WO2008145398A1 - 4-arylpyrrole substituted 2-indoline derivatives active as protein kinase inhibitors - Google Patents
4-arylpyrrole substituted 2-indoline derivatives active as protein kinase inhibitors Download PDFInfo
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- WO2008145398A1 WO2008145398A1 PCT/EP2008/004342 EP2008004342W WO2008145398A1 WO 2008145398 A1 WO2008145398 A1 WO 2008145398A1 EP 2008004342 W EP2008004342 W EP 2008004342W WO 2008145398 A1 WO2008145398 A1 WO 2008145398A1
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- 0 *c1c(C(N*)=O)c([Al]P)c(C=C(C2=C(*)CC(*)=CC=C2N2)C2=O)[n]1 Chemical compound *c1c(C(N*)=O)c([Al]P)c(C=C(C2=C(*)CC(*)=CC=C2N2)C2=O)[n]1 0.000 description 2
- JBPCDXVHSGSOBX-HKWRFOASSA-N CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/C2=CC(N)=CCC2N2)\C2=O)c1-c(cccc1)c1O)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/C2=CC(N)=CCC2N2)\C2=O)c1-c(cccc1)c1O)=O JBPCDXVHSGSOBX-HKWRFOASSA-N 0.000 description 1
- VTIHENAVVVSKEI-UHFFFAOYSA-N CCOC(c1c(C)[nH]cc1O)=O Chemical compound CCOC(c1c(C)[nH]cc1O)=O VTIHENAVVVSKEI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- R 14 is hydrogen
- R 3 is -(CH 2 ) n -CH(R 6 )-(CH 2 ) m R ⁇ ;
- alkyl indicates a saturated aliphatic hydrocarbon radical, including straight chain and branched chain groups of 1 to 6 carbon atoms More preferably, an alkyl group has 1 to 4 carbon atoms
- alkyl are, for instance, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl 0
- cycloalkyl indicates a 3 to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated ⁇ -electron system
- Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, and cyclohexadiene.
- trihalomethyl indicates a -CX 3 group wherein X is a halogen atom, as defined above
- a compound of formula (VIIl) can be obtained from a compound of formula (X),
- Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invitrogen Corp , CA, USA), 10 nM EGF (Gibco BRL 1 USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany) Cells were then fixed in PBS/37% paraformaldehyde for 20 minutes at room temperature, washed X2 with PBS, and permeabilized with PBS/0 3% Triton X-100 for 15 minutes Wells were then saturated with PBS/1% non-fat dry milk (Bio-Rad Laboratories, Hercules, CA 1 USA) for 1 hour, and then probed for 1 hour at 37°C with anti-phospho-S6 (Ser 235/236) antibody (Cell Signaling Technology, Beverly, MA, USA, cat #2211) at 1/200 dilution in PBS/1% milk/03% Tween 20 Wells were then washed twice with PBS, and in
- the substrate used in the assay was a peptide of the following sequence: K V V E E I0 N G N N Y V Y I D P T Q L P Y D H K W E F P R N R
- the peptide was obtained in batches of >95% peptide purity from American Peptide Company, lnc (Sunnyvale, CA, USA).
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e g , sterile water, olive oil, ethyl oleate, glycols, e g , propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
- a pharmaceutically acceptable carrier e g , sterile water, olive oil, ethyl oleate, glycols, e g , propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
- the title compound can be obtained starting from 1-tert-butyl 3- ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-1 ,3-dicarboxylate according to the following procedure: A mixture of 1-tert-butyl 3-ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl- 1H-pyrrole-1,3-dicarboxylate (75 3 mg, 0 194 mmol ) in ethanol (1 mL) and 20% KOH (10 mL) was refiuxed for 1h The cooled reaction mixture was acidified to pH 3 with 2N HCI 1 and extracted with AcOEt (3x15 mL) The organic phases were combined, washed with water (2x15 mL), dried on anhydrous Na 2 SCi 1 filtered and evaporated to dryness to give 59 mg (85% yield) of the desired product as white solid ESI(+) MS: m/z 519 (2M+H),
Abstract
The present invention relates to certain 4-arylpyrrole substituted 2-indolinone compounds of Formula (I), which modulate the activity of protein kinases (PKs). The compounds of this invention are therefore useful in treating disorders related to dysregulated PK activity The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
Description
-I-
4-ARYLPYRROLE SUBSTITUTED 2-iNDOLINONE DERIVATIVES ACTIVE AS PROTEIN
KINASE INHIBITORS
BACKGROUND The present invention relates to certain 4-arylpyrrole substituted 2-indoliπone compounds, which modulate the activity of protein kinases (PKs) The compounds of this invention are therefore useful in treating disorders related to dysregulated PK activity The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds
