, 1H), 7.02-7.09 (m, 2H), 6.70 (d, J2.2 Hz, 1H), 2.32 (s, 3H, CH3). 0493 MS m/z 283.0 M1.

Example 3 0494 4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid Methyl Ester 0495 Oxindole (105 mg, 0.79 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound. 0496 1HNMR (360 MHz, DMSO-d6) 13.98 (s, br, 1H, NH), 10.97 (s, br, 1H, NH), 7.82 (d, J7.6 Hz, 1H), 7.67 (s, 1H, H-vinyl), 7.2 (dt, J1.2 & 7.7 Hz, 1H), 7.01 (dt, J1.2, 7.7 Hz, 1H), 6.90 (d, J7.6 Hz, 1H), 6.77 (d, J2 Hz, 1H). 0497 MS (ES) m/z 283 M1.

Example 4 0498 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester 0499 5-Chloro-1,3-dihydroindol-2-one (2.22 g, 13.2 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.43 g) using method E to give 4.1 g (94%) of the title compound as an orange solid. 0500 1HNMR (360 MHz, DMSO-d6) 13.95 (s, br, 1H, NH), 7.98 (d, J2.2 Hz, 1H, H-4), 7.78 (s, 1H, H-vinyl), 7.18 (dd, J2.2 & 8.3 Hz, 1H, H-6), 6.87 (d, J8.3 Hz, 1H, H-7), 7.34 (d, J1.8 Hz, 1H, H-3), 4.27 (q, J7.2 Hz, 2H, OCH2CH3), 2.33 (s, 3H, CH3), 1.29 (t, J7.2 Hz, 3H, OCH2CH3). 0501 MS-EI m/z 330 M.

Example 5 0502 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid 0503 A mixture of 5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.3 g, 4 mmol) and potassium hydroxide in methanol (25 mL) and ethanol (25 mL) was heated to reflux for overnight. Insoluble materials were removed by filtration and the mixture was neutralized with 6N hydrochloric acid to give 0.876 g (70%) of the title compound. 0504 1HNMR (360 MHz, DMSO-d6) 13.80 (s, br, 1H, NH), 12.90 (s, br, 1H, COOH), 11.06 (s, br, 1H, NH), 8.02 (d, J1.8 Hz, 1H, H-4), 7.81 (s, 1H, H-vinyl), 7.20 (dd, J1.8 & 8.3 Hz, 1H, H-6), 6.89 (d, J8.3 Hz, 1H, H-7), 6.72 (d, J1.8 Hz, 1H, H-3), 2.35 (s, 3H, CH3). 0505 MS-EI m/z 302 M.

Example 6 0506 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-yl-propyl)amide 0507 5-Bromo-1,3-dihydroindol-2-one (0.16 g, 0.76 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (0.2 g, prepared by method C) to give 60 mg (17%) of the title compound as an orange solid. 0508 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 8.42 (t, J5.8 Hz, 1H, CONHCH2), 8.12 (d, J1.8 Hz, 1H, H-4), 7.78 (s, 1H, H-vinyl), 7.30 (dd, J1.8 & 8.4 Hz, 1H, H-6), 6.82 (d, J8.4 Hz, 1H, H-7), 6.77 (d, J2.4 Hz, 1H, H-3), 3.22-3.31 (m, 2H, CH2), 2.38-2.43 (m, 6H, 3CH2), 2.35 (s, 3H, CH3), 1.62-1.71 (m, 6H, 3CH2). 0509 MS-EI m/z 456 and 458 M1 and M2.

Example 7 0510 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0511 5-Bromo-1,3-dihydroindol-2-one (0.16 g, 0.75 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (0.2 g, prepared by method C) to give 30 mg (8%) of the title compound as an orange solid. 0512 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 8.40 (m, 1H, CONHCH2), 8.12 (d, J1.5 Hz, 1H, H-4), 7.78 (s, 1H, H-vinyl), 7.30 (dd, J1.5 & 8.2 Hz, 1H, H-6), 6.82 (d, J8.2 Hz, 1H, H-7), 6.78 (d, J2.4 Hz, 1H, H-3), 3.23 (m, 2H, CH2), 2.38-2.45 (m, 6H, CH2 & N(CH2CH3)2), 2.35 (s, 3H, CH3), 1.61 (m, 2H, CH2), 0.93 (t, J7.1 Hz, 6H, N(CH2CH3)2). 0513 MS-EI m/z 458 and 460 M1 and M2.

Example 8 0514 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)amide 0515 5-Bromo-1,3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid, (2-diethylaminoethyl)amide (prepared from ethyl pyrrole-2-carboxylate by method A, B and then C) to give 162 mg (38%) of the title compound. 0516 1H NMR (300 MHz, DMSO-d6) 13.53 (s, br, 1H, NH), 11.06 (s, br, 1H, NH), 8.37 (t, 1H, CONHCH2), 7.89 (m, 2H), 7.32 (dd, J2.0 Hz, 1H), 6.96 (s, 1H), 6.80-6.84 (m, 2H), 3.3 (m, 2H, CH2), 2.45-2.55 (m, 6H, N(CH2CH3)2 & CH2), 0.95 (t, J7.2 Hz, 6H, N(CH2CH3)2). 0517 MS-EI m/z 430 and 432 M1 and M1.

Example 9 0518 5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)amide 0519 6-Phenyl-1,3-dihydroindol-2-one (209 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)amide to give 182 mg (42%) of the title compound. 0520 1H NMR (300 MHz, DMSO-d6) 13.56 (s, br, 1H, NH), 11.06 (s, br, 1H, NH), 8.36 (t, 1H, CONHCH2), 7.77 (s, 1H, H-vinyl), 7.73 (d, J7.8 Hz, 1H), 7.64 (d, J7.2 Hz, 2H), 7.46 (m, 2H), 7.32 (m, 2H), 7.11 (s, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 3.31-3.32 (m, 2H, CH2), 2.46-2.53 (m, 6H, N(CH2CH3)2 & CH2), 0.96 (t, J6.9 Hz, 6H, N(CH2CH3)2). 0521 MS-EI m/z 428 M.

Example 10 0522 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)-methyl-amide 0523 5-Bromo-1,3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)methylamide to give 246 mg (55%) of the title compound. 0524 1H NMR (360 MHz, DMSO-d6) 13.54 (s, br, 1H, NH), 11.06 (s, br, 1H, NH), 7.90 (m, 2H), 7.33 (dd, J1.8 & 8.4 Hz, 1H), 6.82-6.85 (m, 3H), 3.55 (s, br, 2H, CH2), 3.25 (s, br, 3H, NCH3), 2.57 (t, J6.5 Hz, 2H, CH2), 2.45 (m, 4H, N(CH2CH3)2), 0.91 (m, 6H, N(CH2CH3)2) 0525 MS-EI m/z 444 and 446 M1 and M1.

Example 11 0526 5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)methylamide 0527 6-Phenyl-1,3-dihydroindol-2-one (209 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)methylamide to give 277 mg (63%) of the title compound. 0528 1H NMR (360 MHz, DMSO-d6) 13.58 (s, br, 1H, NH), 11.04 (s, br, 1H, NH), 7.78 (s, 1H, H-vinyl), 7.73 (d, J7.8 Hz, 1H), 7.64 (d, J7.5 Hz, 2H), 7.46 (m, 2H), 7.33-7.36 (m, 2H), 7.11 (s, 1H), 6.84 (m, 1H), 6.78 (m, 1H), 3.55 (s, br, 2H, CH2), 3.25 (s, br, 3H, NCH3), 2.58 (t, 2H, CH2), 2.44 (m, 4H, N(CH2CH3)2), 0.92 (m, 6H, N(CH2CH3)2).

Example 12 0529 3-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0530 Oxindole (66.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 3-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give 39 mg (21%) of the title compound. 0531 1H NMR (300 MHz, DMSO-d6) 13.34 (s, br, 1H, NH), 10.88 (s, br, 1H, NH), 7.62-7.67 (m, 3H), 7.17 (m, 1H), 6.99 (m, 1H), 6.87 (d, J7.6 Hz, 1H), 6.63 (d, J1 Hz, 1H), 3.26-3.32 (m, 2H, CH2), 2.41-2.48 (m, 6H, CH2 & N(CH2CH3)2), 2.29 (s, 3H, CH3), 1.63 (m, 2H, CH2), 0.93 (t, J7.2 Hz, 6H, N(CH2CH3)2). 0532 MS-EI m/z 380 M.

Example 13 0533 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0534 5-Bromo-1,3-dihydroindol-2-one (106 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 35 mg (15%) of the title compound. 0535 1H NMR (300 MHz, DMSO-d6) 13.35 (s, br, 1H, NH), 11.00 (s, br, 1H, NH), 7.89 (d, J1.9 Hz, 1H, H-4), 7.80 (s, 1H, H-vinyl), 7.74 (t, J5.3 Hz, 1H, CONHCH2), 7.31 (dd, J1.9 & 8.4 Hz, 1H, H-6), 6.83 (d, J8.4 Hz, 1H, H-7), 6.63 (s,1H, H-3), 3.26 (m, 2H, CH2), 2.41-2.48 (m, 6H, CH2 & N(CH2CH3)2), 2.29 (s, 3H, CH3), 1.63 (m, 2H, CH2), 0.93 (t, J7.1 Hz, 6H, N(CH2CH3)2). 0536 MS-EI m/z 458 and 460 M1 and M1.

Example 14 0537 3-Methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0538 6-Phenyl-1,3-dihydroindol-2-one (105 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 67.8 (30%) of the title compound. 0539 1H NMR (300 MHz, DMSO-d6) 13.37 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 7.23-7.73 (m, 11H), 3.29 (m, 2H, CH2), 2.41-2.48 (m, 6H, CH2 & N(CH2CH3)2), 2.29 (s, 3H, CH3), 1.64 (m, 2H, CH2), 0.94 (t, J7.0 Hz, 6H, N(CH2CH3)2). 0540 MS-EI m/z 456 M.

Example 15 0541 5-(5-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0542 5-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 80 mg (39%) of the title compound. 0543 1H NMR (300 MHz, DMSO-d6) 13.45 (s, br, 1H, NH), 10.70 (s, br, 1H, NH), 7.68-7.70 (m, 2H), 7.32 (d, J1.8 Hz, 1H), 6.72-6.79 (m, 2H), 6.60 (s, 1H), 3.73 (s, 3H, OCH3), 3.28 (m, 2H, CH2), 2.41-2.48 (m, 6H, CH2 & N(CH2CH3)2), 2.29 (s, 3H, CH3), 1.63 (m, 2H, CH2), 0.93 (t, J7.0 Hz, 6H, N(CH2CH3)2). 0544 MS m/z 410 M.

Example 16 0545 5-(6-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0546 6-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 63 mg (31%) of the title compound. 0547 1H NMR (300 MHz, DMSO-d6) 13.22 (s, br, 1H, NH), 10.86 (s, br, 1H, NH), 7.39-7.63 and 6.37-6.55 (m, 6H), 3.73 (s, 3H, OCH3), 3.3 (m, 2H, CH2), 2.45 (m, 6H, CH2 & N(CH2CH3)2), 2.28 (s, 3H, CH3), 1.63 (m, 2H, CH2), 0.93 (m, 6H, N(CH2CH3)2). 0548 MS m/z 410 M.

Example 17 0549 3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (2-diethylamino-ethyl)amide 0550 4,5,6,7-Tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester (May, Donald A.; Lash, Timothy D.; J. Org. Chem., 1992, 57:18, 4820-4828) was formylated using method A then B to give 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid. 0551 5-Bromo-1,3-dihydroindol-2-one (1.43 g, 6.8 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide (1.97 g) to give 2.2 g (67%) of the title compound as a yellow-orange solid. 0552 1H NMR (360 MHz, DMSO-d6) 13.47 (s, 1H, NH), 11.0 (s, 1H, NH), 8.0 (d, 1H, NH), 7.70 (s, 1H, CH), 7.28 (dd, J2.1 and 8.2 Hz, 1H, ArH), 7.16 (m, 1H, ArH), 6.8 (d, J8.3 Hz, 1H, ArH), 3.3 (s, 2H, CONH), 2.5 (m, 6H, 3NCH2), 2.78 (br m, 2H, pyrrole CH2), 2.72 (br m, 2H, pyrroleCH2), 1.7 (br m, 4H, N(CH2CH3)2), 1.74 (br s, 4H, CH2CH2CH2CH2), 0.96 (t, J7.4 Hz, 6H, N(CH2CH3)2). 0553 MS-EI m/z 484 and 486 M1 and M1.

Example 18 0554 3-(5-Bromo-2-oxo-0.2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (3-diethylamino-propyl)amide 0555 5-Bromo-1,3-dihydroindol-2-one (20 mg, 0.1 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-diethylaminopropyl)amide (30 mg) to give 33 mg (46%) of the title compound as an orange solid. 0556 1H NMR (360 MHz, DMSO-d6) 10.9(s, 1H, NH), 8.0 (m, 1H, NH), 7.68 (m, 1H, ArH), 7.4 (m, 1H, ArH), 7.29 (d, J1.9 and 8.5 Hz, 1H, ArH), 6.8 (d, J8 Hz, 1H, ArH), 2.7 (br m, 4H, 2NCH2), 2.4 (m, 8H, 4NCH2), 1.7 (br m, 4H, N(CH2CH3)2), 1.6 (br m, 2H, CH2CH2CH2), 0.93 (t, J7.4 Hz, 6H, N(CH2CH3)2). 0557 MS-EI m/z 499 and 501 M and M2.

Example 19 0558 3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0559 5-Bromo-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (120 mg) to give 43 mg (22%) of the title compound as a tan-orange solid. 0560 1H NMR (360 MHz, DMSO-d6) 13.4 (s, 1H, NH), 10.9 (s, 1H, NH), 8.0 (m, 1H, NH), 7.69 (m, 1H, ArH), 7.49 (m, 1H, ArH), 7.28 (d, J1.7 and 7.8 Hz, 1H, ArH), 6.8 (d, J8 Hz, 1H, ArH), 3.3 (br m, 2H, 2NCH2), 2.8 (m, 4H, 2pyrroleCH2), 2.5 (br m, 4H, N(CH2CH3)2), 1.6 (br m, 8H, 2pyrroleCH2CH2, CH2CH2CH2 and CONHCH2). 0561 MS-EI m/z 497 and 499 M and M2.

Example 20 0562 3-(2-Oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (2-diethylaminoethyl)amide 0563 6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide (80 mg) to give 50 mg (38%) of the title compound as a reddish solid. 0564 1H NMR (360 MHz, DMSO-d6) 13.4 (s, 1H, NH), 11 (s, 1H, NH), 8.9 (d, 1H, NH), 8.7 (dd, 1H, ArH), 8.1 (dd, 1H, ArH), 7.9 (d, 1H, ArH), 7.6 (s, 1H, CH), 7.5 (dd, 1H, ArH), 7.3 (dd, 1H, ArH), 7.1 (m, 2H, ArH), 3.35 (m, 2H, CONHCH2), 2.8 (m, 4H, 2pyrroleCH2), 2.5 (br m, 6H, N(CH2CH3)2 and NCH2), 1.75 (br s, 4H, 2pyrroleCH2CH2), 0.9 (t, 6H, N(CH2CH3)2). 0565 MS-EI m/z 484 M.

Example 21 0566 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0567 To a mixture of benzoyl chloride (1 equiv.) and aluminum chloride (1 equiv.) in dichloroethane at 0 C. was added ethyl 3,5-dimethyl-2-pyrrolecarboxylate (1 equiv.). The mixture was stirred at 80 C. for 4 hr. The mixture was then extracted with ethyl acetate (EtOAc) and H2O. The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried and concentrated to give (51%) of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid. 0568 A mixture of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.13 g, 15.2 mmol) and ceric ammonium nitrate (33 g, 4 equiv.) in 50 mL of tetrahydrofuran (THF):acetic acid (HOAc):H2O 1:1:1 was refluxed overnight. The reaction mixture was then cooled, extracted with EtOAc and then basified to pH 9 with sodium carbonate. The organic layer was then washed with brine, dried (MgSO4) and concentrated followed by column chromatography to give 3.25 g (75%) of 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a yellow solid. 0569 5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid using method D to give 4-benzoyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic acid. 0570 The above carboxylic acid was then coupled with N,N-diethyl-1,3-propanediamine using method C to give the title compound. 0571 1H NMR (360 MHz, DMSO-d6) 7.96 (m, 1H, CONHCH2), 7.76 (d, J7.0 Hz, 2H), 7.68 (t, 1H), 7.56 (m, 2H), 7.40 (s, 2H) 7.33 (dd, J1.6 & 8.3 Hz, 1H, H-6), 6.84 (d, J8.3 Hz, 1H, H-7), 3.33 (m, 2H, CH2), 2.42-2.46 (m, 6H, 3CH2), 2.10 (s, 3H, CH3), 1.65 (m, 2H, CH2), 0.94 (t, J7.0 Hz, 6H, N(CH2CH3)2). 0572 MS Electron Impact m/z 564 M1.

Example 22 0573 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-morpholin-4-ylpropyl)amide 0574 1H NMR (360 MHz, DMSO-d6) 14.10 (s, 1H, NH), 11.14 (br s, 1H, NH), 7.92 (m, 1H, CONHCH2), 7.75 (m, 2H), 7.69 (t, 1H), 7.56 (m, 2H), 7.42 (m, 2H), 7.33 (dd, J1.9 & 8.3 Hz, 1H, H-6), 6.85 (d, J8.3 Hz, 1H, H-7), 3.56 (m, 4H, 2CH2), 3.33 (m, 2H, CH2), 2.35 (m, 6H, 3CH2), 2.10 (s, 3H, CH3), 1.70 (m, 2H, CH2).

Example 23 0575 4-Benzoyl-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0576 1H NMR (300 MHz, DMSO-d6) 14.18 (s, 1H, NH), 11.14 (br s, 1H, NH), 8.01 (m, 1H, CONHCH2), 7.74 (m, 1H), 7.67 (m, 1H), 7.55 (m, 1H), 7.32 (s, 1H, H-vinyl), 7.17 (m, 1H), 6.92 (m, 1H), 3.36 (m, 2H, CH2), 2.44 (m, 6H, 3CH2), 2.11 (s, 3H, CH3), 1.65-1.75 (m, 6H, 3CH2). 0577 MS Electron Impact m/z 482 M.

Example 24 0578 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0579 1H NMR (360 MHz, DMSO-d6) 14.01 (s, 1H, NH), 11.18 (br s, 1H, NH), 7.98 (m, 1H, CONHCH2), 7.75 (m, 2H), 7.68 (m, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.33 (dd, J2.0 & 8.2 Hz, 1H, H-6), 6.84 (d, J8.2 Hz, 1H, H-7), 3.34 (m, 2H, CH2), 2.42-2.47 (m, 6H, 3CH2), 2.09 (s, 3H, CH3), 1.70 (m, 2H, CH2), 1.64 (m, 4H, 2CH2).

Example 25 0580 4-Benzoyl-3-methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0581 1H NMR (300 MHz, DMSO-d6) 14.15 (s, 1H, NH), 11.16 (br s, 1H, NH), 7.98 (m, 1H, CONHCH2), 7.77 (d, J7.7 Hz, 2H), 7.69 (m, 1H), 7.53-7.63 (m, 4H), 7.44 (m, 2H), 7.33-7.37 (m, 2H), 7.24 (s, 2H), 7.12 (s, 1H), 3.36 (m, 2H, CH2), 2.43-2.48 (m, 6H, 3CH2), 2.12 (s, 3H, CH3), 1.74 (m, 2H, CH2), 1.69 (m, 4H, 2CH2). 0582 MS Electron Impact m/z 558 M.

Example 26 0583 4-Benzoyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0584 1H NMR (300 MHz, DMSO-d6) 13.99 (s, 1H, NH), 11.05 (br s, 1H, NH), 7.93 (m, 1H, CONHCH2), 7.72 (m, 2H), 7.65 (m, 1H), 7.54 (m, 2H), 7.15 (s, 1H, H-vinyl), 7.04 (d, J8.4 Hz, 1H, H-4), 6.51 (dd, J2.3 & 8.4 Hz, 1H, H-5), 6.44 (d, J2.3 Hz, 1H, H-7), 3.74 (s, 3H, OCH3), 3.35 (m, 2H, CH2), 2.42-2.46 (m, 6H, 3CH2), 2.10 (s, 3H, CH3), 1.72 (m, 2H, CH2), 1.65 (m, 4H, 2CH2). 0585 MS Electron Impact m/z 512 M.

Example 27 0586 4-Benzoyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0587 1H NMR (360 MHz, DMSO-d6) 14.24 (s, 1H, NH), 10.90 (br s, 1H, NH), 7.97 (m, 1H, CONHCH2), 7.75 (d, J7.2 Hz, 2H), 7.69 (m, 1H), 7.56 (m, 2H), 7.24 (s, 1H, H-vinyl), 6.79 (m, 2H), 6.66 (m, 1H), 3.67 (s, 3H, OCH3), 3.34 (m, 2H, CH2), 2.43-2.48 (m, 6H, 3CH2), 2.14 (s, 3H, CH3), 1.71 (m, 2H, CH2), 1.66 (m, 4H, 2CH2). 0588 MS Electron Impact m/z 512 M.

Example 28 0589 4-Benzoyl-5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0590 1H NMR (300 MHz, DMSO-d6) 14.20 (s, 1H, NH), 11.14 (br s, 1H, NH), 8.03 (m, 1H, CONHCH2), 7.75 (m, 2H), 7.68 (m, 1H), 7.55 (m, 2H), 7.38 (s, 1H, H-vinyl), 7.08 (m, 1H), 7.01 (m, 1H), 6.87 (m, 1H), 3.34 (m, 2H, CH2), 2.42-2.48 (m, 6H, 3CH2), 2.09 (s, 3H, CH3), 1.70 (m, 2H, CH2), 1.65 (m, 4H, 2CH2). 0591 MS Electron Impact m/z 500 M.

Example 29 0592 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0593 5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give the title compound. 0594 1H NMR (300 MHz, DMSO-d6) 14.19 (s, 1H, NH), 11.19 (br s, 1H, NH), 8.15 (m, 1H, CONHCH2), 8.11 (s, 1H, H-vinyl), 7.72 (d, J1.8 Hz, 1H, H-4), 7.38 (dd, J1.8 & 8.2 Hz, 1H, H-6), 6.87 (d, J8.2 Hz, 1H, H-7), 3.27 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.46 (m, 9H, CH3 & 3CH2), 1.64 (m, 2H, CH2), 0.93 (t, J7.1 Hz, 6H, N(CH2CH3)2).

Example 30 0595 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0596 1H NMR (300 MHz, DMSO-d6) 8.14 (m, 1H, CONHCH2), 8.10 (s, 1H, H-vinyl), 7.70 (d, 1H, H-4), 7.36 (dd, J1.6 & 8.1 Hz, 1H, H-6), 6.85 (d, J8.1 Hz, 1H, H-7), 3.32 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.44 (s, 3H, CH3), 2.35-2.48 (m, 6H, 3CH3), 1.65-1.71 (m, 6H, 3CH2). 0597 MS m/z 499 & 501 M & M2.

Example 31 0598 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-morpholin-4-ylpropyl)amide 0599 1H NMR (300 MHz, DMSO-d6) 14.20 (s, 1H, NH), 11.26 (br s, 1H, NH), 8.09 (m, 2H, H-vinyl & CONHCH2), 7.73 (d, J1.5 Hz, 1H, H-4), 7.38 (dd, J1.5 & 8.3 Hz, 1H, H-6), 6.87 (d, J8.3 Hz, 1H, H-7), 3.55 (m, 4H, 2CH2), 3.26 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.44 (s, 3H, CH3), 2.35 (m, 6H, 3CH3), 1.68 (m, 2H, CH2). 0600 MS-EI m/z 514 & 516 M1 & M1.

