CROSS-REFERENCE INFORMATION 0001 This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application Serial No. 60/182,710, filed Feb. 15, 2000, No. 60/216,422 filed on Jul. 6, 2000 and Serial No. 60/243,532, filed Oct. 27, 2000, the disclosures of which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION 0002 1. Field of Invention 0003 The present invention relates to certain 3-pyrrole 150 substituted 2-indolinone compounds which modulate the activity of protein kinases (PKs). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed. 0004 2. State of the Art 0005 The following is offered as background information only and is not admitted to be prior art to the present invention. 0006 PKs are enzymes that catalyze the phosphorylation of, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer) 0007 The PKs can be conveniently broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). 0008 One of the prime aspects of PTK activity is their involvement with growth factor receptors. Growth factor receptors are cell-surface proteins. When bound by a growth factor ligand, growth factor receptors are converted to an active form which interacts with proteins on the inner surface of a cell membrane. This leads to phosphorylation on tyrosine, residues of the receptor and other proteins and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules that, in turn, effect numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects the extracellular microenvironment, etc. For a more complete discussion, see Schletssinger and Ullrich, Neuron, 9:303-391 (1992) which is incorporated by reference, including any drawings, as if fully set forth herein. 0009 Growth factor receptors with PTK activity are known as receptor tyrosine kinases (RTKs). They comprise a large family of transmembrane receptors with diverse biological activity. At present, at least nineteen (19) distinct subfamilies of RTKs have been identified. An example of these is the subfamily designated the HER RTKs, which include EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. These RTKs consist of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues on proteins. 0010 Another RTK subfamily consists of insulin receptor (1R), insulin-like growth factor I receptor:(IGF-1R) and insulin * receptor related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two entirely extracellular glycosylated subunits and two subunits which cross the cell membrane and which contain the tyrosine kinase domain. 0011 A third RTK subfamily is referred to as the platelet derived growth factor receptor (PDGFR) group, which includes PDGFR, PDGFR, CSFIR, c-kit and c-fms. These receptors consist of glycosylated extracellular domains composed of variable numbers of immunoglobin-like loops and an intracellular domain wherein the tyrosine kinase domain is interrupted by unrelated amino acid sequences. 0012 Another group which, because of its similarity to the PDGFR subfamily, is sometimes subsumed into the later group is the fetus liver kinase (flk) receptor subfamily. This group is believed to be made up of kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGF-R2), flk-1R, flk-4 and fms-like tyrosine kinase 1 (flt-1). 0013 A further member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor (FGF) receptor subgroup. This group consists of four receptors, FGFR1-4, and seven ligands, FGF1-7. While not yet well defined, it appears that the receptors consist of a glycosylated extracellular domain containing a variable number of immunoglobin-like loops and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of unrelated amino acid sequences. 0014 Still another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor (VEGF) receptor subgroup. VEGF is a dimeric glycoprotein similar to PDGF but has different biological functions and target cell specificity in vivo. In particular, VEGF is presently thought to play an essential role is vasculogenesis and angiogenesis. 0015 A more complete listing of the known RTK subfamilies is described in Plowman et al., DN&P, 7(6):334-339 (1994) which is incorporated by reference, including any drawings, as if fully set forth herein. 0016 In addition to the RTKs, there also exists a family of entirely intracellular PTKs called non-receptor tyrosine kinases or cellular tyrosine kinases. This latter designation, abbreviated CTK, will be used herein. CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Src subfamily appear so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 8:2025-2031 (1993), which is incorporated by reference, including any drawings, as if fully set forth herein. 0017 The serine/threonine kinases, STKs, like the CTKs, are predominantly intracellular although there are a few receptor kinases of the STK type. STKs are the most common of the cytosolic kinases; i.e., kinases that perform their function in that part of the cytoplasm other than the cytoplasmic organelles and cytoskelton. The cytosol is the region within the cell where much of the cell's intermediary metabolic and biosynthetic activity occurs; e.g., it is in the cytosol that proteins are synthesized on ribosomes. 0018 RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including, significantly, cancer. Other pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, immunological disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis and a variety of renal disorders. 0019 With regard to cancer, two of the major hypotheses advanced to explain the excessive cellular proliferation that drives tumor development relate to functions known to be PK regulated. That is, it has been suggested that malignant cell growth results from a breakdown in the mechanisms that control cell division and/or differentiation. It has been shown that the protein products of a number of proto-oncogenes are involved in the signal transduction pathways that regulate cell growth and differentiation. These protein products of proto-oncogenes include the extracellular growth factors, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs,(CTKs) and cytosolic STKs, discussed above. 0020 In view of the apparent link between PK-related cellular activities and wide variety of human disorders, it is no surprise that a great deal of effort is being expended in an attempt to identify ways to modulate PK activity. Some of this effort has involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (App. No. WO 94/10202, Kendall and Thomas, Proc. Nat'l Acad. Sci., 90:10705-09 (1994), Kim, et al., Nature, 362:841-844 (1993)); RNA ligands (Jelinek, et al., Biochemistry, 33:10450-56); Takano, et al., Mol. Bio. Cell 4:358A (1993); Kinsella, et al., Exp. Cell Res. 199:56-62 (1992); Wright, et al., J. Cellular Phys., 152:448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al., Proc. Am. Assoc. Cancer Res., 35:2268 (1994)). 0021 In addition to the above, attempts have been made to identify small molecules which act as PK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (PCT WO 92/20642), vinyleneazaindole derivatives (PCT WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have been described as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), quinazoline derivatives (EP App. No.0 566 266 A1), selenaindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) have all been described as PTK inhibitors useful in the treatment of cancer.

SUMMARY OF THE INVENTION 0022 The present invention is directed to certain 3-pyrrole substituted 2-indolinone compounds which exhibit PK modulating ability and are therefore useful in treating disorders related to abnormal PK activity. 0023 Accordingly, in one aspect, the present invention relates to 3-pyrrole substituted 2-indolinones of Formula (I): 1

0024 wherein: 0025 R1 is selected from the group consisting of hydrogen, halo, alkyl, cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, (CO)R15, NR13R14, (CH2)rR16 and C(O)NR8R9; 0026 R2 is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, cyano, NR13R14, NR13C(O)R14, C(O)R15, aryl, heteroaryl, S(O)2NR13R14 and SO2R20 (wherein R20 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl); 0027 R3 is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, (CO)R15, NR13R14, aryl, heteroaryl, S(O)2NR13R14, NR13C(O)R14, 0028 NR13C(O)OR14 and SO2R20 (wherein R20 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl); 0029 R4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, and NR13R14; 0030 R5 is selected from the group consisting of hydrogen, alkyl and C(O)R10, 0031 R6 is selected from the group consisting of hydrogen, alkyl and C(O)R10. 0032 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R17 and C(O)R10; or 0033 R6 and R7 may combine to form a group, selected from the group consisting of (CH2)4, (CH2)5 and (CH2)6; 0034 with the proviso that at least one of R5, R6 or R7 must be: 0035 R8 and R9 are independently selected from the group consisting of hydrogen, alkyl and aryl; 0036 R10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, N(R11)(CH2)nR12, and NR13R14, 0037 R11 is selected from the group consisting of hydrogen and alkyl; 0038 R12 is selected from the group consisting of NR13R14, hydroxy, C(O)R15, aryl, heteroaryl, N(O)R13R14, N(OH)R13, and NHC(O)Ra (wherein Ra is unsubstituted alkyl, haloalkyl, or aralkyl); 0039 R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or 0040 R13 and R14 may combine to form a heterocyclo group; 0041 R15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy; 0042 R16 is selected from the group consisting of hydroxy, C(O)R15, NR13R14 and C(O)NR13R14; 0043 R17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; 0044 R20 is alkyl, aryl, aralkyl or heteroaryl; and 0045 n and r are independently 1, 2, 3, or 4; 0046 or a pharmaceutically acceptable salt thereof. 0047 Preferably, R1 is selected from the group consisting of hydrogen, halo, alkyl, cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, C(O)R15, NR13R14, (CH2)rR16 and C(O)NR8R9; 0048 R2 is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl hydroxy, alkoxy, NR13R14, NR13C(O)R14, C(O)R15 aryl, heteroaryl, and S(O)2NR13R14; 0049 R3 is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, (CO)R15, NR13R14, aryl, heteroaryl, NR13S(O)2R14, S(O)2NR13R14, 0050 R4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and NR13R14; 0051 R5 is selected from the group consisting of hydrogen, alkyl and C(O)R10; 0052 R6 is selected from the group consisting of hydrogen, alkyl and C(O)R10; 0053 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R17 and C(O)R10; 0054 R6 and R7 may combine to form a group selected from the group consisting of (CH2)4, (CH2)5 and (CH2)6; 0055 with the proviso that at least one of R5, R6 or R7 must be C(O)R10; 0056 R8 and R9 are independently selected from the group consisting of hydrogen, alkyl and aryl; 0057 R10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, N(R11)(CH2)nR12 and NR13R14; 0058 R11 is selected from the group consisting of hydrogen and alkyl; 0059 R12 is selected from the group consisting of NR13R14, hydroxy, C(O)R15, aryl and heteroaryl; 0060 R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; 0061 R13 and R14 may combine to form a group selected from the group consisting of (CH2)4, (CH2)5, (CH2)2O(CH2)2, and (CH2)2N(CH3)(CH2)2; 0062 R15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy; 0063 R16 is selected from the group consisting of hydroxy, C(O)R15, NR13R14 and C(O)NR13R14; 0064 R17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; and 0065 n and r are independently 1, 2, 3, or 4; 0066 or a pharmaceutically acceptable salt thereof. 0067 In a second aspect this invention is directed to a pharmaceutical composition comprising one or more compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 0068 In a third aspect, this invention is directed to a method of treating diseases mediated by abnormal protein kinase activity, in particular, receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), in an organism, in particular humans, which method comprises administering to said organism a pharmaceutical composition comprising a compound of Formula (I). Such diseases include by way of example and not limitation, cancer, diabetes, hepatic cirrhosis, cardiovasacular disease such as atherosclerosis, angiogenesis, immunological disease such as autoimmune disease and renal disease. 0069 In a fourth aspect, this invention is directed to a method of modulating of the catalytic activity of PKs, in particular, receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), using a compound of this invention which may be carried out in vitro or in vivo. In particular, the receptor protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR, PDGFR, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. The cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf. 0070 In a fifth aspect, this invention is directed to the use of a compound of Formula (I) in the preparation of a medicament which is useful in the treatment of a disease mediated by abnormal PK activity. 0071 In a sixth aspect, this invention is directed to an intermediate of Formula (II) 2

0072 wherein: 0073 R5 is selected from the group consisting of hydrogen, alkyl and C(O)R10; 0074 R6 is selected from the group consisting of hydrogen, alkyl and C(O)R10; 0075 R7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R17 and C(O)R10; 0076 R6 and R7 may combine to form a group selected from the group consisting of (CH2)4, (CH2)5 and (CH2)6; 0077 with the proviso that at least one of R5, R6 or R7 must be C(O)R10; 0078 R10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, N(R11)(CH2)nR12 and NR13R14; 0079 R11 is selected from the group consisting of hydrogen and alkyl; 0080 R12 is selected from the group consisting of, NR13R14, hydroxy, C(O)R15 aryl and heteroaryl; 0081 R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or 0082 R13 and R14 may combine to form a heterocyclo group; 0083 R15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy; 0084 R17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; and 0085 n is 1, 2, 3, or 4. 0086 Preferaby, R5 or R6, in the compound of formula II, is C(O)R10; 0087 R6 is selected from the group consisting of hydrogen, and alkyl more preferably hydrogen or methyl; 0088 R5 is selected from the group consisting of hydrogen, and alkyl, more preferably hydrogen or methyl when R6 is COR10; 0089 R6 is selected from the group consisting of hydrogen, and alkyl, more preferably hydrogen or methyl when R5 is COR10; 0090 R7 is selected from the group consisting of hydrogen, alkyl, and aryl, more preferably hydrogen, methyl or phenyl; 0091 R10 is selected from the group consisting of hydroxy, alkoxy, N(R11)(CH2)nR12 and NR13R14; 0092 R11 is selected from the group consisting of hydrogen and alkyl, more preferably hydrogen or methyl; 0093 R12 is selected from the group consisting of NR13R14; 0094 R13 and R14 are independently selected from the group, consisting of hydrogen, or alkyl; or 0095 R13 and R14 may combine to form a heterocyclo group; and 0096 n is 1, 2 or 3. 0097 Within the above preferred groups, more preferred groups of intermediate compounds are those wherein R5, R6, R11, R12, R13 or R14 are independently groups described in the section titled preferred embodiments herein below. 0098 In a seventh aspect, this invention is directed to methods of preparing compounds of Formula (I). 0099 Lastly, this invention is also directed to identifying a chemical compound that modulates the catalytic activity of a protein kinase by contacting cells expressing said-protein kinase with a compound or a salt of the present invention and then monitoring said cells for an effect.

