WO2000008202A2 - Modulateurs 3-methylidenyl-2-indolinone de proteine kinase - Google Patents

Modulateurs 3-methylidenyl-2-indolinone de proteine kinase Download PDF

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WO2000008202A2
WO2000008202A2 PCT/US1999/017845 US9917845W WO0008202A2 WO 2000008202 A2 WO2000008202 A2 WO 2000008202A2 US 9917845 W US9917845 W US 9917845W WO 0008202 A2 WO0008202 A2 WO 0008202A2
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dihydroindol
group
indol
hydrogen
methoxybenzylidene
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PCT/US1999/017845
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English (en)
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WO2000008202A9 (fr
WO2000008202A3 (fr
Inventor
Peng Cho Tang
Li Sun
Todd Anthony Miller
Congxin Liang
Ngoc My Tran
Anh Thi Nguyen
Asaad Nematalla
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Sugen, Inc.
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Priority to AU54684/99A priority Critical patent/AU5468499A/en
Priority to CA002383623A priority patent/CA2383623A1/fr
Priority to JP2000563824A priority patent/JP2002522452A/ja
Priority to US09/762,198 priority patent/US6531502B1/en
Publication of WO2000008202A2 publication Critical patent/WO2000008202A2/fr
Publication of WO2000008202A3 publication Critical patent/WO2000008202A3/fr
Publication of WO2000008202A9 publication Critical patent/WO2000008202A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to organic chemistry, biochemistry, pharmacology and medicine. More particularly, it relates to 3-methylidenyl-2-indolinone derivatives, and their physiologically acceptable salts and prodrugs, which modulate the activity of protein kinases ("PKs") and are expected to exhibit a salutary effect against disorders related to abnormal PK activity.
  • PKs protein kinases
  • 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.
  • 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) .
  • the PKs can be conveniently be broken down into two classes, the protein tyrosine kinases (PTKs) and the serine- threonine kinases (STKs) .
  • PTKs protein tyrosine kinases
  • STKs serine- threonine kinases
  • 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 cellular metabolic processes to the extracellular microenvironment , etc.
  • cytoplasmic signaling molecules that, in turn, effect numerous cellular responses such as cell division (proliferation) , cell differentiation, cell growth, expression of cellular metabolic processes to the extracellular microenvironment , etc.
  • RTKs receptor tyrosine kinases
  • HER receptor tyrosine kinases
  • RTK subfamily consists of insulin receptor (IR) , insulin-like growth factor I receptor (IGF-IR) and insulin receptor related receptor (IRR) .
  • IR and IGF-IR 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.
  • 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.
  • PDGFR platelet derived growth factor receptor
  • PDGFR subfamily is sometimes subsumed into the later group is the fetus liver kinase ("flk”) receptor subfamily.
  • flk fetus liver kinase
  • This group is believed to be made of up of kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1) , flk-lR, flk-4 and fms-like tyrosine kinase 1 (flt-1) .
  • a further member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor ("FGF") receptor subgroup.
  • FGF fibroblast growth factor
  • This group consists of four receptors, FGFR1-4, and seven ligands, FGF1-7. While not yet well defined, it appears that, like the PDGF receptors, the FGF 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.
  • 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 .
  • CTK non-receptor tyrosine kinases
  • cellular tyrosine kinases This latter designation, abbreviated “CTK, " will be used herein.
  • CTKs do not contain extracellular and transmembrane domains.
  • Sc, 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.
  • Src serine/threonine kinases
  • STKs serine/threonine kinases
  • 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 .
  • 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.
  • PK regulated 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.
  • RTKs transmembrane growth factor PTK receptors
  • CTKs cytoplasmic PTKs
  • STKs cytosolic STKs
  • the present invention relates generally to 3- • methylidenyl-2-indolinones and their prodrugs and physiologically acceptable salts, which modulate the activity of receptor tyrosine kinases (RTKs) , non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs) .
  • RTKs receptor tyrosine kinases
  • CTKs non-receptor protein tyrosine kinases
  • STKs serine/threonine protein kinases
  • the present invention relates to the preparation and use of pharmaceutical compositions of the disclosed compounds and their physiologically acceptable salts and prodrugs in the treatment or prevention of PK driven disorders such as, 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.
  • PK driven disorders such as, 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.
  • A is carbon or nitrogen.
  • a "3 -methylidenyl-2-indolinone” refers to a molecule having the chemical structure:
  • A can be carbon or nitrogen.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • 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.
  • a further example of a prodrug might be a short polypeptide, for example, without limitation, a 2 - 10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound of this invention wherein the polypeptide is hydrolyzed or metabolized in vivo to release the active molecule.
  • a “physiologically acceptable carrier” or a “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.
  • a “carrier” refers to a chemical compound which faciliates the incorporation of a compound of interest into cells and tissues.
  • An example, without limitation, of a carrier is dimethyl sulfoxide (DMSO) .
  • a “diluent” refers to a chemical compound, usually a liquid, which dissolves or disperses a compound of interest thereby reducing the concentration of the compound to less than that of the compound alone .
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the present invention relate to 2- indolinones having chemical structure 1 . :
  • A is selected from the group consisting of carbon and nitrogen
  • Q is selected from the group consisting of
  • bonds a and b may be either single or double bonds as indicated by the dotted lines with the proviso that a and b are both single bonds or both double bonds in any one compound of this invention;
  • r is 1 when a and b are double bonds
  • r is 2 when a and b are single bonds
  • R° is selected from the group consisting of hydrogen, alkyl, -C(0)OR 19 and -C(0)R 19 ;
  • R 1 is selected from the group consisting of hydrogen, alkyl, aryl, alkoxy, halo, -C(0)0R 19 , - (CH 2 ) n 0C (0) R 19 , -C(0)NR 19 and (CH 2 ) n R 20 , wherein:
  • R 19 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and aryl;
  • n 1, 2, 3 or 4 ;
  • R 20 is selected from the group consisting of hydroxy, halo, -OC(0)NR 21 R 22 ; -OC (S) NR 21 R 22 ; -OC (O) NHS0 2 R 21 , -C(0)OR 19 , -NR 21 R 22 and a heteroalicylic group containing at least one nitrogen atom in the ring, the ring being bonded to the adjacent CH 2 group through the nitrogen atom;
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl , aryl, heteroaryl and heteroalicyclic;
  • R 23 is selected from the group consisting of alkyl, alkenyl , alkynyl , cycloalkyl , aryl and heteroaryl ;
  • R 3 is selected from the group consisting of hydrogen, alkyl, trihalomethyl, alkoxy, aryl, aryloxy, heteroaryl, heteroalicyclic, hydroxy, halo, -S0 2 NR 21 R 22 , -NHS0 2 R 19 , -C(0)OR 19 , -NR 21 R 22 and -NHC (O) R 24 , wherein
  • R 24 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo
  • R 5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, aryl and heteroaryl
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, cycloalkyl, aryl and, combined with R 18 , a heteroalicyclic group having the structure
  • y and y' are independently selected from the group consisting of hydrogen, alkyl and aryl;
  • R 7 is OR 18 , wherein R 18 is selected from the group consisting of alkyl, -(CH) n R 20 and, combined with R 6 or R 8 , a heteroalicyclic group having the structure
  • R 8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl and, combined with R 18 , a heteroalicyclic ring having the structure
  • R 9 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo and -NR 21 R 22 ;
  • R 10 is selected from the group consisting of alkyl and -C(0)OR 19 ;
  • R 11 is selected from the group consisting of hydrogen, alkyl and -C(0)OR 19 ;
  • R 12 is -(CH 2 ) n R 20 ;
  • R 13 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, a group selected from the group consisting of hydrogen and alkyl;
  • R 14 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, a group selected from the group consisting of hydrogen, alkyl and -(CH 2 ) n R 20 ;
  • R 15 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, hydrogen;
  • R 16 and R 17 when a and b are single bonds, are independently selected from the group consisting of hydrogen, alkyl and aryl and, when a and b are double bonds, R 16 is hydrogen and R 17 does not exist; and,
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 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) . More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more independently selected from the group consisting of halo hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more 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 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 atoms of the group being optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower
  • a “cycloalkyl” group 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.
  • cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane and, cycloheptatriene.
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl , halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more 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 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 atoms of the group being optionally substituted with one or more hal
  • alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups 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.
  • the substituted group (s) is preferably one or more 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, R 25 S(0)-, R 25 S(0) 2 -, -C(0)OR 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi- electron system.
  • 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.
  • the substituted group (s) is preferably one or more 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- thiocarba yl, C-amido, N-amido, nitro, N-sulfonamido, S- sulfonamido, R 25 S(0)-, R 5 S(0) 2 -, -C(0)0R 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • heteroalicyclic group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic ring may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more 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, 0- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N- sulfonamido, S-sulfonamido, R 25 S(0)-, R 25 S(0) 2 -, -C(0)0R 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • a “hydroxy” group refers to an -OH group.
  • An “alkoxy” group refers to both an -O- (unsubstituted alkyl) and an -O- (unsubstituted cycloalkyl) group.
  • An “aryloxy” group refers to both an -O-aryl and an -0- heteroaryl group, as defined herein.
  • a “mercapto” group refers to an -SH group.
  • alkylthio refers to both an S- (unsubstituted alkyl) and an -S- (unsubstituted cycloalkyl) group.
  • arylthio refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
  • acyl refers to a -C(0)-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 unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halo and -NR 25 R 26 groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and -NR 25 R 26 groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and -NR 25 R 26 groups.
  • R is selected from the group consisting of hydrogen, unsubstituted lower alky
  • a “thioacyl” group refers to a -C(S)-R" group, with R" as defined herein.
  • ester refers to a -C(0)0-R" group with R" as defined herein except that R" cannot be hydrogen.
  • acetyl refers to a -C(0)CH 3 group.
  • halo refers to fluorine, chlorine, bromine or iodine .
  • trihalomethyl refers to a -CX 3 group wherein X is a halo group as defined herein.
  • a “cyano” group refers to a -C ⁇ N group.
  • a “methylenedioxy” group refers to a -OCH 2 0- group where the two oxygen atoms are bonded to adjacent carbon atoms.
  • ethylenedioxy group refers to a -OCH 2 CH 2 0- where the two oxygen atoms are bonded to adjacent carbon atoms.
  • O-carbamyl refers to a -OC (0)NR 25 R 26 group with R 25 and R 26 as defined herein.