The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is a member of the insulin receptor subfamily of receptor tyrosine kinses (RTKs) IGF-1 R mature protein consists of two alpha chains, which are extracellular and contain ligand-binding function, and two beta chains, which span the cell membrane and contain the intracellular kinase domains This disulphide-liπked (alpha/beta)2 heterodimer complex is able to bind and be activated by the ligands insulin-like growth factor-l and -2 (IGF-1 and IGF-2), two circulating growth factors which are believed to mediate many of the effects of Growth Hormone (GH)1 and which have important physiological roles in foetal and post-natal growth and metabolism. Extracellular ligand binding to IGF-1 R results in intracellular tyrosine kinase activation, and like several other RTKs such as the EGF and PDGF receptors, the activated receptor has potent mitogenic, motogenic and anti-apoptotic activity in a wide range of cell types: notably, it directly activates at least two major cell signalling pathways, the ras/MAPK pathway, through recruitment of SHC1 and the PI-3 kinase/AKT(PKB) pathway, through recruitment and phosphorylation of the IRS adapter proteins There is much evidence, both at preclinical and clinical levels, linking increased IGF-1 R signalling to development and progression of cancer. This evidence includes observation that IGF-1 R is able to induce cellular transformation, that fibroblasts from animals lacking IGF-1 R through genetic ablation are extremely resistant to the transforming activity of a wide range of oncogenes, and that IGFs are potent anti- apoptotic agents Studies of interference with receptor activity through various approaches have demonstrated that inhibition of IGF-1 R dependent signalling can result in single agent antitumor activity, and in the enhancement of the activity of a wide range of chemotherapeutic agents and radiotherapy in human tumor cells cultured in vitro, as well as in animal models of disease, including human tumor xenograft models Such IGF-1 R inhibition strategies have included cellular transfection with dominant negative IGF-1 R constructs or antisense oligonucleotides, use of IGF binding antagonists and blocking monoclonal antibodies directed against the extracellular receptor, and, significantly, selective small molecule inhibitors of IGF- 1R kinase activity Additional indication that IGF-1 R signalling contributes to development of cancer, and thus that inhibition of this receptor may represent a valuable therapeutic option, is
provided by the observation that high circulating levels of IGF- 1 in human are associated with increased lifetime risk of developing several tumor types, including breast, colorectal, prostate and ovarian cancers, and with poor outcome in multiple myeloma Importantly, gene and protein expression studies performed on clinical samples have revealed that IGF-1R and its ligands are frequently expressed in a wide range of human tumors For an overview of IGFs and IGF-1R signalling, physiological function, and detailed description of the evidence supporting involvement of this system in human cancer that is summarised above, as well as in other pathologies, the reader is directed to the many reviews on the subject and references contained therein, for example Baserga R,, Hongo A , Rubini M , Prisco M and Valentinis B
I O Biochim Biophys Acta vol 1332 pages F105-F126, 1997; Khandwala H M , McCutcheon I E., Flyvbjerg A. and Friend K E Endocr Rev vol 21, pages 215-44, 2000; Le Roith D., Bondy C1 Yakar S,, Liu J L and Butler A Endocr Rev vol 22, pages 53-74, 2001; Valentinis B., and Baserga R. MoI Pathol, vol 54, pages 133-7, 2001; Wang Y and Sun Y , Curr Cancer Drug Targets vol 2 pages 191-207, 2002, Laron, Z J Clin Endocrinol Metab vol 89, pages 1031-
15 1044, 2004; Hofmann F and Garcia-Echeverria C Drug Discov Today vol. 10, pages 1041-7, 2005
The present invention is directed to a specific class of 4-arylpyrrole substituted 2- indolinone compounds which exhibit PK modulating ability and are therefore useful in treating disorders related to dysregulated PK activity Surprisingly, it has been found that the 0 compounds of formula (I) are potent inhibitors of the tyrosine kinase activity of the Insulin-like growth factor 1 receptor and inhibit IGF-1R-dependent cell proliferation The presence of the aryl substituent at position 4 of the pyrrole ring is crucial for the activity of the compounds of the present invention as IGF-1R tyrosine kinase inhibitors and their potential to inhibit IGF-IR- dependent cell proliferation 5
SUMMARY OF THE INVENTION
The present invention is directed to a compound of formula (I):
Ar is aryl;
R1 is selected from the group consisting of hydrogen, halogen, -OH1 alkoxy, -NH2, -NHCOR10, -NHSO2R10, and -SO2NHR10; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl;
R3 is selected from the group consisting of hydrogen, cycloalkyl, and -(CH2)n-CH(R6)- (CH2)mR6;
R4 is selected from the group consisting of hydrogen, methyl, and ethyl;
R5 is selected from the group consisting of hydrogen, -OH. -NH2, alkyl, and alkoxy; R6 is selected from the group consisting of hydrogen, -OH, -NR7R8, -COR8, and aryl, or R5 and R6 may combine to form a heterocyclic ring;
