WO2001060814A2 - Pyrrole substituted 2-indolinone protein kinase inhibitors - Google Patents

Pyrrole substituted 2-indolinone protein kinase inhibitors Download PDF

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Publication number
WO2001060814A2
WO2001060814A2 PCT/US2001/004813 US0104813W WO0160814A2 WO 2001060814 A2 WO2001060814 A2 WO 2001060814A2 US 0104813 W US0104813 W US 0104813W WO 0160814 A2 WO0160814 A2 WO 0160814A2
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hydrogen
group
alkyl
compound
aryl
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PCT/US2001/004813
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English (en)
French (fr)
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WO2001060814A3 (en
Inventor
Peng Cho Tang
Todd Miller
Xiaoyuan Li
Li Sun
Chung Chen Wei
Shahrzad Shirazian
Congxin Liang
Tomas Vojkovsky
Asaad S. Nematalla
Michael Hawley
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Sugen, Inc.
Pharmacia & Upjohn Company
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Priority to HK03103304.2A priority Critical patent/HK1051188B/en
Priority to SI200130778T priority patent/SI1255752T1/sl
Priority to EP01914376A priority patent/EP1255752B1/en
Priority to JP2001560198A priority patent/JP3663382B2/ja
Priority to BRPI0108394 priority patent/BRPI0108394B8/pt
Priority to CA002399358A priority patent/CA2399358C/en
Priority to AU2001239770A priority patent/AU2001239770B2/en
Priority to SK1326-2002A priority patent/SK287142B6/sk
Priority to UA2002097427A priority patent/UA73976C2/uk
Priority to HR20020751A priority patent/HRP20020751B1/xx
Priority to MEP-2008-530A priority patent/ME00415B/me
Priority to IL15112701A priority patent/IL151127A0/xx
Priority to DE60129794T priority patent/DE60129794T2/de
Priority to NZ520640A priority patent/NZ520640A/en
Priority to EA200200862A priority patent/EA005996B1/ru
Priority to MXPA02008021A priority patent/MXPA02008021A/es
Priority to BRPI0117360A priority patent/BRPI0117360B8/pt
Priority to DE122008000002C priority patent/DE122008000002I1/de
Priority to HU0204433A priority patent/HU228979B1/hu
Application filed by Sugen, Inc., Pharmacia & Upjohn Company filed Critical Sugen, Inc.
Priority to DK01914376T priority patent/DK1255752T3/da
Priority to DE122010000004C priority patent/DE122010000004I1/de
Priority to AU3977001A priority patent/AU3977001A/xx
Priority to KR1020027010706A priority patent/KR100713960B1/ko
Publication of WO2001060814A2 publication Critical patent/WO2001060814A2/en
Publication of WO2001060814A3 publication Critical patent/WO2001060814A3/en
Priority to NO20023831A priority patent/NO325532B1/no
Priority to IS6501A priority patent/IS2491B/is
Priority to CY20071101186T priority patent/CY1108032T1/el
Priority to NL300332C priority patent/NL300332I2/nl
Priority to LU91407C priority patent/LU91407I2/fr
Priority to FR08C0002C priority patent/FR08C0002I2/fr
Priority to LTPA2008002C priority patent/LTC1255752I2/lt
Priority to CY200800004C priority patent/CY2008004I2/el
Priority to NO2008019C priority patent/NO2008019I2/no
Priority to NL300430C priority patent/NL300430I2/nl
Priority to FR10C0003C priority patent/FR10C0003I2/fr
Priority to NO2010002C priority patent/NO2010002I2/no
Priority to BE2010C009C priority patent/BE2010C009I2/fr
Priority to LU91657C priority patent/LU91657I2/fr
Priority to CY2010004C priority patent/CY2010004I1/el
Priority to NO2019005C priority patent/NO2019005I1/no

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
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    • 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
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Definitions

  • the present invention relates to certain 3-pyrrole substituted 2-indolinone compounds which modulate the activity of protein kinases ("PKs").
  • PKs protein kinases
  • the compounds of this invention are therefore useful in treating disorders related to abnormal PK activity.
  • Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
  • 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 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 metabolic effects 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 metabolic effects 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-1R) and insulin receptor related receptor (IRR) .
  • IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two entirely extracellular glycosylated subunits and two ⁇ subunits which cross the cell membrane and which contain the tyrosine kinase domain.
  • 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.
  • flk fetus liver kinase
  • KDR/FLK-1, VEGF-R2 kinase insert domain-receptor fetal liver kinase-1
  • flk-lR flk-lR
  • flt-1 fetus liver kinase 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 the receptors consist of a glycosylated extracellular domain containing a variable number of immunoglobin-like loops and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of unrelated amino acid sequences.
  • VEGF vascular endothelial growth factor
  • VEGF is a dimeric glycoprotein similar to PDGF but has different biological functions and target cell specificity in vivo .
  • VEGF is presently thought to play an essential role is vasculogenesis and angiogenesis .
  • RTK subfamilies A more complete listing of the known RTK subfamilies is described in Plowman et al . , DN&P, 7(6):334-339 (1994) which is incorporated by reference, including any drawings, as if fully set forth herein.
  • 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 Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • 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.
  • 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 is directed to certain 3-pyrrole substituted 2-indolinone compounds which exhibit PK modulating ability and are therefore useful in treating disorders related to abnormal PK activity.
  • the present invention relates to 3-pyrrole substituted 2-indolinones of Formula (I):
  • R 1 is selected from the group consisting of hydrogen, halo, alkyl, cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, -(CO)R 15 , -NR 13 R 14 , -(CH 2 ) r R 16 and -C(0)NR 8 R 9 ;
  • R 2 is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, cyano, -NR 13 R 14 , - NR 13 C(0)R 14 , -C(0)R 15 , aryl, heteroaryl, -S (0) 2 NR 13 R 14 and -S0 2 R 20 (wherein R 20 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl) ;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, -(C0)R 15 , ' - NR 13 R 14 , aryl, heteroaryl, -NR 13 S (0) 2 R 14 ' -S (0) 2 NR 13 R 14 , - NR 13 C(0)R 14 ,
  • R 20 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and -NR 13 R 14 ;
  • R 5 is selected from the group consisting of hydrogen, alkyl and -C(0) R 10
  • R 6 is selected from the group consisting of hydrogen, alkyl and -C(0)R 10 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, -C(0)R 17 and -C(0)R 10 ; or R 6 and R 7 may combine to form a group selected from the group consisting of -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 -; with the proviso that at least one of R 5 , R 6 or R 7 must be -C(0)R 10 ;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl and aryl;
  • R 10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, -N(R 1X ) (CH 2 ) n R 12 , and -NR 13 R 14 ;
  • R 11 is selected from the group consisting of hydrogen and alkyl
  • R 12 is selected from the group consisting of -NR 13 R 14 , hydroxy, -C(0)R 15 , aryl, heteroaryl, -N + (0 " ) R 13 R 14 , -N (OH) R 13 , and -NHC(0)R a (wherein R a is unsubstituted alkyl, haloalkyl, or aralkyl) ;
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or
  • R 13 and R 14 may combine to form a heterocyclo group
  • R 15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy
  • R 16 is selected from the group consisting of hydroxy, -C(0)R 15 , -NR 13 R 14 and -C (0) NR 13 R 14 ;
  • R 17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl;
  • R 20 is alkyl, aryl, aralkyl or heteroaryl; and n and r are independently 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of hydrogen, halo, alkyl, cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, -C(0)R 15 , -NR 13 R 14 , -(CH 2 ) r R 16 and -C(0)NR 8 R 9 ;
  • R 2 is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, -NR 13 R 14 , - NR 13 C(0)R 14 , -C(0)R 15 , aryl, heteroaryl, and -S (O) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, -(C0)R 15 , - NR 13 R 14 , aryl, heteroaryl, -NR 13 S (0) 2 R 14 ' -S (0) 2 NR 13 R 14 , - NR 13 C(0)R 14 ,and -NR 13 C (0) OR 14 ;
  • R 4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and -NR 13 R 14 ;
  • R 5 is selected from the group consisting of hydrogen, alkyl and -C(0)R 10 ;
  • R 6 is selected from the group consisting of hydrogen, alkyl and -C(0)R 10 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, -C (0) R 17 and -C(0)R 10 ;
  • R 6 and R 7 may combine to form a group selected from the group consisting of -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 _ ; with the proviso that at least one of R 5 , R 6 or R 7 must be -C(0)R 10 ;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl and aryl;
  • R 10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, -N (R u ) (CH 2 ) n R 12 and -NR 13 R 14 ;
  • R 11 is selected from the group consisting of hydrogen and alkyl
  • R 12 is selected from the group consisting of -NR 13 R 14 , hydroxy, -C(0)R 15 , aryl and heteroaryl;
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; R 13 and R 14 may combine to form a group selected from the group consisting of -(CH 2 ) 4 -, -(CH 2 ) 5 -, - (CH 2 ) 2 0 (CH 2 ) 2 -, and -(CH 2 ) 2 N(CH 3 ) (CH 2 ) 2 -;
  • R 15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy
  • R 16 is selected from the group consisting of hydroxy, -C(0)R 15 , -NR 13 R 14 and -C (O) NR 13 R 14
  • R 17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl
  • n and r are independently 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • this invention is directed to a pharmaceutical composition comprising one or more compound (s) of Formula (I) or a pharmaceutically acceptable salt .thereof and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treating diseases mediated by abnormal protein kinase activity, in particular, receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), in an organism, in particular humans, which method comprises administering to said organism a pharmaceutical composition comprising a compound of Formula (I) .