Example 32 0601 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-hydroxypropyl)amide 0602 1H NMR (360 MHz, DMSO-d6) 14.17 (s, 1H, NH), 11.25 (br s, 1H, NH), 8.10 (s, 1H, H-vinyl), 8.03 (m, 1H, CONHCH2), 7.71 (br s, 1H, H-4), 7.37 (br d, J8.4 Hz, 1H, H-6), 6.87 (d, J8.4 Hz, 1H, H-7), 4.51 (br s, 1H, OH), 3.51 (br s, 2H, CH2), 3.36 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.43 (s, 3H, CH3), 1.70 (m, 2H, CH2). 0603 MS-EI m/z 445 & 447 M1 & M1.

Example 34 0604 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (2-morpholin-4-ylethyl)amide 0605 1H NMR (360 MHz, DMSO-d6) 14.19 (s, 1H, NH), 11.14 (br s, 1H, NH), 8.10 (s, 1H, H-vinyl), 7.84 (m, 1H, CONHCH2), 7.71 (d, J1.8 Hz, 1H, H-4), 7.38 (dd, J1.8 & 8.2 Hz, 1H, H-6), 6.87 (d, J8.2 Hz, 1H, H-7), 3.58 (m, 4H, 2CH2), 3.40 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.49 (m, 4H, 2CH2), 2.45 (m, CH3 & CH2). 0606 MS-EI m/z 500 & 502 M1 & M1.

Example 35 0607 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0608 1H NMR (360 MHz, DMSO-d6) 14.17 (s, 1H, NH), 11.23 (s, 1H, NH), 8.11 (s, 1H, H-vinyl), 7.91 (m, 1H, CONHCH2), 7.73 (d, J1.9 Hz, 1H, H-4), 7.39 (dd, J1.9 & 8.3 Hz, 1H, H-6), 6.88 (d, J8.3 Hz, 1H, H-7), 3.40 (m, 2H, CH2), 2.62 (m, 2H, CH2), 2.57 (s, 3H, CH3CO), 2.49 (m, 4H, 2CH2), 2.44 (s, 3H, CH3), 1.69 (m, 4H, 2CH2).

Example 36 0609 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid 2-(4-hydroxyphenyl)ethylamide 0610 1H NMR (300 MHz, DMSO-d6) 14.21 (s, 1H, NH), 11.18 (s, 1H,OH), 9.09 (s, 1H, NH), 8.06-8.10 (m, 2H), 7.73 (s, 1H), 7.38 (d, J7.8 Hz, 1H), 7.04 (d, J7.1 Hz, 2H), 6.88 (d, J7.8 Hz, 1H), 6.67 (d, J7.1 Hz, 2H), 3.42 (m, 2H, CH2), 2.72 (m, 2H, CH2), 2.56 (s, 3H, CH3CO), 2.37 (s, 3H, CH3). 0611 MS-EI m/z 507 & 509 M1 & M1.

Example 37 0612 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0613 A mixture of 2-aminoacetophenone hydrochloride (1 equiv.), ethyl isobutyrylacetate (1.2 equiv.) and sodium acetate (2.4 equiv.) in H2O was stirred at 100 C. for 18 hours and then cooled to room temperature. The aqueous layer was decanted off and the oil was dissolved in ethyl acetate. It was then washed with water and brine and then dried to give (93%) of 2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester as a red brown oil. 0614 1HNMR (300 MHz, DMSO-d6) 11.21 (s, br, 1H, NH), 7.14-7.27 (m, 5H), 6.70 (d, J2.7 Hz, 1H), 4.02 (q, J7.1 Hz, 2H, OCH2CH3), 3.65 (m, 1H, CH(CH3)2), 1.22 (d, J7.5 Hz, 6H, CH(CH3)2), 1.04 (t, J7.1 Hz, 3H, OCH2CH3). 0615 MS-EI m/z 257 M. 0616 The above pyrrole was formylated using method A to give (41%) 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester as a reddish solid. 0617 1HNMR (300 MHz, DMSO-d6) 12.35 (s, br, 1H, NH), 9.14 (s, 1H, CHO), 7.36 (s, 5H), 3.96 (q, J7.1 Hz, 2H, OCH2CH3), 3.74 (m, 1H, CH(CH3)2), 1.29 (d, J6.9 Hz, 6H, CH(CH3)2), 0.90 (t, J7.1 Hz, 3H, OCH2CH3). 0618 MS-EI m/z 285 M. 0619 The pyrrolecarboxylic acid ester was hydrolysed using method B to give (57%) of 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid as a beige solid. 0620 1HNMR (300 MHz, DMSO-d6) 12.28 (s, br, 1H, COOH), 12.02 (s, br, 1H, NH), 9.10 (s, 1H, CHO), 7.35 (s, 5H), 3.81 (m, 1H, CH(CH3)2), 1.28 (d, J6.9 Hz, 6H, CH(CH3)2). 0621 MS-EI m/z 257 M. 0622 5-Bromo-1,3-dihydroindol-2-one (120 mg, 0.31 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (prepared by method C) to give 120 mg (71%) of the title compound. 0623 1HNMR (300 MHz, DMSO-d6) 14.23 (s, br, 1H, NH), 11.08 (s, br, 1H, NH), 7.38-7.55 (m, 7H, ArH & CONHCH2), 7.30 (s, 1H, H-vinyl), 7.26 (dd, J1.8 & 7.8 Hz, 1H), 6.85 (d, J8.7 Hz, 1H), 3.36 (m, 1H, CH(CH3)2), 3.07 (m, 2H, CH2), 2.34 (q, J7.1 Hz, 4H, N(CH2CH3)2), 2.22 (t, J6.9 Hz, 2H, CH2), 1.40 (m, 2H, CH2), 1.31 (d, J6.9 Hz, 6H, CH(CH3)2), 0.86 (t, J7.1 Hz, 6H, N(CH2CH3)2). 0624 MS m/z 565.1 M1.

Example 38 0625 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0626 5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (127 mg, 0.28 mmol) was condensed with 3-pyrrolidin-1-yl-propylamine (43 mg, 0.336 mmol) to give 140 mg (66%) of the title compound. 0627 1HNMR (300 MHz, DMSO-d6) 14.40 (s, br, 1H, NH), 7.38-7.47 (m, 7H), 7.23-7.27 (m, 2H), 6.84 (d, J8.1 Hz, 1H), 3.36 (m, 1H, CH(CH3)2), 3.08 (m, 2H, CH2), 2.30 (m, 4H, 2CH2), 2.20 (t, J7.0 Hz, 2H, CH2), 1.62 (m, 4H, 2CH2), 1.42 (t, J7.0 Hz, 2H, CH2), 1.31 (d, J7.2 Hz, 6H, CH(CH3)2). 0628 MS-EI m/z 560 and 562 M1 and M1.

Example 39 0629 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0630 5-Bromo-1,3-dihydroindol-2-one (57 g. 0.27 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (120 mg) to give 78 mg (53%) of the title compound as a yellow solid. 0631 1HNMR (300 MHz, DMSO-d6) 14.23 (s, br, 1H, NH), 11.09 (s, br, 1H, NH), 7.38-7.51 (m, 6H), 7.25-7.28 (m, 2H), 7.19 (t, 1H, CONHCH2), 6.85 (d, J7.8 Hz, 1H), 3.43 (m, 1H, CH(CH3)2), 3.11 (m, 2H, CH2), 2.28-2.39 (m, 6H, N(CH2CH3)2 & CH2, 1.31 (d, J6.9 Hz, CH(CH3)2), 0.85 (t, J7.0 Hz, 6H, N(CH2CH3)2. 0632 MS-EI m/z 548 and 550 M1 and M1.

Example 40 0633 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid 3-(4-methylpiperazin-1-yl)propylamide 0634 5-Bromo-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid 3-(4-methylpiperazin-1-yl)propylamide (300 mg) to give 65 mg of the title compound. 0635 1HNMR (300 MHz, DMSO-d6) 14.22 (s, br, 1H, NH), 11.08 (s, br, 1H, NH), 7.23-7.50 (m, 9H), 6.85 (d, J8.7 Hz, 1H), 3.37 (m, 1H, CH(CH3)2), 3.05 (m, 2H, CH2), 2.24 (m, 8H, 4CH2), 2.11 (m, 5H, CH2 & CH3),1.42 (m, 2H, CH2), 1.31 (d, J7.2 Hz, 6H, CH(CH3)2). 0636 MS-EI m/z 589; and 591 M1 and M1.

Example 41 0637 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-H-pyrrole-3-carboxylic Acid 0638 5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (205 mg) using method D to give 210 mg (58%) of the title compound as a yellow solid. 0639 1HNMR (300 MHz, DMSO-d6) 14.31 (s, br, 1H, NH), 11.16 (s, br, 1H, NH), 7.26-7.44 (m, 7H), 7.11 (s, 1H, H-vinyl), 6.85 (d, J7.8 Hz, 1H), 3.78 (m, 1H, CH(CH3)2), 1.34 (d, J6.9 Hz, 6H, CH(CH3)2). 0640 MS-EI m/z 452 M1.

Example 42 0641 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0642 5-Bromo-1,3-dihydroindol-2-one (44 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg, prepared in the same manner as the isopropyl analog, above) to give 0.03 g (27%) of the title compound as a yellow solid. 0643 1HNMR (300 MHz, DMSO-d6) 13.87 (s, br, 1H, NH), 11.11 (s, br, 1H, NH), 7.36-7.51 (m, 6H), 7.26 (dd, J1.8 & 8.1 Hz, 1H), 7.2 (s, 1H, H-vinyl), 7.09 (m, 1H, CONHCH2), 6.83 (d, J8.1 Hz, 1H), 3.17 (m, 2H, NCH2), 2.48 (m, CH3), 2.29-2.35 (m, 6H, 3NCH2), 1.59 (m, 4H, 2CH2). 0644 MS-EI m/z 518 and 520 M1 and M1.

Example 43 0645 5-6-(2-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0646 6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (50 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg) to give 0.04 g (35%) of the title compound as a yellow-orange solid. 0647 1HNMR (300 MHz, DMSO-d6) 13.82 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 7.48 (m, 2H), 7.43 (m, 1H), 7.38 (m, 2H), 7.32 (m, 1H), 7.24 (m, 2H), 7.16 (s, 1H, H-vinyl), 7.08 (m, 2H), 7.03 (m, 1H), 7.0 (m, 2H), 3.74 (s, 3H, OCH3), 3.19 (m, 2H, NCH2), 2.49 (m, CH3), 2.32-2.38 (m, 6H, 3NCH2), 1.59 (m, 4H, 2CH2). 0648 MS-EI m/z 546 M.

Example 44 0649 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0650 5-Bromo-1,3-dihydroindol-2-one (46 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 60 mg (55%) of the title compound as a yellow solid. 0651 1HNMR (360 MHz, DMSO-d6) 13.86 (s, br, 1H, NH), 11.09 (s, br, 1H, NH), 7.47-7.49 (m, 2H), 7.38-7.41 (m, 4H), 7.26 (dd, J2.2 & 8.3 Hz, 1H), 7.21 (s, 1H, H-vinyl), 7.04 (m, 1H, CONHCH2), 6.77 (d, J8.3 Hz, 1H), 3.15 (m, 2H, NCH2), 2.48 (m, CH3), 2.16 (t, J6.8 Hz, 2H, 3NCH2), 2.02 (s, 6H, 2NCH3). 0652 MS m/z 493 and 494.8 M and M2.

Example 45 0653 5-6-(2-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0654 6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum. 0655 1HNMR (300 MHz, DMSO-d6) 13.82 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 7.37-7.52 (m, 5H), 7.32 (m, 1H), 7.22-7.27 (m, 2H), 7.16 (s, 1H), 7.08 (m, 2H), 7.03 (m, 1H), 7.0 (m, 2H), 3.74 (s, 3H, OCH3), 3.15 (m, 2H, NCH2), 2.49 (m, CH3), 2.16 (t, J6.5 Hz, 2H, NCH2), 2.02 (s, 6H, 2NCH3). 0656 MS m/z 521 M1.

Example 46 0657 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0658 5-Bromo-1,3-dihydroindol-2-one (60 mg, 0.29 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (75 mg) to give 78 mg (60%) of the title compound as an orange solid. 0659 1HNMR (360 MHz, DMSO-d6) 14.01 (s, br, 1H, NH), 11.13 (s, br, 1H, NH), 7.42-7.46 (m, 3H), 7.27-7.34 (m, 4H), 7.12 (s, 1H), 6.84 (dd, J2.2 & 8.3 Hz, 1H), 3.99-4.03 (m, 2H, OCH2CH3), 2.61 (s, 3H, CH3), 0.98-1.03 (m, 3H, OCH2CH3). 0660 MS-EI m/z 450 and 452 M1 and M1.

Example 47 0661 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0662 5-bromo-1,3-dihydroindol-2-one (0.47 g, 2.2 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.75 g) to give 0.11 g (42%) of the title compound as an orange solid. 0663 1HNMR (300 MHz, DMSO-d6) 13.86 (s, br, 1H, NH), 7.42-7.46 (m, 3H), 7.37-7.50 (m, 7H), 7.24-7.28 (m, 2H), 6.83 (d, J8.1 Hz, 1H), 3.09 (m, 2H, NCH2), 2.45 (s, 3H, CH3), 2.38 (q, J7.1 Hz, 4H, 2NCH2CH3), 2.26 (t, J6.9 Hz, 2H, NCH2), 1.42 (m, 2H, NCH2), 0.87 (t, J7.1 Hz, 6H, 2NCH2CH3). 0664 MS-EI m/z 535.0 and 537 M and M2.

Example 48 0665 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylamino-ethyl)amide 0666 A mixture of tert-butyl 3-oxobutyrate and sodium nitrite (1 equiv.) in acetic acid was stirred at room temperature to give tert-butyl-2-hydroximino-3-oxobutyrate. 0667 Ethyl-3-oxobutyrate (1 equiv.), zinc dust (3.8 equiv.) and the crude tert-butyl-2-hydroximino-3-oxobutyrate in acetic acid was stirred at 60 C. for 1 hr. The reaction mixture was poured into H2O and the filtrate was collected to give (65%) 2-tert-butyloxycarbonyl-3,5-dimethyl-4-ethoxycarbonylpyrrole. 0668 A mixture of 2-tert-butyloxycarbonyl-3,5-dimethyl-4-ethoxycarbonylpyrrole and triethyl orthoformate (1.5 equiv.) in trifluoroacetic acid was stirred at 15 C. for 1 hour. The reaction was concentrated and the residue was purified to give (64%) 2,4-dimethyl-3-ethoxycarbonyl-5-formylpyrrole as yellow needles. 0669 2,4-Dimethyl-3-ethoxycarbonyl-5-formylpyrrole was hydrolyzed using method B to give (90%) 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 0670 1H NMR (360 MHz, DMSO-d6) 12 (br s, 2H, NH and CO2H), 9.58 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3). 0671 MS m/z 267 M. 0672 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g, prepared by method C) using method B to give 0.3 g (83%) of the title compound as a yellow solid. 0673 1HNMR (360 MHz, DMSO-d6) 13.60 (s, br, 1H, NH), 10.94 (s, br, 1H, NH), 8.07 (d, J1.8 Hz, 1H, H-4), 7.75 (s, 1H, H-vinyl), 7.44 (t, J5.2 Hz, 1H, CONHCH2), 7.24 (dd, J1.8 & 8.4 Hz, 1H, H-6), 6.82 (d, J8.4 Hz, 1H, H-7), 3.26-3.33 (m, 2H, NCH2), 2.42 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.38 (t, J6.7 Hz, 2H, NCH2), 2.18 (s, 6H, N(CH3)2). 0674 MS-EI m/z 430 and 432 M1 and M1.

Example 49 0675 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0676 6-Phenyl-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g) to give 0.13 g (36%) of the title compound as a yellow-orange solid. 0677 1HNMR (360 MHz, DMSO-d6) 13.59 (s, br, 1H, NH), 10.93 (, br, 1H, NH), 7.85 (d, J7.92 Hz, 1H, H-4), 7.63-7.65 (m, 3H), 7.40-7.47 (m, 3H,), 7.32-7.36 (m, 1H, ArH), 7.30 (dd, J1.6 & 7.9 Hz, 1H, H-5), 7.11 (d, J1.6 Hz, 1H, H-7), 3.28-3.34 (m, 2H, NCH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.38 (t, J6.8 Hz, 2H, NCH2), 2.18 (s, 6H, N(CH3)2). 0678 MS-EI m/z 428 M.

Example 50 0679 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylamino-ethyl)amide 0680 5-Chloro-1,3-dihydroindol-2-one (0.1 g, 0.6 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.15 g) to give 0.22 g (90%) of the title compound as a yellow solid. 0681 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 7.96 (d, J2.0 Hz, 1H, H-4), 7.75 (s, 1H, H-vinyl), 7.50 (t, J5.5 Hz, 1H, CONHCH2), 7.12 (dd, J2.0 & 8.3 Hz, 1H, H-6), 6.86 (d, J8.3 Hz, 1H, H-7), 3.26-3.31 (m, 2H, NCH2), 2.42 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.36 (t, J6.6 Hz, 2H, NCH2), 2.17 (s, 6H, N(CH3)2). 0682 MS-EI m/z 386 M.

Example 51 0683 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 0684 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 0685 1HNMR (360 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J5.5 Hz, 1H, CONHCH2), 7.24 (dd, J1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J7.2 Hz, 6H, 2NCH2CH3). 0686 MS-EI m/z 458 and 460 M1 and M1.

Example 52 0687 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-yl-ethyl)amide 0688 5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.1 g) to give 0.14 g (81%) of the title compound as a yellow-orange solid. 0689 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J1.9 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.53 (t, J5.5 Hz, 1H, CONHCH2), 7.24 (dd, J1.9 & 8.5 Hz, 1H, H-6), 6.81 (d, J8.5 Hz, 1H, H-7), 3.29-3.35 (m, 2H, NCH2), 2.54 (t, J6.9 Hz, 2H, NCH2), 2.47 (m, under DMSO), 2.42 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.66-1.69 (m, 4H, 2CH2). 0690 MS-EI m/z 456 and 458 M1 and M1.

Example 53 0691 5-(5-Bromo-2-oxo-1.2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-yl-propyl)amide 0692 5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (0.1 g) to give 0.1 g (59%) of the title compound as an orange solid. 0693 1HNMR (300 MHz, DMSO-d6) 13.63 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 8.09 (d, J2.2 Hz, 1H, H-4), 7.77 (s, 1H, H-vinyl), 7.71 (t, J5.7 Hz, 1H, CONHCH2), 7.65 (s, 1H, ArH), 7.25 (dd, J2.2 & 8.4 Hz, 1H, H-6), 7.20 (s, 1H, ArH), 6.89 (s, 1H, ArH), 6.81 (d, J8.4 Hz, 1H, H-7), 4.02 (t, J6.7 Hz, 2H, NCH2), 3.18 (q, J6.7 Hz, 2H, NCH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.93 (m, 2H, CH2). 0694 MS-EI m/z 467 and 469 M1 and M1.

Example 54 0695 5-6-(2-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0696 6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (30 mg, 0.13 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (30 mg) to give 0.06 g (100%) of the title compound as a yellow-orange gum. 0697 1HNMR (300 MHz, DMSO-d6) 13.60 (s, br, 1H, NH), 10.89 (s, br, 1H, NH), 7.79 (d, J8.4 Hz, 1H), 7.63 (s, 1H, H-vinyl), 7.46 (t, J5.5 Hz, 1H, CONHCH2), 7.28-7.35 (m, 2H), 6.99-7.11 (m, 4H), 3.76 (s, 3H, OCH3), 3.27-3.31 (m, 2H, NCH2), 2.43 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.37 (m, 2H, NCH2), 2.18 (s, 6H, N(CH3)2). 0698 MS-EI m/z 458 M.

Example 55 0699 5-6-(3-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0700 6-(3-Methoxyphenyl)-1,3-dihydroindol-2-one (30 mg, 0.13 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (30 mg) to give 8 mg (14%) of the title compound as a yellow-orange solid. 0701 1HNMR (360 MHz, DMSO-d6) 13.59 (s, br, 1H, NH), 10.92 (s, br, 1H, NH), 7.84 (d, J7.6 Hz, 1H), 7.65 (s, 1H, H-vinyl), 7.42 (m, 1H, CONHCH2), 7.36 (d, J7.8 Hz, 1H), 7.29 (dd, J1.6 & 7.6 Hz, 1H), 7.20 (d, J7.8 Hz, 1H), 7.14 (d, J2.8 Hz, 1H), 7.11 (d, J1.6 Hz, 1H), 6.91 (dd, J2.8 & 7.8 Hz, 1H), 3.82 (s, 3H, OCH3), 3.21-3.33 (m, 2H, NCH2), 2.43 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.36-2.40 (m, 2H, NCH2), 2.18 (s, 6H, N(CH3)2). 0702 MS-EI m/z 458 M.

Example 56 0703 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0704 5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) using method B to give 79 mg (46%) of the title compound. 0705 1HNMR (300 MHz, DMSO-d6) 13.66 (s, br, 1H, NH), 10.95 (, br, 1H, NH), 8.15 (d, J1.2 Hz, 1H), 7.81 (s, 1H, H-vinyl), 7.71 (d, J7.5 Hz, 1H), 7.40-7.47 (m, 4H), 7.31 (m, 1H), 6.95 (d, J8.1 Hz, 1H), 3.2-3.31 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 6H, 2CH3), 0.96 (t, J7.4 Hz, 6H, 2NCH2CH3). 0706 MS-EI m/z 456 M.

Example 57 0707 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0708 5-Phenyl-1,3-dihydroindol-2-one (0.04 g, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.04 g) to give the title compound as a yellow-orange solid. 0709 1HNMR (300 MHz, DMSO-d6) 13.65 (s, br, 1H, NH), 10.96 (, br, 1H, NH), 8.15 (d, J1.0 Hz, 1H), 7.80 (s, 1H, H-vinyl), 7.71 (d, J7.2 Hz, 2H), 7.49 (t, J6.3 Hz, 1H, CONHCH2), 7.41-7.46 (m, 3H), 7.31 (m, 1H), 6.95 (d, J7.8 Hz, 1H), 4.08 (m, 4H, 2NCH2), 3.32 (m, 2H, NCH2), 2.55 (t, J7.1 Hz, 2H, NCH2), 2.47 (m, under DMSO), 2.43 (s, 6H, 2CH3), 1.66 (m, 4H, 2CH2). 0710 MS-EI m/z 454 M.

Example 58 0711 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-ylpropyl)amide 0712 5-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 10 mg (59%) of the title compound as an orange solid. 0713 1HNMR (300 MHz, DMSO-d6) 13.67 (s, br, 1H, NH), 10.96 (, br, 1H, NH), 8.16 (d, J1.2 Hz, 1H), 7.81 (s, 1H, H-vinyl), 7.65-7.72 (m, 4H), 7.44 (m, 3H), 7.31 (m, 1H, CONHCH2), 7.21 (s, 1H, ArH), 4.02 (t, J6.5 Hz, 2H, NCH2), 3.19 (q, J6.5 Hz, 2H, CONHCH2), 2.44 (s, 6H, 2CH3), 1.93 (m, 2H, CH2CH2CH2). 0714 MS-EI m/z 465 M.

Example 59 0715 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0716 6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid. 0717 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J7.8 Hz, 1H), 7.62-7.66 (m, 3H), 7.40-7.47 (m, 3H), 7.28-7.36 (m, 2H), 7.10 (d, J1.2 Hz, 1H), 3.26 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J7.2 Hz, 6H, 2NCH2CH3). 0718 MS-EI m/z 456 M.

Example 60 0719 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0720 6-Phenyl-1,3-dihydroindol-2-one (30 mg, 0.15 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (40 mg) to give 5.9 mg (8.5%) of the title compound as a yellow-orange solid. 0721 1HNMR (300 MHz, DMSO-d6) 13.60 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J7.8 Hz, 1H), 7.63-7.66 (m, 3H), 7.51 (m, 1H, CONHCH2), 7.45 (m, 2H), 7.28-7.36 (m, 2H), 7.10 (d, J1.5 Hz, 1H), 3.31 (m, 6H, 3NCH2), 2.55 (t, J6.6 Hz, 2H, NCH2), 2.43 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0722 MS-EI m/z 454 M.