R7 and Rβ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy, cycloalky, -COR9 and aryl, or optionally R7 and Rβ may combine to form a saturated or unsaturated heterocyclic ring or an aryl ring; R8 is selected from the group consisting of -OH, alkoxy, -NH2, and
-NR7R8;
R is selected from the group consisting of alkyl, cycloalkyl, and aryl;
R14 is hydrogen, or R14 and R3 together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted with alkyl, wherein said alkyl may be optionally substituted with a heterocyclic ring;
R16 is independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO2, -NH2, -SH, alkyl optionally substituted with hydroxy or 1 to 3 fluorines, atkylthio, alkoxy optionally substituted with phenyl or 1 to 5 fluorines, -C(O)R9, -C(O)R16, and -SOj-alkyl, or optionally when p is 2, then both R15substituents, together with two adjacent atoms from Ar to which they are attached, form a heterocyclic ring fused to Ar;
R1β is selected from the group consisting of hydrogen, alkyl, trihalomethyl, cycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, -SH, alkyl, trihaloalkyl, alkoxy, alkylthio, -CN1 acyl,
-NO2, -NR7R8, and -SO2-alky|; n and m are independently O, 1, 2 or 3, p is O1 1, 2, or 3; with the proviso that when n is O then R5 is selected from hydrogen and alkyl. and when m is O then only one of R5 and R8 may be -OH or -NH2; and
with the proviso that when R1 is bromine, R2 is hydrogen, R4 is methyl, Ar is phenyl, then R3 is not 2-dimethylaminoethyl, 3-diethylaminopropyl or 2-{pyrrolidin-1-yl)ethyl with the proviso that if R1 is hydrogen, methylaminosulphonyl or benzyl-sulphonyl, than Ar-/R15)p is not 4-cholorophenyl or 2,4-difluorophenyl; with the proviso that the compounds 4-(4-chlorophenyl)-N-[2-(diethylamiπo)ethyl]-2- methyl-5-((Z)-{5-[(methylamino)sulfonyl]-2-oxo-1,2-dihydro-3H-iπdol-3-ylidene}methyl)-1 H- pyrrole-3-carboxamide,
N-[2-(diethylamino)ethyl]-4-(2,4-difluorophenyl)-2-methyl-5-((Z)-{5- [(methylamino)sulfonyl]-2-oxo- 1 ,2-dihydro-3H-indol-3-ylidene}methyl)-1 H-pyrrole-3- carboxamide, and
4-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(4-methyl-2-oxo-1 l2- dihydro-3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide are excluded
In one embodiment, the invention relates to a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of hydrogen, fluorine, -OH. alkoxy, -NH2, -NHCOR10. -NHSO2R10, and -SO2NHR10;
R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl;
R3 is selected from the group consisting of hydrogen and -(CH2)n-CH(R5MCH2)mRβ;
R4 is methyl or ethyl;
R5 is selected from the group consisting of hydrogen and -OH;
R6 is selected from the group consisting of -OH, -NR7R8, and aryl;
R7 and RB are independently selected from hydrogen and alkyl, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring;
R10 is selected from alkyl, cycloalkyl, and aryl; and
R14 is hydrogen
In another embodiment, the invention relates to a compound of formula (I)1 as defined above, or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of hydrogen, fluorine, -OH, alkoxy, -NH2. -NHCOR10, -NHSO2R10, and -SO2NHR10;
R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl;
R3 is -(CH2)n-CH(R5HCH2)mR6; R4 is methyl;
Rs is selected from the group consisting of hydrogen and -OH;
Rβ is selected from the group consisting of -OH, -NR7R8, and aryi;
Rτ and Rβ are independently selected from hydrogen and alkyl, or R7 and Rβ may combine to form a saturated or unsaturated heterocyclic ring;
Rt0 is selected from alkyl, cycloalkyl and aryl;
R14 is hydrogen; and . 5 n and m are independently selected from 0, 1 or 2
In another embodiment, the invention relates to a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof, wherein
Ar is aryl;
R1 is selected from the group consisting of fluorine, alkoxy, -NH2, -NHSO2R10 and - I O SO2NHR'0;
R2 is selected from the group consisting of hydrogen, methyl and hydroxyethyl;
R3 is -(CH2)n-CH(R6)-(CH2)mRβ;
R4 is methyl;
R5 is selected from the group consisting of hydrogen, and -OH; 15 Re is selected from the group consisting of -OH, -NR7R8, and aryl;
R7 and R8 are independently selected from hydrogen and an alkyl group, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring;
R10 is selected from alkyl and aryl;
R14 is hydrogen; and 0 n and m are independently selected from 0 or 1
In another embodiment, the invention relates to a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof, wherein
Ar is aryl;
R1 is selected from the group consisting of fluorine, alkoxy, -NHSO2R10, and 5 SO2NHR10;
R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl;
R3 is -(CH2)n-CH(R5)-(CH2)mRθ;
R4 is methyl;
R5 is selected from the group consisting of hydrogen and -OH; 0 Rβ is -NR7R";
R7 and R8 are independently selected from hydrogen and an alkyl group, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring;
R10 is selected from alkyl and aryl;
R14 is hydrogen; and 5 n and m are independently selected from 0 or 1.