DETAILED DESCRIPTION OF THE INVENTION

Definitions 0100 Unless otherwise stated the following terms used in the specification and claims have the meanings discussed below: 0101 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). 0102 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 unsubstituted 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. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably 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, unsubstituted lower alkoxy, aryl optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, mercapto, (unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl, trihalomethyl, unsubstituted (C3-C6)cycloalkyl, unsubstituted lower alkenyl, unsubstituted 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, unsubstituted lower alkyl or unsubstituted lower alkoxy groups. 0103 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, or NR18R19, wherein R18 and R19 are independently selected from the group consisting of hydrogen, unsubstituted 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. 0104 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. 0105 Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, more preferably one or two substituents, independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, unsubstituted lower alkyl or unsubstituted 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, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, mercapto, (unsubstituted lower alkyl)thio, arylthio optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted 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. 0106 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. 0107 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. 0108 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 unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted 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, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0109 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 unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted 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, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0110 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 bed 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 unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted 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, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0111 Preferably, the heteroalicyclic group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido. 0112 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, unsubstituted lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, mono or dialkylamino. 0113 Hydroxy refers to an OH group. 0114 Alkoxy refers to both an O-(unsubstituted alkyl) and an O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. 0115 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. 0116 Mercapto refers to an SH group. 0117 Alkylthio refers to both an S-(unsubstituted alkyl) and an S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, e.g., methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. 0118 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. 0119 Acyl refers to a C(O)R group, where R is selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, unsubstituted 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 unsubstituted lower alkyl; trihaloalkyl, unsubstituted 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 unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and NR18R19 groups. Representative acy groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like 0120 Aldehyde refers to an acyl group in which R is hydrogen. 0121 Thioacyl refers to a C(S)R group, with R as defined herein. 0122 Ester refers to a C(O)OR group with R as defined herein except that R cannot be hydrogen. 0123 Acetyl group refers to a C(O)CH3 group. 0124 Halo group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. 0125 Trihalomethyl group refers to a CX3 group wherein X is a halo group as defined herein. 0126 Trihalomethanesulfonyl group refers to a X3CS(O)2 groups with X as defined above. 0127 Cyano refers to a CN group. 0128 Methylenedioxy refers to a OCH2O group where the two oxygen atoms are bonded to adjacent carbon atoms. 0129 Ethylenedioxy group refers to a OCH2CH2O where the two oxygen atoms are bonded to adjacent carbon atoms. 0130 S-sulfonamido refers to a S(O)2NR18R19 group, with R18 and R19 as defined herein. 0131 N-sulfonamidol refers to a NR18S(O)2R19 group, with R18 and R19 as defined herein. 0132 O-carbamyl group refers to a OC(O)NR18R19 group with R18 and R19 as defined herein. 0133 N-carbamyl refers to an R18OC(O)NR19 group, with R18 and R19 as defined herein. 0134 O-thiocarbamyl refers to a OC(S)NR18R19 group with R18 and R19 as defined herein. 0135 N-thiocarbamyl refers to a R18OC(S)NR19 group, with R18 and R19 as defined herein. 0136 Amino refers to an NR18R19 group, wherein R18 and R19 are both hydrogen. 0137 C-amido refers to a C(O)NR18R group with R18 and R19 as defined herein. 0138 N-amido refers to a R18C(O)NR19 group, with R18 and R19 as defined herein. 0139 Nitro refers to a, NO2 group. 0140 Haloalkyl means an unsubstituted alkyl, preferably unsubstituted 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. 0141 Aralkyl means unsubstituted alkyl, preferably unsubstituted 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. 0142 Heteroaralkyl group means unsubstituted alkyl, preferably unsubstituted 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. 0143 Monoalkylamino means a radical NHR where R is an unsubstitued alkyl or unsubstituted cycloalkyl group as defined above, e.g., methylamino, (1-methylethyl)amino, cyclohexylamino, and the like. 0144 Dialkylamino means a radical NRR where each R is independently an unsubstitued alkyl or unsubstituted cycloalkyl group as defined above, e.g., dimethylamino, diethylamino, (1-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like. 0145 Cyanoalkyl means unsubstituted alkyl, preferably unsubstituted lower alkyl as defined above, which is substituted with 1 or 2 cyano groups. 0146 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. 0147 The terms 2-indolinone, indolin-2-one and 2-oxindole are used interchangeably herein to refer to a molecule having the chemical structure: 3

0148 The term pyrrole refers to a molecule having the chemical structure: 4

0149 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). 0150 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. 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. 0151 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 them 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 stereoisomers 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). 0152 The compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds 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. 0153 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. 0154 The compound of Formula (I) 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. 0155 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 X 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. 0156 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. 0157 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. 0158 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. 0159 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: 0160 (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 0161 (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 an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. 0162 PK refers to receptor protein tyrosine kinase (RTKs), non-receptor or cellular tyrosine kinase (CTKs) and serine-threonine kinases (STKs). 0163 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. 0164 Modulation or modulating refers to the alteration of the catalytic activity of RTKs, CTKs and STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs. 0165 Catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs. 0166 Contacting refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such contacting can be accomplished in vitro, i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques. 0167 In vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium. 0168 In vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit. 0169 PK related disorder, PK driven disorder, and abnormal PK activity all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or, growth. Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases. 0170 Treat, treating and treatment refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or, its attendant symptoms. 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 will be reduced. 0171 Organism refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being. 0172 Therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of: * 0173 (1) reducing the size of the tumor; 0174 (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; 0175 (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, 0176 (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer. 0177 Monitoring means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well-known in the art. 0178 The above-referenced effect is selected from a change or an absence of change in a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention. 0179 Cell phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art. 0180 Natural binding partner refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction. 0181 Representative compounds of the present invention are shown in Table I below. 1TABLE 1Ex-am-pleStructureName1

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-dihydro- indol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid 3

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

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

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

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

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

5-(5-Bromo-2-oxo-1,2-dihydro- indol-3-ylidenemethyl)-1H-pyrrole-2- caboxylic acid (2-diethylaminoelhyl)amide 9

5-(2-Oxo-6-phenyl-1,2-dihydro- indol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethytaminoethyl)amide 10

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

5-(2-Oxo-6-phenyl-1,2-dihydro- indol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (2-diethylaminoetliyI)methylamide 12

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

5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2- carboxylic acid (3-diethylamsnopropyl)amide 14

3-Methyl-5-(2-oxo-6-phenyl-1,2-dihydro- indol-3-ylidenemethyl)-1H-pyrrole-2- carboxylic acid (3-diethylaminapropyt)amide 15

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

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

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

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

3-(5-Bromo-2-oxo-1,2-dihydro- indol-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-dihydro- indol-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-dihydro- indol-3-ylidenemethyl)-3-methyl- 1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide 22

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

5-(5-Bromo-2-oxo-1,2-dihydro- indol-3-ylidenenethyl)-2-isopropyl-4-phenyl- 1H-pyrrole-3-carboxylic acid 41

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

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

5-6-(2-Metoxy-phenyl)-2-oxo-1,2-dihydro- indol-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-dihydro- indol-3-ylidenemethyl)-2-methyl-phenyl-1H- pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 45

5-6-(2-Methoxy-phenyl)-2-oxo-1,2-dihydro- indol-3-ylidenemethyl-2-methyl- 4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethylamide 46

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

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

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

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

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

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

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

5-(5-Bromo-2-oxo-1,2-dihydro- indol-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-dihydro- indol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide 55

5-6-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro- indol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethylamide 56

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

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

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

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

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

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

56-(3,5-Dichloro-phenyl)-2-oxo-1,2-dihydro- indol-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-dihydro- indol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 64

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

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

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

2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydro- indol-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-dihydro- indol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrol-3-carboxylic acid(3-diethylaminopropyl)amide 71

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

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

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

5-(5-Bromo-2-oxo-1,2-dihydro- indol-3-ylidenemethyl)-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (pyridin-4-yl-methyl)amide 75

5-6-(4-Butyl-phenyl)-2-oxo-1,2-dihydro- indol-3-ylidenemethyl-2,34-dimethyl- 1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethylene)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-ethylamide 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-dihydro- indol-3-yldenemethyl-2,4- dimetyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide 79

5-6-(3-Isopropyl-phenyl)-2-oxo-1,2-dihydro- indol-3-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrridine-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-diethylamninoethylcabamoyl)-3,5- dimethyl-1H-pyrrol-2-ylmethylene- 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid 82

5-(5-Dimethylsurfamoyl-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-dihydro- indol-3-ylidenemethyl-2,4-dimethyl-1H- pyrrola-3-carboxylic acid (2-pyrrolidin-1-yl-ethylamide 84

2,4-Dimethyl-5-2-oxo-5-(pyridin-3-ylsulfamoyl)- 1,2-dihydroindol-3-yldienemethyl-1H-pyrrole-3-carboxy acid (2-pyridin-1-yl-ethylamide 85

3-3,5-Dimethyl-4-(4-methyl-piperazine-1-cabonyl)-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-dihy- droindol-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-ylidenenethyl)- 4,5,6,7-tetrahydro-2H-isoindole-1- carboxylic acid ethyl ester 95

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

100

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

101

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

102

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

103

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

104

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

105

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

106

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

107

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

108

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

109

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

110

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

111

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

112

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

113

3-3-(Morpholine-4-carbonyl)-4,5,8,7-tetrahydro-2H-iso- indol-1-ylmethylene-2-oxo-2,3-dihydro-1H- indole-6-carboxylic acid 110

114

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

115

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

116

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

117

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

118

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

119

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

120

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

121

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

122

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

123

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

124

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

125

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

126

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

127

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

128

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

129

2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5- methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 126

130

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

131

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

132

2,4-Dimethyl-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

133

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

134

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

135

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

136

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)- amide371 M 1 133

137

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

138

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

139

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

140

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

141

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

142

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

143

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

144

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

145

Trifluoro-acetate-2-(5-5-bromo- 2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-1H- pyrrole-3-carbonyl)-amino)- ethyl-2-oxo-piperazin-1-ium;486 M 1488 M 1 142

146

5-5-Cyano-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl-2,4-dimethyl-1H pyrrole-3-carboxylic acid3-(2-oxo- pyrrolidin-1-yl)-propyl-amide430 M 1 143

147

5-5-Bromo-2-oxo-1,2-dihydro-indol- (3Z)- ylidenemethyl-2,4-dimethyl-1H pyrrole-3-carboxylic acid 2-(2-oxo-imidazolin-1-yl)-ethyl-amide470 M 1472 M 1488 M 1 144

148

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

149

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

150

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

151

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

152

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

153

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

154

4-2-(5-5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 2,4-dimethyl-1H-pyrrole-3-carbonylamino)-ethyl-piperazin-1- yl-acetic acid ethyl ester514 M 1 153

155

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

156

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

157

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

158

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

159

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

160

5-5-Cyano-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide460 M 1 156

161

5-5-Bromo-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid 3-(2-oxo-azepan-1-yl)- propyl-amide443 M 1445 M 1 160

162

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

163

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

164

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

165

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

166

5-(5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid2-(2-cyanoethylamino)-ethyl-amide410 M 1456 M 1 165

167

5-5-Fluoro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1394 M 1 166

168

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1376 M 1 167

169

5-5-Cyano-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1401 M 1 168

170

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

171

5-5-Fluoro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1424 M 1 169

172

5-5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1440 M 1 170

173

5-5-Bromo-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid 2-(2-cyanoethylamino)-ethyl-amide454 M 1484 M 1486 M 1 171

174

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

175

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

176

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

177

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

178

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

179

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid3- (4-methyl-piperazin-1-yl-propyl- amide422 M 1 177

180

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid3-(4-methyl-piperazin-1-yl)- propyl-amide438 M 1 178

181

5-5-Chloro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid3-(4-methyl-piperazin-1-yl)- propyl-amide454 M 1 179

182

5-5-Bromo-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid3-(4-methyl-piperazin-1-yl)- propyl-amide498 M 1500 M 1 180

183

2,4-Dimethyl-5-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl- 1H-pyrrole-3-carboxylic acid2- (4-benzyl-piperazin-1-yl)-ethyl- amide482 M 1 181

184

5-5-Fluoro-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid2-(4-benzyl-piperazin-1-yl)- ethyl-amide500 M 1 182

185

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

186

5-5-Bromo-2-oxo-1,2-dihydro- indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid2-(4-benzyl-piperazin-1-yl)- ethyl-amide560 M 1562 M 1 184

187

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

188

Trifluoroacetate 4-(5-5-Chloro-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-2,4- dimethyl-1H-pyrrole-3-carbonylamino)-ethyl2-oxo-piperazin-1-ium440 M 1 186

189

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

190

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

191

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

192

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

193

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

194

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

195

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

196

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

197

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

198

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

199

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

200

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

201

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid2-ethyl-2-(2- hydroxyethyl)aminoethyl-amide 199

202

5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3- carboxylic acid2-ethyl-2-(1- hydroxyethyl)aminoethyl-amide 200

203

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

204

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

0182 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.