  • N-carbamyl refers to an R 25 OC (O) NR 26 - group, with R 25 and R 26 as defined herein.
  • An "O-thiocarbamyl” group refers to a -OC (S) NR 25 R 26 group with R 25 and R 2S as defined herein.
  • An "N-thiocarbamyl” group refers to a R 25 OC (S) NR 26 - group, with R 25 and R 26 as defined herein.
  • amino group refers to an -NR 25 R 26 group, wherein R 25 and R 26 are both hydrogen.
  • C-amido refers to a -C(0)NR 25 R 26 group with R 25 and R 26 as defined herein.
  • N-amido refers to a R 25 C(0)NR 26 - group, with R 25 and R 26 as defined herein.
  • a "nitro” group refers to a -N0 2 group.
  • a presently preferred aspect of this invention is a compound in which Q is
  • Another presently preferred aspect of this invention is a compound in which Q is
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)OR 19 , lower alkoxy, -NR 21 R 22 ,
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (0)0 (lower alkyl) , -NHSO- j R 1 -NHC(0)R 2 trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ; n is 2 or 3 ;
  • R 20 is selected from the group consisting of hydroxy
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl
  • R 24 is selected from the group consisting of hydrogen and lower alkyl .
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)OR 19 , lower alkoxy, -NR 1 R 22 , -(CH 2 ) n R 20 and -NHC(0)OR 19 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (0)0 (lower alkyl) , -NHS0 2 R 19 , -NHC(0)R 24 , trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ; n is 2 or 3; R 20 is selected from the group consisting of hydroxy,
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl;
  • R 24 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 5 is selected from the group consisting of hydrogen, lower alkyl, halo, five-member ring heteroaryl and aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, halo, hydroxy, -NR 21 R 22 and lower alkoxy;
  • R 6 is selected from the group consisting of hydrogen, lower alkyl, 3 to 7-member cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups independently selected from the group consisting of lower alkyl, halo, hydroxy, -NR 1 R 22 and lower alkoxy and, combined with R 18 , a group having the structure
  • y and y' are either both hydrogen or both lower alkyl
  • R is -OR wherein R is selected from the group consisting of lower alkyl, -(CH 2 ) n R 20 and, combined with R 6 or R 8 , a group having the structure
  • R 8 is selected from the group consisting of hydrogen, lower alkyl, 3 to 6-member ring cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy, halo, -NR 21 R 22 and -NHC(O) (lower alkyl), five-member heteroaryl having from 1 to 3 heteroatoms in the ring and 6-member heteroaryl having from 1 to 3 heteroatoms in the ring and, combined with R 18 a group having the structure
  • R 9 is selected from the group consisting of hydrogen, lower alkyl; hydroxy, lower alkoxy, halo and -NR 21 R 22 .
  • a further presently preferred aspect of this invention is a compound in which Q is
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)0H;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)0R 19 , lower alkoxy, -NR 21 R 22 , -(CH 2 ) n R 20 and -NHC (O) OR 19 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (0)0 (lower alkyl) , -NHS0 2 R 19 , -NHC(0)R 24 , trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl; n is 2 or 3;
  • R 20 is selected from the group consisting of hydroxy
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl;
  • R 24 is selected from the group consisting of hydrogen and lower alkyl
  • R 5 is selected from the group consisting of hydrogen, lower alkyl, thien-2-yl, thien-3-yl and aryl optionally substituted with one or more lower alkoxy groups
  • R 6 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member cycloalkyl, aryl optionally substituted with one or more lower alkoxy groups and, combined with R 18 , a group having the structure
  • y and y' are either both hydrogen or both lower alkyl
  • R 7 is -OR 18 , wherein R 18 is selected from the group consisting of lower alkyl, -(CH 2 ) n R 20 and, combined with R 6 or R 8 , a group having the structure
  • n 2 or 3;
  • R 20 is selected from the group consisting of hydroxy, -C(0)0H, morpholin-4-yl, piperidin-1-yl , piperazin-1-yl pyrrol idin- 1 -yl and -NR 21 R 22 ;
  • R 8 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member ring cycloalkyl, lower alkoxy, aryl optionally substituted with a -NHC(O) (lower alkyl) group, thien-2-yl, thien-3-yl, pyridin-2-yl , pyridin-3-yl and, combined with R 18 , a group having the structure
  • R 9 is selected from the group consisting of hydrogen and lower alkyl.
  • Still another presently preferred aspect of this invention is a compound in which Q is:
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3 ;
  • R 20 is selected from the group consisting of hydroxy and
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups; and, R 4 is hydrogen.
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3;
  • R 20 is selected from the group consisting of hydroxy and -C(0)OH
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 10 is selected from the group consisting of lower alkyl and
  • R 11 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OR 19 ;
  • R 12 is - (CH 2 ) n R 20 ;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ; n is 2 or 3 ; and,
  • R 20 is selected from the group consisting of hydroxy, -C (0) 0H, morpholin-4 -yl , piperidin- 1-yl , piperazin- 1-yl , pyrrol idin- 1 -yl and -NR 21 R 22 .
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3;
  • R 20 is selected from the group consisting of hydroxy and -C(0)OH
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 10 is selected from the group consisting of lower alkyl and -C(0)0(lower alkyl);
  • R 11 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OR 19 ;
  • R 12 is -(CH 2 ) n R 20 ;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ; n is 2; and,
  • R 20 is selected from the group consisting of -C(0)OH, morpholin-1-yl , piperidin-1-yl , piperazin-1-yl , pyrrolidin-1-yl and -N (lower alkyl) 2 .
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl, piperidin-1-yl , piperazin-1-yl , pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups, ; and,
  • R 4 is hydrogen
  • a and b are both single bonds; r is 2 ;
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 13 is a covalent bond through which Q is bonded to the rest of the molecule
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 15 is hydrogen
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and lower alkyl .
  • R 20 is -NR 21 R 22 wherein R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl .
  • a and b are both double bonds; r is 1 ;
  • R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 13 is a covalent bond through which Q is bonded to the rest of the molecule
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 15 and R 16 are hydrogen;
  • R 17 does not exist.
  • a and b are both double bonds; r is 1;
  • R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 13 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 14 is a covalent bond through which Q is bonded to the rest of the molecule
  • R 15 and R l ⁇ are hydrogen;
  • R 17 does not exist is another presently preferred aspect of this invention.
  • a and b are double bonds; r is 1;
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)0R 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 13 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 1S is a covalent bond through which Q is bonded to the rest of the molecule;
  • R 16 are hydrogen; and, R 17 does not exist.
  • 1, 3 -dihydroindol-2 -one is also a presently preferred embodiment of this invention.
  • a presently preferred embodiment comprises compounds selected from the group consisting of:
  • An additional aspect of this invention is a combinatorial library of at least ten 3-methylidenyl-2-indolinone compounds that can be formed by reacting oxindoles of structure 5 with aldehydes of structure 6, 7 or 8 :
  • R 15 , R 16 and R 17 have the meanings set forth above.
  • a "combinatorial library” refers to all the compounds formed by the reaction of each compound of one dimension with a compound in each of the other dimensions in a multi-dimensional array of compounds.
  • the array is two dimensional and one dimension represents all the oxindoles of the invention and the second dimension represents all the aldehydes of the invention.
  • Each oxindole may be reacted with each and every aldehyde in order to form a substituted 3-methylidenyl-2-indolinone compound. All substituted 3-methylidenyl-2-indolinone compounds formed in this way are within the scope of the present invention.
  • the oxindole in the above combinatorial library is preferably selected from the group consisting of oxindole itself and substituted oxindoles such as, without limitation, 6- bromooxindole, 5-hydroxyoxindole, 5-methoxyoxindole, 6- methoxyoxindole, 5-phenylaminosulfonyloxindole, 4- [2- (2- isopropylphenoxy) ethyl] oxindole, 4- [2- (3-isopropylphenoxy) - ethyl] oxindole, 4- [2- (4-isopropylphenoxy) ethyl] oxindole, 5- fluorooxindole, ⁇ -fluorooxindole, 7-fluorooxindole, 6- trifluoromethyloxindole, 5-chlorooxindole, ⁇ -chlorooxindole, 4- carboxyindole, 5-bromooxindole, 5-bromo-4-
  • the aldehyde in the above combinatorial library is preferably selected from the group consisting of 3- (l-Benzyl-5- formyl-2, -dimethyl-lH-pyrrol-3-yl) propionic acid, 3-(5-Formyl- l-methoxycarbonylmethyl-2, 4-dimethyl-lH-pyrrol-3-yl) propionic acid, 3- (5-Formyl-l, 2, -trimethyl-lH-pyrrol-3-yl) propionic acid, 3- [5-Formyl-l- (3-methoxybenzyl) -2, 4-dimethyl-lH-pyrrol-3- yl]propionic acid methyl ester, 3- ( l-Cyclohexylmethyl-5-formyl- 2, -dimethyl-lH-pyrrol-3-yl) propionic acid methyl ester, 3-[l- (2,2-Dimethyl-propyl) -5-formyl-2, 4-dimethyl-lH-pyrrol-3
  • Another aspect of this invention provides a method for the synthesis of a 3-methylidenyl-2-indolinone of formula 1 comprising reacting an oxindole of formula 5 with an aldehyde of formula 6, 7 or 8 in a solvent, preferably in the presence of a base.
  • Examples of the oxindoles of formula 5 which may be reacted with an aldehyde of formula 6, 7 or 8 to give the substituted 3- methylidenyl-2-indolinones of formula 1 are oxindole itself and substituted oxindoles such as, without limitation, 6- bromooxindole, 5-hydroxyoxindole, 5-methoxyoxindole, 6- methoxyoxindole, 5-phenylaminosulfonyloxindole, 4- [2- (2- isopropylphenoxy) ethyl] oxindole, 4- [2- (3-isopropylphenoxy) - ethyl] oxindole, 4- [2- (4-isopropylphenoxy) ethyl] oxindole, 5- fluorooxindole, 6-fluorooxindole, 7-fluorooxindole, 6- trifluoromethyloxindole, 5-chlorooxindole, 6-chlorooxind
  • aldehydes of structure 6, 7 or 8 which may be reacted with oxindoles of structure 2 are, without limitation, 3- (l-benzyl-5-formyl-2, 4-dimethyl-lH-pyrrol-3-yl) propionic acid, 3- (5-formyl-l-methoxycarbonylmethyl-2, 4-dimethyl-lH-pyrrol-3-yl) - propionic acid, 3- (5-formyl-l, 2, 4-trimethyl-lH-pyrrol-3-yl) - propionic acid, 3- [5-formyl-l- (3-methoxybenzyl) -2, 4-dimethyl-lH- pyrrol-3-yl] ropionic acid methyl ester, 3- ( l-cyclohexylmethyl-5- formyl-2, -dimethyl-lH-pyrrol-3-yl) propionic acid methyl ester, 3- [1- (2, 2-dimethylpropyl) -5-formyl-2, 4-di
  • step 1 step 2 reducing agent
  • the base can be an inorganic or an organic base.