(n another embodiment, the invention relates to a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof, wherein
Ar is phenyl or thiophene;
R1 is selected from the group consisting of hydrogen, F, Cl, -OH, -OCH3, -NH2, -O-CHrPhenyl, -SO2-N(H)(CH3), -N-SO2-phenyl, -N-C(O)-phenyl, -N-C(O)-OC(CH3)3;
5 R2 is selected from the group consisting of hydrogen, methyl, and
-CH2CH2OH;
R3 is selected from the group consisting of hydrogen, cycloalkyl, and -(CH2)n-CH(R5)- (CH2)mRβ;
R" is -CH3; I O R5 is selected from the group consisting of hydrogen, -OH, -NH2, alkyl, and alkoxy;
Rβ is selected from the group consisting of hydrogen, -OH, -NR7R8, -COR9, and aryl, or R5 and Rβ may combine to form a heterocyclic ring;
R7 and Rβ are independently selected from the group consisting of H, alkyl, alkoxy, cycloalky, -COR9 and aryl,
15 or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring, wherein said heterocyclic ring is selected from morpholine, N-methylpiperazione, and 4- hydroxypiperidine;
R9 is selected from the group consisting of -OH1 alkoxy, -NH2, and -NR7R8;
R14 is hydrogen, 0 or R3 and R14 together with the nitrogen to which they are attached form pyrrolidine ring substituted with methyl, wherein said methyl is substituted with another pyrrolidine ring;
R15 is independently selected from the group consisting of H, F1 Cl, Br, -OH, -CN, -NO2, -NH2, -CH3, CH(CHa)2 -CF3. -OCH3, -OCF3, -OCH2CH3, -CHCH3CH3, -CH2OH. - CH2CH2OH, -C(O)CH3, -O-CHrphenyl, and -SO2CH3; 5 or, when n is 2 and Ar is phenyl, both R15 substituents together form a methylenedioxy group such that the 2 R15 substituents together with Ar form methylenedioxyphenyl; and p is O, 1, or 2.