Preferred Embodiments 0183 While the broadest definition is set forth in the Summary of the Invention, certain compounds of Formula (I) set forth below are preferred. 0184 (1) A preferred group of compounds of Formula (I) is that wherein R1, R3, and R4 are hydrogen. 0185 (2) Another preferred group of compounds of Formula (I) is that wherein R1, R2, and R4 are hydrogen. 0186 (3) Another preferred group of compounds of Formula (I) is that wherein R1, R2, and R3 are hydrogen. 0187 (4) Another preferred group of compounds of Formula (I) is that wherein R2, R3, and R4 are hydrogen. 0188 (5) Another preferred group of compounds of Formula (I) is that wherein R1, R2, R3 and R4 are hydrogen. 0189 (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: 0190 R1 is hydrogen or lower unsubstituted alkyl, preferably hydrogen or methyl; 0191 n is 2, 3 or 4, preferably 2 or 3; and 0192 R12 is NR13R14 wherein R13 and R14 are independently alkyl, more preferably lower unsubstituted 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. 0193 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-ylpropylaminocarbonyl, 3-morpholin-4-ylpropylaminocarbonyl, 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)aminocarbonyl., 0194 (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-ylprpopylaminocarbonyl, triazin-1-ylethylaminocarbonyl, 4-hydroxyphenylethylaminocarbonyl, 3-imidazol-1-ylpropylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, 2-pyridin-2-ylethylaminocarbonyl or 2-imidazol-1-ylethylaminocarbonyl. 0195 (8) 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: 0196 R11 is hydrogen or alkyl, preferably hydrogen or methyl; 0197 n is 2, 3 or 4, preferably 2 or 3; and 0198 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)propylaminocarbonyl, 3-(imidazolidin-1-yl-2-one)propylaminocarbonyl, 3-(tetrahydropyrimidin-1-yl-2-one)-propylaminocarbonyl, 3-(2-oxopyrrolidin-1-yl)propylaminocarbonyl, 2-(2-oxohomopiperidin-1-yl) ethylaminocarbonyl or 3-(2-oxohomopiperidin-1-yl)propylaminocarbonyl. 0199 (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: 0200 (a) R10 is NR11(CH2)nR12 wherein: 0201 R11 is hydrogen or alkyl, preferably hydrogen or methyl; 0202 n is 2, 3 or 4, preferably 2 or 3; and 0203 R2 is NR13R14 wherein R13 is hydrogen and R14 is cyanoalkyl or NHCORa where Ra is alkyl; or 0204 (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-ylcarbonyl, 2-cyanomethylaminoethylaminocarbonyl or piperidin-1-ylcarbonyl. 0205 (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 NR18R9 wherein R18 and R19 are independently hydrogen or lower unsubstituted alkyl, more preferably R5 is 2-(diethylamino)-2-hydroxyethylaminocarbonyl, 2-(N-ethyl-N-2-hydroxyethylamino)ethylaminocarbonyl, carboxymethylamino-carbonyl, or 2-(2-hydroxyethylamino)ethylamino-carbonyl. 0206 (11) Yet another preferred group of compounds 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 unsubstituted alkyl; more preferably R6 is 2-(diethylamino)-2-hydroxyethylaminocarbonyl, 2-(N-ethyl-N-2-hydroxyethyl-amino)ethylaminocarbonyl, carboxymethylaminocarbonyl, or 2-(2-hydroxyethylamino)ethylamino-carbonyl. 0207 (12) Yet another preferred group of compounds of Formula (I) is that wherein R5 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 unsubstituted lower alkyl, preferably R5 is 2-(N-hydroxy-N-ethylamino)ethylaminocarbonyl or 2-N(O)(C2H5)2ethyl-aminocarbonyl 0208 (13) Yet another preferred group of compounds of Formula (I) is that wherein R6 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 unsubstituted lower alkyl, preferably RE is 2-(N-hydroxy-N-ethylamino)ethylaminocarbonyl or 2-N(O)(C2H5)2ethylaminocarbonyl. 0209 (14) In the above preferred groups (6)-(13) when R5 is COR10, then a more preferred group of compounds is that wherein: 0210 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 0211 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. 0212 (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. 0213 (16) In the above preferred groups (6)-(13) when R6 is COR10, then a more preferred group of compounds is that wherein: 0214 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 0215 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. 0216 (17) Within the above preferred and more preferred groups (6)-(16), an even more preferred group of compounds is that wherein: 0217 R1 is hydrogen, alkyl, C(O)NR8R9, unsubstituted cycloalkyl or aryl, preferably hydrogen, phenyl, 3,4-dimethoxyphenylaminocarbonyl, 4-methoxy-3-chlorophenylaminocarbonyl, even more preferably hydrogen or methyl, most preferably hydrogen; 0218 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-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, isopropylamino-sulfonyl, more preferably hydrogen, fluoro, or bromo; 0219 R3 is selected from the group consisting of hydrogen, lower alkoxy, C(O)R5, NR13C(O)R4, 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 0220 R4 is hydrogen. 0221 (18) Another more preferred group of compounds of Formula (I) is that wherein: 0222 R1 is hydrogen, alkyl, C(O)NR8R9, unsubstituted cycloalkyl or aryl, preferably hydrogen, 3,4-dimethoxyphenyl-aminocarbonyl; 4-methoxy-3-chlorophenylaminocarbonyl, even more preferably hydrogen or methyl, particularly hydrogen; 0223 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-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, isopropylamino-sulfonyl, more preferably hydrogen, fluoro, or bromo; 0224 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 0225 R4 is hydrogen. 0226 Within the above preferred group (18) a more preferred group of compounds is wherein: 0227 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. 0228 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 0229 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. 0230 In the above preferred group (18) another more preferred group of compounds is that wherein: 0231 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. 0232 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 0233 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. 0234 (19) Another more preferred group of compounds of Formula (I) is that wherein: 0235 R1 and R4 are hydrogen; 0236 R2 is selected from the group consisting of hydrogen, halo, lower, alkoxy, C(O)R15 and S(O)2NR13R14; 0237 R3 is selected from the group consisting of hydrogen, lower alkoxy, C(O)R15, S(O)2NR13R4, aryl and heteroaryl; 0238 R5 is C(O)R10; 0239 R6 is selected from the group consisting of hydrogen and lower alkyl; and 0240 R7 is selected from the group consisting of hydrogen, lower alkyl and C(O)R17. 0241 It is another presently preferred embodiment of this invention that, in a compound having a structure as described in (15): 0242 R10 is selected from the group consisting of hydroxy, lower alkoxy and NR1 (CH2)nR12 wherein 0243 n is 2 or 3; 0244 R11 is selected from the group consisting of hydrogen and lower alkyl; and, 0245 R12 is selected from the group consisting of aryl and NR13R14. 0246 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)5CH2)2O(CH2)2 or (CH2)2N(CH3)(CH2)2. 0247 (20) Another presently preferred embodiment of this invention is a compound in which: 0248 R1 is selected from the group consisting of hydrogen, lower alkyl, (CH2)rR16 and C(O)NR8R9; 0249 R2 is group consisting hydrogen, halogen, aryl and S(O)2NR13R14; 0250 R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0251 R4 is hydrogen; 0252 R5 is selected from the group consisting of hydrogen and lower alkyl; 0253 R6 is C(O)R10; 0254 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0255 R16 is selected from the group consisting of hydroxy and C(O)R15; and, 0256 r is 2 or 3. 0257 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. 0258 (21) Likewise, it is a presently preferred embodiment of this invention that, in a compound in which: 0259 R1 is selected from the group consisting of hydrogen, lower alkyl, (CH2)R16 and C(O)NR8R9; 0260 R2 is selected from the group consisting of hydrogen, halogen, aryl and S(O)2NR13R14; 0261 R3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0262 R4 is hydrogen; 0263 R5 is selected from the group consisting of hydrogen and lower alkyl; 0264 R6 is C(O)R10; 0265 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0266 R16 is selected from the group consisting of hydroxy and C(O)R15; and, 0267 r is 2 or 3, 0268 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 R2 is selected from the group consisting of hydroxy, lower alkoxy, C(O)R15, heteroaryl: and NR13R14. 0269 (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. 0270 (23) Another presently preferred embodiment of this invention is a compound in which: 0271 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; 0272 R2 is selected from the group consisting of hydrogen, halogen, aryl and S(O)2NR13R14; 0273 R3 is selected from the group consisting-of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and C(O)R15; 0274 R4 is hydrogen; 0275 R5 is selected from the group consisting of hydrogen and lower alkyl; 0276 R6 is C(O)R10; 0277 R7 is selected from the group consisting of hydorgen, lower alkyl and aryl; 0278 R16 is selected from the group consisting of hydroxy and C(O)R15; and, 0279 r is 2 or 3, 0280 (24) A still further presently preferred embodiment of this invention is a compound in which: 0281 R1 is selected from the group consisting of hydrogen and lower alkyl; 0282 R2 is selected from the group consisting of hydrogen, halo, lower alkoxy, aryl, C(O)R15 and S(O)2NR13R14; 0283 R3 is selected from the group consisting of hydrogen, halo, aryl, heteroaryl and C(O)R15; 0284 R4 is hydrogen; 0285 R5 is C(O)R10; and 0286 R6 and R7 combine to form a (CH2)4 group. 0287 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. 0288 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.

Utility 0289 The PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs), and 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. 0290 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. 0291 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. 0292 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. 0293 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 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 this invention 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 this invention useful for targeting any protein with such a site. The compounds 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. 0294 Additionally, the compounds of the present invention 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. 0295 Further examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders. 0296 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. 0297 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. 0298 Two structurally related RTKs have been identified to bind VEGF with high affinity: the fms-like tyrosine, 1 (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. 0299 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., 0.324:1-5. 0300 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. 0301 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. 0302 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-1 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). 0303 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. 0304 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. 0305 Furthermore, this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 receptor. 0306 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. 0307 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 al., 1992, Nature, 360:689-692), the PI-3-kinase, the src-mediated and the plc-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. 0308 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. 0309 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. 0310 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. 0311 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 63:227233, 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. 0312 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. 50:22511-2517). 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. 0313 STKs have-been implicated in many types of cancer including, notably, breast cancer (Cance, et al., Int. J. Cancer, 54:571-77 (1993)). 0314 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. 0315 As noted previously, not only RTKs but CTKs including; but not limited to, src, abl, fps, yes, fyn, lyn, lck, blk, 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 pp60csrc, 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. 0316 Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders. 0317 STKs have been associated with inflamation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis. 0318 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. 0319 Finally, both RTKs and CTKs are currently suspected as being involved in hyperimmune disorders. 0320 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.

Administration and Pharmaceutical Composition 0321 A compound of the present invention or a phearmaceutically 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. 0322 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. 0323 Suitable routes of administration may include, without limitation, oral, rectal, 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. 0324 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. 0325 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 upselectively by the tumor. 0326 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. 0327 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. 0328 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. 0329 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, hydroxypropylmethyl-cellulose, 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. 0330 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. 0331 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. 0332 Pharmaceutical compositions which may also be used include hard gelatin capsules. As a non-limiting example, the active compound capsule oral drug product formulation may be as 50 and 200 mg dose strengths (formulation codes J-011248-AA-00 and J-011248-AA-01, respectively). The two dose strengths are made from the same granules by filling into different size hard gelatin capsules; size 3 for the 50 mg capsule and size 0 for the 200 mg capsule. The composition of the formulation may be, for example, as indicated in Table 2. 2TABLE 2Amount inConcentration200 mgIngredientin GranulationAmount in 50 mgCapsuleName/Grade(% w/w)Capsule (mg)(mg)Formulation CodeJ-011248-AAJ-011248-AA-00J-011248-AA-01Active Compound65.050.0200.0NFMannitol NF23.518.172.4Croscarmellose6.04.618.4sodium NEPovidone K 30 NF5.03.815.2Magnesium0.50.381.52stearate NECapsule, SwedishSize 3Size 0yellow NF

0333 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.). 0334 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. 0335 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. 0336 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. 0337 Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. 0338 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. 0339 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. 0340 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 cosolvent 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. 0341 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. 0342 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. 0343 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. 0344 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.). 0345 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. 0346 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. 0347 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. 0348 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 concentrations 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. 0349 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). 0350 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. 0351 Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen that it maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. 0352 At present, the therapeutically effective amounts of compounds of Formula (I) may range from approximately 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. 0353 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. 0354 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. 0355 The compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may if 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. 0356 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). 0357 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. 0358 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. 0359 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. 0360 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.