  • diseases include by way of example ' and not limitation, cancer, diabetes, hepatic cirrhosis, cardiovasacular disease such as atherosclerosis, angiogenesis, immunological disease such as autoimmune disease and renal disease.
  • this invention is directed to a method of modulating of the catalytic activity of PKs, in particular, receptor tyrosine kinases (RTKs) , non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), using a compound of this invention which may be carried out in vi tro or in vivo .
  • PKs receptor tyrosine kinases
  • CTKs non-receptor protein tyrosine kinases
  • STKs serine/threonine protein 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-1R, 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.
  • the serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.
  • this invention is directed to the use of a compound of Formula (I) in the preparation of a medicament which is useful in the treatment of a disease mediated by abnormal PK activity.
  • this invention is directed to an intermediate of Formula (II) :
  • R is selected from the group consisting of hydrogen, alkyl
  • R is selected from the group consisting of hydrogen, alkyl and -C(0)R 10 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, -C (0) R 17 and -C(0)R 10 ;
  • R 6 and R 7 may combine to form a group selected from the group consisting of -(CH 2 ) -, -(CH 2 ) 5 - and -(CH 2 ) 6 -; with the proviso that at least one of R 5 , R 6 or R 7 must be -C(0)R 10 ;
  • R 10 is selected from the group consisting of hydroxy, alkoxy, aryloxy, -N (R 11 ) (CH 2 ) n R 12 and -NR 13 R 14 ;
  • R 11 is selected from the group consisting of hydrogen and alkyl
  • R 12 is selected from the group consisting of -NR 13 R 14 , hydroxy, -C(0)R 15 , aryl and heteroaryl;
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, cyanoalkyl, cycloalkyl, aryl and heteroaryl; or R 13 and R 14 may combine to form a heterocyclo group;
  • R 15 is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy;
  • R 17 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; and n is 1, 2, 3, or 4.
  • R 5 or R 6 in the compound of formula II, is - C(0)R 10 ;
  • R 6 is selected from the group consisting of hydrogen, and alkyl, more preferably hydrogen or methyl;
  • R 5 is selected from the group consisting of hydrogen, and alkyl, more preferably hydrogen or methyl when R 6 is -COR 10 ;
  • R 6 is selected from the group consisting of hydrogen, and alkyl, more preferably hydrogen or methyl when R 5 is -COR 10 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, and aryl, more preferably hydrogen, methyl or phenyl;
  • R 10 is selected from the group consisting of hydroxy, alkoxy, -N(R n ) (CH 2 ) n R 12 and -NR 13 R 14 ;
  • R 11 is selected from the group consisting of hydrogen and alkyl, more preferably hydrogen or methyl;
  • R 12 is selected from the group consisting of -NR 13 R 14 ;
  • R 13 arid R 14 are independently selected from the group consisting of hydrogen, or alkyl; or
  • R 13 and R 14 may combine to form a heterocyclo group; and n is 1, 2 or 3.
  • more preferred groups of intermediate compounds are those wherein R 5 , R 6 , R 11 , R 12 , R 13 or R 14 are independently groups described in the section titled "preferred embodiments" herein below.
  • this invention is directed to methods of preparing compounds of Formula (I) .
  • this invention is also directed to identifying a chemical compound that modulates the catalytic activity of a protein kinase by contacting cells expressing said protein kinase with a compound or a salt of the present invention and then monitoring said cells for an effect.
  • Alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms (whenever a numerical range; e.g. "1-20", is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms) .
  • Alkyl groups containing from 1 to 4 carbon atoms are refered to as lower alkyl groups. When said lower alkyl groups lack substituents, they are referred to as unsubstituted lower alkyl groups.
  • an alkyl group is a medium size alkyl having 1 to 10 carbon atoms e.g., methyl, ethyl, propyl , 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl , and the like. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, ⁇ -butyl, iso-butyl, or tert-butyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, more preferably one to three, even more preferably one or two substituent (s) independently selected from the group consisting of halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups
  • the alkyl group is substituted with one or two substituents independently selected from the group consisting of hydroxy, 5- or 6 -member heteroalicyclic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen (if present) atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 5 -member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and the nitrogen atoms in the group being optionally substituted with one or more groups, preferably one, two or three groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one
  • the alkyl group is substituted with one or two substituents which are independently of each other hydroxy, dimethylamino, ethylamino, diethylamino, dipropylamino, pyrrolidino, piperidino, morpholino, piperazino, 4-lower alkylpiperazino, phenyl , imidazolyl, pyridinyl , pyridazinyl, pyrimidinyl, oxazolyl, triazinyl, and the like.
  • Cycloalkyl refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6- member/6-member fused bicyclic ring or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, more preferably one or two substituents, independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more, preferably one or two groups independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 5-member
  • Alkenyl refers to a lower alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2- propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkynyl refers to a lower alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1- , 2-, or 3-butynyl, and the like.
  • Aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups of 1 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl , naphthalenyl and anthracenyl . The aryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl , halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted lower alkyl) thio, cyano, acyl , thioacyl , O-carbamyl, N-carbamyl, 0- thiocarbamyl , N-thiocarbamyl , C-amido, N-amido, nitro, N- sulfonamido, S-sulfonamido, R 18 S(0)-, R 18 S(0) 2 -, -C(0)0R 18 , R 18 C(0)0-, and -NR 18 R 19 , with R 18 and R 19 as defined above.
  • the aryl group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido.
  • substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido.
  • Heteroaryl refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi -electron system.
  • unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole.
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more, more preferably one, two, or three, even more preferably one or two, independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted lower alkyl) thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O- thiocarbamyl , N-thiocarbamyl, C-amido, N-amido, nitro, N- sulfonamido, S-sulfonamido, R 18 S(0)-, R 18 0) 2 -, -C(0)OR 18 , R 18 C(0)0-, and -NR 18 R 19 , with R 18 and R 19 as defined above.
  • the heteroaryl group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido .
  • substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido .
  • Heteroalicyclic refers to a monocyclic or fused ring group having in the ring(s) of 5 to 9 ring atoms in which one or two ring atoms are heteroatoms selected from N, 0, or S(0) n (where n is an integer from 0 to 2) , the remaining ring atoms being C.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi- electron system. Examples, without limitation, of unsubstituted heteroalicyclic groups are pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like.
  • the heteroalicyclic ring may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted lower alkyl) thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O- thiocarbamyl , N-thiocarbamyl, C-amido, N-amido, nitro, N- sulfonamido, S-sulfonamido, R 18 S(0)-, R 18 S(0) 2 -, -C(0)OR 18 , R 18 C(0)0-, and -NR 18 R 19 , with R 18 and R 19 as defined above.
  • the heteroalicyclic group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido.
  • substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N- sulfonamido.
  • the heteroalicyclic group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido.
  • substituents independently selected from halo, unsubstituted lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido.
  • Heterocycle means a saturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0) n (where n is an integer from 0 to 2) , the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from optionally substituted lower alkyl (substituted with 1 or 2 substituents independently selected from carboxy or ester), haloalkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl, -COR (where R is alkyl) or ⁇ COOR where R is (hydrogen or alkyl) .
  • heterocyclyl includes, but is not limited to, tetrahydropyranyl , 2 , 2 -dimethyl -1 , 3-dioxolane, piperidino, N-methylpiperidin-3-yl , piperazino, N- methylpyrrolidin-3-yl , 3 -pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino-1 , 1- dioxide, 4 -ethyloxycarbonylpiperazino, 3 -oxopiperazino, 2- imidazolidone, 2 -pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and the derivatives thereof.
  • the heterocycle group is optionally substituted with one or two substituents independently selected from halo, unsubstituted lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, mono or dialkylamino.
  • Halo refers to an -OH group.
  • Alkoxy refers to both an -0- (unsubstituted alkyl) and an -0- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryloxy refers to both an -0-aryl and an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Alkylthio refers to both an -S- (unsubstituted alkyl) and an -S- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, e.g., methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Arylthio refers to both an -S-aryl and an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thientylthio, pyrimidinylthio, and the like and derivatives thereof.
  • 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, preferably one, two, or three substituents selected from the group consisting of unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halo and -NR 18 R 19 groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and -NR 18 R 19 groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of unsubstisti
  • Aldehyde refers to an acyl group in which R" is hydrogen .
  • Thioacyl 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.
  • Aceyl group refers to a -C(0)CH 3 group.
  • Halo refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Trihalomethyl refers to a -CX 3 group wherein X is a halo group as defined herein.
  • Cyano refers to a -C ⁇ N group.
  • Methoxy 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.
  • S-sulfonamido refers to a -S (0) 2 NR 18 R 19 group, with R 18 and R 19 as defined herein.
  • N-sulfonamido refers to a -NR 18 S (0) 2 R 19 group, with R 18 and R 19 as defined herein.
  • O-carbamyl refers to a -OC (0) NR 18 R 19 group with R 18 and R 19 as defined herein.
  • N-carbamyl refers to an R 18 0C (0) NR 19 - group, with R 18 and R 19 as defined herein.
  • O-thiocarbamyl refers to a -OC (S) NR 18 R 19 group with R 18 and R 19 as defined herein.
  • N-thiocarbamyl refers to a R 18 0C (S) NR 19 - group, with R 18 and R 19 as defined herein.
  • Amino refers to an -NR 18 R 19 group, wherein R 18 and R 19 are both hydrogen.
  • C-amido refers to a -C(0)NR 18 R 19 group with R 18 and R 19 as defined herein.
  • N-amido refers to a R 18 C(0)NR 19 - group, with R 18 and R 19 as defined herein.
  • Niro refers to a -N0 2 group.
  • Haloalkyl means an unsubstituted alkyl, preferably unsubstituted lower alkyl as defined above that is substituted with one or more same or different halo atoms, e.g., -CH 2 C1, -CF 3 , -CH 2 CF 3 , -CH 2 CC1 3 , and the like.
  • Alkyl means unsubstituted alkyl, preferably unsubstituted lower alkyl as defined above which is substituted with an aryl group as defined above, e.g., -CH 2 phenyl, - (CH 2 ) 2 phenyl, - (CH 2 ) 3 phenyl, CH 3 CH (CH 3 ) CH 2 phenyl, and the like and derivatives thereof.
  • Heteroaralkyl means unsubstituted alkyl, preferably unsubstituted lower alkyl as defined above which is substituted with a heteroaryl group, e.g., -CH 2 pyridinyl, - (CH 2 ) 2 pyrimidinyl, - (CH 2 ) 3 imidazolyl, and the like, and derivatives thereof.
  • “Monoalkylamino” means a radical -NHR where R is an unsubstitued alkyl or unsubstituted cycloalkyl group as defined above, e.g., methylamino, (1-methylethyl) amino, cyclohexylamino, and the like.
  • Dialkylamino means a radical -NRR where each R is independently an unsubstitued alkyl or unsubstituted cycloalkyl group as defined above, e.g., dimethylamino, diethylamino, (1-methylethyl) -ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like.
  • Cyanoalkyl means unsubstituted alkyl, preferably unsubstituted lower alkyl as defined above, which is substituted with 1 or 2 cyano groups.
  • heterocycle group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
  • pyrrole substituted 2-indolinone and "3- pyrrolidenyl-2-indolinone” are used interchangeably herein to refer to a chemical compound having the general structure shown in Formula (I).
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers” . Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers” . When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • R ⁇ substituent in a compound of formula (I) is 2-hydroxyethyl
  • the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S) -stereoisomer .
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992) .
  • the compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism.
  • the compounds described herein may adopt an E or a Z configuration about the double bond connecting the 2-indolinone moiety to the pyrrole moiety or they may be a mixture of E and Z.
  • This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate RTK, CTK and/or STK activity and is not limited to any one tautomeric or structural isomeric form.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the compound of Formula (I) may also act as a prodrug.
  • a "prodrug” refers to an agent which is converted into the parent drug in vivo . Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • a further example of a prodrug might be a short polypeptide, for example, without limitation, a 2 - 10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound of this invention wherein the polypeptide is hydrolyzed or metabolized in vivo to release the active molecule.
  • the prodrugs of a compound of Formula (I) are within the scope of this invention.
  • a compound of Formula (I) would be metabolized by enzymes in the body of the organism such as human being to generate a metabolite that can modulate the activity of the protein kinases. Such metabolites are within the scope of the present invention.
  • a “physiologically/pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • an "pharmaceutically acceptable 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.
  • salts As used herein, the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • 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
  • Method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known' manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
  • 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 vi tro, " i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • 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.
  • a PK related disorder i.e., the IC 50 of the compound, defined below.
  • In vi tro 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 or rabbit.
  • 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.
  • Treating refers 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.
  • “Therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of:
  • Monitoring means observing or detecting the effect of contacting a compound with a cell expressing a particular PK.
  • the observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner.
  • 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.
  • 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 .
  • Example 1 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.
  • a preferred group of compounds of Formula (I) is that wherein R 1 , R 3 , and R 4 are hydrogen.
  • Another preferred group of compounds of Formula (I) is that wherein R 2 , R 3 , and R 4 are hydrogen.
  • Another preferred group of compounds of Formula (I) is that wherein R 1 , R 2 , R 3 and R 4 are hydrogen.