  • inorganic and organic bases are presented elsewhere herein.
  • the base is sodium acetate.
  • the "solvent” may be any solvent in which base and the other reactants are sufficiently soluble for reaction to take place.
  • Preferred solvents are polar protic solvents (defined elsewhere herein) such as water, methanol and ethanol.
  • the presently preferred solvent is water.
  • the reaction is carried out at temperatures of from about 60° C to about 180° C.
  • the temperature is between about 60° C and 180° C, more preferably between 80° C and 150° C, most preferably between 100 and 120° C.
  • the reaction is allowed to run for from 1 to 30 hours, preferably from 2 to 20 hours, most preferably from 4 to 15 hours.
  • step 2 a carboxylic acid group is converted to an amide group.
  • Procedures for accomplishing this conversion are well-known in the art.
  • the reaction of an amine with the carboxylic acid in the presence of 1, 1 ' -carbonyldiimidazole is the presently preferred method.
  • Any aprotic solvent may be used; in a presently preferred embodiment the solvent is a non-polar aprotic solvent, in particular dichoromethane .
  • the reaction may be carried out at room temperature or at an elevated temperature up to about 100° C; a presently preferred embodiment is to run the reaction at about room temperature.
  • Step 3 is the simultaneous reduction of the keto and the amido group using a reducing agent such as, for example and without limitation, lithium aluminum hydride.
  • a reducing agent such as, for example and without limitation, lithium aluminum hydride.
  • the reaction is carried out in an aprotic solvent (defined elsewhere herein) .
  • a presently preferred solvent is tetrahydrofuran.
  • the reaction is carried out at temperatures from about room temperature to about 80° C, preferrably from about 50° C to about 70° C, most preferably, the reaction is carried out in tetrahydrofuran at reflux.
  • Step 4 is the well-known formylation of the aromatic pyrrole ring using phosphorus oxychloride and N,N- dimethylformamide.
  • Step 5 the condensation of an aldehyde with an oxindole to form a 3-methylidenyl-2-indolinone of this invention is carried out in a solvent which may contain a base.
  • 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-diazabicyclo- [5. .1] ndec-7-ene, pyrrolidine and piperidine.
  • inorganic bases are, without limitation, ammonia, alkali metal or alkaline earth hydroxides, phosphates, carbonates, bicarbonates, acetates, bisulfates and amides.
  • the alkali metals include, lithium, sodium and potassium while the alkaline earths include calcium, magnesium and barium.
  • 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.
  • 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.
  • 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.
  • non-polar aprotic solvents are pentane, hexane, benzene, toluene, methylene chloride and carbon tetrachloride.
  • polar aprotic solvents examples include chloroform, tetrahydro- furan, dimethylsulfoxide and dimethylformamide .
  • the solvent is a protic solvent, preferably water or an alcohol such as ethanol.
  • 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.
  • a temperature range described herein 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
  • Another aspect of this invention relates to a method for the modulation of the catalytic activity of a PK by contacting a PK with a compound of this invention or a physiologically acceptable salt or prodrug thereof.
  • PK refers to receptor protein tyrosine kinase (RTKs) , non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threonine kinases (STKs) .
  • RTKs receptor protein tyrosine kinase
  • CTKs non-receptor or “cellular” tyrosine kinase
  • STKs serine-threonine kinases
  • modulation refers to the alteration of the catalytic activity of RTKs, CTKs and STKs.
  • 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.
  • 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.
  • 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.
  • 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.
  • the ability of a particular compound to affect a PK related disorder i.e., the IC 50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • 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 .
  • a further aspect of this invention is that the modulation of the catalytic activity of PKs using a compound of this invention may be carried out in vitro or in vivo .
  • In vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
  • in vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat, rabbit ot human being.
  • a still further aspect of this invention is that the protein kinase whose catalytic activity is being modulated by a compound of this invention is selected from the group consisting of receptor protein tyrosine kinases, a cellular (or non-receptor) tyrosine kinases and serine-threonine kinases .
  • 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-IR, IRR, PDGFR ⁇ , PDGFR ⁇ , CSFIR, C-Kit, C-fms, Flk-IR, 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.
  • 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 .
  • a pharmaceutical composition of a compound of this invention with a pharmaceutically acceptable carrier or excipient is yet another aspect of this invention.
  • Such pharmaceutical composition may contain both carriers and excipients as well as other components generally known to those skilled in the formulation of pharmaceutical compositions .
  • a method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound, salt or prodrug of this invention to an organism in need of such treatment is another aspect of this invention.
  • PK related disorder As used herein, "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.
  • the terms “prevent”, “preventing” and “prevention” refer to a method for barring an organism from acquiring a PK related disorder in the first place.
  • the terms “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.
  • 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.
  • a 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.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
  • the above- referenced protein kinase related disorder is selected from the group consisting of a receptor protein tyrosine kinase related disorder, a cellular tyrosine kinase disorder and a serine-threonine kinase related disorder.
  • the above referenced protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder.
  • the above referenced protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, sarcomas such as Kaposi ' s sarcoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer and glioma in a further aspect of this invention.
  • squamous cell carcinoma sarcomas such as Kaposi ' s sarcoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer and glioma in a further aspect of this invention.
  • the above referenced protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, von Hippel-Lindau disease, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • 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.
  • immunological disorders such as autoimmune disease (AIDS) and cardiovasular disorders such as atherosclerosis.
  • cardiovasular disorders such as atherosclerosis.
  • a chemical compound that modulates the catalytic activity of a protein kinase may be identified by contacting cells expressing said protein kinase with a compound, salt or prodrug of the present invention and then monitoring said cells for an effect.
  • monitoring is meant 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.
  • 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.
  • 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.
  • a "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.
  • 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.
  • 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, triethylenethiophospho
  • alkylating agents such as flu
  • a compound, salt or prodrug of this invention might be expected to have a beneficial effect 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.
  • 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
  • purine analogs such as mercaptopurine
  • a compound, salt or prodrug of this invention might also be expected to prove efficacious 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-a
  • a compound, salt or prodrug of this invention might be expected to have a beneficial effect 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.
  • substituted ureas such as hydroxyurea
  • methylhydrazine derivatives e.
  • combination of a compound of this invention might be expected to be particularly 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.
  • TABLE 1 shows the chemical structures of some exemplary compounds of this invention.
  • 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.
  • TABLE 2 shows the results of biological testing of some exemplary compounds of this invention. The results are reported in terms of IC 50 , 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.
  • the bioassays used are described in detail below. 2.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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 .
  • 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
  • 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.
  • 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 may thus have utility as in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
  • the protein kinase is a protein tyrosine kinase, more particularly, a receptor protein tyrosine kinase.
  • receptor protein tyrosine kinases whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, EGF, HER2 , HER3 , HER4 , IR, IGF-IR, IRR, PDGFR ⁇ , PDGFR ⁇ , CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.
  • the protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt or a prodrug thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK) .
  • CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with a compound or salt of this invention.
  • Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf .
  • this invention relates to a method for treating or preventing a PK related disorder by administering a therapeutically effective amount of a compound of this invention, or a salt or a prodrug thereof, to an organism. It is also an aspect of this invention that a pharmaceutical composition containing a compound of this invention or a salt or prodrug thereof is administered to an organism for the purpose of preventing or treating a PK related disorder.
  • This invention is therefore directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as 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.
  • disorders related to inappropriate PK activity are cell proliferative disorders, fibrotic disorders and metabolic disorders.
  • 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.
  • VEGF vascular endothelial growth factor
  • 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.
  • 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 ; Folkha , 1991, J. Natl. Cancer Inst . , 82:4-6; Weidner, et al . , 1991, New Engl . J . Med . , 324:1-5.
  • VEGF endothelial growth factor
  • VEGF endothelial growth factor
  • vasculogenesis indicates an important role for the KDR/FLK-l receptor in these processes.
  • Diseases such as diabetes mellitus (Folkman, 198, in Xlth 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.
  • VEGF vascular endothelial growth factor
  • 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-l 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 .
  • one aspect of the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-l 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-l when activated by ligands such as VEGF.
  • KDR/FLK-l receptor signal transduction that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-l when activated by ligands such as VEGF.
  • 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.
  • murine FLK-I binds human VEGF with the same affinity as mouse VEGF, and accordingly, is activated by the ligand derived from either species. Millauer et al . , 1993, Cell, 72:835-846; Quinn et al., 1993, Proc. Natl. Acad. Sci. USA, 90:7533-7537. FLK-1 also associates with and subsequently tyrosine phosphorylates human RTK substrates (e.g., PLC- ⁇ or p85) when co-expressed in 293 cells (human embryonal kidney fibroblasts) .
  • RTK substrates e.g., PLC- ⁇ or p85
  • Models which rely upon the FLK-1 receptor therefore are directly applicable to understanding the KDR receptor.
  • 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.
  • chemical compounds identified as inhibitors of KDR/FLK-l 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-l induced signal transduction pathway.
  • this invention is directed to compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-l receptor and interfering with the signal transduced by KDR/FLK-l.
  • the present invention is directed to compounds which regulate, modulate and/or inhibit the KDR/FLK-l mediated signal transduction pathway as 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.
  • data suggest 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.
  • a further aspect of this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 receptor.
  • 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,
  • the close homology of the intracellular regions of KDR/FLK-l with that of the PDGF- ⁇ receptor (50.3% homology) and/or the related flt-1 receptor indicates the induction of overlapping signal transduction pathways.
  • the PDGF- ⁇ receptor members of the src family (Twamley et al . ,
  • KDR/FLK-l signal transduction pathways activated by KDR/FLK-l include the ras pathway (Rozakis et al . , 1992, Nature ,
  • PI -3 ' -kinase the PI -3 ' -kinase
  • src-mediated the plc ⁇ - mediated pathways.