Example 61 0723 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-ylpropyl)amide 0724 6-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 7.3 mg (43%) of the title compound as an orange solid. 0725 1HNMR (300 MHz, DMSO-d6) 13.62 (s, br, 1H, NH), 10.99 (, br, 1H, NH), 7.86 (d, J8.2 Hz, 1H), 7.62-7.70 (m, 5H), 7.45 (m, 2H), 7.35 (m, 1H), 7.30 (dd, J1.4 & 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J1.4 Hz, 1H), 6.89 (s, 1H), 4.02 (t, J6.9 Hz, 2H, CH2), 3.19 (m, 2H, NCH2CH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.93 (t, J6.9 Hz, 2H, NCH2). 0726 MS-EI m/z 465 M.

Example 62 0727 5-6-(3,5-Dichlorophenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0728 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (60 mg) to give 53 mg (44%) of the title compound as a light brown solid. 0729 1HNMR (360 MHz, DMSO-d6) 13.62 (s, br, 1H, NH), 10.99 (s, 1H, NH), 7.89 (d, J7.9 Hz, 1H, H-4), 7.69-7.71 (m, 3H), 7.55 (m, 1H, CONHCH2), 7.37 (m, 2H), 7.14 (d, J1.4 Hz, 1H, H-7), 3.27 (m, 2H, NCH2), 2.48-2.58 (m, 6H, 3NCH2), 2.45 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.97 (t, J6.8 Hz, 6H, 3NCH2CH3). 0730 MS m/z 526.9 M1.

Example 63 0731 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0732 6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (50 mg) give, 29 mg (33%) of the title compound as a light orange solid. 0733 1HNMR (300 MHz, DMSO-d6) 13.62 (s, br, 1H, NH), 11.05 (s, br, 1H, NH), 8.86 (s, br, 1H), 8.53 (d, J5.8 Hz, 1H), 8.04 (m, 1H), 7.91 (d, J8.1 Hz, 1H), 7.70 (s, 1H, H-vinyl), 7.40-7.48 (m, 2H), 7.35 (d, J7.5 Hz, 1H), 7.14 (s, 1H), 3.26 (m, 2H, NCH2), 2.48-2.55 (m, 3NCH2), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3), 0.96 (t, J6.9 Hz, 6H, 2NCH2CH3). 0734 MS-EI m/z 457 M.

Example 64 0735 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0736 6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.28 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (75 mg) to give 90 mg (71%) of the title compound as a light orange solid. 0737 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 11.05 (s, br, 1H, NH), 8.86 (d, J1.5 Hz, 1H), 8.54 (dd, J1.5 & 4.8 Hz, 1H), 8.05 (m, 1H), 7.91 (d, J7.8 Hz, 1H), 7.70 (s, 1H, H-vinyl), 7.44-7.53 (m, 2H), 7.36 (dd, J1.5 & 8.1 Hz, 1H), 7.15 (d, J1.2 Hz, 1H), 3.33 (m, 2H, NCH2), 2.47-2.57 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0738 MS-EI m/z 455 M.

Example 65 0739 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-dimethylaminopropyl)amide 0740 6-Pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylaminopropyl)amide (50 mg) to give 67 mg (75%) of the title compound as yellow-brown solid. 0741 1HNMR (360 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 11.00 (s, br, 1H, NH), 8.86 (s, br, 1H), 8.54 (s, br, 1H), 8.04 (m, 1H), 7.90 (d, J8.0 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.63 (m, 1H), 7.45-7.48 (m, 1H), 7.35 (dd, J1.7 & 8.0 Hz, 1H), 7.15 (d, J1.7 Hz, 1H), 3.21-3.27 (m, 2H, NCH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.28 (m, 2H, NCH2), 2.14 (s, 6H, 2NCH3), 1.64 (m, 2H, CH2). 0742 MS-EI m/z 443 M.

Example 66 0743 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-dimethylaminopropyl)amide 0744 5-Phenyl-1,3-dihydroindol-2-one (67 mg, 0.32 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylaminopropyl)amide (81 mg) to give 40 mg (28%) of the title compound as an orange solid. 0745 1HNMR (360 MHz, DMSO-d6) 13.66 (s, br, 1H, NH), 10.92 (s, br, 1H, NH), 8.14 (s, 1H), 7.79 (s, 1H), 7.71 (m, 2H), 7.62 (m, 1H), 7.44 (m, 3H), 7.32 (m, 1H), 6.95 (m, 1H), 3.33 (m, 2H, NCH2), 2.43 (s, 6H, 2CH3), 2.27 (m, 2H, NCH2), 2.13 (s, 6H, 2NCH3), 1.63 (m, 2H, CH2). 0746 MS-EI m/z 442 M.

Example 67 0747 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0748 5-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.3 g (40%) of the title compound as a yellow-orange solid. 0749 1HNMR (360 MHz, DMSO-d6) 13.64 (s, 1H, NH), 10.91 (s, 1H, NH), 8.14 (d, J1.4 Hz, 1H, ArH), 7.8 (s, 1H, ArH), 7.7 (dd, J1.2 and 8.5 Hz, 2H, ArH), 7.6 (t, J5.3 Hz, 1H, CONHCH2), 7.4(m, 3H, ArH), 7.3 (t, J7.4 Hz, 1H, ArH), 6.9 (d, J8.0 Hz, 1H, ArH), 3.2 (m, 2H, CONHCH2), 2.5 (m, 12H, 3NCH2 and 2CH3), 1.61 (m, 2H, CH2CH2CH2), 0.93 (t, J6.7 Hz, 6H, NCH2CH3). 0750 MS-EI m/z 470 M.

Example 68 0751 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0752 6-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.9 g (57%) of the title compound as an orange solid. 0753 1HNMR (360 MHz, DMSO-d6) 13.58 (s, 1H, NH), 10.94 (s, 1H, NH), 7.8 (d, J7.9 Hz, 1H, ArH), 7.6 (m, 4H, ArH), 7.4 (t, J7.5 Hz, 2H, ArH), 7.3 (m, 2H), 7.1 (d, J1.4 Hz, 1H, ArH), 3.2 (m, 2H, CONHCH2), 2.5 (m, 12H, 3NCH2 and 2CH3), 1.61 (m, 2H, CH2CH2CH2), 0.93 (t, J6.7 Hz, 6H, NCH2CH3). 0754 MS-EI m/z 470 M.

Example 69 0755 3-4-(3-Diethylaminopropylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene-2-oxo-2,3-dihydro-1H-indole-4-carboxylic Acid (3-chloro-4-methoxyphenyl)amide 0756 2-Oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)amide (1 g, 3.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (1 g, 3.58 mmol) to give 1.7 g (85%) of the title compound as a yellow-orange solid. 0757 MS-EI m/z 578.2 M.

Example 70 0758 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (3-diethylamino-propyl)amide 0759 5-Bromo-1,3-dihydroindol-2-one (0.5 g, 2.36 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.51 g) to give 0.84 g of the title compound as a red-orange solid. 0760 1HNMR (360 MHz, DMSO-d6) 13.61 (s, 1H, NH), 10.99 (s, 1H, NH), 8.09 (d, J, 1.8 Hz, 1H, ArH), 7.7 (m, 4H), 7.2 (dd, J1.8 and 8.3 Hz, 2H, ArH), 6.8 (d, J7.8 Hz, 1H, ArH), 3.3 (br s, 4H, 2NCH2), 3.2 (m, 2H, CONHCH2), 2.6 (br s, 2H, NCH2 and 2CH3), 2.4 (s, 6H, 2CH3), 1.66 (m, 2H, CH2CH2CH2), 0.98 (t, J7.1 Hz, 6H, NCH2CH3). 0761 MS-EI m/z 472 and 474 M1 and M1.

Example 71 0762 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 0763 5-Bromo-1,3-dihydroindol-2-one (100 mg, 0.47 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (150 mg) to give 0.15 g (62%) of the title compound as a yellow-orange solid. 0764 1HNMR (300 MHz, DMSO-d6) 13.97 (s, 1H, NH), 10.95 (s, 1H, NH), 8.09 (d, J1.3 Hz, 1H, ArH), 7.84 (m, 1H), 7.79 (s, 1H), 7.23 (dd, J1.3 and 8.1 Hz, 1H, ArH), 6.8 (d, J8.1 Hz, 1H, ArH), 3.5 (m, 1H, CH), 3.3 (m, 3H, CH and NHCH2), 2.5 (br m, 6H, 3NCH2), 1.28 (d, J6.9 Hz, 6H, 2CH3), 1.23 (d, J6.6 Hz, 6H, 2CH3), 0.96 (m, 6H, 2CH2CH3). 0765 MS-EI m/z 514 and 516 M1 and M1.

Example 72 0766 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (3-diethylamino-propyl)amide 0767 5-Bromo-1,3-dihydroindol-2-one (90 mg, 0.42 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (140 mg) to give 54 mg (25%) of the title compound as red-brown solid. 0768 1HNMR (300 MHz, DMSO-d6) 13.98 (s, 1H, NH), 10.96 (s, 1H, NH), 8.09 (d, J1.7 Hz, 2H), 7.78 (s, 1H, H-vinyl), 7.23 (dd, J1.7 and 8.1 Hz, 1H, ArH), 6.82 (d, J8.1 Hz, 1H, ArH), 3.5 (m, 1H, CH), 3.25 (m, 2H, NHCH2), 3.15 (m, 1H, CH), 2.7 (br s, 6H, 3NCH2), 1.7 (br m, 2H, CH2CH2CH2), 1.28 (d, J6.9 Hz, 6H, 2CH3), 1.24 (d, J5.9 Hz, 6H, 2CH3), 1.06 (m, 6H, 2CH2CH3). 0769 MS-EI m/z 528 and 530 M1 and M1.

Example 73 0770 5-(5-Bromo-2-oxo-1.2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0771 5-Bromo-1,3-dihydroindol-2-one (130 mg, 0.6 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (150 mg, 0.45 mmol) to give 36 mg (15%) of the title compound as a tan-orange solid. 0772 1HNMR (300 MHz, DMSO-d6) 13.98 (s, 1H, NH), 10.97 (s, 1H, NH), 8.10 (d, J1.6 Hz, 2H), 7.78 (s, 1H, H-vinyl), 7.23 (dd, J1.6 and 7.6 Hz, 1H, ArH), 6.82 (d, J7.6 Hz, 1H, ArH), 3.5 (m, 1H, CH), 3.25 (m, 2H, NHCH2),3.15 (m, 1H, CH), 2.7 (br s, 6H, 3NCH2), 1.7 (br m, 6H, 3NCH2CH2), 1.28 (d, J5.6 Hz, 6H, 2CH3), 1.24 (d, J5.7 Hz, 6H, 2CH3). 0773 MS-EI m/z 526 and 528 M1 and M1.

Example 74 0774 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (pyridin-4-ylmethyl)-amide 0775 5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (pyridin-4-ylmethyl)amide (200 mg) to give 14 mg (4%) of the title compound as a yellow solid. 0776 1HNMR (300 MHz, DMSO-d6) 13.67 (s, 1H, NH), 11.01 (s, br, 1H, NH), 8.51 (dd, J1.6 & 4.3 Hz, 2H), 8.23 (t, J6.0 Hz, 1H, CONHCH2), 8.11 (d, J1.9 Hz, 1H), 7.78 (s, 1H, H-vinyl), 7.31 (d, J6.0 Hz, 2H), 7.25 (dd, J1.9 & 8.1 Hz, 1H), 6.82 (d, J8.1 Hz, 1H), 4.45 (d, J6.0 Hz, 2H, NCH2), 2.46 (s, 6H, 2CH3). 0777 MS-EI m/z 450 and 452 M1 and M1.

Example 75 0778 5-6-(4-Butylphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2.4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0779 5-6-(4-Butylphenyl)-1,3-dihydroindol-2-one (50 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 74 mg (76%) of the title compound as an orange solid. 0780 1HNMR (360 MHz, DMSO-d6) 13.58 (s, 1H, NH), 10.93 (s, br, 1H, NH), 7.82 (d, J7.9 Hz, 1H), 7.63 (s, 1H, H-vinyl), 7.54 (d, J7.9 Hz, 2H), 7.46 (m, 1H, CONH), 7.26 (m, 3H), 7.09 (s, 1H), 3.30 (m, 2H, CH2), 2.52-2.63 (m, 4H, 2CH2), 2.49 (m, 4H, 2CH2), 2.43 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.68 (m, 4H, 2CH2), 1.58 (m, 2H, CH2), 1.34 (m, 2H, CH2), 0.91 (t, J7.2 Hz, 3H, CH2CH3). 0781 MS-EI m/z 510 M.

Example 76 0782 5-6-(5-Isopropyl-2-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0783 6-(5-Isopropyl-2-methoxyphenyl)-1,3-dihydroindol-2-one (50 mg, 0.17 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide (45 mg) to give 67 mg (75%) of the title compound as an orange solid. 0784 1HNMR (360 MHz, DMSO-d6) 13.60 (s, 1H, NH), 10.82 (s, br, 1H, NH), 7.77 (d, J7.9 Hz, 1H), 7.61 (s, 1H, H-vinyl), 7.45 (m, 1H, CONH), 7.0-7.19 (m, 5H), 3.73 (s, 3H, OCH3), 3.32 (m, 2H, CH2), 2.87 (m, 1H, CH(CH3)2), 2.56 (m, 2H, CH2), 2.48 (m, 4H, 2CH2), 2.43 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.68 (m, 4H, 2CH2), 1.21 (d, J6.8 Hz, 6H, CH(CH3)2). 0785 MS m/z 527.2 M1.

Example 77 0786 5-6-(4-Ethylphenyl)-2-oxo-1.2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0787 6-(4-Ethylphenyl)-1,3-dihydroindol-2-one (45 mg, 0.19 mmol) was condensed 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 60 mg (65%) of the title compound as a yellow-orange solid. 0788 1HNMR (300 MHz, DMSO-d6) 13.59 (s, 1H, NH), 10.96 (s, br, 1H, NH), 7.83 (d, J8.4 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.51-7.56 (m, 3H), 7.25-7.30 (m, 3H), 7.08 (d, J1 Hz, 1H), 3.31 (m, 2H, CH2), 2.63 (m, 2H, CH2CH3), 2.55 (m, 2H, CH2), 2.49 (m, 4H, 2CH2), 2.42 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.67 (m, 4H, 2CH2), 1.20 (t, J7.5 Hz, 3H, CH2CH3). 0789 MS-EI m/z 482 M.

Example 78 0790 5-6-(2,4-Dimethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0791 6-(2,4-Dimethoxyphenyl)-1,3-dihydroindol-2-one (51 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 30 mg (31%) of the title compound as an orange solid. 0792 1HNMR (300 MHz, DMSO-d6) 13.59 (s, 1H, NH), 10.86 (s, br, 1H, NH), 7.75 (d, J7.8 Hz, 1H), 7.60 (s, 1H, H-vinyl), 749 (m, 1H, CONH), 7.22 (d, J8.4 Hz, 1H), 7.03 (m, 1H), 6.97 (s, 1H), 6.58-6.65 (m, 2H), 3.79 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.33 (m, 2H, CH2), 2.55 (m, 2H, CH2), 2.50 (m, 4H, 2CH2), 2.42 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0793 MS-EI m/z 514 M.

Example 79 0794 5-6-(3-Isopropylphenyl)-2-oxo-1.2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0795 6-(3-Isopropylphenyl)-1,3-dihydroindol-2-one (48 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 59 mg (63%) of the title compound as an orange solid. 0796 1HNMR (300 MHz, DMSO-d6) 13.63 (s, 1H, NH), 10.97 (s, br, 1H, NH), 7.87 (d, J7.8 Hz, 1H), 7.68 (s, 1H, H-vinyl), 7.24-7.55 (m, 6H), 7.13 (s, 1H), 3.34 (m, 2H, CH2), 3.30 (m, 1H, CH(CH3)2), 2.60 (m, 2H, CH2), 2.50 (m, 4H, 2CH2), 2.45 (s, 3H, CH3), 2.43 (s, 3H, CH3), 1.70 (m, 4H, 2CH2), 1.27 (d, J6.9 Hz, 6H, CH(CH3)2). 0797 MS-EI m/z 496 M.

Example 80 0798 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 0799 5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid. 0800 1HNMR (360 MHz, DMSO-d6) 13.66 (s, 1H, NH), 10.83 (s, br, 1H, NH), 7.73 (dd, J2.5 & 9.4 Hz, 1H), 7.69 (s, 1H, H-vinyl), 7.37 (t, 1H, CONHCH2CH2), 6.91 (m, 1H), 6.81-6.85 (m, 1H), 3.27 (m, 2H, CH2), 2.51 (m, 6H, 3CH2), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.96 (t, J6.9 Hz, 6H, N(CH2CH3)2). 0801 MS-EI m/z 398 M.

Example 80

Alternative Synthesis 0802 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 0803 Hydrazine hydrate (55%, 3000 mL) and 5-fluoroisatin (300 g) were heated to 100 C. An additional 5-fluoro-isatin (500 g) was added in portions (100 g) over 120 minutes with stirring. The mixture was heated to 110 C. and stirred for 4 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration to give crude (2-amino-5-fluoro-phenyl)-acetic acid hydrazide (748 g). The hydrazide was suspended in water (700 mL) and the pH of the mixture adjusted to <pH 3 with 12 N hydrochloric acid. The mixture was stirred for 12 hours at room temperature. The solids were collected by vacuum filtration and washed twice with water. The product was dried under vacuum to give 5-fluoro-1,3-dihydro-indol-2-one (600 g, 73% yield) as as a brown powder. 1H-NMR (dimethylsulfoxide-d6) 3.46 (s, 2H, CH2), 6.75, 6.95, 7.05 (3m, 3H, aromatic), 10.35 (s, 1H, NH). MS m/z 152 M1. 0804 3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (2600 g) and ethanol (7800 mL) were stirred vigorously while 10 N hydrochloric acid (3650 mL) was slowly added. The temperature increased from 25 C. to 35 C. and gas evolution began. The mixture was warmed to 54 C. and stirred with further heating for one hour at which time the temperature was 67 C. The mixture was cooled to 5 C. and 32 L of ice and water were slowly added with stirring. The solid was collected by vacuum filtration and washed three times with water. The solid was air dried to constant weight to give of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (1418 g, 87% yield) as a pinkish solid. 1H-NMR (dimethylsulfoxide-d6) 2.10, 2.35 (2s, 23H, 2CH3), 4.13 (q, 2H, CH2), 6.37 (s, 1H, CH), 10.85 (s, 1H, NH). MS m/z 167 M1. 0805 Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4 C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18 C. The mixture was heated to reflux for one hour, cooled to 10 C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15 C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22 C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40 C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55 C. during the addition. After the addition was complete the mixture was cooled to 10 C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100% yield) as a yellow solid. 1H-NMR (DMSO-d6) 1.25 (t, 3H, CH3), 2.44, 2.48 (2s, 23H, 2CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 M1. 0806 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (806 g), potassium hydroxide (548 g), water (2400 mL) and methanol (300 mL) were refluxed for two hours with stirring and then cooled to 8 C. The mixture was extracted twice with dichloromethane. The aqueous layer was adjusted to pH 4 with 1000 mL of 10 N hydrochloric acid keeping the temperature under 15 C. Water was added to facilitate stirring. The solid was collected by vacuum filtration, washed three times with water and dried under vacuum at 50 C. to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic (645 g, 93.5% yield) acid as a yellow solid. NMR (DMSO-d6) 2.40, 2.43 (2s, 23H, 2CH3), 9.57 (s, 1H, CHO), 12.07 (br s, 2H, NHCOOH). MS m/z 168 M1. 0807 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) 0.96 (t, 6H, 2CH3), 2.31, 2.38 (2s, 2CH3), 2.51 (m, 6H 3CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 M1. 0808 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (809 g), 5-fluoro-1,3-dihydro-indol-2-one (438 g), ethanol (8000 mL) and pyrrolidine (13 mL) were heated at 78 C. for 3 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed with ethanol. The solids were stirred with ethanol (5900 mL) at 72 C. for 30 minutes. The mixture was cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol and dried under vacuum at 54 C. for 130 hours to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (1013 g, 88% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) 0.98 (t, 6H, 2CH3), 2.43, 2.44 (2s, 6H, 2CH3), 2.50 (m, 6H, 3CH2), 3.28 (q, 2H, CH2), 6.84, 6.92, 7.42, 7.71, 7.50 (5m, 5H, aromatic, vinyl, CONH), 10.88 (s, 1H, CONH), 13.68 (s, 1H, pyrrole NH). MS m/z 397 M1.

Example 81 0809 3-4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0810 2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid. 0811 1HNMR (360 MHz, DMSO-d6) 13.6 (s, 1H, NH), 7.76 (d, J8.0 Hz, 1H), 7.66 (s, 1H, H-vinyl), 7.57 (dd, J1.5 & 8.0 Hz, 1H), 7.40-7.42 (m, 2H), 3.28 (m, 2H, CH2), 2.88 (m, H-piperidine), 2.54 (m, 6H, 3CH2), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.56 (m, H-piperidine), 0.97 (t, J6.98 Hz, 6H, N(CH2CH3)2). 0812 MS m/z 424 M.

Example 82 0813 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0814 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 100 mg (54%) of the title compound as a yellow solid. 0815 1HNMR (360 MHz, DMSO-d6) 13.65 (s, 1H, NH), 11.30 (s, br, 1H, NH), 8.25 (d, 1H), 7.92 (s, 1H, H-vinyl), 7.48-7.53 (m, 2H), 7.07 (d, J8.2 Hz, 1H), 3.33 (m, 2H, CH2), 2.61 (s, 6H, N(CH3)2), 2.56 (t, 2H, CH2), 2.49 (m, 4H, 2CH2), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0816 MS-EI m/z 485 M.

Example 83 0817 5-5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0818 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 150 mg (69%) of the title compound as a yellow orange solid. 0819 1HNMR (360 MHz, DMSO-d6) 13.55 (s, 1H, NH), 11.26 (br s, 1H, NH), 10.30 (br s,1H, NH), 8.26 (d, 1H), 7.79 (s, 1H, H-vinyl), 7.51-7.57 (m, 2H), 7.22 (t, J8.1 Hz, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 7.0 (m, 2H), 3.44 (m, 2H, CH2), 2.57 (t, J7.0 Hz, 2H, CH2), 2.49 (m, 4H, 2CH2), 2.44 (s, 3H, CH3), 2.43 (s, 3H, CH3), 1.68 (m, 4H, 2CH2). 0820 MS m/z 568 M.

Example 84 0821 2,4-Dimethyl-5-2-oxo-5-(pyridin-3-ylsulfamoyl)-1,2-dihydroindol-3-ylidenemethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0822 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide (110 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 150 mg (74%) of the title compound as an orange solid. 0823 1HNMR (360 MHz, DMSO-d6) 13.58 (s, 1H, NH), 8.21 (d, J2.0 Hz, 2H), 8.04 (m, 1H), 7.76 (s, 1H, H-vinyl), 7.49-7.54 (m, 2H), 7.41 (m, 1H), 7.14 (m, 1H), 6.94 (d, J8.5 Hz, 1H), 3.33 (m, 2H, CH2), 2.56 (t, J7.06 Hz, 2H, CH2), 2.49 (m, 4H, 2CH2), 2.43 (s, 6H, 2CH3), 1.68 (m, 4H, 2CH2). 0824 MS m/z 535 M.

Example 85 0825 3-3.5-Dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene-4-(2-hydroxyethyl)-1,3-dihydroindol-2-one 0826 4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one (71 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give 90 mg (55%) of the title compound as an orange solid. 0827 1HNMR (300 MHz, DMSO-d6) 14.25(s, 1H, NH), 10.88 (s, 1H, NH), 7.57 (s, 1H, H-vinyl), 7.03 (m, 1H), 6.75-6.82 (m, 2H), 4.86 (m, 1H, OH), 3.70 (m, 2H, CH2), 3.04 (m, 2H, CH2), 2.48 (m, 4H, 2CH2), 2.28 (br s, 7H), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3). 0828 MS m/z (ve) 4.09.3 M.