  • Yet another preferred group of compounds of Formula (I) is that wherein R 5 , R 6 or R 7 , preferably R 5 or R 6 , more preferably R 6 is -COR 10 wherein R 10 is -NR 11 (CH 2 ) n R 12 wherein:
  • R 11 is hydrogen or lower unsubstituted alkyl, preferably hydrogen or methyl; n is 2, 3 or 4, preferably 2 or 3; and R 12 is -NR 13 R 14 wherein R 13 and R 14 are independently alkyl, more preferably lower unsubstituted lower alkyl or R 13 and R 14 combine to form a group selected from -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 2 -0-(CH 2 ) 2 - or - (CH 2 ) 2 N (CH 3 ) (CH 2 ) 2 -, preferably R 13 and R 14 are independently hydrogen, methyl, ethyl, or combine to form morpholin-4-yl, pyrrolidin-1- yl, piperazin-1-yl, or 4-methylpiperazin-l-yl .
  • R 5 or R 6 in (6) above is N-(2- dimethylaminoethyl-) aminocarbonyl, N- (2-ethylaminoethyl) - N-methylaminocarbonyl, N- (3-dimethylaminopropyl) - aminocarbonyl, N- (2-diethylaminoethyl ) aminocarbonyl, N- (3-ethylaminopropyl) aminocarbonyl, N- (3- diethylaminopropyl) aminocarbonyl, 3-pyrrolidin-l-yl- propylaminocarbonyl, 3-morpholin-4-ylpropyl- aminocarbonyl, 2-pyrrolidin-l-ylethylaminocarbonyl, 2- morpholin-4-ylethylaminocarbonyl, 2- (4-methylpiperazin-l- yl) ethylaminocarbonyl, 2- (4-methylpiperazin-l- yl) propyla
  • Yet another preferred group of compounds of Formula (I) is that wherein R 5 , R 6 or R 7 , preferably R 5 or R 6 , more preferably R 6 is -COR 10 wherein R 10 is -NR 13 R 14 wherein R 13 is hydrogen and R 14 is alkyl, preferably lower alkyl substituted with hydroxy, aryl, heteroaryl, heteroalicyclic, or carboxy, more preferably methyl, ethyl, propyl or butyl substituted with hydroxy, aryl, heteroalicyclic such as piperidine, piperazine, morpholine and the like, heteroaryl, or carboxy.
  • R 5 or R 6 is 2- ethoxycarbonylmethyl-aminocarbonyl, carboxymethylamino- carbonyl, 3-hydroxypropyl-aminocarbonyl, 2- hydroxyethylaminocarbonyl, 3-triazin-l-ylpropylamino- carbonyl, triazin-1-ylethylaminocarbonyl, 4-hydroxy- phenylethylaminocarbonyl, 3-imidazol-l-ylpropyl- aminocarbonyl, pyridin-4-ylmethylaminocarbonyl, 2- pyridin-2-ylethylaminocarbonyl or 2-imidazol-l- ylethylaminocarbonyl .
  • Yet another preferred group of compounds of Formula (I) is that wherein R 5 , R 6 or R 7 , preferably R 5 or R 6 , more preferably R 6 is -COR 10 wherein R 10 is -NR 11 (CH 2 ) n R 12 wherein:
  • R 11 is hydrogen or alkyl, preferably hydrogen or methyl; n is 2, 3 or 4, preferably 2 or 3; and
  • R 12 is -NR 13 R 14 wherein R 13 and R 14 together combine to form a heterocycle, preferably a 5, 6 or 7 membered heterocycle containing a carbonyl group and 1 or 2 nitrogen atoms.
  • R 5 or R 6 is 2- (3- ethoxycarbonylmethylpiperazin-1-yl) ethylaminocarbonyl, 2- (3-oxopiperazin-l-yl) ethylaminocarbonyl, 2- ( imidazolidin- l-yl-2-one) ethylaminocarbonyl, 2- (tetrahydropyrimidin-1- yl-2-one) ethylaminocarbonyl, 2- (2-oxopyrrolidin-l-yl) - ethylaminocarbonyl, 3- (4-methylpiperazin-l-yl) - propylaminocarbonyl, 3- (3-ethoxycarbonylmethylpiperazin- 1-yl) -propyla
  • R 10 is -NR u (CH 2 ) n R 12 wherein: R 11 is hydrogen or alkyl, preferably hydrogen or methyl; n is 2, 3 or 4, preferably 2 or 3; and R 12 is -NR 13 R 14 wherein R 13 is hydrogen and R 14 is cyanoalkyl or -NHCOR a where R a is alkyl; or
  • R 10 is -NR 13 R 14 wherein R 13 and R 14 together combine to form a heterocycle not containing a carbonyl group within the ring.
  • R 5 or R 6 is 2- (2- cyanoethylamino) ethylaminocarbonyl, 2- (acetylamino) - ethylaminocarbonyl, morpholinocarbonyl, piperidin-1-yl- carbonyl, 2-cyanomethylaminoethylaminocarbonyl or piperidin-1-ylcarbonyl .
  • R 5 is -COR 10 wherein R 10 is -NR 13 R 14 wherein R 13 is hydrogen and R 14 is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or -NR 18 R 19 wherein R 18 and R 19 are independently hydrogen or lower unsubstituted alkyl, more preferably R 5 is 2- [ (diethylamino) -2-hydroxyethyl] aminocarbonyl, 2-(N- ethyl-N-2-hydroxyethylamino) ethylaminocarbonyl, carboxymethylamino-carbonyl, or 2- (2- hydroxyethylamino) ethylamino-carbonyl .
  • R 6 is -COR 10 wherein R 10 is -NR 13 R 14 wherein R 13 is hydrogen and R 14 is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or -NR 18 R 19 wherein R 18 and R 19 are independently hydrogen or lower unsubstituted alkyl; more preferably R ⁇ is [2- (diethylamino) -2-hydroxy] ethylaminocarbonyl, 2- (N- ethyl-N-2-hydroxyethyl-amino) ethylaminocarbonyl, carboxymethylaminocarbonyl, or 2- (2- hydroxyethylamino) ethylamino-carbonyl .
  • R 5 is -COR 10 wherein R 10 is - NR n (CH 2 ) n R 12 wherein R 12 is -N + (0 " ) NR 13 R 14 or -N(OH)R 13 .
  • R 13 and R 14 are independently selected from the group consisting of hydrogen and unsubstituted lower alkyl, preferably R 5 is 2- (N-hydroxy-N-ethylamino) - ethylaminocarbonyl or 2- [N + (0 " ) (C 2 H 5 ) 2 ] ethyl-aminocarbonyl (13)
  • R 6 is -COR 10 wherein R 10 is - NR 11 (CH 2 ) n R 12 wherein R 12 is -N + (0 " ) NR 13 R 14 or -N(0H)R 13 wherein R 13 and R 14 are independently selected from the group consisting of hydrogen
  • R 6 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and -C(0)R 17 wherein R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl .
  • R 5 is -COR 10
  • another more preferred group of compounds is that wherein R 6 and R 7 combine to form -(CH 2 ) 4 -.
  • R 5 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and -C(0)R 17 , wherein R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl.
  • R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl.
  • R 1 is hydrogen, alkyl, -C(0)NR 8 R 9 , unsubstituted cycloalkyl or aryl, preferably hydrogen, phenyl, 3,4- dimethoxyphenylaminocarbonyl, 4-methoxy-3-chlorophenyl- aminocarbonyl, even more preferably hydrogen or methyl, most preferably hydrogen;
  • R 2 is cyano, hydrogen, halo, lower alkoxy, aryl or - S(0) 2 NR 13 R 14 wherein R 13 is hydrogen and R 14 is hydrogen, aryl or alkyl, preferably R 2 is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, dimethylaminosulfonyl, 3-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, isopropylamino-sulfonyl, more preferably hydrogen, fluoro, or bromo;
  • R 3 is selected from the group consisting of hydrogen, lower alkoxy, -C(0)R 15 , -NR 13 C (0) R 14 , aryl preferably aryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy, and heteroaryl, preferably heteroaryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy, ; preferably hydrogen, methoxy, carboxy, phenyl, pyridin-3-yl, 3, 4-dichlorophenyl, 2-methoxy-5- isopropylphenyl, 4-n-butylphenyl, 3-isopropylphenyl, more preferably hydrogen or phenyl; and R 4 is hydrogen.