In another embodiment, the invention relates to a compound of formula (I), as defined 0 above, or pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R1 is selected from the group consisting of hydrogen, F, Cl, -OH, -OCH3, -NH2;
R2 is hydrogen; 5 R3 is -(CH2)H-CH(R5MCH2),^8;
Rs is selected from the group consisting of hydrogen and -OH;
Rβ is -NR7R8;
R7 and R8 are independently selected from the group consisting of H1 alkyl, alkoxy, -COR9;
R9 is selected from the group consisting of -OH, alkoxy, -NH2;
R14 is hydrogen
5 R1S is independently selected from the group consisting of H, F1 Cl, Br, -OH1
-NO2, -NH2. -CH3. -OCH3. -OCF3; and n and m are independently selected from 1 or 2; and p is O, 1, or 2
The invention also includes a compound of formula (I), as defined above, or I O pharmaceutically acceptable salt thereof, selected from the group consisting of
N-[2-(diethylamiπo)ethylJ-2-methyl-5-[(ZM2-oxo-1 ,2-dihydro-3H-indol-3- y lidene)methy ll-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[2-(isopropylamino)ethyl}-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl-1 H-pyrrole-3-carboxamide;
15 N-(2,3-dihydroxypropyl)-2-methyI-5-[(Z)-(2-oxo- 1 ,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl-1 H-pyrrole-3-carboxamide;
N-[(2R)-2l3-dihydroxypropyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide;
2-methyl-N-(3-morpholin-4-ylpropyl)-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- 0 ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide;
2-methyl-N'[3-(4-methylpiperazin-1-yl)propyl]-5-[{Z)-{2-oxo-1l2-dihydro-3H-indol-3- ylideπe)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[2-{dtethylamiπo)ethyl]-2-methyl-5-[{Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-[4-(trifluoromethyl)phenyl]-1 H-pyrrole-3-carboxamide; 5 N-[2-(diethylamino)ethyl]-4-{4-(dimethylamino)phenyl]-2-methyl-5-[(Z)-<2-oxo-1 l2- dihydro-SH-indol-S-ylideneJmethyll-IH-pyrrote-S-carboxamlde carboxamide;
N-(2-(diethylamlπo)ethyl]-2-methyl-4-[4-(methylsulfonyl)phenyll-5-[(Z)-(2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-p-CdiethylaminolethylH^-isopropylphenylJ^-methyl-S-rø^-oxo-i^-dihydro- 0 3H-indo!-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-2-methyl-5-I(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-[3-(trifluoromethyl)phenyl]-1 H-pyrrole-3-carboxamide;
4-(3-acetylphenyl)-N-(2-(diethylamino)ethyll-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide; 5 4-[4-(benzyloxy)phenyl]-N-t2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
4-(4-cyanophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)rnethyl]-1 H-pyrrole-3-carboxamide;
4-(4-ch!orophenyl)-N-[2-(diethylamino)ethyl]-2-methy!-5-[(Z)-(2-oxo-112-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide; N-p-CdiethylaminoJethylJ^-methyM^S-nitropheπyO-S-KZJ^-oxo-i^-dihydro-SH- indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-2-methy!-5-{(ZH2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl)-4-[3-(trifiuoromethoxy)phenyl]-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(3-fluoropheπyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- iπdol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-{3-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethylJ-2-methyl-4-(3-methylphenyl)-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-S-ylideneJmethyll-IH-pyrrole-S-carboxamide; N-[2-(diethylamino)ethyl]-4-(3-ethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- iπdol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethyiamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)meinyl]- 1 H-pyrrole-3-cari5oxamide;
N-[2-(isopropylamino)ethyl]-4-(2-methoxypheπyl)-2-methyl-5-((Z)-(2-oxo-1 ,2-dihydro- 3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-(2-methoxyphenyl)-2-methyl-N-(2-moφholin-4-ylethyl)-5-[(Z)-(2-oxo-1 l2-dihydro- SH-indol-S-ylideπeJmethyll-IH-pyrrole-S-carboxamlde;
N-[(2R)-2,3-dihydroxypropyl]-4-(2-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyt]-4-(2-fluorophenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- iπdol-3-y lidene)methy I]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-2-methyl-4-(2-nitrophenyl)-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- iπdol-3-ylideπe)methylJ- 1 H-pyrrole-3-carboxamide;
4-( 1 ,3-benzodioxol-5-yl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo- 1 ,2-dihydro- 3H-indol-3-ylidene)methyl]-1 H-pyσole-3-carboxamide;
N-[2-{diethylamino)ethyl]-4-(2,4-difluoraphenyl)-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro- 3H-indol-3-ylideπe)methylJ- 1 H-pyrrole-3-carboxamide;
N-(2-(diethylamino)e{hylJ-4-(2,4-dimethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro- 3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide; N-[2-(diethylamiπo)ethyl]-4-(2,5-dimethoxyphenyl)-2-methyl-5-[(Z)-{2-oxo-1,2-dihydro-