Example 86 0829 3-3.5-Dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonic Acid Phenylamide 0830 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide (110 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (100 mg) to give 50 mg (24%) of the title compound as a yellow solid. 0831 1HNMR (300 MHz, DMSO-d6) 13.52(s, 1H, NH), 11.26 (s, 1H, NH), 10.08 (s, 1H, NH), 8.21 (d, J1.6 Hz, 1H), 7.75 (s, 1H, H-vinyl), 7.50 (dd, J1.6 & 8.3 Hz, 1H), 7.19 (m, 2H), 7.10 (m, 2H), 6.97 (m, 2H), 2.49 (m, 4H, 2CH2), 2.28 (m, 10H, 2CH3 & 2CH2), 2.18 (s, 3H, CH3). 0832 MS-EI m/z 519 M.

Example 87 0833 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0834 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (43%) of the title compound as a yellow solid. 0835 1HNMR (300 MHz, DMSO-d6) 11.30 (s, 1H, NH), 8.27 (d, J1.7 Hz, 1H), 7.94 (s, 1H, H-vinyl), 7.49 (dd, J1.7 & 8.0 Hz, 1H), 7.44 (m, 1H, CONHCH2CH2), 7.07 (d, J8.0 Hz, 1H), 3.26 (m, 2H, CH2), 2.60 (s, 6H, N(CH3)2), 2.53 (m, 2H, CH2), 2.45-2.50 (m, 10H, 2CH3 & N(CH2CH3)2, 0.96 (t, J7.2 Hz, 6H, N(CH2CH3)2). 0836 MS-EI m/z 487 M.

Example 88 0837 5-5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0838 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (37%) of the title compound as a yellow solid. 0839 1HNMR (360 MHz, DMSO-d6) 13.55 (s, 1H, NH), 11.24 (s, 1H, NH), 10.29 (s, 1H, NH), 8.25 (d, J1.87 Hz, 1H), 7.79 (s, 1H, H-vinyl), 7.52 (dd, J1.87 & 8.3 Hz, 1H), 7.42 (m, 1H, CONHCH2CH2), 7.22 (t, J8.02 Hz, 1H), 7.15 (t, J2 Hz, 1H), 7.08 (m, 1H), 7.0 (m, 2H), 3.27 (m, 2H, CH2), 2.48-2.57 (m, 6H, 3CH2), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3), 0.97 (t, J7.0 Hz, 6H, N(CH2CH3)2). 0840 MS m/z 570.1 M.

Example 95 0841 3-(2-Oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid Ethyl Ester 0842 1HNMR (360 MHz, DMSO-d6) 13.74 (s, 1H, NH), 11.00 (s, 1H, NH), 8.13 (d, J1.7 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.70 (d, J7.7 Hz, 2H), 7.49 (dd, J1.7 & 8.0 Hz, 1H), 7.44 (t, J7.7 Hz, 2H), 7.32 (m, 1H), 6.96 (d, J8.0 Hz, 1H), 4.26 (q, J7.0 Hz, 2H, OCH2CH3), 2.79 (m, 2H, CH2), 2.72 (m, 2H, CH2), 1.73 (m, 4H, 2CH2), 1.30 (t, J7.0 Hz, 3H, OCH2CH3). 0843 MS-EI m/z 412 M.

Example 99 0844 3-(2-Oxo-5-phenylsulfamoyl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid Ethyl Ester 0845 1HNMR (360 MHz, DMSO-d6) 13.64 (s, 1H, NH), 11.33 (s, 1H, NH), 10.07 (s, 1H, NH), 8.24 (d, J1.8 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.57 (dd, J1.8 & 8.0 Hz, 1H), 7.21 (t, J7.6 Hz, 2H), 7.11 (d, J7.6 Hz, 2H), 6.99 (d, J8.0 Hz, 1H), 6.98 (d, J7.6 Hz, 1H), 4.27 (q, J7.0 Hz, 2H, OCH2CH3), 2.80 (m, 2H, CH2), 2.73 (m, 2H, CH2), 1.73 (m, 4H, 2CH2), 1.30 (t, J7.0 Hz, 3H, OCH2CH3). 0846 MS-EI m/z 491 M.

Example 109 0847 3-3-(Morpholine-4-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0848 1HNMR (360 MHz, DMSO-d6) 13.60 (s, 1H, NH), 12.75 (br s, 1H, COOH), 11.08 (s, 1H, NH), 7.85 (d, J7.8 Hz, 1H), 7.71 (s, 1H, H-vinyl), 7.62 (dd, J1.4 & 7.8 Hz, 1H), 7.41 (d, J1.4 Hz, 1H), 3.65 (m, 4H, 2CH2), 3.55 (m, 4H, 2CH2), 2.81 (m, 2H, CH2), 2.54 (m, 2H, CH2).1.73 (m, 4H, 2CH2). 0849 MS-EI m/z 421 M.

Example 112 0850 5-Bromo-3-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene-1,3-dihydro-indol-2-one 0851 1HNMR (360 MHz, DMSO-d6) 13.56 (s, 1H, NH), 11.00 (s, 1H, NH), 8.05 (d, J1.8 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.28 (dd, J1.3 & 8.3 Hz, 1H), 6.83 (d, J8.3 Hz, 1H), 3.57 (m, 4H, 2CH2), 2.79 (m, 2H, CH2), 2.65 (m, 2H, CH2), 1.88 (m, 4H, 2CH2), 1.71 (m, 4H, 2CH2). 0852 MS-EI m/z 439 & 441 M1 & M1.

Example 114 0853 3-(3-Dimethylcarbamooyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0854 1HNMR (360 MHz, DMSO-d6) 13.60 (s, 1H, NH), 12.72 (br s, 1H, COOH), 11.05 (s, 1H, NH), 7.85 (d, J7.9 Hz, 1H), 7.72 (s, 1H, H-vinyl), 7.62 (dd, J1.3 & 7.9 Hz, 1H), 7.42 (d, J1.3 Hz, 1H), 3.03 (s, 6H, N(CH3)2), 2.81 (m, 2H, CH2), 2.55 (m, 2H, CH2), 1.73 (m, 4H, 2CH2). 0855 MS-EI m/z 379 M.

Example 115 0856 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid 0857 1HNMR (300 MHz, DMSO-d6) 13.56 (br s, 1H, NH), 8.24 (d, J1.5 Hz, 1H), 7.86 (s, 1H, H-vinyl), 7.74 (d, J2.96 Hz, 1H), 7.56 (dd, J1.5 & 8.1 Hz, 1H), 7.20 (br m, 1H, NHCH3), 7.03 (d, J8.1 Hz, 1H), 2.57 (s, 3H, CH3), 2.41 (s, 3H, CH3). 0858 MS-EI m/z 361 M.

Example 116 0859 4-Methyl-5-(4-methyl-5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid Ethyl Ester 0860 4-Methyl-1H-pyrrole-3-carboxylic acid ethyl ester (lit. ref. D. O. Cheng, T. L. Bowman and E. LeGoff; J. Heterocyclic Chem.; 1976; 13; 1145-1147) was formylated using method A, hydrolysed using method B followed by amidation (method C) to give (5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino-acetic acid ethyl ester. 0861 4-Methyl-5-methylaminosulfonyl-2-oxindole (50 mg, 0.21 mmol) was condensed with (5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino-acetic acid ethyl ester (100 mg, 0.42 mmol) and piperidine (0.1 mL) in ethanol (2 mL) to give 50 mg (52%) of the title compound. 0862 1HNMR (360 MHz, DMSO-d6) 13.59 (s, 1H, NH), 11.29 (v.br. s, 1H, NHCO), 8.33 (t, J5.8 Hz, 1H, CONHCH2), 7.83 (d, J3.11 Hz, 1H), 7.80 (s, 1H, H-vinyl), 7.71 (d, J8.5 Hz, 1H), 7.34 (br m, 1H, NHCH3), 6.89 (d, J8.5 Hz, 1H), 4.11 (q, J7.1 Hz, 2H, OCH2CH3), 3.92 (d, J5.8 Hz, 2H, GlyCH2), 2.86 (s, 3H, CH3), 2.48 (s, 3H, CH3), 2.42 (d, J4.71 Hz, 3H, HNCH3), 1.20 (t, J7.1 Hz, 3H, OCH2CH3). 0863 MS-EI m/z 460 M.

Example 117 0864 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid Ethyl Ester 0865 A mixture of 5-methylaminosulfonyl-2-oxindole (0.06 g, 0.22 mmol), (5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino-acetic acid ethyl ester (0.075 g, 0.27 mmol) and piperidine (2 drops) in ethanol (5 mL) was heated in a sealed tube at 90 C. for 12 hrs. After cooling, the precipitate was collected by vacuum filtration, washed with ethanol, triturated with dichloromethane/ether and dried to give 0.035 g (36%) of the title compound as a yellowish brown solid. 0866 1H NMR (360 MHz, DMSO-d6) 13.6 (s, 1H, NH), 11 (v.br. s, 1H, NHCO), 8.30 (t, J5.7 Hz, 1H, CONHCH2), 8.25 (d, J1.2 Hz, 1H), 7.88 (s, 1H, H-vinyl), 7.84 (d, J3.3 Hz, 1H), 7.57 (dd, J1.9 & 8.5 Hz, 1H), 7.14 (br m, 1H, NHCH3), 7.04 (d, J8.5 Hz, 1H), 4.11 (q, J6.7 Hz, 2H, OCH2CH3), 3.92 (d, J5.7 Hz, 2H, GlyCH2), 2.55 (s, 3H, CH3), 2.41 (m, 3H, NCH3), 1.20 (t, J6.7 Hz, 3H, OCH2CH3). 0867 MS m/z 446 M.

Example 118 0868 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid 0869 A mixture of (5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino-acetic acid ethyl ester (0.142 g, 0.59 mmol) and 1N NaOH (1.2 mL) in methanol (10 mL) was stirred at room temperature for 1 hr. The reaction was concentrated and the residue was condensed with 5-methylaminosulfonyl-2-oxindole (0.13 g, 0.48 mmol) and piperidine (0.12 mL) in ethanol (12 mL) to give 0.11 g (52%) of the title compound. 0870 1HNMR (300 MHz, DMSO-d6) 13.98 (br s, 1H, NH), 8.17 (s, 1H), 7.80 (s, 1H), 7.75 (d, J3.1 Hz, 1H), 7.51 (dd, J2 & 8.2 Hz, 1H), 7.21 (m on br s, 2H), 6.97 (d, J8.1 Hz, 1H), 3.41 (d, J4.2 Hz, 2H, CH2NH), 2.54 (s, 3H, pyrrole-CH3), 2.39 (s, 3H, ArCH3). 0871 MS m/z 417 M1.

Example 120 0872 5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid 0873 1HNMR (300 MHz, DMSO-d6) 13.77 (br s, 1H, NH), 12.49 (s, 1H, COOH), 11.07 (s, 1H, NH), 8.39 (s, 1H, H-vinyl), 7.43 (d, J7.47 Hz, 1H), 7.20 (t, J7.47 Hz, 1H), 7.03 (t, J7.47 Hz, 1H), 6.91 (d, J7.47 Hz, 1H), 6.49 (d, J1.53 Hz, 1H), 2.34 (s, 3H, CH3). 0874 MS m/z 269 MH.

Example 121 0875 5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0876 1HNMR (300 MHz, DMSO-d6) 13.79 (s, 1H, NH), 11.08 (s, 1H, NH), 8.31 (s, 1H, H-vinyl), 7.45 (d, J7.52 Hz, 1H), 7.20 (t, J7.52 Hz, 1H), 7.03 (t, J7.52 Hz, 1H), 6.91 (d, J7.52 Hz, 1H), 6.50 (d, J2.1 Hz, 1H), 4.26 (q, J7.2 Hz, 2H, OCH2CH3), 2.33 (s, 3H, CH3), 1.32 (t, J7.2 Hz, 3H, OCH2CH3). 0877 MS m/z 297.1 MH.

Example 122 0878 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0879 1HNMR (360 MHz, DMSO-d6) 13.72(s, 1H, NH), 11.16 (s, 1H, NH), 8.29 (s, 1H, H-vinyl), 7.53 (d, J2.0 Hz, 1H), 7.35 (dd, J2.0 & 8.05 Hz, 1H), 6.87 (t, J8.05 Hz, 1H), 6.53 (d, J2.4 Hz, 1H), 4.28 (q, J7.03 Hz, 2H, OCH2CH3), 2.35 (s, 3H, CH3), 1.33 (t, J7.03 Hz, 3H, OCH2CH3). 0880 MS m/z 375 & 377 MH.

Example 123 0881 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid 0882 1HNMR (300 MHz, DMSO-d6) 13.72(s, 1H, NH), 12.57 (s, 1H, COOH), 11.19 (s, 1H, NH), 8.36 (s, 1H, H-vinyl), 7.51 (d, J1.4 Hz, 1H), 7.34 (dd, J1.4 & 8.17 Hz, 1H), 6.87 (t, J8.17 Hz, 1H), 6.52 (d, J2.5 Hz, 1H), 2.35 (s, 3H, CH3). 0883 MS m/z 347 & 349 MH

Example 124 0884 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)-amide 0885 To a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (250 mg, 1.63 mmol) in dimethylformamide (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (376 mg, 1.2 equiv.), 1-hydroxybenzotriazole (265 mg, 1.2 equiv.), triethylamine (0.45 mL, 2 equiv.) and 1-(2-aminoethyl)pyrrolidine (0.23 mL. 1.1 equiv.). After stirring at room temperature overnight, the reaction was diluted with saturated sodium bicarbonate and brine (with extra salt) and extracted with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 130 mg of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide. 0886 A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (125 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80 C. for 1 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid. 0887 1HNMR (300 MHz, DMSO-d6) 13.62 (s, 1H, NH), 11.06 (br s, 1H, NH), 8.56 (s, 1H, H-vinyl), 8.15 (m, 1H, CONHCH2), 7.48 (d, J1.8 Hz, 1H), 7.31 (dd, J1.8 & 7.9 Hz, 1H), 6.86 (d, J7.9 Hz, 1H), 6.60 (d, J2.3 Hz, 1H), 3.35 (m, 2H, HNCH2CH2), 2.56 (t, J6.91 Hz, 2H, HNCH2CH2), 2.35 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0888 MS m/z 443/445 M and M2.

Example 125 0889 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)-amide 0890 To a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (320 mg, 2.1 mmol) in dimethylformamide (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (483 mg, 1.2 equiv.), 1-hydroxybenzotriazole (340 mg, 1.2 equiv.), triethylamine (0.59 mL, 2 equiv.) and N,N-diethylethylenediamine (0.32 mL, 1.1 equiv.). After stirring at room temperature overnight, the reaction was diluted with saturated sodium bicarbonate and brine (with extra salt) and extracted with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide. 0891 A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (126 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80 C. for 1 hr and then cooled. The precipitate was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid. 0892 1HNMR (360 MHz, DMSO-d6) 13.62 (s, 1H, NH), 11.11 (br s, 1H, NH), 8.54 (s, 1H, H-vinyl), 8.1 (m, 1H, CONHCH2), 7.49 (d, J2.2 Hz, 1H), 7.31 (dd, J2.2 & 8.3 Hz, 1H), 6.86 (d, J8.3 Hz, 1H), 6.58 (d, J2.24 Hz, 1H), 3.31 (m, 2H, HNCH2CH2), 2.59 (m, 6H, 3CH2), 2.36 (s, 3H, CH3), 0.99 (t, J6.8 Hz, 6H, N(CH2CH3)2). 0893 MS m/z 445/447 M and M2.

Example 126 0894 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 0895 A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (I drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid. 0896 1H NMR (400 MHz, DMSO-d6) 13.7 (s, 1H, NH), 10.9 (s, 1H, NH), 7.88 (d, J7.6 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.41 (t, J5.4 Hz, 1H, NH), 7.13 (dt, J1.2 & 7.6 Hz, 1H), 6.99 (dt, J1.2 & 7.6 Hz, 1H), 6.88 (d, J7.6 Hz, 1H), 3.28 (m, 2H), 2.48-2.55 (m, 6H), 2.44 (s, 3H, CH3), 2.41 (s, 3H, CH3), 0.97 (t, J7.2 Hz, 6H, N(CH2CH3)2). 0897 MSve APCI 381 M1.

Example 127 0898 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 0899 A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90 C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid. 0900 1H NMR (400 MHz, DMSO-d6) 13.65 (s, 1H, NH), 11.0 (s, 1H, NH), 7.98 (d, J2.1 Hz, 1H) 7.77 (s, 1H H-vinyl), 7.44 (t, NH), 7.13 (dd, J2,1 & 8.4 Hz, 1H) 6.87 (d, J8.4 Hz, 1H), 3.28 (g, 2H), 2.48-2.53 (m, 6H), 2.44 (s, 3H, CH3), 2.43 (s, 3H, CH3), 0.97 (t, J7.0 Hz, 6H, N(CH2CH3)2) 0901 MSve APCI 415 M1.,

Example 128 0902 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ethyl)-amide 0903 1,3-Dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound. 0904 MSve APCI 379 M1.

Example 129 0905 5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-yl-ethyl)-amide 0906 5-Fluoro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound. 0907 MSve APCI 397 M1. 0908 Scale-Up Procedure: 0909 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) 2.48, 2.50 (2s, 6H, 2CH3), 6.80, 6.88, 7.68, 7.72 (4m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 M1. 0910 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 g) and dimethylformamide (500 mL) were stirred and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 g), 1-(2-aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL) were added. The mixture was stirred for 2 hours at ambient temperature. The solid product was collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by stirring in ethanol (500 mL) for one hour at 64 C. and cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (101.5 g, 77% yield). 1H-NMR (dimethylsulfoxide-d6) 1.60 (m, 4H, 2CH2), 2.40, 2.44 (2s, 6H, 2CH3), 2.50 (m, 4H, 2CH2), 2.57, 3.35 (2m, 4H, 2CH2), 7.53, 7.70, 7.73, 7.76 (4m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrrole NH). MS m/z 396 M1.

Example 130 0911 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-yl-ethyl)-amide 0912 5-Chloro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound. 0913 MSve APCI 413 M1.

Example 131 0914 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)-amide 0915 1,3-Dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide to give the title compound. 0916 1H NMR (400 MHz, DMSO-d6) 13.63 (s, 1H, NH), 10.90 (s, 1H, NH), 7.78 (d, J7.8 Hz, 1H), 7.63 (s, 1H H-vinyl), 7.48 (t, 1H, NH), 7.13 (dt, 1H), 6.98 (dt, 1H), 6.88 (d, J7.7 Hz, 1H), 3.31 (q, J6.6 Hz, 2H), 2.43 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.38 (t, J6.6 Hz, 2H), 2.19 (s, 6H, N(CH2CH3)2) 0917 MSve APCI 353 M1.

Example 132 0918 5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)-amide 0919 5-Fluoro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide to give the title compound. 0920 1H NMR (400 MHz, DMSO-d6) 13.68 (s, 1H, NH), 10.90 (s, 1H, NH), 7.76 (dd, J2.4 & 9.4 Hz, 1H), 7.71 (s, 1H H-vinyl), 7.51 (t, 1H, NH), 6.93 (m, 1H), 6.84 (dd, J4.6 & 8.4 Hz, 1H), 3.31 (q, J6.6 Hz, 2H), 2.43 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.38 (t, J6.6 Hz, 2H), 2.19 (s, 6H, N(CH2CH3)2) 0921 MSve APCI 371 M1.

Example 193 0922 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-ethylamino-ethyl)-amide 0923 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (99 g), ethanol (400 mL), 5-fluoro-2-oxindole (32 g) and pyrrolidine (1.5 g) were refluxed for 3 hours with stirring. The mixture was cooled to room temperature and the solids collected by vacuum filtration. The solids were stirred in ethanol at 60 C., cooled to room temperature and collected by vacuum filtration. The product was dried under vacuum to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (75 g, 95% yield). 1H-NMR (dimethylsulfoxide-d6) 1.03 (t, 3H, CH3), 2.42, 2.44 (2s, 6H, 2CH3), 2.56 (q, 2H, CH2), 2.70, 3.30 (2t, 4H, 2CH2), 6.85, 6.92, 7.58, 7.72, 7.76 (5m, SH, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NE). MS m/z 369 M1.

Example 195 0924 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2.4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethyl-N-oxoamino-ethyl)-amide 0925 Method A: 0926 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (598 mg) and dichloromethane (60 mL) in an ice bath were treated with 3-chloroperbenzoic acid (336 mg) and the mixture stirred at room temperature overnight. The solvent was rotary evaporated and the residue suspended in methanol (20 mL). Water (20 mL) containing sodium hydroxide (240 mg) was added and the mixture stirred for one hour. The precipitate was collected by vacuum filtration, washed with 5 mL of water and dried under a vacuum to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethyl-N-oxoamino-ethyl)-amide (510 mg, 82% yield) as an orange solid. 1H-NMR (DMSO-d6) 13.72 (br s, 1H, NH), 11.02 (br s, 1H, CONH), 9.81 (br s, 1H, CONH), 7.75 (dd, 1H, aromatic), 7.70 (s, 1H, aromatic), 6.93 (td, 1H, aromatic), 6.84 (m, 1H, aromatic), 3.63 (m, 2H, CH2), 3.29 (m, 2H, CH2), 3.14 (m, 4H, 2CH2), 2.47 (s, 1H, CH3), 2.45 (s, 3H, CH3), 1.64 (t, 6H, 2CH3). MS m/z 415 M1. 0927 Method B: 0928 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (10 g) was suspended in dichloromethane (100 mL) and cooled in an ice bath. 3-Chloro-peroxybenzoic acid (13.1 g) was added with stirring and the mixture allowed to warm to room temperature and then stirred ovenight. The mixture was rotary evaporated to dryness and chromatographed on a column of silica gel eluting with 20% methanol in dichloromethane. Fractions containing product were combined and rotary evaporated to dryness to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethyl-N-oxoamino-ethyl)-amide (9 g, 83% yield). 0929 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethyl-N-oxoamino-ethyl)-amide (9 g), 5-fluoro-1,3-dihydro-indol-2-one ((9 g, 83% yield)), and pyrrolidine ((9 g, 83% yield (0.1 g) were refluxed in ethanol (30 mL) for 4 hours. The mixture was cooled in an ice bath and the precipitate collected by vacuum filtration and washed with ethanol. The solids were stirred in ethyl acetate (30 mL), collected by vacuum filtration, washed with ethyl acetate and dried under vacuum to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethyl-N-oxoamino-ethyl)-amide (10.3 g 80% yield) as an orange solid. 1H-NMR (DMSO-d6) 13.72 (br s, 1H, NH), 11.02 (br s, 1H, CONH), 9.81 (br s, 1H, CONH), 7.75 (dd, 1H, aromatic), 7.70 (s, 1H, aromatic), 6.93 (td, 1H, aromatic), 6.84 (m, 1H, aromatic), 3.63 (m, 2H, CH2), 3.29 (m, 2H, CH2), 3.14 (m, 4H, 2CH2), 2.47 (s, 1H, CH3), 2.45 (s, 3H, CH3), 1.64 (t, 6H, 2CH3). MS m/z 415 M1.

Example 190 0930 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethyl-amide. 0931 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was shaken with EDC, HCl (96 mg, 0.5 mmol), anhydrous 1-hydroxy-benztriazole (68 mg, 0.5 mmol), and 2-(2-aminoethylpyridine purchased from Aldrich in anhydrous DMF (3 mL) for 2-3 days at room temperature. The reaction mixture was diluted with 1M NaHCO3 (1.5 ml), then with 8 ml of water. The precipitated crude product was collected by filtration, washed with water, dried and purified by crystallization or chromatography to give 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(pyridin-1-yl)-ethylamide.

Example 189 0932 5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide. 0933 Proceeding as described in previous example but substituting 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (127 mg) provided 5-5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(pyridin-1-yl)ethyl amide.