  • R 1 is hydrogen, alkyl, -C(0)NR 8 R 9 , unsubstituted cycloalkyl or aryl, preferably hydrogen, 3, 4-dimethoxy- phenyl-aminocarbonyl, -methoxy-3- chlorophenylaminocarbonyl, even more preferably hydrogen or methyl, particularly hydrogen;
  • R 2 is cyano, hydrogen, halo, lower alkoxy, aryl or - S(0) 2 NR 13 R 14 wherein R 13 is hydrogen ' and R 14 is hydrogen, aryl or alkyl, preferably R 2 is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, dimethylaminosulfonyl, 3-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfon
  • R 5 is -COR 10 where R 10 is as defined in the Summary of the Invention, preferably -NR 11 (CH 2 ) n R 12 or -NR 13 R 14 as defined in the Summary of the Invention.
  • R 6 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and
  • R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and -C (0) R 17 wherein R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl .
  • R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl .
  • R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl,
  • R 6 is -COR 10 where R 10 is as defined in the Summary of the Invention, preferably -NR 11 (CH 2 ) n R 12 or -NR 13 R 14 as defined in the Summary of the Invention.
  • R 5 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, or n-butyl, more preferably hydrogen or methyl; and R 7 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and -C (0) R 17 wherein R 17 is hydroxy, alkyl or aryl, more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso or tert-butyl, phenyl, benzoyl, acetyl or carboxy, even more preferably methyl, hydrogen or phenyl.
  • R 1 and R 4 are hydrogen
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkoxy, -C(0)R 15 and -S (0) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, lower alkoxy, -C(0)R 15 , -S (O) 2 NR 13 R 14 , aryl and heteroaryl;
  • R 5 is -C(0)R 10 ;
  • R 6 is selected from the group consisting of hydrogen and lower alkyl
  • R 7 is selected from the group consisting of hydrogen, lower alkyl and -C(0)R 17 .
  • R 10 is selected from the group consisting of hydroxy, lower alkoxy and -NR 11 (CH 2 ) n R 12 , wherein n is 2 or 3;
  • R 11 ' is selected from the group consisting of hydrogen and lower alkyl
  • R 12 is selected from the group consisting of aryl and -NR 13 R 14 .
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, lower alkyl, and, combined, - (CH 2 ) 4 -, -(CH 2 ) 5 -, - CH 2 ) 2 0(CH 2 ) 2 - or -(CH 2 ) 2 N(CH 3 ) (CH 2 ) 2 -.
  • R 1 is selected from the group consisting of hydrogen, lower alkyl, -(CH 2 ) r R 16 and -C(0)NR 8 R 9 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, aryl and -S (0) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and -C(0)R 15 ;
  • R 4 is hydrogen;
  • R 5 is selected from the group consisting of hydrogen and lower alkyl
  • R 6 is -C(0)R 10 ;
  • R 7 is selected from the group consisting of hydorgen, lower alkyl and aryl;
  • R 16 is selected from the group consisting of hydroxy and -C(0)R 15 ; and, r is 2 or 3.
  • a presently preferred embodiment of this invention is a compound having as structure described in the paragraph just above in which R 3 is aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy and halo. (21) Likewise, it is a presently preferred embodiment of this invention that, in a compound in which:
  • R 1 is selected from the group consisting of hydrogen, lower alkyl, -(CH 2 ) r R 16 and -C(0)NR 8 R 9 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, aryl and -S (0) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and -C(0)R 15 ;
  • R 4 is hydrogen
  • R 5 is selected from the group consisting of hydrogen and lower alkyl
  • R 6 is -C(0)R 10 ;
  • R 7 is selected from the group consisting of hydorgen, lower alkyl and aryl;
  • R 16 is selected from the group consisting of hydroxy r is 2 or 3,
  • R 10 is selected from the group consisting of hydroxy, lower alkoxy, -NR 13 R 14 and -NR 11 (CH 2 ) n R 12 , wherein n is 1, 2 or 3, R 11 is hydrogen and R 12 is selected from the group consisting of hydroxy, lower alkoxy, -C (0) R 15 , heteroaryl and -NR 13 R 14 .
  • a further presently preferred embodiment of this invention is a compound having a structure as described in the paragraph immediately above in which R 13 and R 14 are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl and, combined, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 2 0(CH 2 ) 2 -, or - (CH 2 ) 2 N (CH 3 ) (CH 2 ) 2 -.
  • R 1 is -C(0)NR 8 R 9 , wherein R 8 is hydrogen and R 9 is aryl optionally substituted with one or more groups selected from the group consisting of halo, hydroxy and lower alkoxy;
  • R 2 is selected from the group consisting of hydrogen, halogen, aryl and -S (O) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, heteroaryl and -C(0)R 15 ;
  • R 4 is hydrogen
  • R 5 is selected from the group consisting of hydrogen and lower alkyl
  • R 7 is selected from the group consisting of hydorgen, lower alkyl and aryl;
  • R 16 is selected from the group consisting of hydroxy and -C(0)R 15 ; and, r is 2 or 3, (24)
  • a still further presently preferred embodiment of this invention is a compound in which:
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkoxy, aryl, -C(0)R 15 and -S (0) 2 NR 13 R 14 ;
  • R 3 is selected from the group consisting of hydrogen, halo, aryl, heteroaryl and -C(0)R 15 ;
  • R 4 is hydrogen
  • R 5 is -C(0)R 10 ; and, R 6 and R 7 combine to form a -(CH 2 ) 4 - group.
  • R 10 is selected from the group consisting of hydroxy, alkoxy, -NR 13 R 14 and -NH (CH 2 ) n NR 13 R 14 wherein n is 2 or 3.
  • R 13 and R 14 are independently selected from the group consisting of hydrogen, lower alkyl, and, combined, -(CH 2 ) 4 -, -(CH 2 ) 5 - , -(CH 2 ) 2 0(CH 2 ) 2 - or -(CH 2 ) 2 N(CH 3 ) (CH 2 ) 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 thus have utility in in vi tro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
  • the compounds of the present invention provide a therapeutic approach to the treatment of many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • 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 ; Folkham, 1991, J. Natl. Cancer Inst. , 82:4-6; Weidner, et al .
  • VEGF endothelial growth factor
  • vasculogenesis indicates an important role for the KDR/FLK-1 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.
  • the receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and/or angiogenesis and a variety of severe diseases which involve abnormal cellular growth caused by such processes. Plowman, et al . , 1994, DN&P, 7 (6) :334-339. More particularly, the KDR/FLK-1 receptor's highly specific role in neovascularization make it a choice target for therapeutic approaches to the treatment of cancer and other diseases which involve the uncontrolled formation of blood vessels.
  • the present invention provides compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-1 when activated by ligands such as VEGF.
  • KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis
  • 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.
  • the nomenclature of the human and murine counterparts of the generic "flk-I" receptor differ, they are, in many respects, interchangeable.
  • the murine receptor, Flk-1, and its human counterpart, KDR share a sequence homology of 93.4% within the intracellular domain.
  • 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) .
  • 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-1 in vi tro can be confirmed in suitable in vivo models. Both in vivo mouse and rat animal models have been demonstrated to be of excellent value for the examination of the clinical potential of agents acting on the KDR/FLK-1 induced signal transduction pathway.
  • the present invention provides compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-1 receptor and interfering with the signal transduced by KDR/FLK-1.
  • the present invention provides a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi's sarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon and epidermoid carcinoma.
  • data suggests the administration of compounds which inhibit the KDR/Flk-1 mediated signal transduction pathway may also be used in the treatment " of hemangioma, restenois and diabetic retinopathy.
  • this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 re'ceptor.