  • Each of these pathways may play a critical role in the angiogenic and/or vasculogenic effect of KDR/FLK-l 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.
  • 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.
  • Fibrotic disorders refer to the abnormal formation of extracellular matrices.
  • 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.
  • 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.
  • PKs have been associated with cell proliferative disorders.
  • PKs such as, for example, members of the RTK family have been associated with the development of cancer.
  • Some of these receptors like EGFR (Tuzi et al . , 1991, Br. J. Cancer 63:227- 233, Torp et al . , 1992, APMIS 100:713-719)
  • HER2/neu Slamon et al., 1989, Science 244:707-712
  • PDGF-R Kerabe et al .
  • 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.
  • 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 .
  • 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.
  • IGF-I small lung tumor cells
  • IGF-I insulin growth factor-I
  • fibroblasts epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)
  • IGF-I the stem cells of the bone marrow
  • Baserga suggests 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.
  • STKs have been implicated in many types of cancer including, notably, breast cancer (Cance, et al . , Int. J. Cancer, 54:571-77 (1993)).
  • RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas .
  • diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas .
  • EGFR has been indicated in corneal and dermal wound healing.
  • Defects in Insulin-R and IGF-IR 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.
  • 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.
  • mutated src v-src
  • pp60 v"src oncoprotein
  • pp60 c"src transmits oncogenic signals of many receptors.
  • Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp60 c src , which is characteristic of malignant cells but absent in normal cells.
  • 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.
  • Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders.
  • STKs have been associated with inflamation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis .
  • the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
  • a method for identifying a chemical compound that modulates the catalytic activity of one or more of the above discussed protein kinases is another aspect of this invention.
  • the method involves contacting cells expressing the desired protein kinase with a compound of this invention (or its salt or prodrug) and monitoring the cells for any effect that the compound has on them.
  • the effect may be any observable, either to the naked eye or through the use of instrumentation, change or absence of change in a cell phenotype.
  • the change or absence of change in the cell phenotype monitored may be, for example, without limitation, a change or absence of change in the catalytic activity of the protein kinase in the cells or a change or absence of change in the interaction of the protein kinase with a natural binding partner.
  • a compound of the present invention, a prodrug thereof or a physiologically acceptable salt of either the compound or its prodrug 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) .
  • suitable carriers or excipient s
  • administer refers to the delivery of a compound, salt or prodrug of the present invention or of a pharmaceutical composition containing a compound, salt or prodrug of this invention to an organism for the purpose of prevention or treatment of a PK-related disorder.
  • 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 ary oral and parenteral.
  • 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.
  • 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.
  • 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.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • 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) .
  • 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.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings 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.
  • 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.
  • 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.
  • 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.
  • a suitable propellant e.g., without limitation, dichlorodifluoromethane , trichlorofluoromethane , dichlorotetra- fluoroethane or carbon dioxide.
  • 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.
  • 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.
  • compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
  • 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.
  • 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.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • 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 .
  • 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.
  • 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 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of such a co- solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM, 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.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • 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.
  • additional strategies for protein stabilization may be employed.
  • compositions herein also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase 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.
  • 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.
  • 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, 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 . ) .
  • an appropriate base e.g. sodium hydroxide (NaOH) , potassium hydroxide (
  • 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, i.e., the modulation of PK activity or the treatment or prevention of a PK-related disorder.
  • 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.
  • the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the IC 50 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.
  • 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 IC 50 and the LD 50 (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.l).
  • 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) .
  • MECs minimal effective concentrations
  • 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.
  • HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • 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 .
  • 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. Packaging.
  • compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration.
  • Such notice for example, may be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like.
  • the compounds of this invention may be readily synthesized using techniques well known in the chemical arts. It will be appreciated by those skilled in the art that other synthetic pathways for forming the compounds of the invention are available and that the following is offered by way of example and not limitation. General synthetic procedures.
  • 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.
  • 5-Nitro-2 -oxindole 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 diester was dissolved in a mixture of 6.4 g of lithium chloride and 2.7 mL of water in 100 mL of dimethylsulfoxide and heated to 100 °C for 3 hours.
  • the reaction was cooled and poured into a mixture of ethyl acetate and brine.
  • the organic phase was washed with brine, dried with sodium sulfate, concentrated and chromatographed on silica gel (10 % ethyl acetate in hexane) . The fractions containing product were evaporated to give 25.7 g of methyl 2-nitro-4- trifluoromethylphenylacetate .
  • reaction mixture was then stirred at 100 °C for 1.0 h and then cooled to room temperature.
  • 2-Chloro-3-methoxycarbonyl- nitrobenzene (2.15 g) was added to the above mixture in one portion and the mixture was heated to 100 °C for 1.5 h.
  • the reaction mixture was then cooled to room temperature and 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-nitrophenylmalonate .
  • Chloral hydrate (9.6 g) was dissolved in 200 mL of water containing 83 g of sodium sulfate. The solution was warmed to 60 °C, a solution of 11.4 g of hydroxylamine hydrochloride in 50 mL of water was added and the mixture was held at 60 °C. In a separate flask, 6.4 g of 4-anisidine and 4.3 mL of concentrated hydrochloric acid in 80 L of water was warmed to 80 °C. The first solution was added to the second and the mixture refluxed for 2 minutes after which it was cooled slowly to room temperature and then cooled in an ice bath. The tan precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 8.6 g ( 85% yield) of N- (2-hydroximino-acetyl) anisidine .
  • the reaction mixture was cooled to room temperature and 50 mL of water was added.
  • the mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid.
  • the solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4- anisidine.
  • the filtrate was concentrated and chromatographed on silica gel eluting with ethyl acetate : hexane (1:1) to give 0.7 g of 5 -methoxy-2 -oxindole as a yellow solid.
  • 3-Dibromo-7-azaoxindole (2.9 g) was dissolved in a mixture of 20 mL of acetic acid and 30 mL of acetonitrile . To the solution was added 6.5 g of zinc dust. The mixture was stirred for 2 hrs at room temperature. The solid was filtered from the mixture and the solvent evaporated. The residue was slurried with ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel. The collected ethyl acetate solution was evaporated and the residue dried under vacuum to give 1.8 g (yield 91%) of 7-azaoxindole acetic acid salt.
  • 5-Dimethylaminosulfonyl-2 -oxindole A suspension of 2.3 g 5-chlorosulfonyl-2-oxindole in 10 mL 2M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid formed. The precipitate was collected by vacuum filtration, washed with 5 mL of IN sodium hydroxide and 5 mL of IN hydrochloric ] _ o g
  • Tetrakis (triphenylphosphine) palladium (0.8 g) was added to a mixture of 5 g 3-methoxyphenylboronic acid, 5 g 5-bromo- 2-fluoro- nitrobenzene and 11 mL of 2 M sodium carbonate solution in 100 mL of toluene. The mixture was refluxed for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and brine and then dried and concentrated to give an oily solid.
  • the anisole (1 equivalent) , dimethylformamide (1-3 equivalents) and phosphorus oxychloride (1-3 equivalents) are heated to 100° C for 1-3 hours.
  • the reaction mixture is cooled to room temperature and dichloromethane is added.
  • the mixture is cooled in ice and water is then added, followed by 4-12 equivalents of concentrated sodium hydroxide until a pH of 9- 10 is reached.
  • the organic layer is separated and washed with water and then with brine, dried over anhydrous sodium sulfate and evaporated to give the crude aldehyde.
  • the crude aledehyde is dissolved in boiling hexane containing activated carbon and the hexane solution is decanted and filtered hot through a layer of silica gel. The filtrate is evaporated to dryness to give the benzaldhyde derivative.
  • POCl 3 (1.1 equiv.) is added dropwise to dimethylformamide (3 equiv. ) in dichloromethane at -10° C followed by the appropriate pyrrole. After stirring for two hours, the reaction mixture is diluted with H 2 0 and basified to pH 11 with 10 N KOH. The precipitate which forms is collected by filtration, washed with H 2 0 and dried in a vacuum oven to give the desired aldehyde.
  • Ethyl indole-2-carboxylate (10 g, 52.8 mmol) was formylated using POCl 3 (1.3 equiv.) and DMF (1.3 equiv.) as above to give 3 -formyl-lH-indole-2 -carboxylic acid ethyl ester as a white solid.
  • Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl) triphenylphosphonium bromide in THF (0.2 M) at 0°C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3 -formyl-lH-indole-2 -carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM.
  • 3- (3-Dimethylaminopropenyl) -lH-indole-2 -carboxylic acid ethyl ester was hydrogenated using 10% palladium over carbon to reduce the double bond followed by a lithium aluminum hydride (LAH) reduction of the ester group to an alcohol resulting in the formation of [3- (3-dimethylaminopropyl) -1H- indol -2 -yl] methanol as an orange oil.
  • LAH lithium aluminum hydride
  • Lithium aluminum hydride (LAH, 4 equiv.) is added dropwise to a suspension of the appropriate amido-keto-tetrahydroindole (1 equiv.) in THF (0.5 M) . The mixture is refluxed overnight. The mixture is then cooled and water is added carefully until no more gas is generated, then a few drops of 15% NaOH/water is added. The mixture is then stirred at room temperature for 0.5 hr and filtered to remove insoluble materials. The filtrate is concentrated to give the amino-tetrahydroindole .
  • LAH Lithium aluminum hydride
  • Step 2 To a suspension of 10 g of the product of step 1 (48 mmol) in dichloromethane (60 mL) was added 9.3 g (57.6 mmol) of 1, 1 ' -carbonyldiimidazole . The mixture was stirred at room temperature for 2 hours and then 5.3 mL (48 mmol) 1- methylpiperazine and 8.4 mL (48 mmol) N,N-diisopropylethyl- amine was added. The dark red reaction mixture was then stirred at room temperature overnight.
  • Step 3 LAH (2.6 g, 68 mmol) was added dropwise to a suspension of 3- [3- (4-methylpiperazin-l-yl) -3 -oxo-propyl] - 1, 5, 6, 7-tetrahydroindol-4-one (5g, 17 mmol) in THF (300 mL) . The mixture was then refluxed overnight . The mixture was then cooled and 2.6 mL each of water followed by a few drops of 15% NaOH was added. The reaction was stirred at room temperature for 30 min and then filtered to remove insolubles .