General Synthetic Procedure 0361 The following general methodology may be employed to prepare the compounds of this invention: 0362 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. 0363 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. 0364 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. 0365 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. 0366 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. 0367 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. 0368 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, tetrahydrofuran, dimethylsulfoxide and dimethylformamide. 0369 In a presently preferred embodiment of this invention, the solvent is a protic solvent, preferably water or an alcohol such as ethanol. 0370 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. 0371 2-Oxindoles and aldehydes, may be readily synthesized fusing 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.

EXAMPLES 0372 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.

SYNTHETIC EXAMPLES 0373 Method A: Formylation of Pyrroles 0374 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. 0375 Method B: Saponification of Pyrrolecarboxylic Acid Esters 0376 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 1N HCl. The precipitate which forms is collected by filtration, washed with H2O and dried in a vacuum oven to give the desired pyrrolecarboxylic acid. 0377 Method C: Amidation 0378 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. 0379 Method D: Condensation of Aldehydes and Oxindoles Containing Carboxylic Acid Substituents 0380 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 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. 0381 Method E: Condensation of Aldehydes and Oxindoles not Containing Carboxylic Acid Substituents 0382 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. 0383 C. Examples of Oxindole Syntheses 0384 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. 0385 5-Amino-2-oxindole 0386 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. 0387 5-Bromo-2-oxindole 0388 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. 0389 4-Methyl-2-oxindole 0390 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. 0391 7-Bromo-5-chloro-2-oxindole 0392 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. 0393 5-Fluoro-2-oxindole 0394 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. 0395 5-Nitro-2-oxindole 0396 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. 0397 5-Aminosulfonyl-2-oxindole 0398 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. 0399 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. 0400 5-Isopropylaminosulfonyl-2-oxindole 0401 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. 0402 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. 0403 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). 0404 5-Phenylaminosulfonyl-2-oxindole 0405 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. 0406 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). 0407 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic Acid Pyridin-3-ylamide 0408 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. 0409 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). 0410 MS m/z (APCI) 290.2. 0411 5-Phenyloxindole 0412 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. 0413 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). 0414 MS m/z 209 M. 0415 In similar fashion, the following oxindoles can be prepared: 0416 6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one 0417 1H NMR (360 MHz, DMSO-d6) 10.46 (br, 1H, NH), 7.664 (d, J1.8 Hz, 2H), 7.57 (m, 1H), 7.27 (m, 2H), 7.05 (d, J1.1 Hz, 1H), 3.5 (s, 2H). 0418 MS-EI m/z 277/279 M. 0419 6-(4-Butylphenyl)-1,3-dihydroindol-2-one 0420 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). 0421 6-(5-Isopropyl-2-methoxyphenyl)-1,3-dihydroindol-2-one 0422 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). 0423 MS-EI m/z 281, M. 0424 6-(4-Ethylphenyl)-1,3-dihydroindol-2-one 0425 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). 0426 MS-EI m/z 237 M. 0427 6-(3-Isopropylphenyl)-1,3-dihydroindol-2-one 0428 1H NMR (360 MHz, DMSO-d6) 10.37 (br s, 1H, NH), 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). 0429 MS-EI m/z 251 M. 0430 6-(2.4-Dimethoxyphenyl)-1,3-dihydroindol-2-one 0431 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). 0432 MS-EI m/z 269 M. 0433 6-Pyridin-3-yl-1,3-dihydroindol-2-one 0434 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). 0435 MS m/z 210 M. 0436 2-Oxo-2,3-dihydro-1H-indole-4-carboxylic Acid (3-chloro-4-ethoxyphenyl)-amide 0437 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. 0438 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). 0439 MS-EI m/z 316 M. 0440 4-Carboxy-2-oxindole 0441 A solution of trimethylsilyldiazomethane in hexane (2 M) was added dropwise to a solution of 2.01 g 2-chloro-3-carboxynitrobenzene 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. 0442 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. 0443 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. 0444 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). 0445 D. Synthesis of Pyrrole Substituted 2-indolinones.

Example 1 0446 4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid 0447 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%). 0448 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. 0449 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). 0450 MS (negative mode) 266.8 M1.

Example 2 0451 4-Methyl-5-(1-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid 0452 1-Methyl-1,3-dihydroindol-2-one (147 mg, 11 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. 0453 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). 0454 MS m/z 283.0 M1.

Example 3 0455 4-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid Methyl Ester 0456 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. 0457 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, J0.2 Hz, 1H). 0458 MS (ES) m/z 283 M1.

Example 4 0459 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester 0460 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. 0461 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). 0462 MS-EI m/z: 330 M.

Example 5 0463 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid 0464 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. 0465 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). 0466 MS-EI m/z 302 M.

Example 6 0467 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-yl-propyl)amide 0468 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. 0469 1HNMR (300 MHz, DMSO-d6) 13.61 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 8.42 (t, J50.8 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), 3.22-3.1 (m, 2H, CH2), 2.38-2.43 (m, 6H, 3CH2), 2.35 (s, 3H, CH3), 1.62-1.71 (m, 6H, 3CH2). 0470 MS-EI m/z 456 and 458 M1 and M2.

Example 7 0471 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0472 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. 0473 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). 0474 MS-EI m/z 458 and 460 M1 and M2.

Example 8 0475 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)amide 0476 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. 0477 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). 0478 MS-EI m/z 430 and 432 M1 and M1.

Example 9 0479 5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)amide 0480 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. 0481 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, 0.2H), 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). 0482 MS-EI m/z 428 M.

Example 10 0483 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)-methyl-amide 0484 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. 0485 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). 0486 MS-EI m/z 444 and 446 M1 and M1.

Example 11 0487 5-(2-Oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (2-diethylaminoethyl)methylamide 0488 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. 0489 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 0490 3-Methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0491 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. 0492 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). 0493 MS-EI m/z 380 M.

Example 13 0494 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0495 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. 0496 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). 0497 MS-EI m/z 458 and 460 M1 and M1.

Example 14 0498 3-Methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0499 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. 0500 1H NMR (300 MHz, DMSO-d6) 13.37 (s, br, 1H, NH), 11.02 (s, br, 1H, NH), 7.23-7.73 (m, 1H), 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). 0501 MS-EI m/z 456 M.

Example 15 0502 5-(5-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0503 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. 0504 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). 0505 MS m/z 410 M.

Example 16 0506 5-(6-Methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylamino-propyl)amide 0507 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. 0508 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). 0509 MS m/z 410 M.

Example 17 0510 3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (2-diethylaminoethyl)amide 0511 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. 0512 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. 0513 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), 29.72 (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). 0514 MS-EI m/z 484 and 486 M1 and M1.

Example 18 0515 3-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid (3-diethylaminopropyl)amide 0516 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. 0517 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). 0518 MS-EI m/z 499 and 501 M and M2.

Example 19 0519 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 0520 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. 0521 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). 0522 MS-EI m/z 497 and 499 M and M2.

Example 20 0523 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 0524 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. 0525 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). 0526 MS-EI m/z 484 M.

Example 21 0527 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0528 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. 0529 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. 0530 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. 0531 The above carboxylic acid was then coupled with N,N-diethyl-1,3-propanediamine using method C to give the title compound. 0532 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). 0533 MS Electron Impact m/z 564 M1.

Example 22 0534 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-morpholin-4-ylpropyl)amide 0535 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 0536 4-Benzoyl-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0537 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). 0538 MS Electron Impact m/z 482 M.

Example 24 0539 4-Benzoyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0540 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 0541 4-Benzoyl-3-methyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0542 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), 70.69 (m, 1H), 7.53-7.63 (m, 4H), 7.44 (m, 2H), 7.33-7.37 (m, 2H), 7.24 (s, 2H), 7.12 (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). 0543 MS Electron Impact m/z 558 M.

Example 26 0544 4-Benzoyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0545 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 & 81.4 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, 6 H, 3CH2), 2.10 (s, 3H, CH3), 1.72 (m, 2H, CH2), 1.65 (m, 4H, 2CH2). 0546 MS Electron Impact m/z 512 M.

Example 27 0547 4-Benzoyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0548 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), 7.5 (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, 6 H, 3CH2), 2.14 (s, 3H, CH3), 1.71 (m, 2H, CH2), 1.66 (m, 4H, 2CH2). 0549 MS Electron Impact m/z 512 M.

Example 28 0550 4-Benzoyl-5-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0551 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). 0552 MS Electron Impact m/z 500 M.

Example 29 0553 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-diethylaminopropyl)amide 0554 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. 0555 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 0556 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0557 1H NMR (300 MHz, DMSO-d6) 8.14 (m, 1H, CONHCH2), 8.10 (s, 1H, H-vinyl), 70.70 (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, 0.3CH2). 0558 MS m/z 499 & 501 M & M2.

Example 31 0559 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-morpholin-4-ylpropyl)amide 0560 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, J10.5 & 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). 0561 MS-EI m/z 514 & 516 M1 & M1.

Example 32 0562 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (3-hydroxypropyl)amide 0563 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). 0564 MS-EI m/z 445 & 447 M1 & M1.

Example 34 0565 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid (2-morpholin-4-ylethyl)amide 0566 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, CH3C), 2.49 (m, 4H, 2CH2), 2.45 (m, CH3 & CH2). 0567 MS-EI m/z 500 & 502 M1 & M1.

Example 35 0568 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl))-3-methyl-1H-pyrrole-2-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0569 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 0570 4-Acetyl-5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic Acid 2-(4-hydroxyphenyl)ethylamide 0571 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). 0572 MS-EI m/z 507 & 509 M1 & M1.

Example 37 0573 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0574 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. 0575 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). 0576 MS-EI m/z 257 M. 0577 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. 0578 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), 33.74 (m, 1H, CH(CH3)2), 1.29 (d, J6.9 Hz, 6H, CH(CH3)2), 0.90 (t, 7.1 Hz, 3H, OCH2CH3). 0579 MS-EI m/z 285 M. 0580 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. 0581 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). 0582 MS-EI m/z 257 M. 0583 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. 0584 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, J06.9 Hz, 6H, CH(CH3)2), 0.86 (t, J7.1 Hz, 6H, N(CH2CH3)2). 0585 MS m/z 565.1 M1.

Example 38 0586 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0587 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. 0588 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). 0589 MS-EI m/z 560 and 562 M1 and M1.

Example 39 0590 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0591 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. 0592 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), 33.43 (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. 0593 MS-EI m/z 548 and 550 M1 and M1.

Example 40 0594 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 0595 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. 0596 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)2. 0597 MS-EI m/z 589 and 591 M1 and M1.

Example 41 0598 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic Acid 0599 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. 0600 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). 0601 MS-EI m/z 452 M1.

Example 42 0602 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0603 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. 0604 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). 0605 MS-EI m/z 518 and 520 M1 and M1.

Example 43 0606 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 0607 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. 0608 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). 0609 MS-EI m/z 546 M.

Example 44 0610 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0611 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. 0612 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). 0613 MS m/z 493 and 494.8 M and M2.

Example 45 0614 5-6-(2-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0615 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 a orange gum. 0616 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). 0617 MS m/z 521 M1.

Example 46 0618 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0619 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. 0620 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). 0621 MS-EI m/z 450 and 452 M1 and M1.

Example 47 0622 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0623 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. 0624 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). 0625 MS-EI m/z 535.0 and 537 M and M2.

Example 48 0626 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0627 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. 0628 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. 0629 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. 0630 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. 0631 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). 0632 MS m/z 267 M. 0633 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. 0634 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, J6.77 Hz, 2H, NCH2), 2.18 (6H, N(CH3)2). 0635 MS-EI m/z 430 and 432 M1 and M1.

Example 49 0636 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0637 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. 0638 1HNMR (360 MHz, DMSO-d6) 13.59 (s, br, 1H, NH), 10.93 (, br, 1H, NH), 7.85 (d, J7.92 Hz, 1H, H), 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). 0639 MS-EI m/z 428 M.

Example 50 0640 5-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0641 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. 0642 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-O vinyl), 7.50 (t, J5.5 Hz, 1H, CONHCH2), 7.12 (dd, J2.0 & 0.3 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). 0643 MS-EI m/z 386 M.

Example 51 0644 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0645 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. 0646 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), 3.23-13.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J70.2 Hz, 6H, 2NCH2CH3). 0647 MS-EI m/z 458 and 460 M1 and M1.

Example 52 0648 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-yl-ethyl)amide 0649 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. 0650 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). 0651 MS-EI m/z 456 and 458 M1 and M1.