  • 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,
  • KDR/FLK-1 with that of the PDGF- ⁇ receptor (50.3% homology) and/or the related flt-1 receptor indicates the induction of overlapping signal transduction pathways.
  • members of the src family Twamley et al . , 1993, Proc. Natl. Acad. Sci. USA, 90:7696-7700
  • phosphatidylinositol-3 ' -kinase Hu et al . , 1992, Mol. Cell. Biol . , 12:981-990
  • phospholipase c ⁇ Yamashian & Cooper
  • KDR/FLK-1 signal transduction pathways activated by KDR/FLK-1 include the ras pathway (Rozakis et al . , 1992, Nature, 360:689-692), the PI-3 ' -kinase, the src-mediated and the plc ⁇ - mediated pathways.
  • ras pathway Roskis et al . , 1992, Nature, 360:689-692
  • PI-3 ' -kinase the src-mediated
  • plc ⁇ - mediated pathways may play a critical role in the angiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells. Consequently, a still further aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis as such processes are controlled by these pathways.
  • 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 a l .
  • 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.
  • IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al . , 1989, J. Clin. Invest. 84:1418-1423) and small lung tumor cells (Macauley et al . , 1990, Cancer Res. , 50:2511-2517).
  • IGF-I while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas.
  • IGF-IR insulin growth factor-IR
  • fibroblasts epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)
  • IGF-I insulin growth factor-I
  • Baserga and Coppola suggest that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, 1995, Cancer Res .
  • 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, restenosis, 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, restenosis, 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
  • 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 cDsrc , 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.
  • PKs have also been implicated in embryo implantation.
  • the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
  • Additional disorders which may be treated or prevented using the compounds of this invention are immunological disorders such as autoimmune disease, AIDS and cardiovasular disorders such as atherosclerosis.
  • a compound of the present invention or a phearmaceutically acceptable salt thereof can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient (s) .
  • suitable carriers or excipient s
  • Techniques for formulation and administration of drugs may be found in "Remington's Pharmacological Sciences,” Mack Publishing Co., Easton, PA., latest edition.
  • administer refers to the delivery of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof of this invention to an organism for the purpose of prevention or treatment of a PK-related disorder.
  • Suitable routes of administration may include, without limitation, oral, rectal, transmucosal or intestinal administration or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular injections.
  • the preferred routes of administration are oral and parenteral.
  • the liposomes will be targeted to and taken up selectively by the tumor.
  • 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.
  • compositions 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.
  • compositions which may also be used include hard gelatin capsules.
  • the active compound capsule oral drug product formulation may be as 50 and 200 mg dose strengths (formulation codes J-011248- AA-00 and J-011248-AA-01, respectively) .
  • the two dose strengths are made from the same granules by filling into different size hard gelatin capsules, size 3 for the 50 mg capsule and size 0 for the 200 mg capsule.
  • the composition of the formulation may be, for example, as indicated in Table 2.
  • the capsules may be packaged into brown glass or plastic bottles to protect the active compound from light.
  • the containers containing the active compound capsule formulation must be stored at ⁇ controlled room temperature (15-30°C).
  • 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.
  • 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 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co- solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • 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 80, the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars or polysaccharides may substitute for dextrose.
  • 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, malate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid.
  • Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. sodium hydroxide (NaOH) , potassium hydroxide (KOH) , Calcium hydroxide (Ca(0H) 2 ), etc. ) .
  • an appropriate base e.g. sodium hydroxide (NaOH) , potassium hydroxide (KOH) , Calcium hydroxide (Ca(0H) 2 ), etc.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, e.g., the modulation of PK activity or the treatment or prevention of a PK-related disorder.
  • 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).
  • MEC minimal effective concentrations
  • the MEC will vary for each compound but can be estimated from in vi tro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
  • 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 therapeutically effective amounts of compounds of Formula (I) may range from approximately 25 mg/m 2 to 1500 mg/m 2 per day; preferably about 3 mg/m 2 /day. Even more preferably 50mg/qm qd till 400 mg/qd.
  • 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.
  • 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.
  • 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
  • Wilm's tumor and rhabdomyosarcoma Wilm's tumor and rhabdomyosarcoma
  • estramustine ifosfamide, novembrichin, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin ' s lymphoma, Hodgkin's disease and ovarian cancer)
  • triazines e.g., dacarbazine (used in the treatment of soft tissue sarcoma) .
  • a compound, salt or prodrug of this invention can also be used in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias.
  • 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 and thioguan
  • a compound, salt or prodrug of this invention can also be used in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer) , vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer) , dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer) ; and the enzymatic chemotherapeutic agents such as
  • a compound, salt or prodrug of this invention could also be used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticosteriods (e.g., prednisone) , progestins (e.g., hydroxyprogesterone caproate) ; estrogens (e.g., diethylstilbesterol) ; antiestrogens such as tamoxifen; androgens, e.g., testosterone propionate; and aromatase inhibitors such as anastrozole.
  • substituted ureas such as hydroxyurea
  • methylhydrazine derivatives e.g., procarbazin
  • a compound of this invention will be effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.
  • mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.
  • the following general methodology may be employed to prepare the compounds of this invention:
  • the appropriately substituted 2-oxindole (1 equiv.), the appropriately substituted aldehyde (1.2 equiv.) and a base (0.1 equiv.) are mixed in a solvent (1-2 ml/mmol 2-oxindole) and the mixture is then heated for from about 2 to about 12 hours. After cooling, the precipitate that forms is filtered, washed with cold ethanol or ether and vacuum dried to give the solid product. If no precipitate forms, the reaction mixture is concentrated and the residue is triturated with dichloromethane/ether, the resulting solid is collected by filtration and then dried.
  • the product may optionally be further purified by chromatography.
  • the base may be an organic or an inorganic base. If an organic base is used, preferably it is a nitrogen base.
  • organic nitrogen bases include, but are not limited to, diisopropylamine, trimethylamine, triethylamine, aniline, pyridine, 1, 8-diazabicyclo [5.4.1] undec-7-ene, pyrrolidine and piperidine.
  • inorganic bases are, without limitation, ammonia, alkali metal or alkaline earth hydroxides, phosphates, carbonates, bicarbonates, bisulfates and amides.
  • the alkali metals include, lithium, sodium and potassium while the alkaline earths include calcium, magnesium and barium.
  • 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 are 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.
  • about is meant that the temperature range is preferably within 10 degrees Celcius of the indicated temperature, more preferably within 5 degrees Celcius of the indicated temperature and, most preferably, within 2 degrees Celcius of the indicated temperature.
  • 75° C is meant 75° C ⁇ 10° C, preferably 75° C ⁇ 5° C and most preferably, 75° C ⁇ 2° C.
  • 2-Oxindoles and aldehydes may be readily synthesized using techniques well known in the chemical arts. It will be appreciated by those skilled in the art that other synthetic pathways for forming the compounds of the invention are available and that the following is offered by way of example and not limitation.
  • 5-Nitro-2-oxindole (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of the title compound as a white solid.
  • 5-Bromo-2-oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to - 10 °C and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 °C and 2 hours at 0 °C. The precipitate was collected, washed with water and dried to give 1.9 g (90 % yield) of the title compound.
  • 5-Chloro-2-oxindole (16.8 g) and 19.6 g of N- bromosuccinimide were suspended in 140 mL of acetonitrile and refluxed for 3 hours.
  • Thin layer chromatography (silica, ethyl acetate) at 2 hours of reflux showed 5-chloro-2-oxindole or N- bromosuccinimide (Rf 0.8), product (Rf 0.85) and a second product (Rf 0.9) whose proportions did not change after another hour of reflux.