Example 192 0934 5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide. 0935 Proceeding as described in Example 190 above but substituting 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-5-bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (145 mg) provided 5-5-bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(pyridin-1-yl)ethylamide.

Example 191 0936 5-2-Oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide 0937 Proceeding as described in Example 190 above but substituting 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidene-methyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (113 mg) provided 5-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(pyridin-1-yl)ethylamide.

Example 203 0938 5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide 0939 Proceeding as described in Example 190 above but substituting 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-5-cyano-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (123 mg) provided 5-5-cyano-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(pyridin-1-yl)ethylamide.

Examples 142, 186, 187, 188 and 204 0940 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 1-(2-aminoethyl)pyrrolidine, purchased from Aldrich Chemical Company, Inc. provided the desired compounds.

Examples 143-147 0941 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 1-(2-aminoethyl)imidazolin-2-one (prepared by heating dimethyl carbonate with bis(2-aminoethyl) amine (2 equivalents) in a sealed flask to 150 C. for 30 min., following the procedure described in U.S. Pat. No. 2,613,212 (1950), to Rohm & Haas Co. The crude product was purified on silica using an eluent mixture chloroform-methanol-aqueous ammonia 80:25:2) provided the desired compounds.

Examples 148-151 and 184 0942 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 4-(2-aminoethyl)piperazine-1-acetic acid ethyl ester (prepared as follows: Piperazine-1-acetic acid ethyl ester (11.22 g) was treated with iodoacetonitrile (5.0 mL) in the presence of potassium carbonate (6.9 g) in ethyl acetate (260 mL) at 0 C. After complete iodoacetonitrile addition (45 min), the reaction mixture was subsequently stirred at room temperature for 11 hours. The reaction mixture was filtered and the filtrates evaporated. The residue was hydrogenated in a presence of cobalt boride (prepared from CoCl2 and sodium borohydride) at room temperature at 50 psi for 2 days in ethanol. Filtration, evaporation and chromatographic purification using an eluent mixture chloroform-methanol-aqueous ammonia 80:25:2 provided the desired amine (3.306 g) as a pale yellow oil) provided the desired compounds.

Example 152-153 0943 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 2-(2-aminoethylamino)acetonitrile (prepared as follows: A solution of iodoacetonitrile (50 mmol) in ethyl alcohol (80 ml) was added to a solution of ethylene diamine (150 ml) in ethyl alcohol (60 ml) at 0 C. over a period of 30 minutes. The stirring was continued for another 1 hr at 0 C., then at room temperature for 14 hours. 55 mmol of potassium carbonate was added, stirred for 30 minutes, filtered and the filtrate was concentrated at room temperature. The residue was purified on silica using an eluent mixture chloroform-methanol-aqueous ammonia 80:15:1.5 to give 2-(2-aminoethylamino)-acetonitrile (3.550 g) which was used immediately) provided the desired compounds.

Example 154-158 0944 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 1-(3-aminopropyl)-azepin-2-one (prepared according to the procedure in Kraft A.: J. Chem. Soc. Perkin Trans. 1, 6, 1999, 705-14, except that the hydrolysis of DBU was performed at 145 C. neat in a presence of lithium hydroxide (1 hr, 5 ml of DBU, 2 ml of water, 420 mg of lithium hydroxyde hydrate). Purification of the crude product on silica using an eluent mixture chloroform-methanol-aqueous ammonia 80:40:4 provided 1-(3-aminopropyl)azepin-2-one (4.973 g, 87% yield)) provide the desired compounds.

Examples 133-135, 159 and 200 0945 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with N-acetyl ethylene diamine, (prepared by heating a mixture of ethyl acetate with ethylene diamine (1.5 equivalents) to 160 C. for 1 hr in a sealed vessel. The vacuum distillation provided the desired product in 56% yield. N-acetylethylene diamine is also available from Aldrich) provide the desired compounds.

Examples 146-140 0946 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 1-(3-aminopropyl)-tetrahydro-pyrimidin-2-one (prepared in the same way as 1-(3-aminopropyl)-azepin-2-one according to the procedure in Kraft A.: J. Chem. Soc. Perkin Trans. 1, 6, 1999, 705-14: Briefly, 1,3,4,6,7,8-hexahydro-2H-pyrimido1,2-apyrimidine (4.939 g), lithium hydroxyde hydrate (918 mg) and 2 ml of water was heated without a solvent in a sealed vessel to 145 C. for 1 hr. The crude product was purified on a column of silica in chloroform-methanol-aqueous ammonia 80:40:4 to give pure amine (5.265 g, 94% yield).

Examples 141, 160-162 and 185 0947 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 1-(2-aminoethyl)-piperazine-2-one (prepared as follows: Neat tert-butyldiphenylsilyl chloride (25 mL, 97.7 mmol) was added dropwise into a solution of DBU (19.5 ml, 130 mmol) and bis(2-aminoethyl)amine (4.32 mL, 40 mmol) in anhydrous dimethyl acetamide (80 mL) at room temperature upon cooling on water bath within 5 minutes. The mixture was stirred for 5 hours. Bromoacetic acid ethyl ester (6.70 mL, 60 mmol) was added neat upon cooling to room temperature. The reaction was stirred for 25 minutes, then evaporated on high vacuum. The residue was dissolved in methanol (200 ml), KHCO3 (10 g) and KF (12 g, 200 mmol) were added and the mixture was stirred at 60 C. for 5 hours. 10 g of Na2CO3 was added, stirred for 10 minutes, cooled and filtered. The filtrates were evaporated. The residue was extracted with hexanes (2 times 250 ml). The hexane-insoluble material was dissolved in ethanol (60 ml), filtered and evaporated. The residue was purified on a column of silica in chloroform-methanol-aqueous ammonia 80:40:4 to give pure amine (4.245 g, 74% yield)) provided the desired compounds.

Examples 163-167 0948 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2-(2-aminoethyl)pyridine with 3-(2-aminoethyl)aminopropionitrile (prepared from ethylene diamine (150 mmol) and acrylonitrile (50 mmol) in THF at room temperature, as described in Israel, M. et al: J. Med Chem. 7, 1964, 710-16., provided the desired amine (4.294 g)) provided the desired compounds.

Example 168 0949 5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2.4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(4-methylpiperazin-1-yl)-ethyl-amide 0950 To a stirred yellow muddy mixture of 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (90 mg), DMF (0.8 mL) and TEA (0.084 mL) in a 20 mL reaction tube, was added BOP reagent (199 mg). The mixture became clear in 5 min. 2-(4-Methylpiperazin-1-yl)ethylamine1 (51 mg) was added into the clear mixture. The resulting solution was stirred at room temperature over night. Yellow solid products precipitated from the reaction system. Thin layer chromatography (10% methanol in methylene chloride) showed that all the starting material had been converted into the product. The solid was isolated by vacuum filtration and washed once with ethanol (1 mL). The solid was sonicated in diethyl ether (2 mL) for 20 min and collected by vacuum filtration. After drying under vacuum, 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-methylpiperazin-1-yl-ethyl)-amide (79 mg, 62% yield) was obtained. 0951 1H NMR (DMSO-d6) 2.13 (s, 3H, CH3), 2.40, 2.42 (2s, 6H, 2CH3), 2.41 (m, 2H, CH2), 2.47 (m, 8H, 4CH2), 3.30 (m, 2H, CH2), 6.82 (dd, J4.5, 8.7 Hz, 1H), 6.91(td, J2.4, 3J8.8 Hz, 1H), 7.43 (t, J5.6 Hz, 1H), 7.70 (s, 1H), 7.75 (dd, J2.8, 9.6 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, NH). LC-MS (m/z) 424.4 (M1).

Example 169 0952 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-yl-ethyl)-amide 0953 Following the procedure in Example 168 above but substituting 5-5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (95 mg, 0.3 mmol) gave 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-methylpiperazin-1-yl-ethyl)-amide (76 mg, 58%). 0954 1H NMR (DMSO-d6) 2.13 (s, 3H, CH3), 2.41, 2.42 (2s, 6H, 2CH3), 2.42 (m, 2H, CH2), 2.48 (m, 8H, 4CH2), 3.30 (m, 2H, CH2), 6.84 (d, J8.0 Hz, 1H), 7.11 (dd, J2.0, 8.0 Hz,1H), 7.44 (t, J5.6 Hz, 1H), 7.76 (s, 1H), 7.97 (d, J2.0 Hz, 1H) (aromatic and vinyl), 10.98 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 440.2 (M1).

Example 170 0955 5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-yl-ethyl)-amide 0956 Following the procedure described in Example 168, but substituting 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid gave 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-methylpiperazin-1-yl-ethyl)-amide (39 mg, 54%) was obtained from SU011670 (54 mg, 0.15 mmol). 0957 1H NMR (DMSO-d6) 2.14 (s, 3H, CH3), 2.41, 2.42 (2s, 6H, 2CH3), 2.42 (m, 2H, CH2), 2.48 (m, 8H, 4CH2), 3.31 (m, 2H, CH2), 6.80 (d, J8.0 Hz, 1H), 7.23 (dd, J2.0, 8.0 Hz, 1H), 7.44 (t, J5.6 Hz, 1H), 7.76 (s, 1H), 8.09 (d, J2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.61 (s, 1H, NH). LC-MS (m/z) 486.6 (M).

Example 172 0958 5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-yl-ethyl)-amide 0959 Following the procedure described in Example 168 above but substituting 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid SU014900 with 5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid gave 5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-methylpiperazin-1-yl-ethyl)-amide, (136 mg, 84%) was obtained (112.8 mg, 0.4 mmol). 0960 1H-NMR (DMSO-d6) 2.13 (s, 3H, CH3), 2.39, 2.42 (2s, 6H, 2CH3), 2.42 (m, 2H, CH2), 2.48 (m, 8H, 4CH2), 3.30 (t, 2H, CH2), 6.86 (d, J8.0 Hz, 1H), 6.96 (t, J7.4 Hz, 1H), 7.10 (t, J7.8 Hz, 1H), 7.41 (t, J5.4 Hz, 1H), 7.62 (s, 1H), 7.76 (d, J7.6 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.61 (s, 1H, NH). LC-MS (m/z) 406.6 (M1).

Example 171 0961 5-2-Oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(3.5-dimethylpiperazin-1-yl)ethyl)amide 0962 To a stirred yellow muddy mixture of 5-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (112.8 mg, 0.4 mmol), DMF (0.5 mL) and triethylamine (0.111 mL) in a 20 mL reaction tube, was added BOP reagent (265 mg). The mixture became clear in 5 min. 2-(2,6-dimethylpiperazin-1-yl)ethylamine (68.6 mg) (see., Tapia, L. Alonso-Cires, P. Lopez-Tudanca, R. Mosquera, L. Labeaga, A. Innerarity, A. Odales, J. Med. Chem., 1999, 42, 2870-2880) was added into the clear mixture. The resulting solution was stirred at room temperature over night. Thin layer chromatography (10% methanol in methylene chloride) showed that all the starting material had been converted into the product. The reaction mixture was evaporated to dryness and then purified by flash chromatography (CH2Cl2/CH3OH20/1-15/1) followed by recrystalization to give 5-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(3,5-dimethylpiperazin-1-yl)ethyl)amide (83 mg, 50% yield). 0963 1H NMR (DMSO-d6) 61.15, 1.16 (2s, 6H, 2CH3), 1.95 (t, J11.6 Hz, 2H, CH2), 2.41,2.47 (2s, 6H, 2CH3), 2.50 (m, 2H, CH2), 3.03 (d, J10 Hz, 2H), 3.19 (m, 2H), 3.30 (m, 2H, CH2), 6.86 (d, J8.0 Hz, 1H), 6.97 (t, J7.2 Hz, 1H), 7.11 (t, J7.8 Hz, 1H), 7.48 (t, J5.6 Hz, 1H), 7.61 (s, 1H), 7.75 (d, J7.6 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 422.2 (M1).

Example 173 0964 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(3,5-dimethylpiperazin-1-yl)ethyl)amide 0965 Following the procedure described in Example 168 above the desired compound was obtained (60 mg, 0.2 mmol). 0966 1H NMR (DMSO-d6) 0.891, 0.907 (2s, 6H, 2CH3), 1.49 (t, J10.4 Hz, 2H), 2.40, 2.42 (2s, 6H, 2CH3), 2.41 (m, 2H, CH2), 2.74 (m, 4H), 3.30 (m, 2H), 6.82 (dd, J4.5, 8.7 Hz, 1H), 6.90 (td, 2J2.4, 3J8.4 Hz, 1H), 7.42 (t, J5.6 Hz, 1H), 7.70 (s, 1H), 7.74 (dd, J4.6, 8.4 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.65 (s, 1H, NH). LC-MS (m/z) 438.4 (M1).

Example 174 0967 5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(3,5-dimethylpiperazin-1-yl)ethyl)amide 0968 Following the procedure for Example 171 above the desired compound (31.2 mg, 34%) was obtained from 5-5-chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (63 mg, 0.2 mmol). 0969 1H NMR (DMSO-d6) 1.15, 1.16 (2s, 6H, 2CH3), 1.95 (t, J11.6 Hz, 2H, CH2), 2.40,2.42 (2s, 6H, 2CH3), 2.50 (m, 2H, CH2), 3.03 (d, J11.2 Hz, 2H), 3.19 (m, 2H), 3.30 (m, 2H, CH2), 6.85 (d, J8.4 Hz, 1H), 7.11 (dd, J2.0, 8.0 Hz,1H), 7.52 (t, J5.6 Hz, 1H), 7.76 (s, 1H), 7.97 (d, J2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.63 (s, 1H, NH). LC-MS (m/z) 456.2 (M1).

Example 175 0970 5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(3,5-dimethylpiperazin-1-yl)ethyl)amide 0971 Following the procedure described in Example 171 the desired compound (40 mg, 40%) was obtained from 5-5-bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (74 mg, 0.2 mmol). 0972 1H NMR (DMSO-d6) 1.15, 1.16 (2s, 6H, 2CH3), 1.95 (t, J11.6 Hz, 2H, CH2), 2.40, 2.42 (2s, 6H, 2CH3), 2.50 (m, 2H, CH2), 3.03 (d, J10.4 Hz, 2H), 3.19 (m, 2H), 3.30 (m, 2H, CH2), 6.81 (d, J8.4 Hz, 1H), 7.24 (dd, J2.0, 8.4 Hz, 1H), 7.51 (t, J5.6 Hz, 1H), 7.76 (s, 1H), 8.10 (d, J2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 498.4 (M1).

Example 205 0973 (3Z)-3-(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene-1-1-(4-methylpiperazinyl)methyl-1,3-dihydro-2H-indol-2-one 0974 N-Methylpiperazine (10 g, 100 mmol) was added to a stirred solution of aqueous formaldehyde (10 g of 38% solution, 100 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one, (2.38 g, 10 mmol) in methanol (100 mL). The solution heated at 60 C. for 1 h, concentrated to a low volume and the precipitate was filtered off, washed with methanol, and dried to give 2.38 g of the title compound, mp 160-164 C. HPLC Rt 4.72 min. 1H NMR (CDCl3) 2.26 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 2.43 (br s, 4H), 2.70 (br s, 4H), 4.59 (s, 2H), 5.96 (d, 1H), 7.02-7.08 (m, 2H), 7.15 (dd, 1H), 7.38 (s, 1H), 7.48 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found: C, 71.75; H, 7.46; N, 15.87. 0975 (3Z)-3-(3,5-Dimethyl-1H-pyrrol-2-yl)-methylidene-1-1-(4-methylpiperazinyl)-methyl-1,3-dihydro-2H-indol-2-one was converted to a dihydrochloride salt.

Example 206 0976 Synthesis of (3Z)-3-(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one 0977 Pyrrolidine (450 mg, 6.3 mmol) was added to a stirred solution of aqueous formaldehyde (500 mg of 38% solution, 6.0 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one, (900 mg, 3.8 mmol) in methanol (50 mL). After 15 min, the solution was cooled to 0 C. and the precipitate was filtered off, washed with water, and dried to give 1.08 g of the title compound, mp 129-132 C. HPLC Rt 4.87 min. 1H NMR (CD3)2SO 1.65 (m, 4H), 2.32 (s, 3H), 2.34 (s, 3H), 2.62 (m, 4H), 4.72 (s, 2H) 6.07 (d, 1H), 7.00 (m, 1H), 7.15 (m, 2H), 7.61 (s, 1H), 7.76 (d, 2H) and 13.1 (br s, 1H). Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.61; H, 7.25; N, 13.03.