Example 53 0652 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-ylpropyl)amide 0653 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. 0654 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). 0655 MS-EI m/z 467 and 469 M1 and M1.

Example 54 0656 5-6-(2-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0657 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. 0658 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). 0659 MS-EI m/z 458 M.

Example 55 0660 5-6-(3-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemehyl2,4-dimethyl-3H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)amide 0661 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. 0662 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). 0663 MS-EI m/z 458 M.

Example 56 0664 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0665 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. 0666 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). 0667 MS-EI m/z 456 M.

Example 57 0668 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0669 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. 0670 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). 0671 MS-EI m/z 445 M.

Example 58 0672 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-ylpropyl)amide 0673 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. 0674 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). 0675 MS-EI m/z 465 M.

Example 59 0676 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0677 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. 0678 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). 0679 MS-EI m/z 456 M.

Example 60 0680 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0681 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. 0682 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). 0683 MS-EI m/z 454 M.

Example 61 0684 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-imidazol-1-ylpropyl)amide 0685 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. 0686 1HNMR (300 MHz, DMSO-d6) 13.62 (s br, 1H, NH), 10.99 (, br, 1H, NH), 786 (d, J8.2 Hz, 0.1H), 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). 0687 MS-EI m/z 465 M.

Example 62 0688 5-6-(3,5-Dichlorophenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrol-3-carboxylic Acid (2-diethylaminoethyl)amide 0689 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. 0690 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). 0691 MS m/z 526.9 M1.

Example 63 0692 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0693 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. 0694 1HNMR (300 MHz, DMSO-d6) 13.62 (3, 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). 0695 MS-EI m/z 457 M.

Example 64 0696 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 0697 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. 0698 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 Hz 1H), 7.15 (d, J1.2 Hz, 1 Hz), 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). 0699 MS-EI m/z 455 M.

Example 65 0700 2,4-Dimethyl-5-(2-oxo-6-pyridin-3-yl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-dimethylaminopropyl)amide 0701 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. 0702 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). 0703 MS-EI m/z 443 M.

Example 66 0704 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-dimethylaminopropyl)amide 0705 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. 0706 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). 0707 MS-EI m/z 442 M.

Example 67 0708 2,4-Dimethyl-5-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide 0709 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. 0710 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). 0711 MS-EI m/z 470 M.

Example 68 0712 2,4-Dimethyl-5-(2-oxo-6-phenyl-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0713 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. 0714 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). 0715 MS-EI m/z 470 M.

Example 69 0716 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 0717 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. 0718 MS-EI m/z 578.2 M.

Example 70 0719 5-(5-Bromo-2-oxo-1,12-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0720 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. 0721 1HNMR (360 MHz, DMSO-d6) 13.61 (s, 1H, NH), 10.99 (s, 1H, NH), 8.09 (d, J1.8 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). 0722 MS-EI m/z 472 and 474 M1 and M1.

Example 71 0723 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0724 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. 0725 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). 0726 MS-EI m/z 514 and 516 M1 and M1.

Example 72 0727 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (3-diethylaminopropyl)amide 0728 5-Bromo-1,3-dihydroindol-2-one (90 mg, 0.42 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3carboxylic acid (3-diethylaminopropyl)amide (140 mg) to give 54 mg (25%) of the title compound as red-brown solid. 0729 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, CH2CH2H), 1.28 (d, J6.9 Hz, 6H, 2CH3), 1.24 (d, J5.9 Hz, 6H, 2CH3), 1.06 (m, 6H, 2CH2CH3). 0730 MS-EI m/z 528 and 530 M1 and M1.

Example 73 0731 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-diisopropyl-1H-pyrrole-3-carboxylic Acid (3-pyrrolidin-1-ylpropyl)amide 0732 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. 0733 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). 0734 MS-EI m/z 526 and 528 M1 and M1.

Example 74 0735 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (pyridin-4-ylmethyl)amide 0736 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. 0737 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). 0738 MS-EI m/z 450 and 452 M1 and M1.

Example 75 0739 5-6-(4-Butylphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0740 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. 0741 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, J77.2 Hz, 3H, CH2CH3). 0742 MS-EI m/z 510 M.

Example 76 0743 5-6-(5-Isopropyl-2-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0744 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. 0745 1HNMR (360 MHz, DMSO-d6) 13.60 (s, 1H, NH), 10.82 (s, br, 1H, NH), 7.770 (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). 0746 MS m/z 527.2 M1.

Example 77 0747 5-6-(4-Ethylphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0748 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. 0749 1HNMR (300 MHz, DMSO-d6) 13.59 (s, 1H, NH), 10.96 (s, br, 1H), 7.8 (d J84 Hz, 1H), 7.64 (s, 1H, H-vinyl), 7.51-70.56 (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). 0750 MS-EI m/z 482 M.

Example 78 0751 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 0752 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. 0753 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), 2.427 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.67 (m, 4H, 2CH2). 0754 MS-EI m/z 514 M.

Example 79 0755 5-6-(3-Isopropylphenyl)-2-oxo-1,2-dihydroindol 3-ylidenemethyl-2,4-dimethyl-1H-pyrrole 3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0756 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. 0757 1HNMR (300 MHz, DMSO-d6) 13.63 (s, 1H, NH), 10.97 (s, br, 1H, NH), 7.87 (d, J77.8 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). 0758 MS-EI m/z 496 M.

Example 80 0759 5-(5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0760 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. 0761 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). 0762 MS-EI m/z 398 M.

Example 80

Alternative Synthesis 0763 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 0764 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). 0765 MS m/z 152 M1. 0766 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. 0767 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. 0768 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 sold. 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. 0769 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. 0770 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 0771 3-4-(2-Diethylaminoethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0772 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. 0773 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). 0774 MS m/z 424 M.

Example 82 0775 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0776 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. 0777 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). 0778 MS-EI m/z 485 M.

Example 83 0779 5-5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide 0780 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)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. 0781 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), 3.444 (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). 0782 MS m/z 568 M.

Example 84 0783 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 0784 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. 0785 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). 0786 MS m/z 535 M .

Example 85 0787 3-3,5-Dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene-4-(2-hydroxyethyl)-1,3-dihydroindol-2-one 0788 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. 0789 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). 0790 MS m/z (ve) 4.09.3 M.

Example 86 0791 3-3,5-Dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonic Acid Phenylamide 0792 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. 0793 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, 0.2H), 7.10 (m, 2H), 6.97 (m, 2H), 2.49 (m, 4H, 2CH2), 2.28 (m, 10H, 2CH3 & 2CH2), 2.18 (s, 3H, CH3). 0794 MS-EI m/z 519 M.

Example 87 0795 5-(5-Dimethylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0796 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. 0797 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). 0798 MS-EI m/z 487 M.

Example 88 0799 5-5-(3-Chlorophenylsulfamoyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)amide 0800 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)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. 0801 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). 0802 MS m/z 570.1 M.

Example 95 0803 3-(2-Oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid Ethyl Ester 0804 1HNMR (360 MHz, DMSO-d6) 613.74 (s, 1H, NH), 11.00 (s, 1H NH), 8.13 (d, J1.7 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.70 (d, 7.7 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). 0805 MS-EI m/z 412 M.

Example 99 0806 3-(2-Oxo-5-phenylsulfamoyl-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic Acid Ethyl Ester 0807 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, J18 & 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). 0808 MS-EI m/z 491 M.

Example 109 0809 3-3-(Morpholine-4-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0810 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). 0811 MS-EI m/z 421 M.

Example 112 0812 5-Bromo-3-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene-1,3-dihydro-indol-2-one 0813 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). 0814 MS-EI m/z 439 & 441 M1 & M1.

Example 114 0815 3-(3-Dimethylcarbamoyl-4,5,6,7-tetrahydro-2H-isoindol-1-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid 0816 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). 0817 MS-EI m/z 379 M.

Exapmle 115 0818 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid 0819 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). 0820 MS-EI m/z 361 M.

Example 116 0821 4-Methyl-5-(4-methyl-5-methylsulfamoyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid Ethyl Ester 0822 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. 0823 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. 0824 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). 0825 MS-EI m/z 460 M.

Example 117 0826 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid Ethyl Ester 0827 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. 0828 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). 0829 MS m/z 446 M.

Example 118 0830 4-Methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carbonyl-amino-acetic Acid 0831 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. 0832 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). 0833 MS m/z 417 M1.

Example 120 0834 5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid 0835 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). 0836 MS m/z 269 MH.

Example 121 0837 5-Methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0838 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). 0839 MS m/z 297.1 MH.

Example 122 0840 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester 0841 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, J0.5 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). 0842 MS m/z 375 & 377 MH.

Example 123 0843 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid 0844 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 (4, J2.5 Hz, 1H), 2.35 (s, 3H, CH3). 0845 MS m/z 347 & 349 MH.

Example 124 0846 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)-amide 0847 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, 1.22 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. 0848 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. 0849 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). 0850 MS m/z 443/445 M and M2.

Example 125 0851 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-methyl-1H-pyrrole-3-carboxylic Acid (2-diethylaminoethyl)-amide 0852 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. 0853 A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-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. 0854 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). 0855 MS m/z 445/447 M and M2.

Example 126 0856 2,4-Dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 0857 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 (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 422 mg (55%) of the title compound as a light yellow solid. 0858 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). 0859 MSve APCI 381 M1.

Example 127 0860 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)-amide 0861 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. 0862 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). 0863 MSve APCI 415 M1.

Example 128 0864 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ethyl)-amide 0865 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. 0866 MSve APCI 379 M1.

Example 129 0867 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 0868 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. 0869 MSve APCI 397 M1. 0870 Scale-Up Procedure: 0871 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. 0872 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 0873 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)-amide 0874 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. 0875 MSve APCI 413 M1.

Example 131 0876 2,4-Dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)-amide 0877 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. 0878 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). 0879 MSve APCI 353 M1.

Example 132 0880 5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-dimethylaminoethyl)-amide 0881 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. 0882 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) 0883 MSve APCI 371 M1.

Example 193 0884 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-ethylamino-ethyl)-amide 0885 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-dihydroindol-(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, 5H, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NH). 0886 MS m/z 369 M1.

Example 195 0887 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 0888 Method A: 0889 5-5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-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, 0.2H, 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. 0890 Method B: 0891 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-Chloroperoxybenzoic 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). 0892 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethyl-N-oxoamino-ethyl)-amide (9 g), 5-fluoro-1,3-dihydroindol-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, 1 Hr CH3), 2.45 (s, 3H, CH3), 1.64 (t, 6H, 2CH3). MS m/z 415 M1.

Example 190 0893 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. 0894 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 0895 5-5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide. 0896 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-carboxylicacid 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)ethylamide.

Example 192 0897 5-5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide. 0898 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 0899 5-2-Oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide. 0900 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 5-2-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 0901 5-5-Cyano-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid 2-(pyridin-1-yl)ethylamide 0902 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 0903 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 0904 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 0905 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 0906 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 0907 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 0908 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 0909 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 0910 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 0911 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 0912 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 0913 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 mm 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. 0914 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, 2J2.4, 3J8.8 Hz, 1H), 7.43 (t, J5.6 Hz, 1H), 7.70 (s, 1H), 7.75 (dd, J20.8, 9.6 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, NH). LC-MS (m/z) 424.44 (M1).

Example 169 0915 5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-ylethyl)-amide 0916 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-1,2-7-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-ylethyl)-amide (76 mg, 58%). 0917 1HNMR (DMSO-d6) 2.13 (s, 3H, CH3), 2.41, 2.042 (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 0918 5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-ylethyl)-amide 0919 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). 0920 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 0921 5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (4-methylpiperazin-1-yl-ethyl)-amide 0922 Following the procedure described in Example 168 above but substituting 5-(0.5-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, SU014903 (136 mg, 84%) was obtained from SU012120 (112.8 mg, 0.4 mmol). 0923 1H-NMR(DMSO-d6) 2.13 (s, 3H, CH3), 2.39, 2.42 (2s, 6H, 2CH3), 2.42 (m, 2H, CH2), 22.48 (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 0924 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 0925 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. Orjales, 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-dihydroindol-(3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-(3,5-dimethylpiperazin-1-yl)ethyl)amide (83 mg, 50% yield). 0926 1H NMR (DMSO-d6) 1.15, 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 0927 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 0928 Following the procedure described in Example 168 above the desired compound was obtained (60 mg, 0.2 mmol). 0929 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 0930 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 0931 Following the procedure for Example 171 above the desired compound (31.2 mg, 0.34%) 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). 0932 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 0933 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 0934 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). 0935 1H NMR (DMSO-d6) 1.15, 1.16 (2s, 6H, 2CH3), 1-0.95 (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).