3H-indol-3-ylideπe)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyO-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-thien-3-yl-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H-indol-3- ylidene)methyl]-4-thien-2-yM H-pyrrole-3-carboxamlde; 4-(5-chlorothien-2-yl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-(5-acetylthien-2-yl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
5-[{Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (isopropylamino)ethyl]-2-methyl-4-pheπyl-1 H-pyrrole-3-carboxamide;
N-(2,3-dihydroxypropyl)-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidenβ)methyl]- 2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
5-[(ZH5-fluoro-2-oxo-1,2-diriydro-3H-indol-3-ylidene)methyl]-2-rnethyl-N-{3-(4- methy Ipiperazin- 1 -yl)propy l]-4-phenyl- 1 H-pyrrole-3-carboxamide; 5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene)methyl]-2-methyl-N-(3- morpholin-4-ylpropyl)-4-phenyl- 1 H-pyrrole-3-carboxamide;
Methyl 5-[({5-{(Z)-(5-fluoro-2-oxo- 1 ^-dihydro-SH-iπdol-S-ylideneJmethylJ^-methyM- phenyl-1H-pyrrol-3-yl}carboπyl)amino]pentanoate;
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-yIidene)methyl]-N-[2-(4- hydroxypiperidin- 1 -yl)ethyl]-2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene)methyl]-N-(4- hydroxycyclohexyl)-2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyll-5-[(Z)-(5-fluoro-2-oxo-1,2-dirιydro-3H-iπdol-3- ylidene)methyl]-4-{4-fluorophenyl)-2-methyl-1 H-pyrrole-3-carboxamide; 5-[(Z)-(5-nuoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-4-(4-fluorophenyl)-N-[2-
(isopropylamino)ethyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
N-[3-(diethylamino)-2-hydroxypropyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methylH-(4-fluorophenyl)-2-methyl-1 H-pyrrole-3-carboxamide;
N-[2-{diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydro-3H-indol-3- y lidene)methy l]-4-(4-methoxypheπyl)-2-methy 1-1 H-pyrrole-3-carboxamide;
4-(4-chlorophenyl)-N-I2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide;
4-(4-cyanophenyl)-N-[2-(diethy[amino)ethylJ-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyll-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methylJ-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(2l4-difluorophenyl)-5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1H-pyrrole-3-carboxamide;
N-[2-{diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methylJ-2-methyl-4-phenyl-1H-pyrrole-3-carboxamide; N-[2-(diethytamino)ethyl]-4-(4-fluoropHenyl)-5-[{Z)-(5-methoxy-2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl- 1 H-pyrro!e-3-carboxamide;
4-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1 ,2-dihydro-3H- iπdol-3-ylidene)methyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3- ylideπe)methyl]-4-(2-methoxyphenyl)-2-methyl-1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-2-methyl-4-{2-πitrophenyl)-1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(2,4-difluorophenyl)-5-f(Z)-(5-methoxy-2-oxo-1 ,2-dihydro- 3H-indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide; 5-[(Z)-(5-chloro-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-
(diethylamino)ethyl]-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-iπdol-3-ylidene)methyl]-4-(4-chlorophenyl)-N-[2- (diethylamino)ethyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-4-(2,4-difluorophenyl)-2-metrιyl- 1 H-pyrrole-3-carboxamide;
N-t2-(isopropylamino)ethyl]-2-methyl-5-((Z)-{5-[(methylamino)sulfonyl]-2-oxo-1,2- dihydro-3H-indol-3-ylidene}methyl)-4-phenyl-1H-pyrrole-3-carboxamide;
N-[3-(diethylamino)-2-hydroxypropylJ-2-methyl-5-((Z)-{5-{(rπethylamiπo)sulfonyl]-2- oxo-1 ,2-dihydro-3H-indol-3-ylidene}methyl)-4-phenyl- 1 H-pyrrole-3-carboxamide; 4-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-({Z)-{5-
[(methylamino)sulfonyl]-2-oxo-1,2-dihydro-3H-indol-3~ylidene}methyl)-1H-pyrrole-3- carboxamide;
N-[2-(diethylamiπo)ethyl]-4-(2.4-difiuoropheπirl)-2-methyi-5-((Z)-{5- [(methylamino)sulfonyl]-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene}methyl)-1H-pyrrole-3- carboxamide;
N-[2-(diethylamino)ethyl]-4-[3-(hydroxymethyl)phenyl]-2-methyl-5-[(Z)-(2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyll-1 H-pyrrole-3-carboxamide;
5-{(Z)-[4-(2-hydroxyethyl)-2-oxo-1,2-dihydro-3H-indol-3-yfidene]methyl}-2-methyl-4- phenyl- 1 H-pyrrole-3-carboxamide); N-[2-(diethylamino)ethyl]-5-{(Z)-[4-(2-hydroxyethyl)-2-oxo-1 ,2-dihydro-3H-indol-3- ylidene]methyl}-2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-p-tdiethylaminoJethyll^-methyl-S-KZJ-CΦmethyl-a-oxo-i.a-dihydro-SH-indol-a- ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamiπo)ethyl]-4-(4-fluorophenyl)-2-methyl-5-[(Z)-(4-methyl-2-oxo-1,2- dihydro-3H-iπdol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide; 4-{4-chloraphenyl)-N-[2-(die(hylamino)ethyl]-2-methyl-5-[(Z)-{4-methyl-2-oxo- 1 ,2- dihydro-3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(2,4-difluorophenyl)-2-methyl-5-l(Z)-(4-methyl-2-oxo-1,2- dihydro-SH-indol-S-ylideneJmethylJ-I H-pyrrole-S-carboxamide;