  • 5-Bromo-2-oxindole (5 g, 23.5 mmol) was dissolved in 110 mL toluene and 110 mL ethanol with stirring and a little heat. Tetrakis (triphenylphosphine) palladium (0) (1.9 g, 1.6 mmol) was added followed by 40 mL (80 mmol) 2M aqueous sodium carbonate. To this mixture was added benzene boronic acid (3.7 g, 30.6 mmol) and the mixture was heated in a 100° C oil bath for 12 hours. The reaction was cooled, diluted with ethyl acetate
  • Oxindole (133 mg, 1 mmol) was condensed with 5-formyl-4- methyl-lH-pyrrole-2-carboxylic acid (153 mg) using method D to give 268 mg (100%) of the title compound as an orange-red solid.
  • Oxindole (105 mg, 0.79 mmol) was condensed with 5-formyl- 4-methyl-lH-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound.
  • 5-Bromo-l, 3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-lH-pyrrole-2-carboxylic acid (2- diethylaminoethyl) amide (prepared from ethyl pyrrole-2- carboxylate by method A, B and then C) to give 162 mg (38%) of the title compound.
  • 6-Phenyl-l, 3-dihydroindol-2-one (209 mg, lmmol) was condensed with 5-formyl-lH-pyrrole-2-carboxylic acid (2- diethylaminoethyl) amide to give 182 mg (42%) of the title compound .
  • Oxindole (66.5 mg, 0.5 mmol) was condensed with 5-formyl- 3-methyl-lH-pyrrole-2-carboxylic acid (3- diethylaminopropyl) amide (prepared from 3-formyl-3-methyl-lH- pyrrole-2-carboxylic acid ethyl ester by method B then C) to give 39 mg (21%) of the title compound.
  • 6-Phenyl-l, 3-dihydroindol-2-one (105 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-lH-pyrrole-2-carboxylic acid (3-diethylaminopropyl) amide to give 67.8 (30%) of the title compound.
  • 6-Phenyl-l, 3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2, 4-dimethyl-lH-pyrrole-3-carboxylic acid (2-dimethylaminoethyl) amide (0.2 g) to give 0.13 g (36%) of the title compound as a yellow-orange solid.
  • the mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40 ° C.
  • the aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55 °C during the addition.
  • the mixture was extracted twice with 5000 mL each time of 10 % methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness.
  • the mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness.
  • the residue was triturated with 3:1 hexane : diethyl ether (4000 mL) .
  • Example 191 5- [2-Oxo-1, 2-dihydro-indol- (3Z) -ylidenemethyl] -2 , 4-dimethyl- lH-pyrrole-3-carboxylic acid [2- (pyridin-1-yl) ethyl] amide Proceeding as described in Example 190 above but substituting 5- [5-fluoro-2-oxo-l, 2-dihydro-indol- (3Z) -ylidenemethyl] -2 , 4-dimethyl-lH-pyrrole-3-carboxylic acid with 5- [2- oxo-1, 2-dihydro-indol- (3Z) -ylidenemethyl] -2, 4-dimethyl-lH- pyrrole-3-carboxylic acid (113 mg) provided 5- [2-oxo-l, 2- dihydro-indol- (3Z) -ylidenemethyl] -2, 4-dimethyl-lH-pyrrole-3- carboxylic
  • the crude product was purified on silica using an eluent mixture chloroform-methanol-aqueous ammonia 80:25:2) provided the desired compounds.
  • Examples 148-151 and 184 Proceeding as described in Examples 190, 189, 191, 192, and 203 above but substituting 2- (2-aminoethyl) pyridine with 4- (2-aminoethyl) piperazine-1-acetic acid ethyl ester (prepared as follows: Piperazine-1-acetic acid ethyl ester (11.22 g) was treated with iodoacetonitrile (5.
  • Bromoacetic acid ethyl ester (6.70 mL, 60 mmol) was added neat upon cooling to room temperature. The reaction was stirred for 25 minutes, then evaporated on high vacuum. The residue was dissolved in methanol (200 ml), KHC0 3 (lOg) and KF (12 g, 200 mmol) were added and the mixture was stirred at 60 °C for 5 hours. lOg of Na 2 C0 3 was added, stirred for 10 minutes, cooled and filtered. The filtrates were evaporated. The residue was extracted with hexanes (2 times 250 ml) . The hexane-insoluble material was dissolved in ethanol (60ml), filtered and evaporated. The residue was purified ona column of silica in chloroform-methanol-aqueous ammonia 80:40:4 to give pure amine (4.245g,74% yield)) provided the desired compounds. Examples 163-167
  • the following assays may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art.
  • the cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound.
  • the presently preferred protocols for conducting the ELISA experiments for specific PKs is provided below. However, adaptation of these protocols for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.
  • test kinase measures the amount of DNA made in response to activation of a test kinase, which is a general measure of a proliferative response.
  • the general procedure for this assay is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. After incubation at least overnight, a DNA labeling reagent such as 5-bromodeoxyuridine (BrdU) or H 3 -thymidine is added. The amount of labeled DNA is detected with either an anti- BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound.
  • PrdU 5-bromodeoxyuridine
  • H 3 -thymidine is added.
  • the amount of labeled DNA is detected with either an anti- BrdU antibody or by measuring radioactivity and is compared to
  • This assay analyzes the tyrosine kinase activity of GST- Flkl on poly (glu, tyr) peptides.
  • Materials and Reagents 1. Corning 96-well ELISA plates (Corning Catalog No. 5805-96) .
  • PBS Buffer for 1 L, mix 0.2 g KH 2 P0 4 , 1.15 g Na 2 HP0 4 , 0.2 g KC1 and 8 g NaCl in approx. 900ml dH 2 0. When all reagents have dissolved, adjust the pH to 7.2 with HC1. Bring total volume to 1 L with dH 2 0.
  • PBST Buffer to 1 L of PBS Buffer, add 1.0 ml Tween- 20.
  • TBB - Blocking Buffer for 1 L, mix 1.21 g TRIS,
  • KDB Kinase Dilution Buffer
  • EDTA mix 14.12 g ethylenediaminetetraacetic acid (EDTA) to approx. 70 ml dH 2 0. Add 10 N NaOH until EDTA dissolves. Adjust pH to 8.0. Adjust total volume to 100 ml with dH 2 0.
  • This assay is used to measure the in vi tro kinase activity of HA epitope-tagged full length pyk2 (FL.pyk2-HA) in an ELISA assay.
  • PBS Dulbecco's Phosphate-Buffered Saline (Gibco Catalog # 450-1300EB)
  • TBST Buffer for 1 L, mix 8.766 g NaCl, 6.057 g TRIS and 1 ml of 0.1% Triton X-100 in approx. 900 ml dH 2 0. Adjust pH to 7.2, bring volume to 1 L.
  • Blocking Buffer for 1 L, mix 100 g 10% BSA, 12.1 g 100 mM TRIS, 58.44 g IM NaCl and 10 mL of 1% TWEEN-
  • Antibody dilution buffer for 100 mL, 1 mL 5% BSA/PBS and 1 mL 10% Tween-20 in 88 mL TBS.
  • This assay is used to measure the in vi tro kinase activity of FGF1-R in an ELISA assay.
  • Blocking Buffer (5% BSA/PBS).
  • ATP/MnCl 2 phosphorylation mix mix 20 ⁇ L ATP, 400 ⁇ L IM MnCl 2 and 9.56 ml dH 2 0. 10.
  • NUNC 96-well V bottom polypropylene plates (Applied Scientific Catalog # AS-72092).
  • step 10 Wash as in step 10. 14. Add 100 ⁇ l per well of Biosource Goat anti-rabbit IgG peroxidase conjugate (1:6000 dilution in ADB). Incubate, with shaking for 1 hr. at room temperature .
  • This assay is used to the in vi tro kinase activity of FGF1-R in an ELISA assay.
  • Materials and Reagents 1. Corning 96-well Elisa plates. 2. SUMOl monoclonal anti-EGFR antibody (SUGEN, Inc.).