BIOLOGICAL EXAMPLES 0936 The following assays are employed to find those compounds: demonstrating the optimal degree of the desired activity. 0937 A. Assay Procedures. 0938 The following assays may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. 0939 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 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. 0940 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 RTKs, as well as for CTKs and 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. 0941 GST-FLK-1 Bioassay 0942 This assay analyzes the tyrosine kinase activity of GST-Flk1 on poly(glu,tyr) peptides. 0943 Materials and Reagents: 0944 1. Corning 96-well ELISA plates (Corning Catalog No. 5805-96). 0945 2. poly(glu,tyr) 4:1, lyophilizate (Sigma Catalog P0275). 0946 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. 0947 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. 0948 5. PBST Buffer: to 1 L of PBS Buffer, add 1.0 ml Tween-20. 0949 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. 0950 7. 1% BSA in PBS: To make a 1 working 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. 0951 8. 50 mM Hepes pH 7.5. 0952 9. GST-Flk1cd purified from sf9 recombinant baculovirus transformation (SUGEN, Inc.). 0953 10. 4% DMSO in dH2O. 0954 11. 10 mM ATP in dH2O. 0955 12. 40 mM MnCl2 0956 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. 0957 14. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog AS-72092 0958 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. 0959 16. 10 Antibody Dilution Buffer: mix 10 ml of 5% BSA in PBS buffer with 89.5 ml TBST. 0960 17. Anti-phosphotyrosine monoclonal antibody conjugated to horseradish peroxidase (PY99 HRP, Santa Cruz Biotech). 0961 18. 2,2-Azinobis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS, Moss, Cat. No. ABST). 0962 19. 10% SDS. 0963 Procedure: 0964 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. 0965 2. Remove unbound liquid from wells by inverting plate. Wash once with TBST. Pat the plate on a paper towel to remove excess liquid. 0966 3. Add 100 l of 1% BSA in PBS to each well. Incubate, with shaking, for 1 hr. at room temperature. 0967 4. Repeat step 2. 0968 5. Soak wells with 50 mM HEPES (pH 7.5) (150 l/well). 0969 6. Dilute test compound with dH2O/4% DMSO to 4 times the desired final assay concentration in 96-well polypropylene plates. 0970 7. Add 25 l diluted test compound to ELISA plate. In control wells, place 25 l of dH2O/4% DMSO. 0971 8. Add 25 l of 40 mM MnCl2 with 4ATP (2 M) to each well. 0972 9. Add 25 l 0.5M EDTA to negative control wells. 0973 10. Dilute GST-Flk1 to 0.005 g (5 ng)/well with KDB. 0974 11. Add 50 l of diluted enzyme to each well. 0975 12. Incubate, with shaking, for 15 minutes at room temperature. 0976 13. Stop reaction by adding 50 l of 250 mM EDTA (pH 8.0). 0977 14. Wash 3 with TBST and pat plate on paper towel to remove excess liquid. 0978 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. 0979 16. Wash as in step 14. 0980 17. Add 100 l of room temperature ABTS solution to each well. 0981 18. Incubate, with shaking, for 10 to 15 minutes. Remove any bubbles. 0982 19. Stop reaction by adding 20 l of 10% SDS to each well. 0983 20. Read results on Dynatech MR7000 ELISA reader with test filter at 410 nM and reference filter at 630 nM. 0984 PYK2 Bioassay 0985 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. 0986 Materials and Reagents: 0987 1. Corning 96-well Elisa plates. 0988 2. 12CA5 monoclonal anti-HA antibody (SUGEN, Inc.) 0989 3. PBS (Dulbecco's Phosphate-Buffered Saline (Gibco Catalog 450-1300EB) 0990 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. 0991 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. 0992 6. FL.pyk2-HA from sf9 cell lysates (SUGEN, Inc.). 0993 7. 4% DMSO in MilliQue H2O. 0994 8. 10 mM ATP in dH2O. 0995 9. 1M MnCl2. 0996 10. 1M MgCl2. 0997 11. 1M Dithiothreitol (DTT). 0998 12. 10 Kinase 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. 0999 13. NUNC 96-well V bottom polypropylene plates. 1000 14. 500 mM EDTA in dH2O. 1001 15. Antibody dilution buffer: for 100 mL, 1 mL 5% BSA/PBS and 1 mL 10% Tween-20 in 88 mL TBS. 1002 16. HRP-conjugated anti-Ptyr PY99), Santa Cruz Biotech Cat. No. SC-7020. 1003 17. ABTS, Moss, Cat. No. ABST-2000. 1004 18. 10% SDS. 1005 Procedure: 1006 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. 1007 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. 1008 3. Add 150 l Blocking Buffer to each well. Incubate, with shaking, for 30 min at room temperature. 1009 4. Wash plate 4 with TBS-T. 1010 5. Dilute lysate in PBS (1.5 g lysate/100 l PBS). 1011 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 1 hr. 1012 7. Wash as in step 4. 1013 8. Add 50 l of 2 kinase Buffer to ELISA plate containing captured pyk2-HA. 1014 9. Add 25 L of 400 M test compound in 4% DMSO to each well. For control wells use 4% DMSO alone. 1015 10. Add 25 L of 0.5 M EDTA to negative control wells. 1016 11. Add 25 l of 20 M ATP to all wells. Incubate, with shaking, for 10 minutes. 1017 12. Stop reaction by adding 25 l 500 mM EDTA (pH 8.0) to all wells. 1018 13. Wash as in step 4. 1019 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. 1020 15. Wash plate 3 with TBST and 1 with PBS. 1021 16. Add 100 L of ABST solution to each well. 1022 17. If necessary, stop the development reaction by adding 20 L 10% SDS to each well. 1023 18. Read plate on ELISA-reader with test filter at 410 nM and reference filter at 630 nM. 1024 FGER1 Bioassay 1025 This assay is used to measure the in vitro kinase activity of FGF1-R in an ELISA assay. 1026 Materials and Reagents: 1027 1. Costar 96-well Elisa plates (Corning Catalog 3369). 1028 2. Poly(Glu-Tyr) (Sigma Catalog PO275). 1029 3. PBS (Gibco Catalog 450-1300EB) 1030 4. 50 mM Hepes Buffer Solution. 1031 5. Blocking Buffer (5% BSA/PBS). 1032 6. Purified GST-FGFR1 (SUGEN, Inc.) 1033 7. Kinase Dilution Buffer. 1034 Mix 500 l 1M Hepes (GIBCO), 20 l 5% BSA/PBS, 10 l 100 mM sodium orthovanadate and 50 l 5M NaCl. 1035 8. 10 mM ATP 1036 9. ATP/MnCl2 phosphorylation mix: mix 20 L ATP, 400 L 1M MnCl2 and 9.56 ml dH2O. 1037 10. NUNC 96-well V bottom polypropylene plates (Applied Scientific Catalog AS-72092). 1038 11. 0.5M EDTA. 1039 12. 0.05% TBST 1040 Add 500 mL TWEEN to 1 liter TBS. 1041 13. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1042 14. Goat anti-rabbit IgG peroxidase conjugate (Biosource, Catalog ALI0404) 1043 15. ABTS Solution. 1044 16. ABTS/H2O2 solution. 1045 Procedure: 1046 1. Coat Costar 96 well ELISA plates with 1 g per well Poly(Glu,Tyr) in 100 l PBS. Store overnight at 4 C. 1047 2. Wash coated plates once with PBS. 1048 3. Add 150 L of 5% BSA/PBS Blocking Buffer to each well. Incubate, with shaking, for 1 hr. room temperature. 1049 4. Wash plate 2 with PBS, then once with 50 mM Hepes. Pat plates on a paper towel to remove excess liquid and bubbles. 1050 5. Add 25 L of 0.4 mM test compound in 4% DMSO or 4% DMSO alone (controls) to plate. 1051 6. Dilute purified GST-FGFR1 in Kinase Dilution Buffer (5 ng kinase/50 ul KDB/well). 1052 7. Add 50 L of diluted kinase to each well. 1053 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). 1054 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. 1055 10. Wash plate 4 with fresh TBST. 1056 11. Make up Antibody Dilution Buffer: Per 50 ml: 1057 Mix 5 ml of 5% BSA, 0.250 l of 5% milk and 50 l of 100 mM sodium vanadate, bring to final volume with 0.05% TBST. 1058 12. Add 100 l per well of anti-phosphotyrosine (1:10000 dilution in ADB). Incubate, with shaking for 1 hr. at room temperature. 1059 13. Wash as in step 10. 1060 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. 1061 15. Wash as in step 10 and then with PBS to remove bubbles and excess TWEEN. 1062 16. Add 100 l of ABTS/H2O2 solution to each well. 1063 17. Incubate, with shaking, for 10 to 20 minutes. Remove any bubbles. 1064 18. Read assay on Dynatech MR7000 elisa reader: test filter at 410 nM, reference filtrate 630 nM. 1065 EGFR Bioassay 1066 This assay is used to the in vitro kinase activity of FGF1-R in an ELISA assay. 1067 Materials and Reagents: 1068 1. Corning 96-well Elisa plates. 1069 2. SUMO1monoclonal anti-EGFR antibody (SUGEN Inc.). 1070 3. PBS 1071 4. TBST Buffer 1072 5. Blocking Buffer: for 100 ml, mix 5.0 g Carnation Instant Non-fat Milk with 100 ml of PBS. 1073 6. A431 cell lysate (SUGEN, Inc.) 1074 7. TBS Buffer: 1075 8. TBS10% DMSO: for 1L, mix 1.514 g TRIS, 2.192 g NaCl and 25 ml DMSO; bring to 1 liter total volume with dH2O. 1076 9. ATP (Adenosine-5-triphosphate, from Equine muscle, Sigma Cat. No. A-5394), 1.0 nM solution in dH2O. This reagent should be made up immediately prior to use and kept on ice. 1077 10. 1.0 mM MnCl2. 1078 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. 1079 12. NUNC 96-well V bottom polypropylene plates. 1080 13. EDTA. 1081 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1082 15. Goat anti-rabbit IgG peroxidase conjugate (Biosource Cat. No. ALI0404). 1083 16. ABTS. 1084 17. 30% Hydrogen peroxide. 1085 18. ABTS/H2O2. 1086 19. 0.2 M HCl. 1087 Procedure: 1088 1. Coat Corning 96 well ELISA plates with 0.5 g SUMO1 in 100 l PBS per well, store overnight at 4 C. 1089 2. Remove unbound SUMO1 from wells by inverting plate to remove liquid. Wash 1 with dH2O. Pat the plate on a paper towel to remove excess liquid. 1090 3. Add 150 l of Blocking Buffer to each well. Incubate, with shaking, for 30 min. at room temperature. 1091 4. Wash plate 3 with deionized water, then once with TBST. Pat plate on a paper towel to remove excess liquid and bubbles. 1092 5. Dilute lysate in PBS (7 g lysate/100 l PBS). 1093 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 1 hr. 1094 7. Wash plates as in 4, above. 1095 8. Add 120 l TBS to ELISA plate containing captured EGFR. 1096 9. Dilute test compound 1:10 in TBS, place in well 1097 10. Add 13.5 l diluted test compound to ELISA plate. To control wells, add 13.5 l TBS in 10% DMSO. 1098 11. Incubate, with shaking, for 30 minutes at room temperature. 1099 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. 1100 13. Stop reaction by adding 16.5 l of EDTA solution while shaking. Shake for additional 1 min. 1101 14. Wash 4 with deionized water, 2 with TBST. 1102 15 Add 100 l anti-phosphotyrosine (1:3000 dilution in TBST) per well. Incubate, with shaking, for 30-45 min. at room temperature. 1103 16. Wash as in 4, above. 1104 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. 1105 18. Wash as in 4, above. 1106 19. Add 100 l of ABTS/H2O2 solution to each well. 1107 20. Incubate 5 to 10 minutes with shaking. Remove any bubbles. 1108 21. If necessary, stop reaction by adding 100 l 0.2 M HCl per well. 1109 22. Read assay on Dynatech MR7000 ELISA reader: test filter at 410 nM, reference filter at 630 nM. 1110 PDGFR Bioassay 1111 This assay is used to the in vitro kinase activity of FGF1-R in an ELISA assay. 1112 Materials and Reagents: 1113 1. Corning-96-well Elisa plates 1114 2. 28D4C10 monoclonal anti-PDGFR antibody (SUGEN, Inc.). 1115 3. PBS. 1116 4. TBST Buffer. 1117 5. Blocking Buffer (same as for EGFR bioassay). 1118 6. PDGFR- expressing NIH 3T3 cell lysate (SUGEN, Inc.). 1119 7. TBS Buffer. 1120 8. TBS10% DMSO. 1121 9. ATP. 1122 10. MnCl2. 1123 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. 1124 12. NUNC 96-well V bottom polypropylene plates. 1125 13. EDTA. 1126 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 1127 15. Goat anti-rabbit IgG peroxidase conjugate (Biosource Cat. No. ALI0404). 1128 16. ABTS. 1129 17. Hydrogen peroxide, 30% solution. 1130 18. ABTS/H2O2. 1131 19. 0.2 M HCl. 1132 Procedure: 1133 1. Coat Corning 96 well ELISA plates with 0.5 g. 28D4C10 in 100 l PBS per well, store overnight at 4 C. 1134 2. Remove unbound 28D4C10 from wells by inverting plate to remove liquid. Wash 1 with dH2O. Pat the plate on a paper towel to remove excess liquid. 1135 3. Add 150 l of Blocking Buffer to each well. Incubate for 30 min. at room temperature with shaking. 1136 4. Wash plate 3 with deionized water, then once with TBST. Pat plate on a paper towel to remove excess liquid and bubbles. 1137 5. Dilute lysate in HNTG (10 g lysate/100 l HNTG). 1138 6. Add 100 l of diluted lysate to each well. Shake at room temperature for 60 min. 1139 7. Wash plates as described in Step 4. 1140 8. Add 80 l working kinase buffer mix to ELISA plate containing captured PDGFR. 1141 9. Dilute test compound 1:10 in TBS in 96-well polypropylene plates. 1142 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. 1143 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. 1144 12. Stop reaction by adding 10 l of EDTA solution to each well. 1145 13. Wash 4 with deionized water, twice with TBST. 1146 14. Add 100 l anti-phosphotyrosine (1:3000 dilution in TBST) per well. Incubate with shaking for 30-45 min. at room temperature. 1147 15. Wash as in Step 4. 1148 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. 1149 17. Wash as in Step 4. 1150 18. Add 100 l of ABTS/H2O2 solution to each well. 1151 19. Incubate 10 to 30 minutes with shaking. Remove any bubbles. 1152 20. If necessary stop reaction with the addition of 100 l 0.2 M HCl per well. 1153 21. Read assay on Dynatech MR7000 ELISA reader with test filter at 410 nM and reference filter at 630 nM. 1154 Cellular HER-2 Kinase Assay 1155 This assay is used to measure HER-2 kinase activity in whole cells in an ELISA format. 1156 Materials and Reagents: 1157 1. DMEM (GIBCO Catalog 11965-092). 1158 2. Fetal Bovine Serum (FBS, GIBCO Catalog 16000-044), heat inactivated in a water bath for 30 min. at 56 C. 1159 3. Trypsin (GIBCO Catalog 25200-056). 1160 4. L-Glutamine (GIBCO Catalog 25030-081); 1161 5. HEPES (GIBCO Catalog 15630-080). 1162 6. Growth Media 1163 Mix 500 ml DMEM, 55 ml heat inactivated FBS, 10 ml HEPES and 5.5 ml L-Glutamine. 1164 7. Starve Media 1165 Mix 500 ml DMEM, 2.5 ml heat inactivated FBS, 10 ml HEPES and 5.5 ml L-Glutamine. 1166 8. PBS. 1167 9. Flat Bottom 96-well Tissue Culture Micro Titer Plates (Corning Catalog 25860). 1168 10. 15 cm Tissue Culture Dishes (Corning Catalog 08757148). 1169 11. Corning 96-well ELISA Plates. 1170 12. NUNC 96-well V bottom polypropylene plates. 1171 13. Costar-Transfer Cartridges for the Transtar 96 (Costar Catalog. 7610). 1172 14. SUMO 1: monoclonal anti-EGFR antibody (SUGEN, Inc.) 1173 15. TBST Buffer. 1174 16. Blocking Buffer: 5% Carnation Instant Milk in PBS. 1175 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 ray to use. 1176 18. HNTG Lysis Buffer 1177 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. 1178 For 1HNTG*, mix 2 ml HNTG, 100 L 0.1M Na3VO4, 250 L 0.2M Na4P2O7 and 100 L EDTA. 1179 19. EDTA. 1180 20. Na3VO4. To make stock solution, mix 0.84 g Na3VO4 with 90 ml dH2O. Adjust pH to 10. Boil in microwave for one minute (solution becomes clear). Cool to room temperature. Adjust pH to 10. Repeat heating/cooling cycle until pH remains at 10. 1181 21. 200 mM Na4P2O7. 1182 22. Rabbit polyclonal antiserum specific for phosphotyrosine (anti-Ptyr antibody SUGEN, Inc). 1183 23. Affinity purified antiserum, goat anti-rabbit IgG antibody, peroxidase conjugate (Biosource Cat ALI0404). 1184 24. ABTS Solution. 1185 25. 30% Hydrogen peroxide solution. 1186 26. ABTS/H2O2. 1187 27. 0.2 M HCl. 1188 Procedure: 1189 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. 1190 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. 1191 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. 1192 4. Use EGFr/HER-2 chimera/3T3-C7 cell, line for this assay. 1193 5. Choose dishes having 80-90% confluence. Collect cells by trypsinization and centrifuge at 1000 rpm at room temperature for 5 min. 1194 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. 1195 7. Start the assay two days after seeding. 1196 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. 1197 9. Incubate under 5% CO2 at 37 C. for 2 hours. 1198 10. Prepare EGF ligand by diluting stock EGF (16.5 uM) in warm DMEM to 150 nM. 1199 11. Prepare fresh HNTG* sufficient for 100 ul per well place on ice. 1200 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. 1201 13. Remove test compound, EGF, and DMEM. Wash cells once with PBS. 1202 14. Transfer HNTG* to cells, 100 ul per well. Place on ice for 5 minutes. Meanwhile, remove blocking buffer from ELISA plate and wash. 1203 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 thee plate. 1204 16. Incubate, with shaking, at room temperature for 1 hr. 1205 17. Remove lysate, wash. Transfer freshly diluted anti-Ptyr antibody (1:3000 in TBST) to ELISA plate, 100 ul per well. 1206 18. Incubate, with shaking, at room temperature, for 30 min. 1207 19. Remove anti-Ptyr antibody, wash. Transfer freshly diluted BIOSOURCE antibody to ELISA plate (1:8000 in TBST, 100 ul per well). 1208 20. Incubate, with shaking, at room temperature for 30 min. 1209 21. Remove BIOSOURCE antibody wash. Transfer freshly prepared ABTS/H2O2Solution to ELISA plate, 100 ul per well. 1210 22. Incubate, with shaking, or 51 minutes. Remove any bubbles. 1211 23. Stop reaction with the addition of 100 ul of 0.2M HCl per well. 1212 24. Read assay on Dynatech MR7000 ELISA reader with test filter set at 410 nM and reference filter at 630 nM. 1213 CDK2/Cyclin A Assay 1214 This assay is used to measure the in vitro serine/threonine kinase activity of human cdk2/cyclin A in a Scintillation Proximity Assay (SPA). 1215 Materials and Reagents. 1216 1. Wallac 96-well polyethylene terephthalate (flexi) plates (Wallac Catalog 1450-401). 1217 2. Amersham Redivue 33P ATP (Amersham catalog AH 9968). 1218 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. 1219 4. Activated cdk2/cyclin A enzyme complex purified from Sf9 cells (SUGEN, Inc.). 1220 5. Biotinylated peptide substrate (Debtide). Peptide biotin-X-PKTPKKAKKL is dissolved in dH2O at a concentration of 5 mg/ml. 1221 6. Peptide/ATP Mixture: for 10 ml, mix 9.979 ml dH2O, 0.0015 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. 1222 7. Kinase buffer: for 10 ml, mix 8.85 ml dH2O, 0.625 ml TRIS (pH 7.4), 0.25 ml 1M MgCl, 0.25 ml 10% NP40 and 0.025 ml 1M DTT, added fresh just prior to use. 1223 8. 10 mM ATP in dH2O. 1224 9. 1M Tris, pH adjusted to 7.4 with HCl. 1225 10. 1M MgCl2. 1226 11. 1M DTT. 1227 12. PBS (Gibco Catalog 14190-144). 1228 13. 0.5M EDTA. 1229 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. 1230 Procedure: 1231 1. Prepare solutions of test compounds at 5 the desired final concentration in 5% DMSO. Add 10 ul to each well. For negative controls, use 10 ul 5% DMSO alone in wells. 1232 2. Dilute 5 l of cdk2/cyclin A solution with 2.1 ml 2 kinase buffer. 1233 3. Add 20 ul enzyme to each well. 1234 4. Add 10 L of 0.5 M EDTA to the negative control wells. 1235 5. To start kinase reaction, add 20 L of peptide/ATP mixture to each well. Incubate for 1 hr. without shaking. 1236 6. Add 200 l stop solution to each well. 1237 7. Hold at least 10 min. 1238 8. Spin plate at approx. 2300 rpm for 3-5 min. 1239 9. Count plate using Trilux or similar reader. 1240 Met Transphosphorylation Assay 1241 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. 1242 Materials and Reagents: 1243 1. Corning 96-well Elisa plates, Corning Catalog 25805-96. 1244 2. Poly(glu, tyr) 4:1, Sigma; Cat; No; P 0275. 1245 3. PBS, Gibco Catalog 450-1300EB 1246 4. 50 mM HEPES 1247 5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat. No A-7888, in 500 ml PBS, filter through a 4 m filter. 1248 6. Purified GST fusion protein containing the Met kinase domain, Sugen, Inc. 1249 7. TBST Buffer. 1250 8. 10% aqueous (MilliQue H2O) DMSO. 1251 9. 10 mM aqueous (dH2O) Adenosine-5-triphosphate, Sigma Cat. No. A-5394. 1252 10. 2 Kinase 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. 1253 11. 4 ATP 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 1254 12. 4 Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL dH2O. 1255 13. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog S-72092 1256 14. 500 mM EDTA. 1257 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. 1258 16. Rabbit polyclonal antophosphotyrosine antibody, Sugen, Inc. 1259 17. Goat anti-rabbit horseradish peroxidase conjugated antibody, Biosource, Inc. 1260 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. 1261 19. ABTS/H2O2: mix 15 mL ABST solution with 2 L H2O2 five minutes before use. 1262 20. 0.2 M HCl 1263 Procedure: 1264 1. Coat ELISA plates with 2 g Poly(Glu-Tyr) in 100 L PBS, store overnight at 4 C. 1265 2. Block plate with 150 L of 5% BSA/PBS for 60 min. 1266 3. Wash plate twice with PBS, once with 50 mM Hepes buffer pH 7.40. 1267 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.) 1268 5. Add 25 L of the test compound (in 4% DMSO) or DMSO alone (4% in dH2O) for controls to plate. 1269 6. Incubate the kinase/compound mixture for 15 minutes. 1270 7. Add 25 L of 40 mM MnCl2 to the negative control wells. 1271 8. Add 25 L ATP/MnCl2 mixture to the all other wells (except the negative controls). Incubate for 5 min. 1272 9. Add 25 L 500 mM EDTA to stop reaction. 1273 10. Wash plate 3 with TBST. 1274 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 forgone hour. 1275 12. Wash plate 3 with TBST. 1276 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. 1277 14. Wash plate 1 with PBS. 1278 15. Add 100 l of ABTS/H2O2 solution to each well. 1279 16. If necessary, stop the development reaction with the addition of 100 l of 0.2M HCl per well. 1280 17. Read plate on Dynatech MR7000 elisa reader with the test filter at 410 nM and the reference filter at 630 nM. 1281 IGF-1 Transphosphorylation Assay 1282 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. 1283 Materials and Reagents: 1284 1. Corning 96-well Elisa plates. 1285 2. Poly (Glu-tyr) (4:1), Sigma Cat. No. P 0275. 1286 3. PBS, Gibco Catalog 450-1300EB. 1287 4. 50 mM HEPES 1288 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. 1289 6. Purified GST fusion protein containing the IGF-1 kinase domain (Sugen, Inc.) 1290 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. 1291 8. 4% DMSO in Milli-Q H2O. 1292 9. 10 mM ATP in dH2O. 1293 10. 2 Kinase 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. 1294 11. 4 ATP 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. 1295 12. 4 Negative Controls Mixture: mix 0.4 mL 1 M manganese chloride in 9.60 mL dH2O. 1296 13. NUNC 96-well V bottom polypropylene plates. 1297 14. 500 mM EDTA in dH2O. 1298 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. 1299 16. Rabbit Polyclonal antiphosphotyrosine antibody, Sugen, Inc. 1300 17. Goat anti-rabbit HRP conjugated antibody, Biosource. 1301 18. ABTS Solution. 1302 20. ABTS/H2O2: mix 15 mL ABTS with 2 L H2O2 5 minutes before using. 1303 21. 0.2 M HCl in dH2O. 1304 Procedure: 1305 1. Coat ELISA plate with 2.0 g/well Poly(Glu, Tyr), 4:1 (Sigma P0275) in 100 l PBS. Store plate overnight at 4 C. 1306 2. ash plate once with PBS. 1307 3. Add 100 l of TBB Blocking Buffer to each well. Incubate plate for 1 hour with shaking at room temperature. 1308 4. Wash plate once with PBS, then twice with 501 mM Hepes buffer pH 7.5. 1309 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. 1310 6. Add 10.0 ng of gst-IGF-1 kinase in 50 l Kinase Dilution Buffer) to all wells. 1311 7. Start kinase reaction by adding 25 l 4 ATP Reaction Mixture to all test wells and positive controls wells. Add 25 l 4 Negative Controls Mixture to all negative control wells. Incubates for 10 minutes with shaking at room temperature. 1312 8. Add 25 l 0.5M EDTA (pH 8.0) to all wells. 1313 9. Wash plate 4 with TBST Buffer. 1314 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. 1315 11. Wash plate as in step 9. 1316 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. 1317 13. Wash plate as in step 9, follow with one wash with PBS to reduce bubbles and excess Tween-20. 1318 14. Develop by adding 100 l/well ABTS/H2O2 to each well. 1319 15. After about 5 minutes, read on ELISA reader with test filter at 410 nm and referenced filter at 630 nm. 1320 BrdU Incorporation Assays 1321 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. 1322 The following materials, reagents and procedure are general to each of the following BrdU incorporation assays. Variances in specific assays are noted. 1323 Materials and Reagents: 1324 1. The appropriate ligand. 1325 2. The appropriate engineered cells. 1326 3. BrdU Labeling Reagent: 10 mM, in PBS (pH 7.4) (Boehringer Mannheim, Germany). 1327 4. FixDenat: fixation solution (ready to use) (Boehringer Mannheim, Germany). 1328 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Boehringer Mannheim, Germany). 1329 6. TMB Substrate Solution: tetramethylbenzidine (TMB, Boehringer Mannheim, Germany). 1330 7. PBS Washing Solution: 1 PBS, pH 7.4. 1331 8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA). 1332 General Procedure: 1333 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. 1334 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. 1335 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. 1336 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. 1337 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. 1338 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. 1339 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. 1340 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. 1341 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. 1342 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. 1343 EGF-Induced BrdU Incorporation Assay 1344 Materials and Reagents: 1345 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1346 2. 3T3/EGFRc7. 1347 EGF-Induced Her-2-Driven BrdU Incorporation Assay 1348 Materials and Reagents: 1349 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1350 2. 3T3/EGFr/Her2/EGFr (EGFr with a Her-2 kinase domain). 1351 EGF-Induced Her-4-Driven BrdU Incorporation Assay 1352 Materials and Reagents: 1353 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan). 1354 2. 3T3/EGFr/Her4/EGFr (EGFr with a Her-4 kinase domain). 1355 PDGF-Induced BrdU Incorporation Assay 1356 Materials and Reagents: 1357 1. Human PDGF B/B (Boehringer Mannheim, Germany). 1358 2. 3T3/EGFRc7. 1359 FGF-Induced BrdU Incorporation Assay 1360 Materials and Reagents: 1361 1. Human FGF2/bFGF (Gibco, BRL, USA). 1362 2. 3T3c7/EGFr 1363 IGF1-Induced BrdU Incorporation Assay 1364 Materials and Reagents: 1365 1. Human, recombinant F (G511, PromegaCorp., USA) 1366 2. 3T3/IGF1r. 1367 Insulin-Induced BrdU Incorporation Assay 1368 Materials and Reagents: 1369 1. Insulin, crystalline, bovine, Zinc (13007, Gibco BRL, USA). 1370 2. 3T3/H25. 1371 HGF-Induced BrdU Incorporation Assay 1372 Materials and Reagents: 1373 1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc. USA). 1374 2. BxPC-3 cells (ATCC CRL-1687). 1375 Procedure: 1376 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. 1377 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. 1378 3. On day 3, 25 l containing ligand (prepared at 0.1 g/ml in RPMI with 0.1% BSA; final HGF conc. is 200 ng/ml) and test compounds are added to the cells. 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. 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). 1379 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. 1380 5. Same as General Procedure. 1381 6. Same as General Procedure. 1382 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. 1383 8. Same as General Procedure. 1384 9. Same as General Procedure. 1385 10. Same as General Procedure. 1386 HUV-EC-C Assay 1387 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. 1388 Day 0 1389 1. Wash and trypsinize HUV-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). 1390 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. 1391 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. 1392 Day 1 1393 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 (4 the 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. 1394 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-lasts 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. 1395 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. 1396 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 4 the 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., 0.5% 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 4 concentrations of test compound and growth factors become 1 once everything has been added to the wells. 1397 Day 2 1398 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. 1399 Day 3 1400 1. Freeze plates overnight at 20 C. 1401 Day 4 1402 Thaw plates and harvest with a 96-well plate harvester (Tomtec Harvester 96) onto filter mats (Wallac, catalogue no. 1205-401), read counts oh a Wallac Betaplate liquid scintillation counter. 1403 TABLE 3 shows the results of biological testing of some exemplary compounds of this invention. 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. 3TABLE 3bioHer2flkGSTbio FGFR1bio PDCFbio EGFcell EGFKinasecdk2spabio pyk2IC50IC50 IC50IC50IC50IC50 C50IC50Example(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>10.0>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>1000.00201191.3861.63>100>100<0.0005