  • Step 4 POCl 3 (1.8 mL, 18.9 mmol) was added dropwise to N,N-dimethylformamide (DMF, 3.8 mL, 51.6 mmol) at -5° C. The mixture was then allowed to come to room temperature and then stirred for 30 minutes after which it was again cooled to -5°C. A solution of 3- [3- (4-methylpiperazin-l-yl) -propyl] -4 , 5, 6, 7- tetrahydro-lH-indole (4.5 g, 17.2 mmol) in DMF (9 mL) was added dropwise. The mixture was again allowed to come to room temperature and then stirred at that temperature overnight. The reaction was then quenched with ice, followed by 10 N NaOH to adjust the pH to 10-11. After stirring at room temperature for 1 hr, the reaction was extracted with ethyl acetate
  • Step 2 N, N-Dimethyl -3 - (4-oxo-4, 5,6, 7-tetrahydro-lH- indol-3-yl) -propionamide:
  • Step 3 Dimethyl- [3- (4, 5, 6, 7-tetrahydro-lH-indol-3- yl ) propyl 1 - amine :
  • Step 4 3- (3 -Dimethylaminopropyl) -4,5,6, 7-tetrahydro-lH- indole-2-carbaldehyde:
  • Step 2 3- (3-Oxo-3-pyrrolidin-l-ylpropyl) -1,5,6,7- tetrahvdroindol-4-one : 'HNMR (300 MHz, DMSO-d6) ⁇ 11.05 (br s, IH, NH) , 6.46 (d,
  • Step 4 3- (3-Pyrrolidin-l-ylpropyl) -4,5,6, 7-tetrahydro- lH-indole-2-carbaldehvde :
  • Step 2 N, N-Diethyl - 3 - (4-oxo-4 ,5,6, 7-tetrahydro-lH-indol- 3-yl) -propionamide:
  • Step 4 3- (3-Diethylaminopropyl) -4,5,6, 7-tetrahydro-lH- indole-2-carbaldehyde :
  • Step 1 A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol) , 5, 5-dimethyl-l, 3-cyclohexandione (1.4 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was stirred at 110° C for 4 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with 30% of ethanol (EtOH) in water and dried under vacuum to give 1.6 g (68%) of 3- (4-oxo-6-dimethyl-4 , 5, 6, 7-tetrahydro-lH- indol -3 -yl) propionic acid.
  • Step 2 To a suspension of 1.18 g (5 mmol) of the product of step 1 in dichloromethane (25 mL) was added 0.97 g (6 mmol) of CDI . After stirring at room temperature for 2 hr, 2.1 mL (20 mmol) diethylamine was added. The mixture was stirred at room temperature overnight. The reaction was concentrate and the residue was dissolved in dichloromethane, washed with brine, dried and concentrated to give 1.2 g (83%) of 3- (6, 6- dimethyl-4-oxo-4, 5,6, 7-tetrahydro-lH-indol-3-yl) - ⁇ N-diethyl propionamide as a white solid.
  • Step 3 LAH (0.57 g, 15.1 mmol) was added dropwise to a suspension of 3- (6 , 6-dimethyl -4 -oxo-4 , 5 , 6 , 7-tetrahydro-lH- indol-3-yl) -N, N-diethylpropionamide (1.1 g, 3.8 mmol) in THF (80 mL) . The mixture was refluxed overnight. The reaction was cooled and ice was added until no more gas was generated. A few drops of 15% ⁇ aOH in water was then added. The mixture was stirred at room temperature for 30 minutes and then filtered to remove insolubles .
  • Step 4 P0C1 3 (0.35 mL, 3.74 mmol) was added dropwise to DMF (0.8 mL, 10.3 mmol) at -5° C. After stirring at room temperature for 30 min, the mixture was cooled to -5°C. A solution of [3- (6, 6-dimethyl-4 , 5, 6, 7-tetrahydro-lH-indol-3- yl) -propyl] -diethylamine (0.9 g, 3.4 mmol) in DMF (2 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours and then quenched with ice, followed by 10 N KOH to adjust pH to 10-11.
  • Step 2 6 , 6-Dimethyl-3- (3-oxo-3-pyrrolidin-l-ylpropyl) -
  • Step 3 s 6 6-Dimethyl-3- (3-pyrrolidin-l-ylpropyl) -4,5,6,7- tetrahydro-lH-indole
  • Step 2 6 , 6-Dimethyl-3- f3- (4-methylpiperazin-l-yl) -3-oxo- propyll -1,5,6, 7-tetrahydroindol-4-one
  • Step 3 6 , 6-Dimethyl-3- ⁇ 3- (4-methylpiperazin-l-yl) - propyl] -4,5,6, 7-tetrahvdro-lH-indole
  • Step 4 6 , 6-Dimethyl-3- [3- (4-methylpiperazin-l-yl) - propyl] -4,5,6, 7-tetrahvdro-lH-indole-2-carbaldehvde
  • Step 2 6 , 6-Dimethyl-3- (3-morpholin-4-yl-3-oxopropyl) - 1.5,6, 7-tetrahvdroindol-4-one
  • Step 3 6, 6-Dimethyl-3 - (3-morpholin-4-ylpropyl) -4,5,6,7- tetrahvdro-lH-indole
  • Step 4 6, 6-Dimethyl-3- (3-morpholin-4-ylpropyl) -4,5,6,7- tetrahvdro-lH-indole-2-carbaldehyde 1 HNMR (360 MHz, DMS0-d6) ⁇ 11.25 (br, s, IH, NH) , 9.43 (s, IH, CHO), 3.54 (m, 4H, 2xCH 2 ) , 2.63 (t, 2H, CH 2 ) , 2.20-2.37 (m, 10 H, 5xCH 2 ) , 1.62 (m, 2H, CH 2 ) , 1.45 (t, 2H, CH 2 ) , 0.93 (s, 6H, 2xCH 3 ) .
  • Step 2 3- (6, 6 -Dimethyl -4 -oxo- 4 , 5,6, 7-tetrahydro-lH- indol - 3 -yl ) -N, N-dimethylpropionamide
  • Step 3 f3- (6, 6-Dimethyl-4 , 5,6, 7-tetrahydro-lH-indol-3- 10 yl) -propyl] dimethyl amine
  • the aminooxindole is first protected with a BOC- group. After the condensation with the appropriate aldehyde, the solid which forms is deprotected using trifluoroacetic acid to yield the desired product.
  • Example 1 3- (3 , 5-Piisopropyl-4 -methoxybenzylidene) -1,3- dihydroindol-2 -one 3, 5-Diisopropyl-4-hydroxybenzaldehyde was methylated to give 3, 5-diisopropyl-4-methoxybenzaldehyde .
  • 5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5 -chloro-2 -oxindole to give 0.3 g of 5-chloro-3- (3 , 5- diisopropyl -4 -methoxybenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 ml). The mixture was heated at 90° C for 10 hours. The reaction mixture was cooled and adjusted to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 ml) . Insoluble materials were removed by filtration and washed with ethanol (5 x 60 ml) . The combined ethanol solutions were evaporated and the solid obtained was dried under vacuum to give 15g of 6-amino-2 -oxindole as a brown powder.
  • 5-Diisopropyl-4 -methoxybenzaldehyde was condensed with 5-acetyl-2 -oxindole to give 0.3 g of 5-Acetyl-3- (3 , 5- diisopropyl -4 -methoxybenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • 2-Oxindole (82.9 g) was suspended in 630 ml of acetic acid in a reaction vessel equipped with mechanical stirring and the mixture cooled to 10° C in an ice water bath.
  • Solid N- iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1 hour at 10° C. The suspended solid which was always present became very thick at this time. The solid was collected by vacuum filtration, washed with 100 ml of 50% acetic acid in water and then with 200 ml of water and subjected to vacuum filtration for 20 minutes to partially air dry it. The product was then dried under vacuum to give 93.5 g (36%) of 5-iodo-2- oxindole containing about 5% 2-oxindole by proton NMR.
  • Example 7 3- (3-Isopropyl-4-methoxybenzylidene) -1.3- dihvdroindol-2 -one 2-Isopropylphenol was methylated and then formylated to give 3 -isopropyl-4 -methoxybenzaldehyde . 3 -Isopropyl -4- methoxybenzaldehyde was condensed with 2-oxindole to give 0.3 g of 3- (3 -isopropyl -4 -methoxybenzylidene) -1, 3 -dihydroindol -2- one as a yellow-orange solid.
  • 5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-chloro-2 -oxindole to give 0.3 g of 5-Chloro-3- (5- isopropyl-4 -methoxy-2 -methylbenzylidene) -1 , 3 -dihydroindol-2- one as a yellow-orange solid.
  • 3 -Cyclopentyl-4 -methoxybenzaldehyde was condensed with 2- oxindole to give 0.25 g of 3- (3 -Cyclopentyl -4- methoxybenzylidene) -1, 3 -dihydro-indol -2 -one as a yellow-orange solid.
  • Example 11 3- (3 -Cyclopentyl-4 -methoxybenzylidene) -5- fluoro-1.3 -dihydroindol-2 -one
  • the aldehyde was condensed with oxindole to give 0.3 g of 3- (3 -Cyclohexyl -4 -methoxybenzylidene) -1, 3 -dihydroindol-2 -one as a yellow-orange solid.
  • Triphenylphosphine (7.47 g, 19.58 mmol) was added to a solution of 2-cyclohexyl-4-chlorophenol (6 g, 28.48 mmol) and 2-hydroxyethylmorpholine (3.5 g, 28.48 mmol) in tetrahydrofuran (50 ml) , followed by the dropwise addition of diethylazodicarboxylate (4.5 ml, 28.48 mmol). The mixture stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and triturated with dichloromethane/ hexanes and then washed with more hexanes.
  • the acid wash was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2 x 200 ml) .
  • the combined organic layers were washed with brine (200 ml) , dried over magnesium sulfate and concentrated.
  • the combined solids were dissolved in dichloromethane (25 ml) and precipitated with diethyl ether (500 ml) to afford 1.6g of a mustard yellow solid.
  • the solid was dissolved in methanol
  • Example 17 3- (3 , 5-Diisopropyl-4-methoxybenzylidene) -5- methoxy-1, 3 -dihydroindol-2 -one 3, 5-Diisopropyl-4-hydroxybenzaldehyde was methylated to give 3, 5-diisopropyl-4-methoxybenzaldehyde .