  • Blocking Buffer for 100 ml, mix 5.0 g Carnation Instant Non-fat Milk® with 100 ml of PBS.
  • A431 cell lysate (SUGEN, Inc.).
  • TBS + 10% DMSO for IL, mix 1.514 g TRIS, 2.192 g NaCl and 25 ml DMSO; bring to 1 liter total volume with dH 2 0.
  • ATP Adiosine-5 ' -triphosphate, from Equine muscle, Sigma Cat. No. A-5394
  • ATP/MnCl 2 phosphorylation mix to make 10 ml, mix 300 ⁇ l of 1 mM ATP, 500 ⁇ l MnCl 2 and 9.2 ml dH 2 0. Prepare just prior to use, keep on ice.
  • This assay is used to the in vi tro kinase activity of FGF1-R in an ELISA assay.
  • Blocking Buffer (same as for EGFR bioassay) .
  • PDGFR- ⁇ expressing NIH 3T3 cell lysate (SUGEN, Inc. ) .
  • Kinase buffer phosphorylation mix for 10 ml, mix 250 ⁇ l IM TRIS, 200 ⁇ l 5M NaCl, 100 ⁇ l IM MnCl 2 and 50 ⁇ l 100 mM Triton X-100 in enough dH 2 0 to make 10 ml.
  • This assay is used to measure HER-2 kinase activity in whole cells in an ELISA format.
  • Fetal Bovine Serum FBS, GIBCO Catalog #16000-044
  • FBS Fetal Bovine Serum
  • SUMO 1 monoclonal anti-EGFR antibody (SUGEN, Inc. ) .
  • EGF Ligand EGF-201, Shinko American, Japan.

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PCT/US2001/004813 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors WO2001060814A2 (en)

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KR1020027010706A KR100713960B1 (ko) 2000-02-15 2001-02-15 피롤 치환 2-인돌리논 단백질 인산화 효소 저해제
DK01914376T DK1255752T3 (da) 2000-02-15 2001-02-15 Pyrrolsubstituerede 2-indolinonproteinkinaseinhibitorer
AU3977001A AU3977001A (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
JP2001560198A JP3663382B2 (ja) 2000-02-15 2001-02-15 ピロール置換２−インドリノン蛋白質キナーゼ阻害剤
BRPI0108394 BRPI0108394B8 (pt) 2000-02-15 2001-02-15 inibidores de proteína de quinase de 2-indolinona de pirrol substituído, seus sais e composições farmacêuticas compreendendo os mesmos
CA002399358A CA2399358C (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
AU2001239770A AU2001239770B2 (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
SK1326-2002A SK287142B6 (sk) 2000-02-15 2001-02-15 Inhibítory proteínkináz na báze pyrolom substituovaného 2-indolinónu, farmaceutický prípravok s ich obsahom a ich použitie
UA2002097427A UA73976C2 (uk) 2000-02-15 2001-02-15 Заміщені піролом 2-індолінони, фармацевтична композиція, спосіб модуляції каталітичної активності протеїнкінази та спосіб лікування або профілактики захворювання, пов'язаного з протеїнкіназою
HR20020751A HRP20020751B1 (hr) 2000-02-15 2001-02-15 Pirolom supstituirani 2-indolinoni kao inhibitori protein kinaze
MEP-2008-530A ME00415B (me) 2000-02-15 2001-02-15 Pirol supstituisani 2-indol protein kinazni inhibitori
IL15112701A IL151127A0 (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
DE60129794T DE60129794T2 (de) 2000-02-15 2001-02-15 Pyrrol substituierte indolin-2-on protein kinase inhibitoren
NZ520640A NZ520640A (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
EA200200862A EA005996B1 (ru) 2000-02-15 2001-02-15 Пирролзамещенный 2-индолинон, фармацевтическая композиция (варианты), способ модулирования каталитической активности протеинкиназы, способ лечения или профилактики нарушения в организме, связанного с протеинкиназой
MXPA02008021A MXPA02008021A (es) 2000-02-15 2001-02-15 Indolinonas sustituidas con pirroles inhibidoras de proteinquinasas.
BRPI0117360A BRPI0117360B8 (pt) 2000-02-15 2001-02-15 inibidores de proteína de quinase de 2-indolinona de pirrol substituído, seus sais e composições farmacêuticas compreendendo os mesmos
DE122008000002C DE122008000002I1 (de) 2000-02-15 2001-02-15 Pyrrol substituierte indolin-2-on protein kinase inhibitoren
HU0204433A HU228979B1 (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
HK03103304.2A HK1051188B (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
DE122010000004C DE122010000004I1 (de) 2000-02-15 2001-02-15 Pyrrol substituierte indolin-2-on protein kinase inhibitoren
SI200130778T SI1255752T1 (sl) 2000-02-15 2001-02-15 S pirolom substituirani zaviralci 2-indolinon protein kinaza
EP01914376A EP1255752B1 (en) 2000-02-15 2001-02-15 Pyrrole substituted 2-indolinone protein kinase inhibitors
IS6501A IS2491B (is) 2000-02-15 2002-08-13 Pýrról-setnir 2-indólínón prótín kínasa hindrar
NO20023831A NO325532B1 (no) 2000-02-15 2002-08-13 Pyrrolsubstituerte 2-indolinoner, farmasoytisk preparat omfattende slike, fremgangsmate for a modulere den katalytiske aktiviteten til en proteinkinase in vitro basert pa bruk av slike forbindelser, samt anvendelse av slike forbindelser til fremstilling av medikamenter for behandling av sykdommer.
CY20071101186T CY1108032T1 (el) 2000-02-15 2007-09-13 Πυρρολο υποκατεστημενης 2-ινδολινονης αναστολεις κινασης πρωτεϊνης
NL300332C NL300332I2 (nl) 2000-02-15 2008-01-08 Met pyrrol gesubstitueerde 2-indolinon proteine kinase remmers
LU91407C LU91407I2 (fr) 2000-02-15 2008-01-09 Sunitinib optionnellement sous la forme d'un sel pharmaceutiquement acceptable y compris le sel l-malate (sutent)
FR08C0002C FR08C0002I2 (fr) 2000-02-15 2008-01-15 Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
LTPA2008002C LTC1255752I2 (lt) 2000-02-15 2008-02-04 Pirolu pakeisti 2-indolinono proteinkinazės inhibitoriai
CY200800004C CY2008004I2 (el) 2000-02-15 2008-02-08 Πυρρολο υποκατεστημενης 2-ινδολινονης αναστολεις κινασης πρωτεϊνης
NO2008019C NO2008019I2 (no) 2000-02-15 2008-12-08 Sunitinib
NL300430C NL300430I2 (nl) 2000-02-15 2009-12-29 Met pyrrol gesubstitueerde 2-indolinon proteine kinase remmers.
FR10C0003C FR10C0003I2 (fr) 2000-02-15 2010-01-15 Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
NO2010002C NO2010002I2 (no) 2000-02-15 2010-02-09 Toceranibfosfat.
BE2010C009C BE2010C009I2 (en, 2012) 2000-02-15 2010-02-11
LU91657C LU91657I2 (fr) 2000-02-15 2010-03-03 Tocéranibe et ses dérivés pharmaceutiquement acceptables (PALLADIA®)
CY2010004C CY2010004I1 (el) 2000-02-15 2010-03-09 Πυρρολο υποκατεστημενης 2-ινδολινονης αναστολεις κινασης πρωτεϊνης
NO2019005C NO2019005I1 (no) 2000-02-15 2019-02-05 N-[2-(dietylamino)etyl]-5-[(Z)-(5-fluoro-2-okso-1,2-dihydro-3H-indol-3-yliden)metyl]-2,4-dimetyl-1H-pyrrol-3-karboksamid (sunitinib), samt farmasøytisk akseptable salter

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US18271000P 2000-02-15 2000-02-15
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