BIOLOGICAL EXAMPLES 0978 Protein Kinase Inhibitors of Formula (I): 0979 The following assays may be used to determine the level of activity and effect of the compounds of Formula (I) on one or more of the protein kinases (hereinafter PKs). Similar assays can be designed along the same lines for any PK using techniques well known in the art. 0980 A. Assay Procedures. 0981 Several of the assays described herein are performed in an ELISA (Enzyme-Linked Immunosorbent Sandwich Assay) format (Voller, et al, 1980, Enzyme-Linked Immunosorbent Assay, Manual of Clinical Immunology, 2d ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington, D.C., pp. 359-371). The general procedure is as follows: a compound of Formula (I) is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound. 0982 The presently preferred protocols for conducting the ELISA experiments for specific PKs is provided below. However, adaptation of these protocols for determining the activity of compounds against other receptor tyrosine kinases (RTKs), as well as for cytoplasm tryrosine kinases (CTKs) and serine threonine tyrosine kinases (STKs), is well within the scope of knowledge of those skilled in the art. Other assays described herein measure the amount of DNA made in response to activation of a test kinase, which is a general measure of a proliferative response. The general procedure for this assay is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. After incubation at least overnight, a DNA labeling reagent such as 5-bromodeoxyuridine (BrdU) or H3-thymidine is added. The amount of labeled DNA is detected with either an anti-BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound. 0983 GST-FLK-1 Bioassay 0984 This assay analyzes the tyrosine kinase activity of GST-Flk1 on poly(glu,tyr) peptides. 0985 Materials and Reagents: 0986 1. Corning 96-well ELISA plates (Corning Catalog No. 5805-96). 0987 2. poly(glu,tyr) 4:1, lyophilizate (Sigma Catalog PO275). 0988 3. Preparation of poly(glu,tyr)(pEY) coated assay plates: Coat 2 ug/well of poly(glu,tyr)(pEY) in 100 ul PBS, hold at room temperature for 2 hours or at 4 C. overnight. Cover plates well to prevent evaporation. 0989 4. PBS Buffer: for 1 L, mix 0.2 g KH2PO4, 1.15 g Na2HPO4, 0.2 g KCl and 8 g NaCl in approx. 900 ml dH2O. When all reagents have dissolved, adjust the pH to 7.2 with HCl. Bring total volume to 1 L with dH2O. 0990 5. PBST Buffer: to 1 L of PBS Buffer, add 1.0 ml Tween-20. 0991 6. TBBBlocking Buffer: for 1 L, mix 1.21 g TRIS, 8.77 g NaCl, 1 ml TWEEN-20 in approximately 900 ml dH2O. Adjust pH to 7.2 with HCl. Add 10 g BSA, stir to dissolve. Bring total volume to 1 L with dH2O. Filter to remove particulate matter. 0992 7. 1% BSA in PBS: To make a 1working solution, add 10 g BSA to approx. 990 ml PBS buffer, stir to dissolve. Adjust total volume to 1 L with PBS buffer, filter to remove particulate matter. 0993 8. 50 mM Hepes pH 7.5. 0994 9. GST-Flk1cd purified from sf9 recombinant baculovirus transformation (SUGEN, Inc.). 0995 10. 4% DMSO in dH2O. 0996 11. 10 mM ATP in dH2O. 0997 12. 40 mM MnCl2 0998 13. Kinase Dilution Buffer (KDB): mix 10 ml Hepes (pH 7.5), 1 ml 5M NaCl, 40 L 100 mM sodium orthovanadate and 0.4 ml of 5% BSA in dH2O with 88.56 ml dH2O. 0999 14. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog AS-72092 1000 15. EDTA: mix 14.12 g ethylenediaminetetraacetic acid (EDTA) to approx. 70 ml dH2O. Add 10 N NaOH until EDTA dissolves. Adjust pH to 8.0. Adjust total volume to 100 ml with dH2O. 1001 16. 1 Antibody Dilution Buffer: mix 10 ml of 5% BSA in PBS buffer with 89.5 ml TBST. 1002 17. Anti-phosphotyrosine monoclonal antibody conjugated to horseradish peroxidase (PY99 HRP, Santa Cruz Biotech). 1003 18. 2,2-Azinobis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS, Moss, Cat. No. ABST). 1004 19. 10% SDS. 1005 Procedure: 1006 1. Coat Corning 96-well ELISA plates with 2 g of polyEY peptide in sterile PBS as described in step 3 of Materials and Reagents. 1007 2. Remove unbound liquid from wells by inverting plate. Wash once with TBST. Pat the plate on a paper towel to remove excess liquid. 1008 3. Add 100 l of 1% BSA in PBS to each well. Incubate, with shaking, for 1 hr. at room temperature. 1009 4. Repeat step 2. 1010 5. Soak wells with 50 mM HEPES (pH 7.5) (150 l/well). 1011 6. Dilute test compound with dH2O/4% DMSO to 4 times the desired final assay concentration in 96-well polypropylene plates. 1012 7. Add 25 l diluted test compound to ELISA plate. In control wells, place 25 l of dH2O/4% DMSO. 1013 8. Add 25 l of 40 mM MnCl2 with 4ATP (2 M) to each well. 1014 9. Add 25 l 0.5M EDTA to negative control wells. 1015 10. Dilute GST-Flk1 to 0.005 g (5 ng)/well with KDB. 1016 11. Add 50 l of diluted enzyme to each well. 1017 12. Incubate, with shaking, for 15 minutes at room temperature. 1018 13. Stop reaction by adding 50 l of 250 mM EDTA (pH 8.0). 1019 14. Wash 3with TBST and pat plate on paper towel to remove excess liquid. 1020 15. Add 100 l per well anti-phosphotyrosine HRP conjugate, 1:5,000 dilution in antibody dilution buffer. Incubate, with shaking, for 90 min. at room temperature. 1021 16. Wash as in step 14. 1022 17. Add 100 l of room temperature ABTS solution to each well. 1023 18. Incubate, with shaking, for 10 to 15 minutes. Remove any bubbles. 1024 19. Stop reaction by adding 20 l of 10% SDS to each well. 1025 20. Read results on Dynatech MR7000 ELISA reader with test filter at 410 nM and reference filter at 630 nM. 1026 PYK2 Bioassay 1027 This assay is used to measure the in vitro kinase activity of HA epitope-tagged full length pyk2 (FL.pyk2-HA) in an ELISA assay. 1028 Materials and Reagents: 1029 1. Corning 96-well Elisa plates. 1030 2. 12CA5 monoclonal anti-HA antibody (SUGEN, Inc.) 1031 3. PBS (Dulbecco's Phosphate-Buffered Saline (Gibco Catalog 450-1300EB) 1032 4. TBST Buffer: for 1 L, mix 8.766 g NaCl, 6.057 g TRIS and 1 ml of 0.1% Triton X-100 in approx. 900 ml dH2O. Adjust pH to 7.2, bring volume to 1 L. 1033 5. Blocking Buffer: for 1 L, mix 100 g 10% BSA, 12.1 g 100 mM TRIS, 58.44 g 1M NaCl and 10 mL of 1% TWEEN-20. 1034 6. FL.pyk2-HA from sf9 cell lysates (SUGEN, Inc.). 1035 7. 4% DMSO in MilliQue H2O. 1036 8. 10 mM ATP in dH2O. 1037 9. 1M MnCl2. 1038 10. 1M MgCl2. 1039 11. 1M Dithiothreitol (DTT). 1040 12. 10Kinase buffer phosphorylation: mix 5.0 ml 1M Hepes (pH 7.5), 0.2 ml 1M MnCl2, 1.0 ml 1 M MgCl2, 1.0 ml 10% Triton X-100 in 2.8 ml dH2O. Just prior to use, add 0.1 ml 1M DTT. 1041 13. NUNC 96-well V bottom polypropylene plates. 1042 14. 500 mM EDTA in dH2O. 1043 15. Antibody dilution buffer: for 100 mL, 1 mL 5% BSA/PBS and 1 mL 10% Tween-20 in 88 mL TBS. 1044 16. HRP-conjugated anti-Ptyr PY99), Santa Cruz Biotech Cat. No. SC-7020. 1045 17. ABTS, Moss, Cat. No. ABST-2000. 1046 18. 10% SDS. 1047 Procedure: 1048 1. Coat Corning 96 well ELISA plates with 0.5 g per well 12CA5 anti-HA antibody in 100 l PBS. Store overnight at 4 C. 1049 2. Remove unbound HA antibody from wells by inverting plate. Wash plate with dH2O. Pat the plate on a paper towel to remove excess liquid. 1050 3. Add 150 l Blocking Buffer to each well. Incubate, with shaking, for 30 min at room temperature. 1051 4. Wash plate 4with TBS-T. 1052 5. Dilute lysate in PBS (1.5 g lysate/100 l PBS). 1053 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 1 hr. 1054 7. Wash as in step 4. 1055 8. Add 50 l of 2kinase Buffer to ELISA plate containing captured pyk2-HA. 1056 9. Add 25 L of 400 M test compound in 4% DMSO to each well. For control wells use 4% DMSO alone. 1057 10. Add 25 L of 0.5 M EDTA to negative control wells. 1058 11. Add 25 l of 20 M ATP to all wells. Incubate, with shaking, for 10 minutes. 1059 12. Stop reaction by adding 25 l 500 mM EDTA (pH 8.0) to all wells. 1060 13. Wash as in step 4. 1061 14. Add 100 L HRP conjugated anti-Ptyr diluted 1:6000 in Antibody Dilution Buffer to each well. Incubate, with shaking, for 1 hr. at room temperature. 1062 15. Wash plate 3with TBST and IX with PBS. 1063 16. Add 100 L of ABST solution to each well. 1064 17. If necessary, stop the development reaction by adding 20 L 10% SDS to each well. 1065 18. Read plate on ELISA reader with test filter at 410 nM and reference filter at 630 nM. 1066 FGFR1 Bioassay 1067 This assay is used to measure the in vitro kinase activity of FGF1-R in an ELISA assay. 1068 Materials and Reagents: 1069 1. Costar 96-well Elisa plates (Corning Catalog 3369). 1070 2. Poly(Glu-Tyr) (Sigma Catalog PO275). 1071 3. PBS (Gibco Catalog 450-1300EB) 1072 4. 50 mM Hepes Buffer Solution. 1073 5. Blocking Buffer (5% BSA/PBS). 1074 6. Purified GST-FGFR1 (SUGEN, Inc.) 1075 7. Kinase Dilution Buffer. 1076 Mix 500 l 1M Hepes (GIBCO), 20 l 5% BSA/PBS, 10 l 100 mM sodium orthovanadate and 50 l 5M NaCl. 1077 8. 10 mM ATP 1078 9. ATP/MnCl2 phosphorylation mix: mix 20 L ATP, 400 L 1M MnCl2 and 9.56 ml dH2O. 1079 10. NUNC 96-well V bottom polypropylene plates (Applied Scientific Catalog AS-72092). 1080 11. 0.5M EDTA. 1081 12. 0.05% TBST 1082 Add 500 L TWEEN to 1 liter TBS. 1083 13. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1084 14. Goat anti-rabbit IgG peroxidase conjugate (Biosource, Catalog ALI0404). 1085 15. ABTS Solution. 1086 16. ABTS/H2O2 solution. 1087 Procedure: 1088 1. Coat Costar 96 well ELISA plates with 1 g per well Poly(Glu,Tyr) in 100 l PBS. Store overnight at 4 C. 1089 2. Wash coated plates once with PBS. 1090 3. Add 150 L of 5%BSA/PBS Blocking Buffer to each well. Incubate, with shaking, for 1 hr.room temperature. 1091 4. Wash plate 2with PBS, then once with 50 mM Hepes. Pat plates on a paper towel to remove excess liquid and bubbles. 1092 5. Add 25 L of 0.4 mM test compound in 4% DMSO or 4% DMSO alone (controls) to plate. 1093 6. Dilute purified GST-FGFR1 in Kinase Dilution Buffer (5 ng kinase/50 ul KDB/well). 1094 7. Add 50 L of diluted kinase to each well. 1095 8. Start kinase reaction by adding 25 l/well of freshly prepared ATP/Mn (0.4 ml 1M MnCl2, 40 L 10 mM ATP, 9.56 ml dH2O), freshly prepared). 1096 9. This is a fast kinase reaction and must be stopped with 25 L of 0.5M EDTA in a manner similar to the addition of ATP. 1097 10. Wash plate 4with fresh TBST. 1098 11. Make up Antibody Dilution Buffer: Per 50 ml: 1099 Mix 5 ml of 5% BSA, 250 l of 5% milk and 50 l of 100 mM sodium vanadate, bring to final volume with 0.05% TBST. 1100 12. Add 100 l per well of anti-phosphotyrosine (1:10000 dilution in ADB). 1101 Incubate, with shaking for 1 hr. at room temperature. 1102 13. Wash as in step 10. 1103 14. Add 100 l per well of Biosource Goat anti-rabbit IgG peroxidase conjugate (1:6000 dilution in ADB). Incubate, with shaking for 1 hr. at room temperature. 1104 15. Wash as in step 10 and then with PBS to remove bubbles and excess TWEEN. 1105 16. Add 100 l of ABTS/H2O2 solution to each well. 1106 17. Incubate, with shaking, for 10 to 20 minutes. Remove any bubbles. 1107 18. Read assay on Dynatech MR7000 elisa reader: test filter at 410 nM, reference filtrate 630 nM. 1108 EGFR Bioassay 1109 This assay is used to the in vitro kinase activity of FGF1-R in an ELISA assay. 1110 Materials and Reagents: 1111 1. Corning 96-well Elisa plates. 1112 2. SUMOL1 monoclonal anti-EGFR antibody (SUGEN, Inc.). 1113 3. PBS 1114 4. TBST Buffer 1115 5. Blocking Buffer: for 100 ml, mix 5.0 g Carnation Instant Non-fat Milk with 100 ml of PBS. 1116 6. A431 cell lysate (SUGEN, Inc.). 1117 7. TBS Buffer: 1118 8. TBS10% DMSO: for 1L, mix 1.514 g TRIS, 2.192 g NaCl and 25 ml DMSO; 1119 bring to 1 liter total volume with dH2O. 1120 9. ATP (Adenosine-5-triphosphate, from Equine muscle, Sigma Cat. No. A-5394), 1.0 mM solution in dH2O. This reagent should be made up immediately prior to use and kept on ice. 1121 10. 1.0 mM MnCl2. 1122 11. ATP/MnCl2 phosphorylation mix: to make 10 ml, mix 300 l of 1 mM ATP, 500 l MnCl2 and 9.2 ml dH2O. Prepare just prior to use, keep on ice. 1123 12. NUNC 96-well V bottom polypropylene plates. 1124 13. EDTA. 1125 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1126 15. Goat anti-rabbit IgG peroxidase conjugate (Biosource Cat. No. ALI0404). 1127 16. ABTS. 1128 17. 30% Hydrogen peroxide. 1129 18. ABTS/H2O2 1130 19. 0.2 M HCl. 1131 Procedure: 1132 1. Coat Corning 96 well ELISA plates with 0.5 g SUMO1 in 100 l PBS per well, store overnight at 4 C. 1133 2. Remove unbound SUMO1 from wells by inverting plate to remove liquid. Wash 1with dH2O. Pat the plate on a paper towel to remove excess liquid. 1134 3. Add 150 l of Blocking Buffer to each well. Incubate, with shaking, for 30 min. at room temperature. 1135 4. Wash plate 3with deionized water, then once with TBST. Pat plate on a paper towel to remove excess liquid and bubbles. 1136 5. Dilute lysate in PBS (7 g lysate/100 l PBS). 1137 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 1 hr. 1138 7. Wash plates as in 4, above. 1139 8. Add 120 l TBS to ELISA plate containing captured EGFR. 1140 9. Dilute test compound 1:10 in TBS, place in well 1141 10. Add 13.5 l diluted test compound to ELISA plate. To control wells, add 13.5 l TBS in 10% DMSO. 1142 11. Incubate, with shaking, for 30 minutes at room temperature. 1143 12. Add 15 l phosphorylation mix to all wells except negative control well. Final well volume should be approximately 150 l with 3 M ATP/5 mM MnCl2 final concentration in each well. Incubate with shaking for 5 minutes. 1144 13. Stop reaction by adding 16.5 l of EDTA solution while shaking. Shake for additional 1 min. 1145 14. Wash 4with deionized water, 2with TBST. 1146 15. Add 100 l anti-phosphotyrosine (1:3000 dilution in TBST) per well. Incubate, with shaking, for 30-45 min. at room temperature. 1147 16. Wash as in 4, above. 1148 17. Add 100 l Biosource Goat anti-rabbit IgG peroxidase conjugate (1:2000 dilution in TBST) to each well. Incubate with shaking for 30 min. at room temperature. 1149 18. Wash as in 4, above. 1150 19. Add 100 l of ABTS/H2O2 solution to each well. 1151 20. Incubate 5 to 10 minutes with shaking. Remove any bubbles. 1152 21. If necessary, stop reaction by adding 100 l 0.2 M HCl per well. 1153 22. Read assay on Dynatech MR7000 ELISA reader: test filter at 410 nM, reference filter at 630 nM. 1154 PDGFR Bioassay 1155 This assay is used to the in vitro kinase activity of FGF1-R in an ELISA assay. 1156 Materials and Reagents: 1157 1. Corning 96-well Elisa plates 1158 2. 28D4C10 monoclonal anti-PDGFR antibody (SUGEN, Inc.). 1159 3. PBS. 1160 4. TBST Buffer. 1161 5. Blocking Buffer (same as for EGFR bioassay). 1162 6. PDGFR- expressing NIH 3T3 cell lysate (SUGEN, Inc.). 1163 7. TBS Buffer. 1164 8. TBS10% DMSO. 1165 9. ATP. 1166 10. MnCl2. 1167 11. Kinase buffer phosphorylation mix: for 10 ml, mix 250 l 1M TRIS, 200 l 5M NaCl, 100 l 1M MnCl2 and 50 l 100 mM Triton X-100 in enough dH2O to make 10 ml. 1168 12. NUNC 96-well V bottom polypropylene plates. 1169 13. EDTA. 1170 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1171 15. Goat anti-rabbit IgG peroxidase conjugate (Biosource Cat. No. ALI0404). 1172 16. ABTS. 1173 17. Hydrogen peroxide, 30% solution. 1174 18. ABTS/H2O2. 1175 19. 0.2 M HCl. 1176 Procedure: 1177 1. Coat Corning 96 well ELISA plates with 0.5 g 28D4C10 in 100 l PBS per well, store overnight at 4 C. 1178 2. Remove unbound 28D4C10 from wells by inverting plate to remove liquid. 1179 Wash 1with dH2O. Pat the plate on a paper towel to remove excess liquid. 1180 3. Add 150 l of Blocking Buffer to each well. Incubate for 30 min. at room temperature with shaking. 1181 4. Wash plate 3with deionized water, then once with TBST. Pat plate on a paper towel to remove excess liquid and bubbles. 1182 5. Dilute lysate in HNTG (10 g lysate/100 l HNTG). 1183 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 60 min. 1184 7. Wash plates as described in Step 4. 1185 8. Add 80 l working kinase buffer mix to ELISA plate containing captured PDGFR. 1186 9. Dilute test compound 1:10 in TBS in 96-well polypropylene plates. 1187 10. Add 10 l diluted test compound to ELISA plate. To control wells, add 10 l TBS10% DMSO. Incubate with shaking for 30 minutes at room temperature. 1188 11. Add 10 l ATP directly to all wells except negative control well (final well volume should be approximately 100 l with 20 M ATP in each well.) Incubate 30 minutes with shaking. 1189 12. Stop reaction by adding 10 l of EDTA solution to each well. 1190 13. Wash 4with deionized water, twice with TBST. 1191 14. Add 100 l anti-phosphotyrosine (1:3000 dilution in TBST) per well. Incubate with shaking for 30-45 min. at room temperature. 1192 15. Wash as in Step 4. 1193 16. Add 100 l Biosource Goat anti-rabbit IgG peroxidase conjugate (1:2000 dilution in TBST) to each well. Incubate with shaking for 30 min. at room temperature. 1194 17. Wash as in Step 4. 1195 18. Add 100 l of ABTS/H2O2 solution to each well. 1196 19. Incubate 10 to 30 minutes with shaking. Remove any bubbles. 1197 20. If necessary stop reaction with the addition of 100 l 0.2 M HCl per well. 1198 21. Read assay on Dynatech MR7000 ELISA reader with test filter at 410 nM and reference filter at 630 nM. 1199 Cellular HER-2 Kinase Assay 1200 This assay is used to measure HER-2 kinase activity in whole cells in an ELISA format. 1201 Materials and Reagents: 1202 1. DMEM (GIBCO Catalog 11965-092). 1203 2. Fetal Bovine Serum (FBS, GIBCO Catalog 16000-044), heat inactivated in a water bath for 30 min. at 56 C. 1204 3. Trypsin (GIBCO Catalog 25200-056). 1205 4. L-Glutamine (GIBCO Catalog 25030-081) 1206 5. HEPES (GIBCO Catalog 15630-080). 1207 6. Growth Media 1208 Mix 500 ml DMEM, 55 ml heat inactivated FBS, 10 ml HEPES and 5.5 ml L-Glutamine. 1209 7. Starve Media 1210 Mix 500 ml DMEM, 2.5 ml heat inactivated FBS, 10 ml HEPES and 5.5 ml L-Glutamine. 1211 8. PBS. 1212 9. Flat Bottom 96-well Tissue Culture Micro Titer Plates (Corning Catalog 25860). 1213 10. 15 cm Tissue Culture Dishes (Corning Catalog 08757148). 1214 11. Corning 96-well ELISA Plates. 1215 12. NUNC 96-well V bottom polypropylene plates. 1216 13. Costar Transfer Cartridges for the Transtar 96 (Costar Catalog 7610). 1217 14. SUMO 1: monoclonal anti-EGFR antibody (SUGEN, Inc.). 1218 15. TBST Buffer. 1219 16. Blocking Buffer: 5% Carnation Instant Milk in PBS. 1220 17. EGF Ligand: EGF-201, Shinko American, Japan. Suspend powder in 100 uL of 10 mM HCl. Add 100 uL 10 mM NaOH. Add 800 uL PBS and transfer to an Eppendorf tube, store at 20 C. until ready to use. 1221 18. HNTG Lysis Buffer 1222 For Stock 5HNTG, mix 23.83 g Hepes, 43.83 g NaCl, 500 ml glycerol and 100 ml Triton X-100 and enough dH2O to make 1 L of total solution. 1223 For 1HNTG*, mix 2 ml HNTG, 100 uL 0.1M Na3VO4, 250 L 0.2M Na4P2O7 and 100 L EDTA. 1224 19. EDTA. 1225 20. Na3VO4. To make stock solution, mix 1.84 g Na3VO4 with 90 ml dH2O. 1226 Adjust pH to 10. Boil in microwave for one minute (solution becomes clear). 1227 Cool to room temperature. Adjust pH to 10. Repeat heating/cooling cycle until pH remains at 10. 1228 21. 200 mM Na4P2O7. 1229 22. Rabbit polyclonal antiserum specific for phosphotyrosine (anti-Ptyr antibody, SUGEN, Inc.). 1230 23. Affinity purified antiserum, goat anti-rabbit IgG antibody, peroxidase conjugate (Biosource Cat ALI0404). 1231 24. ABTS Solution. 1232 25. 30% Hydrogen peroxide solution. 1233 26. ABTS/H2O2. 1234 27. 0.2 M HCl. 1235 Procedure: 1236 1. Coat Corning 96 well ELISA plates with SUMO1 at 1.0 ug per well in PBS, 100 ul final volume/well. Store overnight at 4 C. 1237 2. On day of use, remove coating buffer and wash plate 3 times with dH2O and once with TBST buffer. All washes in this assay should be done in this manner, unless otherwise specified. 1238 3. Add 100 ul of Blocking Buffer to each well. Incubate plate, with shaking, for 30 min. at room temperature. Just prior to use, wash plate. 1239 4. Use EGFr/HER-2 chimera/3T3-C7 cell line for this assay. 1240 5. Choose dishes having 80-90% confluence. Collect cells by trypsinization and centrifuge at 1000 rpm at room temperature for 5 min. 1241 6. Resuspend cells in starve medium and count with trypan blue. Viability above 90% is required. Seed cells in starve medium at a density of 2,500 cells per well, 90 ul per well, in a 96 well microtiter plate. Incubate seeded cells overnight at 37 under 5% CO2. 1242 7. Start the assay two days after seeding. 1243 8. Test compounds are dissolved in 4% DMSO. Samples are then further diluted directly on plates with starve-DMEM. Typically, this dilution will be 1:10 or greater. All wells are then transferred to the cell plate at a further 1:10 dilution (10 L sample and media into 90 l of starve media. The final DMSO concentration should be 1% or lower. A standard serial dilution may also be used. 1244 9. Incubate under 5% CO2 at 37 C. for 2 hours. 1245 10. Prepare EGF ligand by diluting stock EGF (16.5 uM) in warm DMEM to 150 nM. 1246 11. Prepare fresh IINTG* sufficient for 100 ul per well; place on ice. 1247 12. After 2 hour incubation with test compound, add prepared EGF ligand to cells, 50 ul per well, for a final concentration of 50 nM. Positive control wells receive the same amount of EGF. Negative controls do not receive EGF. Incubate at 37 C. for 10 min. 1248 13. Remove test compound, EGF, and DMEM. Wash cells once with PBS. 1249 14. Transfer HNTG* to cells, 100 ul per well. Place on ice for 5 minutes. 1250 Meanwhile, remove blocking buffer from ELISA plate and wash. 1251 15. Scrape cells from plate with a micropipettor and homogenize cell material by repeatedly aspirating and dispensing the HNTG* lysis buffer. Transfer lysate to a coated, blocked, washed ELISA plate. Or, use a Costar transfer cartridge to transfer lysate to the plate. 1252 16. Incubate, with shaking, at room temperature for 1 hr. 1253 17. Remove lysate, wash. Transfer freshly diluted anti-Ptyr antibody (1:3000 in TBST) to ELISA plate, 100 ul per well. 1254 18. Incubate, with shaking, at room temperature, for 30 min. 1255 19. Remove anti-Ptyr antibody, wash. Transfer freshly diluted BIOSOURCE antibody to ELISA plate (1:8000 in TBST, 100 ul per well). 1256 20. Incubate, with shaking, at room temperature for 30 min. 1257 21. Remove BIOSOURCE antibody, wash. Transfer freshly prepared ABTS/H2O2 solution to ELISA plate, 100 ul per well. 1258 22. Incubate, with shaking, for 5-10 minutes. Remove any bubbles. 1259 23. Stop reaction with the addition of 100 ul of 0.2M HCl per well. 1260 24. Read assay on Dynatech MR7000 ELISA reader with test filter set at 410 nM and reference filter at 630 nM. 1261 CDK2/CYCLIN A Assay 1262 This assay is used to measure the in vitro serine/threonine kinase activity of human cdk2/cyclin A in a Scintillation Proximity Assay (SPA). 1263 Materials and Reagents. 1264 1. Wallac 96-well polyethylene terephthalate (flexi) plates (Wallac Catalog 1450-401). 1265 2. Amersham Redivue 33P ATP (Amersham catalog AH 9968). 1266 3. Amersham streptavidin coated polyvinyltoluene SPA beads (Amersham catalog RPNQ0007). The beads should be reconstituted in PBS without magnesium or calcium, at 20 mg/ml. 1267 4. Activated cdk2/cyclin A enzyme complex purified from Sf9 cells (SUGEN, Inc.). 1268 5. Biotinylated peptide substrate (Debtide). Peptide biotin-X-PKTPKKAKKL is dissolved in dH2O at a concentration of 5 mg/ml. 1269 6. Peptide/ATP Mixture: for 10 ml, mix 9.979 ml dH2O, 0.00125 ml cold ATP, 0.010 ml Debtide and 0.010 ml 33P ATP. The ultimate concentration per well will be 0.5 M cold ATP, 0.1 g Debtide and 0.2 Ci 33P ATP. 1270 7. Kinase buffer: for 10 ml, mix 8.85 ml dH2O, 0.625 ml TRIS (PH 7.4), 0.25 ml 1 M MgCl2, 0.25 ml 10% NP40 and 0.025 ml 1 M DTT, added fresh just prior to use. 1271 8. 10 mM ATP in dH2O. 1272 9. 1M Tris, pH adjusted to 7.4 with HCl. 1273 10. 1M MgCl2. 1274 11. 1M DTT. 1275 12. PBS (Gibco Catalog 14190-144). 1276 13. 0.5M EDTA. 1277 14. Stop solution: For 10 ml, mix 9.25 ml PBS, 0.005 ml 100 mM ATP, 0.1 ml 0.5 M EDTA, 0.1 ml 10% Triton X-100 and 1.25 ml of 20 mg/ml SPA beads. 1278 Procedure: 1279 1. Prepare solutions of test compounds at 5the desired final concentration in 5% DMSO. Add 10 ul to each well. For negative controls, use 10 ul 5% DMSO alone in wells. 1280 2. Dilute 5 l of cdk2/cyclin A solution with 2.1 ml 2kinase buffer. 1281 3. Add 20 ul enzyme to each well. 1282 4. Add 10 L of 0.5 M EDTA to the negative control wells. 1283 5. To start kinase reaction, add 20 L of peptide/ATP mixture to each well. 1284 Incubate for 1 hr. without shaking. 1285 6. Add 200 l stop solution to each well. 1286 7. Hold at least 10 min. 1287 8. Spin plate at approx. 2300 rpm for 3-5 min. 1288 9. Count plate using Trilux or similar reader. 1289 MET Transphosphorylation Assay 1290 This assay is used to measure phosphotyrosine levels on a poly(glutamic acid:tyrosine (4:1)) substrate as a means for identifying agonists/antagonists of met transphosphorylation of the substrate. 1291 Materials and Reagents: 1292 1. Corning 96-well Elisa plates, Corning Catalog 25805-96. 1293 2. Poly(glu, tyr) 4:1, Sigma, Cat. No; P 0275. 1294 3. PBS, Gibco Catalog 450-1300EB 1295 4. 50 mM HEPES 1296 5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat. No A-7888, in 500 ml PBS, filter through a 4 m filter. 1297 6. Purified GST fusion protein containing the Met kinase domain, Sugen, Inc. 1298 7. TBST Buffer. 1299 8. 10% aqueous (MilliQue H2O) DMSO. 1300 9. 10 mM aqueous (dH2O) Adenosine-5-triphosphate, Sigma Cat. No. A-5394. 1301 10. 2Kinase Dilution Buffer: for 100 ml, mix 10 mL 1M HEPES at pH 7.5 with 0.4 mL 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5M sodium chloride in 88.4 mL dH2O. 1302 11. 4ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride and 0.02 mL 0.1 M ATP in 9.56 mL dH2O. 1303 12. 4Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL dH2O. 1304 13. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog S-72092 1305 14. 500 mM EDTA. 1306 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL 5% Carnation Instant Milk in PBS and 0.1 mL 0.1 M sodium orthovanadate in 88.4 mL TBST. 1307 16. Rabbit polyclonal antophosphotyrosine antibody, Sugen, Inc. 1308 17. Goat anti-rabbit horseradish peroxidase conjugated antibody, Biosource, Inc. 1309 18. ABTS Solution: for 1 L, mix 19.21 g citric acid, 35.49 g Na2HPO4 and 500 mg ABTS with sufficient dH2O to make 1 L. 1310 19. ABTS/H2O2: mix 15 mL ABST solution with 2 L H2O2 five minutes before use. 1311 20. 0.2 M HCl 1312 Procedure: 1313 1. Coat ELISA plates with 2 g Poly(Glu-Tyr) in 100 L PBS, store overnight at 4 C. 1314 2. Block plate with 150 L of 5% BSA/PBS for 60 min. 1315 3. Wash plate twice with PBS, once with 50 mM Hepes buffer pH 7.4. 1316 4. Add 50 l of the diluted kinase to all wells. (Purified kinase is diluted with Kinase Dilution Buffer. Final concentration should be 10 ng/well.) 1317 5. Add 25 L of the test compound (in 4% DMSO) or DMSO alone (4% in dH2O) for controls to plate. 1318 6. Incubate the kinase/compound mixture for 15 minutes. 1319 7. Add 25 mL of 40 mM MnCl2 to the negative control wells. 1320 8. Add 25 L ATP/MnCl2 mixture to the all other wells (except the negative controls). Incubate for 5 min. 1321 9. Add 25 L 500 mM EDTA to stop reaction. 1322 10. Wash plate 3with TBST. 1323 11. Add 100 L rabbit polyclonal anti-Ptyr diluted 1:10,000 in Antibody Dilution Buffer to each well. Incubate, with shaking, at room temperature for one hour. 1324 12. Wash plate 3with TBST. 1325 13. Dilute Biosource HRP conjugated anti-rabbit antibody 1:6,000 in Antibody Dilution buffer. Add 100 L per well and incubate at room temperature, with shaking, for one hour. 1326 14. Wash plate IX with PBS. 1327 15. Add 100 l of ABTS/H2O2 solution to each well. 1328 16. If necessary, stop the development reaction with the addition of 100 l of 0.2M HCl per well. 1329 17. Read plate on Dynatech MR7000 elisa reader with the test filter at 410 nM and the reference filter at 630 nM. 1330 IGF-1 Transphosphorylation Assay 1331 This assay is used to measure the phosphotyrosine level in poly(glutamic acid:tyrosine)(4:1) for the identification of agonists/antagonists of gst-IGF-1 transphosphorylation of a substrate. 1332 Materials and Reagents: 1333 1. Corning 96-well Elisa plates. 1334 2. Poly (Glu-tyr) (4:1), Sigma Cat. No. P 0275. 1335 3. PBS, Gibco Catalog 450-1300EB. 1336 4. 50 mM HEPES 1337 5. TBB Blocking Buffer: for 1 L, mix 100 g BSA, 12.1 gTRIS (pH 7.5), 58.44 g sodium chloride and 10 mL 1%TWEEN-20. 1338 6. Purified GST fusion protein containing the IGF-1 kinase domain (Sugen, Inc.) 1339 7. TBST Buffer: for 1 L, mix 6.057 g Tris, 8.766 g sodium chloride and 0.5 ml TWEEN-20 with enough dH2O to make 1 liter. 1340 8. 4% DMSO in Milli-Q H2O. 1341 9. 10 mM ATP in dH2O. 1342 10. 2Kinase Dilution Buffer: for 100 mL, mix 10 mL 1 M HEPES (pH 7.5), 0.4 mL 5% BSA in dH2O, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5 M sodium chloride with enough dH2O to make 100 mL. 1343 11. 4ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M MnCl2 and 0.008 mL 0.01 M ATP and 9.56 mL dH2O. 1344 12. 4Negative Controls Mixture: mix 0.4 mL 1 M manganese chloride in 9.60 mL dH2O. 1345 13. NUNC 96-well V bottom polypropylene plates. 1346 14. 500 mM EDTA in dH2O. 1347 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA in PBS, 0.5 mL 5% Carnation Instant Non-fat Milk in PBS and 0.1 mL 0.1 M sodium orthovanadate in 88.4 mL TBST. 1348 16. Rabbit Polyclonal antiphosphotyrosine antibody, Sugen, Inc. 1349 17. Goat anti-rabbit HRP conjugated antibody, Biosource. 1350 18. ABTS Solution. 1351 20. ABTS/H2O2: mix 15 mL ABTS with 2 L H2O2 5 minutes before using. 1352 21. 0.2 M HCl in dH2O. 1353 Procedure: 1354 1. Coat ELISA plate with 2.0 g/well Poly(Glu, Tyr) 4:1 (Sigma PO275) in 100 l PBS. Store plate overnight at 4 C. 1355 2. ash plate once with PBS. 1356 3. Add 100 l of TBB Blocking Buffer to each well. Incubate plate for 1 hour with shaking at room temperature. 1357 4. Wash plate once with PBS, then twice with 50 mM Hepes buffer pH 7.5. 1358 5. Add 25 L of test compound in 4% DMSO (obtained by diluting a stock solution of 10 mM test compound in 100% DMSO with dH2O) to plate. 1359 6. Add 10.0 ng of gst-IGF-1 kinase in 50 l Kinase Dilution Buffer) to all wells. 1360 7. Start kinase reaction by adding 25 l 4ATP Reaction Mixture to all test wells and positive control wells. Add 25 l 4Negative Controls Mixture to all negative control wells. Incubates for 10 minutes with shaking at room temperature. 1361 8. Add 25 l 0.5M EDTA (pH 8.0) to all wells. 1362 9. Wash plate 4with TBST Buffer. 1363 10. Add rabbit polyclonal anti-phosphotyrosine antisera at a dilution of 1:10,000 in 100 l Antibody Dilution Buffer to all wells. Incubate, with shaking, at room temperature for 1 hour. 1364 11. Wash plate as in step 9. 1365 12. Add 100 L Biosource anti-rabbit HRP at a dilution of 1:10,000 in Antibody dilution buffer to all wells. Incubate, with shaking, at room temperature for 1 hour. 1366 13. Wash plate as in step 9, follow with one wash with PBS to reduce bubbles and excess Tween-20. 1367 14. Develop by adding 100 l/well ABTS/H2O2 to each well. 1368 15. After about 5 minutes, read on ELISA reader with test filter at 410 nm and referenced filter at 630 nm. 1369 BRDU Incorporation Assays 1370 The following assays use cells engineered to express a selected receptor and then evaluate the effect of a compound of interest on the activity of ligand-induced DNA synthesis by determining BrdU incorporation into the DNA. 1371 The following materials, reagents and procedure are general to each of the following BrdU incorporation assays. Variances in specific assays are noted. 1372 Materials and Reagents: 1373 1. The appropriate ligand. 1374 2. The appropriate engineered cells. 1375 3. BrdU Labeling Reagent: 10 mM, in PBS (pH 7.4)(Boehringer Mannheim, Germany). 1376 4. FixDenat: fixation solution (ready to use)(Boehringer Mannheim, Germany). 1377 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Boehringer Mannheim, Germany). 1378 6. TMB Substrate Solution: tetramethylbenzidine (TMB, Boehringer Mannheim, Germany). 1379 7. PBS Washing Solution: 1PBS, pH 7.4. 1380 8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA). 1381 General Procedure: 1382 1. Cells are seeded at 8000 cells/well in 10% CS, 2 mM Gln in DMEM, in a 96 well plate. Cells are incubated overnight at 37 C. in 5% CO2. 1383 2. After 24 hours, the cells are washed with PBS, and then are serum-starved in serum free medium (0% CS DMEM with 0.1% BSA) for 24 hours. 1384 3. On day 3, the appropriate ligand and the test compound are added to the cells simultaneously. The negative control wells receive serum free DMEM with 0.1% BSA only; the positive control cells receive the ligand but no test compound. Test compounds are prepared in serum free DMEM with ligand in a 96 well plate, and serially diluted for 7 test concentrations. 1385 4. After 18 hours of ligand activation, diluted BrdU labeling reagent (1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU (final concentration10 M) for 1.5 hours. 1386 5. After incubation with labeling reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. FixDenat solution is added (50 l/well) and the plates are incubated at room temperature for 45 minutes on a plate shaker. 1387 6. The FixDenat solution is thoroughly removed by decanting and tapping the inverted plate on a paper towel. Milk is added (5% dehydrated milk in PBS, 200 l/well) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker. 1388 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution (1:200 dilution in PBS, 1%, BSA) is added (50 l/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker. 1389 8. The antibody conjugate is thoroughly removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel. 1390 9. TMB substrate solution is added (100 l/well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection. 1391 10. The absorbance of the samples are measured at 410 nm (in dual wavelength mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader. 1392 EGF-Induced BrdU Incorporation Assay 1393 Materials and Reagents: 1394 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1395 2. 3T3/EGFRc7. 1396 EGF-Induced Her-2-Driven BrdU Incorporation Assay 1397 Materials and Reagents: 1398 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1399 2. 3T3/EGFr/Her2/EGFr (EGFr with a Her-2 kinase domain). 1400 EGF-Induced Her-4-driven BrdU Incorporation Assay 1401 Materials and Reagents: 1402 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1403 2. 3T3/EGFr/Her4/EGFr (EGFr with a Her-4 kinase domain). 1404 PDGF-Induced BrdU Incorporation Assay 1405 Materials and Reagents: 1406 1. Human PDGF B/B (Boehringer Mannheim, Germany). 1407 2. 3T3/EGFRc7. 1408 FGF-Induced BrdU Incorporation Assay 1409 Materials and Reagents: 1410 1. Human FGF2/bFGF (Gibco BRL, USA). 1411 2. 3T3c7/EGFr 1412 IGF1-Induced BrdU Incorporation Assay 1413 Materials and Reagents: 1414 1. Human, recombinant (G511, Promega Corp., USA) 1415 2. 3T3/IGFlr. 1416 Insulin-Induced BrdU Incorporation Assay 1417 Materials and Reagents: 1418 1. Insulin, crystalline, bovine, Zinc (13007, Gibco BRL, USA). 1419 2. 3T3/H25. 1420 HGF-Induced BrdU Incorporation Assay 1421 Materials and Reagents: 1422 1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc. USA). 1423 2. BxPC-3 cells (ATCC CRL-1687). 1424 Procedure: 1425 1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 well plate. Cells are incubated overnight at 37 C. in 5% CO2. 1426 2. After 24 hours, the cells are washed with PBS, and then are serum starved in 100 l serum-free medium (RPMI with 0.1% BSA) for 24 hours. 1427 3. On day 3, 25 l containing ligand (prepared at 1 g/ml in RPMI with 0.1% BSA; final HGF conc. is 200 ng/ml) and test compounds are added to the cells. 1428 The negative control wells receive 25 l serum-free RPMI with 0.1% BSA only; the positive control cells receive the ligand (HGF) but no test compound. 1429 Test compounds are prepared at 5 times their final concentration in serum-free RPMI with ligand in a 96 well plate, and serially diluted to give 7 test concentrations. Typically, the highest final concentration of test compound is 100 M, and 1:3 dilutions are used (i.e. final test compound concentration range is 0.137-100 M). 1430 4. After 18 hours of ligand activation, 12.5 l of diluted BrdU labeling reagent (1:100 in RPMI, 0.1% BSA) is added to each well and the cells are incubated with BrdU (final concentration is 10 M) for 1 hour. 1431 5. Same as General Procedure. 1432 6. Same as General Procedure. 1433 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS, 1% BSA) is added (100 l/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker. 1434 8. Same as General Procedure. 1435 9. Same as General Procedure. 1436 10. Same as General Procedure. 1437 HUV-EC-C Assay 1438 This assay is used to measure a compound's activity against PDGF-R, FGF-R, VEGF, aFGF or Flk-1/KDR, all of which are naturally expressed by HUV-EC cells. 1439 Day 0 1440 1. Wash and trypsinize HV-EC-C cells (human umbilical vein endothelial cells, (American Type Culture Collection, catalogue no. 1730 CRL). Wash with Dulbecco's phosphate-buffered saline (D-PBS, obtained from Gibco BRL, catalogue no. 14190-029) 2 times at about 1 ml/10 cm2 of tissue culture flask. Trypsinize with 0.05% trypsin-EDTA in non-enzymatic cell dissociation solution (Sigma Chemical Company, catalogue no. C-1544). The 0.05% trypsin is made by diluting 0.25% trypsin/1 mM EDTA (Gibco, catalogue no. 25200-049) in the cell dissociation solution. Trypsinize with about 1 ml/25-30 cm2 of tissue culture flask for about 5 minutes at 37 C. After cells have detached from the flask, add an equal volume of assay medium and transfer to a 50 ml sterile centrifuge tube (Fisher Scientific, catalogue no. 05-539-6). 1441 2. Wash the cells with about 35 ml assay medium in the 50 ml sterile centrifuge tube by adding the assay medium, centrifuge for 10 minutes at approximately 200g, aspirate the supernatant, and resuspend with 35 ml D-PBS. Repeat the wash two more times with D-PBS, resuspend the cells in about 1 ml assay medium/15 cm2 of tissue culture flask. Assay medium consists of F12K medium (Gibco BRL, catalogue no. 21127-014) and 0.5% heat-inactivated fetal bovine serum. Count the cells with a Coulter Counter (Coulter Electronics, Inc.) and add assay medium to the cells to obtain a concentration of 0.8-1.0105 cells/ml. 1442 3. Add cells to 96-well flat-bottom plates at 100 l/well or 0.8-1.0104 cells/well, incubate 24 h at 37 C., 5% CO2. 1443 Day 1 1444 1. Make up two-fold test compound titrations in separate 96-well plates, generally 50 M on down to 0 M. Use the same assay medium as mentioned in day 0, step 2 above. Titrations are made by adding 90 l/well of test compound at 200 M (4the final well concentration) to the top well of a particular plate column. Since the stock test compound is usually 20 mM in DMSO, the 200 M drug concentration contains 2% DMSO. 1445 A diluent made up to 2% DMSO in assay medium (F12K0.5% fetal bovine serum) is used as diluent for the test compound titrations in order to dilute the test compound but keep the DMSO concentration constant. Add this diluent to the remaining wells in the column at 60 l/well. Take 60 l from the 120 l of 200 M test compound dilution in the top well of the column and mix with the 60 l in the second well of the column. Take 60 l from this well and mix with the 60 l in the third well of the column, and so on until two-fold titrations are completed. When the next-to-the-last well is mixed, take 60 l of the 120 l in this well and discard it. Leave the last well with 60 l of DMSO/media diluent as a non-test compound-containing control. Make 9 columns of titrated test compound, enough for triplicate wells each for: (1) VEGF (obtained from Pepro Tech Inc., catalogue no. 100-200, (2) endothelial cell growth factor (ECGF) (also known as acidic fibroblast growth factor, or aFGF) (obtained from Boehringer Mannheim Biochemica, catalogue no. 1439 600), or, (3) human PDGF B/B (1276-956, Boehringer Mannheim, Germany) and assay media control. ECGF comes as a preparation with sodium heparin. 1446 2. Transfer 50 l/well of the test compound dilutions to the 96-well assay plates containing the 0.8-1.0104 cells/100 l/well of the HUV-EC-C cells from day 0 and incubate 2 h at 37 C., 5% CO2 . 1447 3. In triplicate, add 50 l/well of 80 g/ml VEGF, 20 ng/ml ECGF, or media control to each test compound condition. As with the test compounds, the growth factor concentrations are 4the desired final concentration. Use the assay media from day 0 step 2 to make the concentrations of growth factors. Incubate approximately 24 hours at 37 C., 5% CO2. Each well will have 50 l test compound dilution, 50 l growth factor or media, and 100 l cells, which calculates to 200 l/well total. Thus the 4concentrations of test compound and growth factors become 1X once everything has been added to the wells. 1448 Day 2 1449 1. Add 3H-thymidine (Amersham, catalogue no. TRK-686) at 1 Ci/well (10 l/well of 100 Ci/ml solution made up in RPMI media10% heat-inactivated fetal bovine serum) and incubate 24 h at 37 C., 5% CO2. RPMI is obtained from Gibco BRL, catalogue no. 11875-051. 1450 Day 3 1451 1. Freeze plates overnight at 20 C. 1452 Day 4 1453 Thaw plates and harvest with a 96-well plate harvester (Tomtec Harvester 96) onto filter mats (Wallac, catalogue no. 1205-401), read counts on a Wallac Betaplate liquid scintillation counter. 1454 TABLE 2 shows the results of biological testing of some exemplary compounds of Formula (I). The results are reported in terms of IC50, the micromolar (M) concentration of the compound being tested which causes a 50% change in the activity of the target PKT compared to the activity of the PTK in a control to which no test compound has been added. Specifically, the results shown indicate the concentration of a test compound needed to cause a 50% reduction of the activity of the target PTK. Bioassays which have been or can be used to evaluate compounds are described in detail below. 4TABLE 2biobiobioHer2flkGSTFGFR1PDGFbio EGFcell EGFKinasecdk2spabio pyk2IC50IC50IC50IC50IC50IC50C50IC50Example(M)(M)(M)(M)(M)(M)(M)(M)157.6815.16>100>100>100>1002>100>100>100>10039.859.62>100>100>100>10043.57>20>100>100>100>10058.316.06>100>100>100>10064.04>1003.267.822.4377.74>1005.079.84.24812.1>10051.3420.085.590.96>100>100>10016.38105.72>10094.0415.868.06119.77>100>100>100>10012>2021.46>10027.7313>2081.928.172.661413.0142.41>10066.0215>20>100>10098.6116>2098.06>10023.32178.252.4794.350.8311.4715.94>10182.672.579.234.99197.56.8634.188.372011.53>10041.168217.18>10040.3427.6922>20>100>10087.6723>20>10036.644.0524>10016.845.312512.55>10023.487.92616.0366.8734.6710.0427>10026.53.91284.571.2753.662.672910.12>10026.723.98309.4>10018.694.131>50>1009.8347.193245.745.94>100>10034>50>100>100>10035>20>10080.454.1436>20>100>100>100370.223.0610.789.841.4384.173.066.048.972.16393.384.693.6714.543.53404.57.96.526.27420.10.1211.9574.5520.43431.128.38>10037.3353.3744<0.050.0220.7367.466.99451.71>100>10029.95>1004630.626.18>100>100>100470.081.560.0611.4241.548.4>201.05480.0060.3<0.7817.8821.587.930.0949<0.78>10043.86>10050<0.78>10020.34>100510.0061.660.0118.121.6123.2416.690.35520.081.26<0.7812.53>100>10010.660.4553<0.78>100>100>100541.98<0.7823.889.767.02550.270.536.0335.9977.82562.323.19>10010.037.11570.067.98>1009.976.945821.14>100>100>10059<0.78>100>100>10060<0.78>100>100>10061<0.78>100>100>100628.008.32>100>100>100630.21<0.788.59>100>100640.55<0.7830.49>100>100650.37<0.05>10074.3615.9766<0.05>10011.842.76670.3924.7731.3819.792.56681.160.03>10023.5234.13690.356.55>10097.54>100700.091.500.003010.576.427.9912.620.637115.2122.5>1009.91726.0610.54>10039.949.65735.9514.12>10039.58.59741.20.0946.75>100752.761.55>100>100763.3319.185.113.01770.4925.01>100>100781.9470.629.334.25791.49>10027.39>100800.134.290.001>10050.1917.190.28810.210.18>100>100822.037.696.88>100>1000.31830.340.419.462.1886.90.008841.3812.5167.25.860.006850.20.82.59>1003.76861.451.319.641.8>1003.58873.277.566.46>1009.10.17880.351.188.062.36>1000.09897.8447.588.539.6715.971157.37.48>100>1000.006116>20>100>100>100<0.00051170.9112.9>100>1000.0061181.931.2>100>1000.0021191.3861.63>100>100<0.0005