  • Example 18 N- [3- (4-Methoxy-3-thiophene-3-ylbenzylidene) -2- oxo-2 , 3 -dihydro-IH-indol-6-yll -acetamide Tetrakis (triphenylphos ⁇ hine)palladium(O) (1.35 g) was added to a solution of 4-methoxy-3-bromobenzaldehyde (6.72 g) in toluene (45 ml) and ethanol (45 ml) , followed by addition of 2M aqueous sodium carbonate (80 ml) .
  • Example 20 5-Amino-3- (3 , 5-diisopropyl-4 -methoxybenzylidene) -1, 3 -dihydroindol-2 -one 2 -Oxindole (6.5 g) was dissolved in concentrated sulfuric acid (25 ml) and the mixture maintained at -10 to 15°C while fuming nitric acid (2.1 ml) was added dropwise. After the addition of the nitric acid the reaction mixture was stirred at 0°C for 0.5 hour and poured into ice-water. The precipitate which formed was collected by filtration, washed with water and crystallized from 50% acetic acid.
  • Example 22 3- (3 , 5-Diisopropyl-4-methoxybenzylidene) -6- fluoro-1.3-dihydroindol-2 -one
  • Example 23 3- (2.2 -Dimethylchroman-6-ylmethylene) -5-fluoro- 1, 3-dihydroindol-2 -one 2 , 2-Dimethyl-6-formylchromane (commercially available) was condensed with 5-fluoro-2 -oxindole to give 0.3 g of 3- (2 , 2 -Dimethylchroman-6-ylmethylene) -5-fluoro-1, 3 -dihydroindol- 2-one as a yellow-orange solid.
  • Example 24 5-Chloro-3- [3 , 5-diisopropyl-4- (2-morpholin-4- ylethoxy) -benzylidene] -1.3 -dihydroindol-2 -one
  • Triphenylphosphine (5.14 g, 19.58 mmol) was added to a solution of 3 , 5-diisopropyl-4 -hydroxybenzaldehyde (4 g, 19.58 mmol) in tetrahydrofuran (40 ml) followed by addition of 2- hydroxyethylmorpholine (2.57 g, 19.58 mmol) and then the dropwise addition of diethylazodicarboxylate (3.41 g, 19.58 mmol) . The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml) .
  • the aqueous layer was extracted with ethyl acetate (2 x 150ml) , basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3 x 150 ml) .
  • the organic layers were combined, dried over magnesium sulfate and concentrated to afford 900 mg (14%) of 3 , 5-diisopropyl-4- (2- morpholin-4-ylethoxy) -benzaldehyde as a yellowish oil.
  • Example 25 3- (3 , 5-Diisopropyl-4 -methoxybenzylidene) -7- fluoro-1, 3-dihvdroindol-2-one 3 , 5-Diisopropyl-4-methoxybenzaldehyde was condensed with 7-fluoro-2 -oxindole to give 0.25 g of 3- (3 , 5 -diisopropyl-4- methoxybenzylidene) -7-fluoro-1, 3-dihydroindol-2-one as a yellow-orange solid.
  • Example 26 3- (4-Methoxy-3-thiophen-3-ylbenzylidene) -5- (2- morpholin-4-yl-ethyl) -1, 3 -dihydroindol-2 -one
  • Example 28 3- (3 , 5-Diisopropyl-4 -methoxybenzylidene) -5- ethyl-1,3 -dihydroindol-2-one 2 -Oxindole (3 g) suspended in 1 , 2-dichloroethane was slowly treated with 3.2 ml of acetyl chloride. The resulting suspension was stirred at 50°C for 5 hours, cooled, and poured into water. The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73 % yield) of 5-acetyl-2-oxindole as a brown solid.
  • Tetrakis (triphenylphosphine) palladium (0) (0.02 g, 0.02 mmol) was added to a solution of 3- (3 -Bromo-4 -methoxybenzylidene) -1, 3 -dihydroindol-2 -one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (2 ml) , followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol) . To this mixture was added 3-acetamidophenylboronic acid (0.12 g, 0.67 mmol), and the mixture was heated to 100°C in a sealed tube and held there for 12 hours.
  • the reaction was then poured into water (50 ml) and extracted with ethyl acetate (2x100 ml) .
  • the combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml) .
  • the organic layer was dried over magnesium sulfate and concentrated.
  • Tetrakis (triphenylphosphine) palladium(O) (0.24 g) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g) in toluene (15 ml) and ethanol (15 ml) , followed by addition of 2M aqueous sodium carbonate (14 ml) .
  • To this mixture was added thiophene-2 -boronic acid (0.98 g) , and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 ml) and ethyl acetate (250 ml) .
  • 5-Diisopropyl-4 -methoxybenzaldehyde was condensed with 6-amino-2 -oxindole to give 0.3 g of 6-amino-3- (3 , 5- diisopropyl-4-methoxybenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Tetrakis (triphenylphosphine) palladium (0) (0.02 g, 0.02 mmol) was added to a solution of 3- (3 -bromo-4 -methoxybenzylidene) -1, 3 -dihydroindol-2 -one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml) , followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added thiophene-3-boronic acid (0.09 g, 0.67 mmol) and the mixture was held at 100°C in a sealed tube for 12 hours.
  • Example 36 5-Bromo-3 - (5-isopropyl-4-methoxy-2 -methyl- benzylidene) -1, 3 -dihydroindol-2 -one 5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-bromo-2 -oxindole to give 0.3 g of 5-bromo-3- (5- isopropyl-4 -methoxy-2 -methylbenzylidene) -1, 3 -dihydroindol-2- one as a yellow-orange solid.
  • Example 37 5-Fluoro-3- (6-me hoxybiphenyl-3 -ylmethylene) - 1, 3 -dihydroindol-2 -one 4 -Methoxy-3 -phenylbenzaldehyde was condensed with 5- fluoro-2 -oxindole to give 0.3 g of 5-fluoro-3- (6- methoxybiphenyl-3 -ylmethylene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Example 38 3- (3 -Isopropyl-4 -methoxybenzylidene) -4 -methyl- 1.3-dihvdroindol-2-one
  • Example 39 3- (4.5-Dimethoxy-2-thiophen-2-ylbenzylidene) - 1, 3-dihydroindol-2-one
  • a mixture of 6-bromoveratraldehyde (1 g, 4.08 mmol), oxindole (0.54 g, 4.08 mmol) and pyrrolidine (1.7 ml, 20.4 mmol) in dimethylformamide (6 ml) was held in a sealed tube at 100°C for 12 hours.
  • the reaction mixture was cooled and added to IN hydrochloric acid (100 ml) .
  • the precipitate which formed was filtered and washed with water.
  • Tetrakis (triphenylphosphine) palladium (0) (0.03 g, 0.03 mmol) was added to a solution of 3- (3-bromo-4 , 5- dimethoxybenzylidene) -1, 3 -dihydroindol -2 -one (0.32 g, 0.89 mmol) in toluene (2 ml) and ethanol (2 ml) , followed by additiona of 2M aqueous sodium carbonate (1.8 ml, 3.6 mmol). To this mixture was added thiophene-2 -boronic acid (0.13 g, 0.98 mmol), and the mixture was held at 100°C in a sealed tube for 12 hours.
  • Example 40 N- ⁇ 3- [4- (2-Morpholin-4-ylethoxy) -3-thiophen-2- ylbenzylidene] -2 -oxo-2,3-dihydro-IH-indol-6 -yl ⁇ -acetamide
  • Triphenylphosphine (6.85 g) was added to a solution of 3- bromo-4-hydroxybenzaldehye (5 g) in tetrahydrofuran (40 ml) , followed by addition of 2-hydroxyethylmorpholine (3.01 ml) and then the dropwise addition of diethylazodicarboxylate (4.11 ml) . After 12 hours, the reaction was concentrated under reduced pressure, poured into 2N hydrochloric acid (200 ml) and extracted with ethyl acetate (2x 150 ml) . The aqueous layer was basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (2 x 150 ml) . The organic layers were dried over magnesium sulfate and concentrated to afford 4.4 g (56%) of 4-morpholinoethoxy-3-bromobenzaldehyde as a reddish oil.
  • Tetrakis (triphenylphosphine) palladium (0) (0.23) was added to a solution of 4-morpholinoethoxy-3-bromobenzaldehyde (2.13 g) in toluene (10 ml) and ethanol (10 ml) , followed by addition of 2M aqueous sodium carbonate (13 ml) . To this mixture was added thiophene-2-boronic acid (1.13 g) , and the mixture was refluxed for 12 hours. The reaction mixture was then poured into water (100 ml) and extracted into ethyl acetate (3 x' 100 ml) .
  • Example 41 3- (2 , 2 -Dimethylchroman-6-ylmethylene) -4-methyl- 1.3 -dihydroindol-2 -one
  • Example 42 3- (2 , 3 -Dihydrobenzofuran-5-ylmethylene) -5- fluoro-1, 3-dihvdroindol-2-one 2 , 3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 5-fluoro-2 -oxindole to give 0.25 g of 3-
  • Tetrakis (triphenylphosphine) palladium (0) (0.02 g, 0.02 mmol) was added to a solution of 3- (bromo-4-methoxybenzylidene) -1 , 3 -dihydroindol-2 -one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml) , followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol) . To this mixture was added 3-ethoxyphenylboronic acid (0.11 g, 0.67 mmol), and the mixture was held atl00°C in a sealed tube for 12 hours.
  • the reaction mixture was added to water (40 ml) and extracted with ethyl acetate (75 ml) .
  • the combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml) .
  • the organic layer was dried over magnesium sulfate and concentrated.
  • the resulting solid was triturated with dichloromethane/ hexanes to afford 0.9 g (39%) of 3-(3'- ethoxy-6-methoxy-biphenyl-3 -ylmethylene) -1 , 3 -dihydroindol -2 - one as a yellow solid.
  • Example 48 3- (3 -Cyclopentyl-4-methoxybenzylidene) -4- methyl-1, 3 -dihydroindol-2 -one 3 -Cyclopentyl-4 -methoxybenzaldehyde was condensed with 4- methyl-2 -oxindole to give 0.25 g of 3- (3-cyclopentyl-4- methoxybenzylidene) -4-methyl-l, 3 -dihydroindol-2- as a yellow- orange solid.