N-[2-(diethylamlno)ethyl]-4-(4-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrate-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(3-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-{2-{diethylamino)ethyl]-4-{2-hydroxyphβnyl)-2-methyl-5-((Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide; 4-(2-hydroxypheπyl)-N-[2-(isopropy!amino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-
3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[(2R)-2,3-dihydroxypropyl]-4-(2-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro- 3H-indol-3-ylideπe)methyl]- 1 H-pyrrole-3-carboxamide;
4-(2-hydroxyphenyl)-2-methyl-N-(2-morpholin-4-yIethyl)-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(214-dihydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- SH-indol-S-ylideneJmethylJ-IH-pyrrole-S-carboxamide;
N-[2-(diethylamino)ethyl]-5-f(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-iπdσl-3- ylidene)methyl]-4-(2-hydroxypheπyl)-2-methyl-1 H-pyrrole-3-carboxamide; N-[2-{diethylamιno)ethyl]-5-[(Z)-(5-hydroxy-2-oxo-1 ,2-dihydro-3H-indol-3- y lidene)methyl]-2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-p-CdiethylaminoJethyll-S-ftZJ-CS-hydroxy^-oxo-i ^-dihydro-SH-indol-S- ylcdene)methyl]-4-(2-hydroxypheπyl)-2-methyl-1 H-pyrrole-3-carboxamide;
4-(3-aminophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1l2-dihydro-3H- indol-3-y lidene)methyl]- 1 H-pyrrole-3-carboxamide;
4-{3-aminopheπyl)-N-[2-{isopropylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1H-pyrτole-3-carboxamide;
4-(3-aminophenyl)-N-[(2R)-2,3-dihydroxypropyl]-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro- 3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide; 4-(2-aminophenyl)-N-[2-(diethylamino)ethyll-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-(3-aminophenyl)-N-[2-(diethylamino)ethyl]-5-[{Z)-(5-methoxy-2-oxo-1 l2-dihyclro-3H- indol-3-ylidβne)methyl]-2-methyl-1H-pyrrole-3-carboxamide;
4-(2-aminophenyl)-N-[2-{diethylarnino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1 ,2-dihydro-3H- iπdol-3-ylidene)methyl]-2-methyl- 1 H-pyrrole-3-carboxamide; 4-{3-amiπopheπyl)-N-{2-(diethylamino)ethylJ-5-{(Z)-f4-{2-hydroxyethyl)-2-oxo- 1 ,2- dihydro-3H-indol-3-ylidene]methyl)-2-methyl-1 H-pyrrole-3-carboxamide;
5-[({5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2-methyl-4-phenyl- 1 H-pyrrol-3-yl}carbonyl)amino]pentaπoic acid;
4-(2-fIuorophenyl)-N-[2-(isopropylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3HHndol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-fiuoro-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene)methyl]-N-[3-(1 H-imidazol- 1 - yl)propyl]-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide carboxamide; N-[3-(diethylamino)-2-hydroxypropyl]-5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydrc~3H-indol-3- ylidene)methyl]-4-{4-bromophenyl)-2-methyl-1 H-pyrrole-3-carboxamide;
N-[3-(diethylamino)-2-hydroxypropyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-(4-methoxyphenyl)-2-methyl-1 H-pyrrole-3-carboxamide;
4'(4-bromophenyl)-N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fIuoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-(3-methoxyphenyl)-2-methyl-1H-ρyrrole-3-carboxamide;
5-{(Z)-[5-<benzyloxy)'2-oxo-1,2-dirιydro-3H-indol-3-ylideπe]methyl}-N-[2- (diethylamino)ethyl]-2-rnethyl-4-phenyl-1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-5-((ZH2-oxo-5-
[(phenylsulfonyl)amino]-1,2-dihydro-3H-indol-3-ylidene}methyl)-1 H-pyrrole-3-carboxamide;
5-{(Z)-[5-(benzoylamiπo)-2-oxo-1 ,2-dihydra-3H-indol-3-ylidene]methyl}-N-[2- (diethylamino)ethyl]-4-(2-me(hoxyphenyl)-2-me(hyl-1H-pyrrole-3-carboxamide; tert-butyl (3Z)-3-{[4-({[2-(diethylamino)ethyl]amino}carboπyl)-3-{2-methoxypheπyl)-5- methyl-1 H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1 H-indol-5-ylcarbamate;
N-{2-(diethylamiπo)ethyl]-4-(2-hydroxyphenyl)-2-methyl-5-((Z)'{2-oxo-5- [(phenylsulfonyl)amino]-1 ,2-diriydro-3H-indol-3-ylidene}methyl)- 1 H-pyrrole-3-carboxamide;
5-{(Z)-[5-(benzoylamiπo)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}-N-[2- (diethylamino)ethyl]-4-(2-hydroxypheπyl)-2-methyl-1 H-pyrrole-3-carboxamide; 5-{(ZH5-(benzyloxy)-2-oxo- 1 ,2-dihydro-3H-indol-3-ylideπe]methyl}-N-[2-
(diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-melhyl-1H-pyrrole-3-carboxamide;
5-[(Z)-{5-aππino-2-oxo-1 ,2-dihydro-3H-inclol-3-ylidene)mettiyl]-N-l2- (diethylamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-1 H-pyrrole-3-carboxanπide; and
5-[(Z)-(5-amino-2-oxo-1 ,2-dihydro-3H-indol-3-y!idene)methyl]-N-[2- (diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide The invention is also directed to a method for treating a disease caused by, or associated with, dysregulated protein kinase activity, particularly IGF- 1 R kinase activity, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof.