1455 In vivo Animal Models 1456 Xenograft Animal Models 1457 The ability of human tumors to grow as xenografts in athymic mice (e.g., Balb/c, nu/nu) provides a useful in vivo model for studying the biological response to therapies for human tumors. Since the first successful xenotransplantation of human tumors into athymic mice, (Ryggard and Povlsen, 1969, Acta Pathol. Microbial. Scand. 77:758-760), many different human tumor cell lines (e.g., mammary, lung, genitourinary, gastro-intestinal, head and neck, glioblastoma, bone, and malignant melanomas) have been transplanted and successfully grown in nude mice. The following assays may be used to determine the level of activity, specificity and effect of the different compounds of Formula (I). 1458 Three general types of assays are useful for evaluating compounds of Formula (I): cellular/catalytic, cellular/biological and in vivo. The object of the cellular/catalytic assays is to determine the effect of a compound of Formula (I) on the ability of a TK to phosphorylate tyrosines on a known substrate in a cell. The object of the cellular/biological assays is to determine the effect of a compound of Formula (I) on the biological response stimulated by a TK in a cell. The object of the in vivo assays is to determine the effect of a compound of Formula (I) in an animal model of a particular disorder such as cancer. 1459 Suitable cell lines for subcutaneous xenograft experiments include C6 cells (glioma, ATCC CCL 107), A375 cells (melanoma, ATCC CRL 1619), A431 cells (epidermoid carcinoma, ATCC CRL 1555), Calu 6 cells (lung, ATCC HTB 56), PC3 cells (prostate, ATCC CRL 1435), SKOV3TP5 cells and NIH 3T3 fibroblasts genetically engineered to overexpress EGFR, PDGFR, IGF-1R or any other test kinase. The following protocol can be used to perform xenograft experiments: 1460 Female athymic mice (BALB/c, nu/nu) are obtained from Simonsen Laboratories (Gilroy, Calif.). All animals are maintained under clean-room conditions in Micro-isolator cages with Alpha-dri bedding. They receive sterile rodent chow and water ad libitum. 1461 Cell lines are grown in appropriate medium (for example, MEM, DMEM, Ham's F10, or Ham's F12 plus 5%-10% fetal bovine serum (FBS) and 2 mM glutamine (GLN)). All cell culture media, glutamine, and fetal bovine serum are purchased from Gibco Life Technologies (Grand Island, N.Y.) unless otherwise specified. All cells are grown in a humid atmosphere of 90-95% air and 5-10% CO2 at 37 C. All cell lines are routinely subcultured twice a week and are negative for mycoplasma as determined by the Mycotect method (Gibco). 1462 Cells are harvested at or near confluency with 0.05% Trypsin-EDTA and pelleted at 450g for 10 min. Pellets are resuspended in sterile PBS or media (without FBS) to a particular concentration and the cells are implanted into the hindflank of the mice (8-10 mice per group, 2-10106 cells/animal). Tumor growth is measured over 3 to 6 weeks using venier calipers. Tumor volumes are calculated as a product of lengthwidthheight unless otherwise indicated. P values are calculated using the Students t-test. Test compounds of Formula (I) in 50-100 L excipient (DMSO, or VPD:D5W) can be delivered by IP injection at different concentrations generally starting at day one after implantation. 1463 Tumor Invasion Model 1464 The following tumor invasion model has been developed and may be used for the evaluation of therapeutic value and efficacy of the compounds of Formula (I) identified to selectively inhibit KDR/FLK-1 receptor. 1465 Procedure 1466 Eight week old nude mice (female) (Simonsen Inc.) are used as experimental animals. Implantation of tumor cells can be performed in a laminar flow hood. For anesthesia, Xylazine/Ketamine Cocktail (100 mg/kg ketamine and 5 mg/kg Xylazine) are administered intraperitoneally. A midline incision is done to expose the abdominal cavity (approximately 1.5 cm in length) to inject 107 tumor cells in a volume of 100 l medium. The cells are injected either into the duodenal lobe of the pancreas or under the serosa of the colon. The peritoneum and muscles are closed with a 6-0 silk continuous suture and the skin is closed by using wound clips. Animals are observed daily. 1467 Analysis 1468 After 2-6 weeks, depending on gross observations of the animals, the mice are sacrificed, and the local tumor metastases to various organs (lung, liver, brain, stomach, spleen, heart, muscle) are excised and analyzed (measurement of tumor size, grade of invasion, immunochemistry, in situ hybridization determination, etc.). 1469 C-Kit Assay 1470 This assay is used to detect the level of c-kit tyrosine phosphorylation. 1471 MO7E (human acute myeloid leukemia) cells were serum starved overnight in 0.1% serum. Cells were pre-treated with the compound of Formula (I) (concurrent with serum starvation), prior to ligand stimulation. Cells were stimulated with 250 ng/ml rh-SCF for 15 minutes. Following stimulation, cells were lysed and immunoprecipitated with an anti-c-kit antibody. Phosphotyrosine and protein levels were determined by Western blotting. 1472 MTT Proliferation Assay 1473 MO7E cells were serum starved and pre-treated with a compound of Formula (I) as described for the phosphorylation experiments. Cells were plated 4105 cells/well in a 96 well dish, in 100 l RPMI10% serum. rh-SCF (100 ng/mL) was added and the plate was incubated for 48 hours. After 48 hours, 10 l of 5 mg/ml MTT 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide) was added and allowed to incubate for 4 hours. Acid isopropanol (100 l of 0.04N HCl in isopropanol) was added and the optical density was measured at a wavelength of 550 nm. 1474 Apoptosis Assay 1475 MO7E cells were incubated /SCF and /compound of Formula (I) in 10% FBS with rh-GM-CSF (10 ng/mL) and rh-IL-3 (10 ng/mL). Samples were assayed at 24 and 48 hours. To measure activated caspase-3, samples were washed with PBS and permeabilized with ice-cold 70% ethanol. The cells were then stained with PE-conjugated polyclonal rabbit anti-active caspase-3 and analyzed by FACS. To measure cleaved PARP, samples were lysed and analyzed by western blotting with an anti-PARP antibody. 1476 Additional Assays 1477 Additional assays which may be used to evaluate the compounds of Formula (I) include, without limitation, a bio-flk-1 assay, an EGF receptor-HER2 chimeric receptor assay in whole cells, a bio-src assay, a bio-lck assay and an assay measuring the phosphorylation function of raf. The protocols for each of these assays may be found in U.S. application Ser. No. 09/099,842, which is incorporated by reference, including any drawings, herein. 1478 Measurement of Cell Toxicity 1479 Therapeutic compounds should be more potent in inhibiting receptor tyrosine kinase activity than in exerting a cytotoxic effect. A measure of the effectiveness and cell toxicity of a compound can be obtained by determining the therapeutic index, i.e., IC50/LD50. IC50, the dose required to achieve 50% inhibition, can be measured using standard techniques such as those described herein. LD50, the dosage which results in 50% toxicity, can also be measured by standard techniques as well (Mossman, 1983, J. Immunol. Methods, 65:55-63), by measuring the amount of LDH released (Korzeniewski and Callewaert, 1983, J. Immunol. Methods, 64:313, Decker and Lohmann-Matthes, 1988, J. Immunol. Methods, 115:61), or by measuring the lethal dose in animal models. Compounds with a large therapeutic index are preferred. The therapeutic index should be greater than 2, preferably at least 10, more preferably at least 50. 1480 B. Example of Cellular Assay Results Using 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80). 1481 To confirm the potency of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) detected in biochemical assays (vide infra), the ability of said compound to inhibit ligand-dependent RTK phosphorylation was evaluated in cell-based assays using NIH-3T3 mouse cells engineered to overexpress Flk-1 or human PDGFRP. 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited VEGF-dependent Flk-1 tyrosine phosphorylation with an IC50 value of approximately 0.03 M. This value is similar to the 0.009 M Ki value determined for inhibition of Flk-1 by 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) determined in biochemical assays. This indicates that 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) readily penetrates into cells. Consistent with the biochemical data (vide infra) indicating that 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) had comparable activity against Flk-1 and PDGFR, it was also found that it inhibited PDGF-dependent receptor phosphorylation in cells with an IC50 value of approximately 0.03 M. The ability of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) to inhibit c-kit, a closely related RTK that binds stem cell factor (SCF), was determined using MO7E cells that express this receptor. In these cells, 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited SCF-dependent c-kit phosphorylation with an IC50 value of 0.01-0.1 M. This compound also inhibited SCF-stimulated c-kit phosphorylation in acute myeloid leukemia (AML) blasts isolated from the peripheral blood of patients. 1482 In addition to testing the ability of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) to inhibit ligand-dependent receptor phosphorylation in cells, its effect on ligand-dependent proliferative response of cells was also examined in vitro (see Table 4). In these studies, cells quiesced by overnight serum starvation were induced to undergo DNA synthesis upon addition of the appropriate mitogenic ligand. As shown in Table 3, 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited the PDGF-induced proliferation of NIH-3T3 cells overexpressing PDGFR or PDGFR with IC50 values 0.031 and 0.069 M, respectively, and the SCF-induced proliferation of MO7E cells with an IC50 value of 0.007 M. 5TABLE 3Bio-chemicalCellular IC50Ki1ReceptorLigand-dependentReceptor(M)Phosphorylation (M)Proliferation (M)Flk-1/KDR0.0090.0320.0043PDGFR0.0080.0340.0314PDGFRNDND0.0695FGFR0.83ND0.73c-kitND0.01-0.160.0076ND Not Determined 1Determined using recombinant enzyme 2Determined using serum-starved NIH-3T3 cells expressing Flk-1 3Determined using serum-starved HUVECs 4Determined using serum-starved NIH-3T3 cells expressing PDGFR 5Determined using serum-starved NIH-3T3 cells expressing PDGFR 6Determined using serum-starved MO7E cells