  • Example 49 3- (4.5 , 2 ' -Trimethoxybiphenyl-2-ylmethylene) - 1, 3 -dihydroindol-2 -one Tetrakis (triphenylphosphine) palladium(O) (0.02 g, 0.02 mmol) was added to a solution of 3- (3-bromo-4 , 5- dimethoxybenzylidene) -1, 3 -dihydroindol -2 -one (0.20 g, 0.56 mmol) in toluene (1ml) and ethanol (1 ml) , followed by addition of 2M aqueous sodium carbonate (1.1 ml, 2.2 mmol) .
  • Example 50 N- ⁇ 3- [4- (2-Morpholin-4-ylethoxy) -3-th.ioph.en-3- ylbenzylidene] -2-oxo-2 , 3-dihydro-lH-indol-6-yl ⁇ -acetamide
  • Tetrakis (triphenylphosphine) palladium(O) (0.21 g) was added to a solution of 4-morpholinoethoxy-3-bromobenzaldehyde (1.92 g) in toluene (10 ml) and ethanol (10 ml), followed by addition of 2M aqueous sodium carbonate (12 ml) .
  • To this mixture was added thiophene-3 -boronic acid (1.02 g) , and the mixture was heated to reflux. After 12 hours, the reaction mixture was added to water (100 ml) and extracted into ethyl acetate (3 x 100 ml) .
  • Example 52 [3- (3 , 5-Diisopropyl-4-methoxybenzylidene) -2- oxo-2 ,3-dihvdro-lH-indol-6-yl] -carbamic acid tert-butyl ester 3 , 5-Diisopropyl-4 -methoxybenzaldehyde was condensed with
  • Example 53 3- (3 , 5-Diisopropyl-4-methoxybenzylidene) -4- methyl-1, 3 -dihydroindol-2 -one 3, 5-Diisopropyl-4 -methoxybenzaldehyde was condensed with
  • Triphenylphosphine (5.89 g, 22.44 mmol) was added to a solution of 3-tert-butyl-4-hydroxybenzaldehyde (4 g, 22.44 mmol) in tetrahydrofuran (40 ml) , followed by addition of 2- hydroxyethylmorpholine (2.94 g, 22.44 mmol) and then the dropwise addition of diethylazodicarboxylate (3.91 g, 22.44 mmol) . The mixture was allowed to stir at room temperature for 3 days. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml) .
  • the aqueous layer was extracted with ethyl acetate (2 x 150 ml) , basified to pH 9 with solid sodium bicarbonate, saturated with solid sodium chloride and extracted with ethyl acetate (3 x 150 ml) .
  • the combined organic layers were dried over magnesium sulfate and concentrated to afford 2.8 g (44%) of 3-tert-butyl-4- (2- morpholin-4-ylethoxy) benzaldehyde as a yellowish oil.
  • the aldehyde was condensed with 7-aza-2-oxindole to give 0.2 g of 3- (4-methoxy-3 , 5-dimethylbenzylidene) -1, 3- dihydropyrrolo [2 , 3 -b] pyridin-2 -one as a yellow-orange solid.
  • Tetrakis (triphenylphosphine) palladium(O) (0.02 g, 0.02 mmol) was added to a solution of 3- (3-bromo- , 5- dimethoxybenzylidene) -1, 3 -dihydroindol -2 -one (0.2 g, 0.56 mmol) in toluene (1 ml) and ethanol (1 ml) , followed by addition of 2M aqueous sodium carbonate (1 ml, 2mmol) . To this mixture was added 3-ethoxyphenylboronic acid (0.1 g, 0.62 mmol) and the mixture was held at 100°C in a sealed tube for 12 hours.
  • Tetrakis (triphenylphosphine) palladium (0) (0.2 g) was added to a solution of 3-bromo-4-methoxybenzldehyde (1.25 g) in toluene (10 ml) and ethanol (10 ml) , followed by addition of 2M aqueous sodium carbonate (11 ml) .
  • To this mixture was added pyridine-3-boronic acid propane diol (1 g) , and the mixture was heated to reflux. After 2 hours, the reaction was added to water (75 ml) and extracted with ethyl acetate (2x 75 ml) .

Abstract

L'invention concerne de nouveaux composés 3-méthylidényl-2-indolinone ainsi que leurs sels physiologiquement acceptables et leurs promédicaments. Ces composés modulent l'activité des protéines kinases et par conséquent sont supposés convenir à la prévention et au traitement des troubles cellulaires liés à la protéine kinase, comme par exemple le cancer.
PCT/US1999/017845 1998-01-21 1999-08-04 Modulateurs 3-methylidenyl-2-indolinone de proteine kinase WO2000008202A2 (fr)

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JP2000563824A JP2002522452A (ja) 1998-08-04 1999-08-04 蛋白質キナーゼの調節剤３−メチリデニル−２−インドリノン
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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6130239A (en) * 1998-12-17 2000-10-10 Hoffmann-La Roche Inc. 4-Alkenyl- and 4-alkynyloxindoles
US6153634A (en) * 1998-12-17 2000-11-28 Hoffmann-La Roche Inc. 4,5-azolo-oxindoles
US6221867B1 (en) 1998-12-17 2001-04-24 Hoffmann-La Roche Inc. 4,5-pyrazinoxindoles
US6307056B1 (en) 1998-12-17 2001-10-23 Hoffman-La Roche Inc. 4-aryloxindoles
US6313310B1 (en) 1999-12-15 2001-11-06 Hoffmann-La Roche Inc. 4-and 5-alkynyloxindoles and 4-and 5-alkenyloxindoles
WO2001090104A2 (fr) * 2000-05-24 2001-11-29 Pharmacia & Upjohn Company Derives de 1-(pyrrlolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone
WO2001094312A2 (fr) * 2000-06-02 2001-12-13 Sugen, Inc. Derives d'indolinone comme inhibiteurs de phosphatase/proteine kinase
WO2001037820A3 (fr) * 1999-11-24 2001-12-13 Sugen Inc Formulations pour agents pharmaceutiques ionisables comme acides libres ou bases libres
WO2002055517A3 (fr) * 2000-12-20 2002-09-26 Sugen, Inc Indolinones 4-aryl substituees
WO2002081466A1 (fr) * 2001-04-09 2002-10-17 Sugen, Inc. Promedicaments a base de derives 3-(pyrrol-2-ylmethylidene)-2-indolinone
WO2002094809A1 (fr) * 2001-05-24 2002-11-28 Yamanouchi Pharmaceutical Co., Ltd. Derives de 3-quinoleine-2-(1h)-ylideneindoline-2-one
WO2003022815A1 (fr) * 2001-09-10 2003-03-20 Sugen, Inc. Derives de 3-(4,5,6,7-tetrahydroindol-2-ylmethylidene)-2-indolinone comme inhibiteurs de kinases
WO2003027111A1 (fr) * 2001-09-27 2003-04-03 Smithkline Beecham Corporation Composes chimiques
US6569868B2 (en) 1998-04-16 2003-05-27 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
US6599902B2 (en) 2001-05-30 2003-07-29 Sugen, Inc. 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors
WO2004048366A1 (fr) * 2002-11-22 2004-06-10 Yamanouchi Pharmaceutical Co., Ltd. Derives 2-oxoindoline
US6878733B1 (en) 1999-11-24 2005-04-12 Sugen, Inc. Formulations for pharmaceutical agents ionizable as free acids or free bases
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity
US7214700B2 (en) 2000-05-02 2007-05-08 Sugen Inc. (2-Oxindol-3-ylidenyl) acetic acid derivatives and their use as protein kinase inhibitors
EP1814545A2 (fr) * 2004-11-09 2007-08-08 Irm, Llc Composes et compositions utilises comme inhibiteurs de la proteine kinase
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
EP1883403A2 (fr) * 2005-04-29 2008-02-06 The Ohio State University Research Foundation Inhibiteurs specifiques contre la tyrosine du recepteur du facteur de croissance des keratinocytes utiles pour prevenir les metastases cancereuses
WO2009030270A1 (fr) * 2007-09-03 2009-03-12 Novartis Ag Dérivés dhydroindoles utilisés pour traiter la maladie de parkinson
WO2010115279A1 (fr) 2009-04-06 2010-10-14 University Health Network Inhibiteurs de kinases et procédé de traitement du cancer avec ceux-ci
CN101970426A (zh) * 2007-12-21 2011-02-09 大学健康网络 吲唑基、苯并咪唑基、苯并***基取代的二氢吲哚酮衍生物作为癌症治疗中有用的激酶抑制剂
US8193001B2 (en) * 2003-02-05 2012-06-05 Applied Biosystems, Llc Compositions and methods for preserving RNA in biological samples
WO2012142029A2 (fr) * 2011-04-10 2012-10-18 Florida A&M University Modulateurs sélectifs des récepteurs des œstrogènes pour traitement de troubles à médiation par les récepteurs des œstrogènes
WO2014040969A1 (fr) 2012-09-13 2014-03-20 F. Hoffmann-La Roche Ag 2-oxo-2,3-dihydro-indoles destinés au traitement de troubles du snc
US9296730B2 (en) 2012-10-26 2016-03-29 Regents Of The University Of Minnesota Aurora kinase inhibitors
US10487054B2 (en) 2017-04-21 2019-11-26 Regents Of The University Of Minnesota Therapeutic compounds
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5339992A (en) * 1991-07-10 1994-08-23 Societe De Prospection Et D'inventions Techniques (S.P.I.T. Tubular cartridge for storing and applying a non-solid product, and a drive and thrust assembly for the cartridge
US5374652A (en) * 1990-02-28 1994-12-20 Farmitalia Carlo Erba S R L 2-oxindole compounds which are useful as tyrosine kinase inhibitors
US5382593A (en) * 1992-07-21 1995-01-17 Adir Et Compagnie New 3-(hydroxybenzylidenyl)-indolin-2-ones
US5409949A (en) * 1991-07-12 1995-04-25 Farmitalia Carlo Erba S.R.L. Methylen-oxindole derivatives compositions and tyrosine kinase inhibition therewith
US5650415A (en) * 1995-06-07 1997-07-22 Sugen, Inc. Quinoline compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374652A (en) * 1990-02-28 1994-12-20 Farmitalia Carlo Erba S R L 2-oxindole compounds which are useful as tyrosine kinase inhibitors
US5339992A (en) * 1991-07-10 1994-08-23 Societe De Prospection Et D'inventions Techniques (S.P.I.T. Tubular cartridge for storing and applying a non-solid product, and a drive and thrust assembly for the cartridge