1404 In Vivo Animal Models 1405 Xenograft Animal Models 1406 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 an tumors into athymic mice, (Rygaard 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 the present invention. Three general types of assays are useful for evaluating compounds: cellular/catalytic, cellular/biological and in vivo. The object of the cellular/catalytic assays is to determine the effect of a compound 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 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 in an animal model of a particular disorder such as cancer. 1407 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: 1408 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. 1409 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). 1410 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 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. 1411 Tumor Invasion Model 1412 The following tumor invasion model has been developed and may be used for the evaluation of therapeutic value and efficacy of the compounds identified to selectively inhibit KDR/FLK-1 receptor. 1413 Procedure 1414 8 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. 1415 Analysis 1416 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.). 1417 c-Kit Assay, 1418 This assay is used to detect the level of c-kit tyrosine phosphorylation. 1419 MO7E (human acute myeloid leukemia) cells were serum starved overnight in 0.1% serum. Cells were pre-treated with the compound (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. 1420 MTT Proliferation Assay 1421 MO7E cells were serum starved and pre-treated with compound 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. 1422 Apoptosis Assay 1423 MO7E cells were incubated /SCF and /compound 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. 1424 Additional Assays 1425 Additional assays which may be used to evaluate the compounds of this invention 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. 1426 Measurement of Cell Toxicity 1427 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. 1428 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. 1429 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 PDGFR. 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. 1430 In addition to testing the ability of 5-(5-fluoro-2oxo-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 4, 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 PDGFRwith 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. 4TABLE 4Cellular IC50BiochemicalReceptorKi1PhosphorylationLigand-dependentReceptor(M)(M)Proliferation (M)Flk-0.0090.0320.00431/KDRPDGFR0.0080.0340.0314PDGFRNDND0.0695FGFR0.83ND0.73c-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 PDGFR5Determined using serum-starved NIH-3T3 cells expressing PDGFR6Determined using serum-starved MO7E cells