1483 As shown in Table 3, there is a general agreement between the biochemical and cellular activities of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) supporting the conclusion that this compound crosses cellular membranes. Further, it can be concluded that the cellular responses are a result of the activity of compound 80 against the indicated target. In contrast, when tested in the presence of complete growth medium in vitro, substantially higher concentrations of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) (>10 M) were required to inhibit the growth of a variety of human tumor cells (see Table 4). This indicates that the compound did not directly inhibit the growth of these cells at concentrations required to inhibit ligand-dependent receptor phosphorylation and cell proliferation. 6TABLE 4Cell LineOriginIC50 (M)LD50 (M)HT29Colon carcinoma1022A549Lung carcinoma9.522NCI-H460NSC lung carcinoma8.920SF767TGlioma7.914A431Epidermoid6.018carcinoma

1484 Briefly, the results shown in Table 4 were obtained by incubating cells for 48 hr in complete growth medium in the presence of serial dilutions 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide. At the end of the growth period, the relative number of cells was determined. IC50 values were calculated as the concentration of compound that inhibited the growth of cells by 50% relative to untreated cells. LD50 values were calculated as the concentration of compound that caused a 50% reduction in the number of cells relative to those at the start of the experiment. 1485 A more relevant cell-based assay in which to evaluate the anti-angiogenic potential of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) is the in vitro mitogenesis assay using human umbilical vein endothelial cells (HUVECs) as a model system for the endothelial cell proliferation critical to the angiogenic process. In this assay, a mitogenic response, measured as an increase in DNA synthesis, is induced in serum-starved HUVECs upon addition of VEGF or FGF. In these cells, 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited the VEGF- and FGF-induced mitogenic response in a dose-dependent manner with IC50 values of 0.004 M and 0.7 M, respectively, when compound was present throughout the 48-hr assay. 1486 Briefly, the aforementioned results were obtained using Serum-starved HUVECs that were incubated with mitogenic concentrations of VEGF (100 ng/ml) or FGF (30 ng/ml) in the presence of serial dilutions of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) for 24 hrs. The mitogenic response during the following 24 hrs. in the presence of ligand and inhibitor was quantitated by measurement of DNA synthesis based on incorporation of bromodeoxyunridine into cellular DNA. 1487 In separate experiments, compound 80 inhibited the VEGF-dependent phosphorylation of ERK 1/2 (p42/44MAP kinase), an early downstream target of Flk-1/KDR, in a dose-dependent manner. The inhibitory activity of compound 80 was also shown to be long-lasting in this system; inhibiting VEGF-dependent phosphorylation of ERK 1/2 for as long as 48 hours after removal of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) from the medium following a short (2 hr) exposure to micromolar concentrations of the compound. 1488 VEGF has been recognized to be an important survival factor for endothelial cells. Since 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibits the VEGF-dependent mitogenic response of HUVECs, the effect of the compound on HUVEC survival was investigated. In these experiments, cleavage of the caspase 3 substrate poly-ADP-ribosyl polymerase (PARP) was used as a readout for apoptosis. HUVECs cultured in serum-free conditions for 24 hours exhibited substantial levels of PARP cleavage, as detected by the accumulation of the 23 kDa PARP cleavage fragment. This was largely prevented by the addition of VEGF to the cell medium, indicating that VEGF acts as a survival factor in this assay. 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) has been shown to inhibit KDR signaling. Accordingly, 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited VEGF-mediated HUVEC survival in a dose-dependent manner. Thus, these data indicate that compound 80 induced apoptosis in endothelial cells in culture in the presence of VEGF. 1489 C. In vivo Efficacy Studies 1490 i. Efficacy Against Established Tumor Xenografts 1491 The in vivo efficacy of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) was studied in subcutaneous (SC) xenograft models using human tumor cells implanted into the hindflank region of athymic mice. Following implantation, tumors were allowed to become established to a size of 100550 mm3 prior to starting oral treatment with the compound. 1492 Daily oral administration of compound 80 caused a dose-dependent inhibition of A431 tumor growth when treatment was initiated after tumors had grown to a size of 400 mm3. Statistically significant (P<0.05) inhibition of tumor growth was seen at doses of 40 mg/kg/day (74% inhibition) and 80 mg/kg/day (84% inhibition) (see Table 6). In preliminary experiments, a higher (160 mg/kg/day) dose of the compound was not more efficacious against established A431 tumors than the 80 mg/kg/day dose. In addition, mice treated at the 160 mg/kg/day dose of the compound lost body weight, indicating that the higher dose was not as well tolerated. Similar results were obtained in an experiment in which A431 tumors were only allowed to reach 100 mm3 in size (see Table 4). In this second experiment, complete regression of the tumors occurred in six of the eight animals treated at the 80 mg/kg/day for 21 days. In these six animals, the tumors did not regrow during a 110-day observation period following the end of treatment. In the two animals in which the tumors regrew to a large size (2000-3000 mm3), the tumors regressed in response to a second round of treatment with compound 80. Importantly, in all efficacy experiments, 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) at 80 mg/kg/day has been well tolerated, even when dosed continuously for more than 100 days. 7TABLE 5Initial TumorCompound1% InhibitionVolume (mm3)(mg/kg/day)(day)P-Value4008084 (36)0.0014074 (36)0.0032051 (36)0.1301008093 (40)0.0024075 (40)0.0151061 (40)0.0591Compound 80.

1493 Briefly, the results shown in Table 5 were obtained using A431 cells (0.5106 cells/mouse) which were implanted SC into the hindflank region of athymic mice. Daily oral administration of 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) in a Cremophore-based vehicle or vehicle control began when tumors reached the indicated average volume. Tumors were measured using vernier calipers and tumor volume was calculated as the product of lengthwidthheight. P-values were calculated by comparing the size of the tumors for animals that were treated with compound 80 (n8) to those of animals that were treated with a vehicle (n16) on the last day of the experiment, using the two-tailed Student's t-test. 1494 The efficacy compound 80 against established human tumors of different origins was determined using Colo25 (colon carcinoma), SF763T (glioma), and NCI-H460 (non-small cell lung carcinoma) xenografts (see Table 6). These experiments were conducted using 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) administered orally at 80 mg/kg/day; a dose that was effective and well tolerated. 8TABLE 6Initial TumorVolume% InhibitionTumor Type(mm3)(day)P-ValueA4311Epidermoid10093 (40)0.002A4311Epidermoid40084 (36)0.001Colo205Colon37077 (54)0.028NCI-H460Lung30061 (54)0.003SF763TGlioma55053 (30)0.0011Data are from experiment reported in Table 5.

1495 In the abovementioned experiments, compound 80 was administered once daily at 80 mg/kg in a Cremophor-based vehicle once tumors reached the indicated size. Percent inhibition compared to the vehicle-treated control group was calculated at termination of the experiments. P-values were calculated by comparing tumor sizes of the animals that had been treated with the compound to tumor sizes of those animals that had been treated with the vehicle, using the two-tailed Student's t-test. 1496 Although 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (Compound 80) inhibited the growth of all the tumor types shown in Table 7, there was a difference in the response of the different xenograft models. Specifically, the growth of NCIH460 and SF763T tumors was arrested or greatly slowed whereas the Colo205 tumors, like A431 tumors, regressed when treated with 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide. 1497 In order to determine the molecular basis for the difference in response between xenograft models, the SF763T tumors were studied. Therefore, SF763T tumors, which were less responsive to treatment with 5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide, have been evaluated at the molecular level using immunohistological techniques to determine the effect of treatment with the compound. These studies were initially conducted in this tumor type because SF763T tumors are highly vascularized with microvessels that strongly express the endothelial cell marker CD31 and are hence well suited for studies of tumor microvessel density (MVD). Immunohistological evaluation of SF763T tumors indicated that tumors from treated animals had reduced MVD relative to vehicle-treated controls, consistent with an anti-angiogenic mechanism of action for compound 80; MVD was 24.24.1 in animals treated with compound 80, compared to 39.35.7 for those that were treated with just the vehicle. As anticipated from the associated tumor growth arrest, a pronounced inhibition of tumor cell proliferation was evident in tumors that were treated with compound 80. These tumors had half the mitotic index of those in vehicle-treated tumors (data not shown). The effect compound 80 on MVD and tumor cell proliferation indicates that the compound has profound anti-angiogenic and anti-tumor effects, even under conditions in which tumors do not regress. 1498 The ability of compound 80 to inhibit PDGFR phosphorylation and subsequent signaling in vivo was also evaluated in the SF763T tumors, which express high levels of PDGFR. Treatment of the SF763T tumors with compound 80 strongly inhibited PDGFR tyrosine phosphorylation in established SF763T tumors. Compound 80 also reduced the levels of phosphorylated (activated) phospholipase C gamma (PLC-), an immediate downstream indicator of PDGFR activation. These data demonstrate that oral administration of compound 80 causes a direct effect on target (PDGFR) activity in tumors in vivo. 1499 Based on the demonstration that the ability of compound 80 to inhibit VEGF-dependent signaling in HUVECs in vitro was long-lasting (vide supra), the efficacy of the compound was evaluated when the compound was administered infrequently in the Colo205 tumor model. As shown in Table 7, 80 mg/kg (91% inhibition) and 40 mg/kg (84% inhibition) were efficacious when administered daily, but not when administered twice weekly. In contrast, a higher dose of compound 80 (160 mg/kg) did inhibit (52% inhibition) the growth of established Colo205 tumors when administered twice weekly, suggesting that this compound can demonstrate efficacy when administered infrequently at a higher dose. It should be noted that dosing regimens may be determined by those with ordinary skill in the art without undue experimentation. 9TABLE 7Dose(mg/kg)Frequency% InhibitionP-Value160Twice weekly520.085Once weekly17NS80Daily910.039Twice weekly19NSOnce weekly0NS40Daily840.028Twice weekly36NSNS: not significant (P > 0.05)

1500 Briefly, the results shown in Table 7 were obtained using Colo205 cells (0.5106 cells/mouse) that had been implanted SC into the hindflank region of athymic mice. Oral administration of compound 80 according to the indicated schedule began when tumors reached 400 mm3. Tumors were measured using vernier calipers and tumor volume was calculated as the product of lengthwidthheight. P-values were calculated by comparing the size of the tumors for animals that were treated with compound 80 to those of animals that were treated with a vehicle on the last day of the experiment, using the two-tailed Student's t-test. 1501 ii. Efficacy of Compound 80 in a Model of Disseminated Disease 1502 In addition to supporting the sustained growth of solid primary tumors, angiogenesis is also an essential component supporting the development of disseminated disease due to metastasis from the primary tumor. The effect of compound 80 on the development of disseminated disease was examined in the B16-F1 mouse melanoma lung colonization model. In this model, B16-F1 cells inoculated intravenously via the tail vein of athymic mice colonize the lungs and form tumors. As shown in Table 7, oral administration of compound 80 at 80 mg/kg/day effectively reduced the burden of B16-F1 cells in the lung as evaluated by measurements of total lung weight. These data suggest that compound 80 can inhibit disseminated disease in vivo. 10TABLE 8Lung Weight (g)% InhibitionP-ValueVehicle0.83 0.07Compound10.41 0.0450<0.0011Compound 80

1503 Briefly, the results shown in Table 8 were obtained using athymic mice that had been inoculated with B16-F1 tumor cells (5105 cells/mouse) via the tail vein. Mice were treated daily with orally administered compound 80 at 80 mg/kg/day (n10) or vehicle (n18) for 24 days after tumor cell inoculation. At the end of the treatment period, the mice were sacrificed and their lungs removed and weighed. Percent inhibition was calculated by comparing the lung weight of those animals that had been treated with compound 80, with the lung weight of the animals that had only been treated with vehicle. P-values were determined using the two-tailed Student's t-test. 1504 II. COX-2 Inhibitors 1505 The ability of COX-2 inhibitors to retard the growth of tumors was tested using the Lewis Lung Model described below. 1506 Mice were injected subcutaneously in the left paw (1106 tumor cells suspended in 30% Matrigel) and tumor volume was evaluated using a phlethysmometer twice a week for 30-60 days. Blood was drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data are expressed as the mean/SEM. Student's and Mann-Whitney tests were used to assess differences between means using the InStat software package. Celecoxib given in the diet at doses between 160-3200 ppm retarded the growth of these tumors. The inhibitory effect of celecoxib was dose-dependent and ranged from 48% to 85% as compared with the control tumors. Analysis of lung metastasis was done in all the animals by counting metastasis in a stereomicroscope and by histochemical analysis of consecutive lung sections. Celecoxib did not affect lung metastasis at the lower dose of 160 ppm, however surface metastasis was reduced by more than 50% when given at doses between 480-3200 ppm. In addition, histopathological analysis revealed that celecoxib dose-dependently reduced the size of the metastasic lesions in the lung. 1507 2. HT-29 Model: 1508 Mice were injected subcutaneously in the left paw (1106 tumor cells suspended in 30% Matrigel) and tumor volume was evaluated using a phlethysmometer twice a week for 30-60 days. Implantation of human colon cancer cells (HT-29) into nude mice produces tumors that will reach 0.6-2 ml between 30-50 days. Blood was drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data are expressed as the mean/SEM. Student's and Mann-Whitney tests were used to assess differences between means using the InStat software package. 1509 A. Mice injected with HT-29 cancer cells were treated with cytoxin i.p at doses of 50 mg/kg on days 5,7 and 9 in the presence or absence of celecoxib in the diet. The efficacy of both agents were determined by measuring tumor volume. Treatment using a celecoxib related COX-2 inhibitor (SC-58236) reduced tumor volume by 89%. In the same assay, indomethacin given at near the maximum tolerated dose of 2 mg/kg/day in the drinking water inhibited tumor formation by 77%. Moreover, the COX-2 selective inhibitor completely inhibited the formation of lung metastasis while the non-selective NSAID indomethacin was ineffective. The results from these studies demonstrate that celecoxib administered in the diet to tumor bearing mice can delay the growth of tumors and metastasis when administered as sole therapy. Moreover, a positive benefit is observed when celecoxib is administered in combination with a cytotoxic agent such as cyclophosphamide. 1510 B. In a second assay, mice injected with HT-29 colon cancer cells were treated with celecoxib (10, 40 or 160 ppm) in the diet beginning at day 10. An approximate dose dependent effect was observed. (Table 9). 11TABLE 9Celecoxib Inhibitis HT-29 Human Colon CarcinomaDaysvehicle10 ppm40 ppm160 ppm140.1140.1240.1250.120220.250.250.190.14280.450.360.270.21350.790.570.40.3421.380.890.680.49501.91.491.040.8Volume (ml)

1511 III. In vivo Assays Using Protein Kinases in Combination with a Cyclooxygenase-2 Selective Inhibitor for Treating Cancer. 1512 The ability of a protein kinase inhibitor to retard the growth of tumors in combination with a COX-2 selective inhibitor can be tested in 1483 xenograft model described below. 1513 1483 xenograft is an animal xenograft that models human epithelial cancers expressing cyclooxgenase-2 (COX-2) in the tumor cells and in the vasculature. 1514 A human tumor xenograft nude mouse model of head and neck squamous cell carcinoma (1483 cell line) that expresses COX-2 in the tumor cells and in the vascularture, similar to human epithelial cancers. We believe this model represents human epithelial cancers and would be a good model to correlate efficacy of anti-cancer drugs including COX-2 inhibitors to efficacy in humans. 1515 Materials and Methods: 1516 Cell Culture: 1517 1483 human head and neck squamous cell carcinoma (HNSCC) cells are stored in frozen vials containing 3106 cells, 90% fetal bovine serum (FBS) and 10% dimethyl sulfoxide (DMSO). Take a frozen vial and quickly thaw at 37 C. and placed in a T-162 cm2 (Corning) flask containing D-MEM/F12 media (GibcoBRL) with 15 mM Hepes buffer, L-glutamine, pyridoxine hydrochloride and 10% FBS. Cells are grown in an incubator with 5% CO2 and temperature at 37 C. Media is changed every other day and cells are passed when at 80-90% confluence. For passing of cells, wash flask with 10 ml of phosphate buffered saline (PBS), aspirate off and add 2 ml of trypsin/EDTA (0.25% 1 mM, GibcoBRL) place back in incubator, after 5 min., cells will detach. Add 8 ml of above media to flask rinse and transfer to a sterile 50 ml centrifuge tube. Add 30 ml more of media and mix and count cells using a hemacytometer, plate out cells in a T-162 cm containing 3-4106 cells. 1518 1483 Animal Model: 1519 Change media 24 hours before harvest of 1483 cells before injection in to nude mice. Trypsinize 1483 cells as described above in cell culture section. Count cells and determine number of cells. Centrifuge cells down at 1000 rpm for 5 minutes at room temperature. Resuspened cell pellets and pool them (if multiple 50 ml centrifuge tubes) into one 50 ml centrifuge tube with Hank's buffered saline solution (HBSS, GibcoBRL) and centrifuge as before. You will want to have about 25% more cells then what you really need for injection to have extra cells. If you are injecting 72 mice and you have 100106 cells, prepare all the cells for injecting into mice. Inject 1483 cells at 1106 cells in 0.03 ml/mouse. 1520 Inject cells with 30% Matrigel (Collaborative Biomedical Products) and 70% HBSS. Resuspend pooled pellet with 2.1 ml (70%) of cold HBSS then add 0.9 ml (30%) of thawed liquefied cold Matrigel and mix well on ice. Keep this cell preparation on ice at all times prior to injecting into mice. Male nude mice age 4-6 weeks old are used in these studies (Harlen). Anesthetize the mice using CO2/O2 gas and then inject them in the middle of the right hind paw using a 0.5 cc tuberculin syringe (Beckerson & Dickerson). Weigh the mice for body weight on day of injection (Day 0) for baseline weight for start of study. Weigh the mice on day 7 and measure the right hind paw for paw tumor volume using a plethysmometer (Stoelting Co.). The plethysmometer is a machine that measure paw volume by water displacement. Measure a few left non-injected paws and average for a background measurement to subtract from the right tumor bearing paw. 1521 Place the animals on test compounds in chow meal when tumors are 100-200 ul in size and continue on compound meal throughout study. Some mice are given only a protein kinase inhibitor or a cyclooxygenase-2 selective inhibitor. Some mice are given both a protein kinase inhibitor and a cyclooxygenase-2 selective inhibitor daily at a suitable dose determined based on the in vitro assay results. 1522 Weigh and measure the mice throughout the study on days 7, 10, 14, 17, 21, 24 and 28. Animals can be started on compound treatment on day 0 (prophylactic) or once there is an established tumor around day 7 (therapeutic). Around day 30 vehicle (control) mice will have large tumors (1.0-1.5 ml) and start to lose weight, at this time terminate the vehicle animals. If tumor inhibition is seen in treated groups and they are in good health, euthanize half of the treated groups and keep half of the treated group alive to determine the delay in tumor growth. 1523 One skilled in the art would also readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent herein. The molecular complexes and the methods, procedures, treatments, molecules, specific compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention are defined by the scope of the claims. 1524 It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. 1525 All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. 1526 This application claims priority to U.S. Serial No. 60/312,413, filed Aug. 15, 2001, which is hereby incorporated by reference in its entirety.