US5409949A (en) * 1991-07-12 1995-04-25 Farmitalia Carlo Erba S.R.L. Methylen-oxindole derivatives compositions and tyrosine kinase inhibition therewith
US5382593A (en) * 1992-07-21 1995-01-17 Adir Et Compagnie New 3-(hydroxybenzylidenyl)-indolin-2-ones
US5650415A (en) * 1995-06-07 1997-07-22 Sugen, Inc. Quinoline compounds

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6569868B2 (en) 1998-04-16 2003-05-27 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
US6153634A (en) * 1998-12-17 2000-11-28 Hoffmann-La Roche Inc. 4,5-azolo-oxindoles
US6197804B1 (en) 1998-12-17 2001-03-06 Hoffmann-La Roche Inc. 4,5-azolo-oxindoles
US6221867B1 (en) 1998-12-17 2001-04-24 Hoffmann-La Roche Inc. 4,5-pyrazinoxindoles
US6252086B1 (en) * 1998-12-17 2001-06-26 Hoffmann-La Roche Inc. 4-alkenyl-and 4-alkynyloxindoles
US6303793B1 (en) 1998-12-17 2001-10-16 Hoffmann-La Roche Inc. 4-alkenyl-and 4-alkynyloxindoles
US6307056B1 (en) 1998-12-17 2001-10-23 Hoffman-La Roche Inc. 4-aryloxindoles
US6130239A (en) * 1998-12-17 2000-10-10 Hoffmann-La Roche Inc. 4-Alkenyl- and 4-alkynyloxindoles
US6878733B1 (en) 1999-11-24 2005-04-12 Sugen, Inc. Formulations for pharmaceutical agents ionizable as free acids or free bases
WO2001037820A3 (fr) * 1999-11-24 2001-12-13 Sugen Inc Formulations pour agents pharmaceutiques ionisables comme acides libres ou bases libres
US6313310B1 (en) 1999-12-15 2001-11-06 Hoffmann-La Roche Inc. 4-and 5-alkynyloxindoles and 4-and 5-alkenyloxindoles
US7214700B2 (en) 2000-05-02 2007-05-08 Sugen Inc. (2-Oxindol-3-ylidenyl) acetic acid derivatives and their use as protein kinase inhibitors
WO2001090068A3 (fr) * 2000-05-24 2002-06-06 Sugen Inc Promedicaments a base de mannich de derives de 3-(pyrrol-2-ylmethylidene)-2-indolinone
WO2001090104A2 (fr) * 2000-05-24 2001-11-29 Pharmacia & Upjohn Company Derives de 1-(pyrrlolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone
US6716870B2 (en) 2000-05-24 2004-04-06 Sugen, Inc. Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US6451838B1 (en) 2000-05-24 2002-09-17 Pharmacia & Upjohn Company 1-(pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US6710067B2 (en) 2000-05-24 2004-03-23 Sugen Incorporated Mannich base prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
WO2001090068A2 (fr) * 2000-05-24 2001-11-29 Sugen, Inc. Promedicaments a base de mannich de derives de 3-(pyrrol-2-ylmethylidene)-2-indolinone
US6482848B2 (en) 2000-05-24 2002-11-19 Sugen Incorporated Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US7112603B2 (en) 2000-05-24 2006-09-26 Agouron Pharmaceuticals, Inc. Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US7008943B2 (en) 2000-05-24 2006-03-07 Pharmacia & Upjohn Company 1-(Pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US7053113B2 (en) 2000-05-24 2006-05-30 Sugen, Inc. Mannich base prodrugs of 3-(pyrrol-2-yl-methylidene)-2-indolinone derivatives
WO2001090104A3 (fr) * 2000-05-24 2002-06-13 Upjohn Co Derives de 1-(pyrrlolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone
US7071332B2 (en) 2000-06-02 2006-07-04 Sugen, Inc. Indolinone derivatives as protein kinase/phosphatase inhibitors
US6706709B2 (en) 2000-06-02 2004-03-16 Sugen, Inc. Indolinone derivatives as protein kinase/phosphatase inhibitors
WO2001094312A2 (fr) * 2000-06-02 2001-12-13 Sugen, Inc. Derives d'indolinone comme inhibiteurs de phosphatase/proteine kinase
WO2001094312A3 (fr) * 2000-06-02 2002-08-08 Sugen Inc Derives d'indolinone comme inhibiteurs de phosphatase/proteine kinase
WO2002055517A3 (fr) * 2000-12-20 2002-09-26 Sugen, Inc Indolinones 4-aryl substituees
US6861418B2 (en) 2000-12-20 2005-03-01 Sugen, Inc. 4-aryl substituted indolinones
US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity
US7223757B2 (en) 2001-03-28 2007-05-29 Bristol-Myers Squibb Company Tyrosine kinase inhibitors
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US6797725B2 (en) 2001-04-09 2004-09-28 Sugen, Inc. Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
WO2002081466A1 (fr) * 2001-04-09 2002-10-17 Sugen, Inc. Promedicaments a base de derives 3-(pyrrol-2-ylmethylidene)-2-indolinone
US7053114B2 (en) 2001-04-09 2006-05-30 Sugen, Inc. Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
WO2002094809A1 (fr) * 2001-05-24 2002-11-28 Yamanouchi Pharmaceutical Co., Ltd. Derives de 3-quinoleine-2-(1h)-ylideneindoline-2-one
US6599902B2 (en) 2001-05-30 2003-07-29 Sugen, Inc. 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors
US6777417B2 (en) 2001-09-10 2004-08-17 Sugen, Inc. 3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene-2-indolinone derivatives as kinase inhibitors
WO2003022815A1 (fr) * 2001-09-10 2003-03-20 Sugen, Inc. Derives de 3-(4,5,6,7-tetrahydroindol-2-ylmethylidene)-2-indolinone comme inhibiteurs de kinases
WO2003027111A1 (fr) * 2001-09-27 2003-04-03 Smithkline Beecham Corporation Composes chimiques
US7015231B2 (en) 2001-09-27 2006-03-21 Smithkline Beecham Corporation Chemical compounds
WO2004048366A1 (fr) * 2002-11-22 2004-06-10 Yamanouchi Pharmaceutical Co., Ltd. Derives 2-oxoindoline
US8193001B2 (en) * 2003-02-05 2012-06-05 Applied Biosystems, Llc Compositions and methods for preserving RNA in biological samples
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
JP4917041B2 (ja) * 2004-11-09 2012-04-18 アイアールエム・リミテッド・ライアビリティ・カンパニー タンパク質キナーゼ阻害剤としての化合物および組成物
JP2008519762A (ja) * 2004-11-09 2008-06-12 アイアールエム・リミテッド・ライアビリティ・カンパニー タンパク質キナーゼ阻害剤としての化合物および組成物
EP1814545A4 (fr) * 2004-11-09 2009-06-10 Irm Llc Composes et compositions utilises comme inhibiteurs de la proteine kinase
AU2005304719B2 (en) * 2004-11-09 2009-07-23 Irm Llc Compounds and compositions as protein kinase inhibitors
EP1814545A2 (fr) * 2004-11-09 2007-08-08 Irm, Llc Composes et compositions utilises comme inhibiteurs de la proteine kinase
US8101608B2 (en) 2004-11-09 2012-01-24 IRM LLC, a Delware Limited Corporation Compounds and compositions as protein kinase inhibitors
EP1883403A2 (fr) * 2005-04-29 2008-02-06 The Ohio State University Research Foundation Inhibiteurs specifiques contre la tyrosine du recepteur du facteur de croissance des keratinocytes utiles pour prevenir les metastases cancereuses
EP1883403A4 (fr) * 2005-04-29 2011-02-16 Univ Ohio State Res Found Inhibiteurs specifiques contre la tyrosine du recepteur du facteur de croissance des keratinocytes utiles pour prevenir les metastases cancereuses
WO2009030270A1 (fr) * 2007-09-03 2009-03-12 Novartis Ag Dérivés dhydroindoles utilisés pour traiter la maladie de parkinson
CN101970426A (zh) * 2007-12-21 2011-02-09 大学健康网络 吲唑基、苯并咪唑基、苯并***基取代的二氢吲哚酮衍生物作为癌症治疗中有用的激酶抑制剂
EP2417127A1 (fr) * 2009-04-06 2012-02-15 University Health Network Inhibiteurs de kinases et procédé de traitement du cancer avec ceux-ci
WO2010115279A1 (fr) 2009-04-06 2010-10-14 University Health Network Inhibiteurs de kinases et procédé de traitement du cancer avec ceux-ci
EP2417127A4 (fr) * 2009-04-06 2012-08-29 Univ Health Network Inhibiteurs de kinases et procédé de traitement du cancer avec ceux-ci
WO2012142029A2 (fr) * 2011-04-10 2012-10-18 Florida A&M University Modulateurs sélectifs des récepteurs des œstrogènes pour traitement de troubles à médiation par les récepteurs des œstrogènes
WO2012142029A3 (fr) * 2011-04-10 2013-03-14 Florida A&M University Modulateurs sélectifs des récepteurs des œstrogènes pour traitement de troubles à médiation par les récepteurs des œstrogènes
WO2014040969A1 (fr) 2012-09-13 2014-03-20 F. Hoffmann-La Roche Ag 2-oxo-2,3-dihydro-indoles destinés au traitement de troubles du snc
US9296730B2 (en) 2012-10-26 2016-03-29 Regents Of The University Of Minnesota Aurora kinase inhibitors
US9796671B2 (en) 2012-10-26 2017-10-24 Regents Of The University Of Minnesota Aurora kinase inhibitors
US10487054B2 (en) 2017-04-21 2019-11-26 Regents Of The University Of Minnesota Therapeutic compounds
CN113227049A (zh) * 2018-10-05 2021-08-06 艾科诺斯科技股份有限公司 用作map4k1抑制剂的吲哚啉酮化合物
GR1010103B (el) * 2020-07-02 2021-10-18 Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε, 3-ινδολ-2-υλομεθυλιδενο-ινδολιν-2-ονες με δραση αναστολης της αυτοταξινης
WO2022006412A3 (fr) * 2020-07-02 2022-02-03 The Regents Of The University Of Colorado, A Body Corporate Conjugués d'inhibiteurs d'ampk et d'agents de dégradation de protac et utilisations associées

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AU5468499A (en) 2000-02-28

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