1431 As shown in Table 4, there is a general agreement between the biochemical and cellular activities of 5-(5-fluoro-2-oxo-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 5). This indicates that the compound did not directly inhibit the growth of these tells at concentrations required to inhibit ligand dependent receptor phosphorylation and cell proliferation. 5TABLE 5CellLineOriginIC50 (M)LD50 (M)HT29Colon carcinoma1022A549Lung carcinoma9.522NCI-H460NSC lung8.920carcinomaSF767TGlioma7.914A431Epidermoid6.018carcinoma

1432 Briefly, the results shown in Table 5 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-diethylamino-ethyl)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. 1433 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. 1434 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 bromodeoxyuridine into cellular DNA. 1435 In separate experiments, compound 80 inhibited the VEGF-dependents 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. 1436 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-diethylamine-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. 1437 C. In Vivo Efficacy Studies 1438 i. Efficacy Against Established Tumor Xenografts 1439 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 100-550 mm3 prior to starting oral treatment with the compound. 1440 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 5). 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. 6TABLE 6InitialTumor%VolumeCompound1Inhibition(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.

1441 Briefly, the results shown in Table 6 were obtained using A431 cells (0.510 6 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. 1442 The efficacy compound 80 against established human tumors of different origins was determined using Colo205 (colon carcinoma), SF763T (glioma), and NCI-H460 (non-small cell lung carcinoma) xenografts (see Table 7). 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. 7TABLE 7InitialTumor%VolumeInhibitionTumor Type(mg/kg/day)(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.

1443 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. 1444 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 NCI-H460 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. 1445 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. 1446 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. 1447 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 8, 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. 8TABLE 8Dose(mg/kg)Frequency% InhibitionP-Value160Twice weekly520.085Once weekly17NS80Daily910.039Twice weekly19NSOnce weekly0NS40Daily840.028Twice weekly36NSNS: not significant (P > 0.05)

1448 Briefly, the results shown in Table 8 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. 1449 ii. Efficacy of Compound 80 in a Model of Disseminated Disease 1450 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 8, 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. 9TABLE 9Lung Weight (g)% InhibitionP-ValueVehicle0.83 0.07Compound10.41 0.0450<0.0011Compound 80

1451 Briefly, the results shown in Table 9 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. 1452 D. Examples of Biological Activity. 1453 Examples of the in vitro potency of compounds of this invention are shown in Table 2.

CONCLUSION 1454 In studies to investigate the pharmacokinetic characteristics of the compounds of the preferred embodiments of the present invention it has been demonstrated that oral administration of a single dose of said compounds resulted in high oral bioavailability in mice. The good oral bioavailability and linear pharmacokinetics indicate that the compounds of the preferred embodiments of the present have favorable pharmacokinetic characteristics. 1455 In addition, the compounds of the preferred embodiments of the present invention are potent inhibitor of the tyrosine kinase activity of the split-kinase domain RTKs Flk-1/KDR and PDGFR, which are involved in angiogenesis, and the RTK c-kit, a receptor for stem cell factor (SCF), that is involved in certain hematologic cancers. At higher concentrations, the compounds of the preferred embodiments of the present invention also inhibit the tyrosine kinase activity of FGFR-1, a third RTK involved in angiogenesis. Consistent with their biochemical activity, the compounds of the preferred embodiments of the present invention inhibit the ligand-dependent tyrosine phosphorylation of target RTKs and the in vitro mitogenic response of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF or FGF, of PDGFR-expressing NIH-3T3 cells stimulated with PDGF, and of MO7E acute myeloid leukemia cells stimulated with SCF. In contrast, the compounds of the preferred embodiments of the present invention do not directly inhibit the proliferation of tumor cells in complete growth medium except at concentrations 2 to 3 orders of magnitude higher than those required to inhibit the ligand-dependent mitogenic responses. In mouse xenograft studies, the compounds of the prefered embodiments of the present invention inhibited the growth of established human tumors of various origins in a dose-dependent manner and at concentrations that were well tolerated even upon extended (>100 days) dosing. At 80 mg/kg/day, the compounds of the preferred embodiments of the present invention induced regression of large established A431 and Colo205 tumors, and caused substantial growth inhibition or stasis of SF763T and NCI-H460 tumors. In mice bearing SF763T tumors, the compounds of the preferred embodiments of the present invention caused reductions in microvessel density, phosphorylation of PDGFR in the tumors, and mitotic index in the tumor cells. At this dose, the compounds of the preferred embodiments of the present invention also inhibited lung colonization by B16-F1 tumor cells in a model of tumor metastasis. Regimen studies demonstrated that the compounds of the preferred embodiments of the present invention are most efficacious when administered daily. Direct evidence of the anti-angiogenic activity of the compounds of the preferred embodiments of the present invention was detected in SF763T tumors in which microvessel density was reduced. Direct evidence that the compounds of the preferred embodiments of the present invention inhibit PDGFR phosphorylation and signaling in vivo was also obtained in SF763T tumors. 1456 Taken together, these data support the notion that orally administered compounds of the preferred embodiments of the present invention are anti-angiogenic agents for the treatment of cancers, including solid tumors and hematological malignancies in which angiogenesis and/or signaling through c-kit are important in the disease pathology. 1457 It will be appreciated that the compounds, methods and pharmaceutical compositions of the present invention are effective in modulating PK activity and therefore are expected to be effective as therapeutic agents against RTK, CTK-, and STK-related disorders. 1458 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. 1459 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. 1460 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. 1461 The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms comprising, consisting essentially of and consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. 1462 In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. 1463 Other embodiments are within the following claims.