The invention is also directed to a method to treat a disease caused by or associated with dysregulated protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies, diabetic retinopathies, neonatal retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neσintimal formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia induced tissue damage, obesity, and metabolic disorders in which elevated IGF levels or IGF-1R activity are implicated, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof The invention is also directed to a method to treat a disease selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthomas, thyroid follicular cancer, and Kaposi's sarcoma, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof.
The invention is also directed to a method to a disease selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and medulloblastoma, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof
The invention is also directed to a method to treat cell proliferative disorders selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, post-surgical stenosis and
restenosis, comprising administering to a mammal in need thereof an effective amount a compound of formula (I)1 as defined above, or pharmaceutically acceptable salt thereof.
The invention is also directed to a method of promoting tumor angiogenesis or metastasis inhibition, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof
The invention is also directed to a method for synthesizing a compound for formula (I), as defined above, prepared through a process consisting of standard synthetic transformations The invention is also directed to a pharmaceutical composition comprising of one or more compounds of formula (I), as defined above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient, carrier or diluent
The invention is also directed to a pharmaceutical composition comprising a compound of formula (I), as defined above, or pharmaceutically acceptable salt thereof, in combination with one or more chemotherapeutic agents or radiotherapy selected from the group consisting of antiestrogens, antiandrogens, aromatase inhibitors, topoisomerase I inhibitors, topoisomerase Il inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, kinase inhibitors, anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response
Several indoliπone derivatives possessing kinase inhibitory activity have been disclosed in WO01/37820, WO01/60814, WO02/02551, WO2/55517 and WO02/66463 A compound of formula (I) may exhibit the phenomenon of structural isomerism. For example, the compounds described herein may adopt an E or a Z configuration of the double bond connecting the 2-indolinone moiety to the pyrrole ring, as depicted above
This invention encompasses also any tautomeric or structural isomeric form and 5 mixtures thereof, which possess the ability to modulate protein kinase activity and is not limited to any one tautomeric or structural isomeric form
The compounds of formula (I) may have one or more asymmetric centres, and may therefore exist as individual optical isomers or racemic mixtures. Accordingly, all the possible isomers, and their mixtures, of the compounds of formula (I) are within the scope of the 10 present invention
Derivatives of compounds of formula (I) originating from metabolism in a mammal, and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro-drugs) of the compounds of formula (I) are also within the scope of the present invention.
The general terms used in the specification and in the claims have the meanings ! S reported below, unless otherwise stated
The term "alkyl" indicates a saturated aliphatic hydrocarbon radical, including straight chain and branched chain groups of 1 to 6 carbon atoms More preferably, an alkyl group has 1 to 4 carbon atoms Non-limiting examples of alkyl are, for instance, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl 0 The term "cycloalkyl" indicates a 3 to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated π-electron system Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, and cyclohexadiene.
The term "alkynyl" indicates an alkyl group, as defined herein, consisting of at least 5 two carbon atoms and containing at least one carbon-carbon triple bond Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and the like
The term "aryl" indicates an all-carbon monocyclic or fused-ring polycyclic (i e rings which share an adjacent pair of carbon atoms) system of 6 to 10 carbon atoms having a 0 completely conjugated π -electron system; or a monocyclic or fused-ring polycyclic system of
5 to 10 atoms and containing from one to three heteroatoms selected from nitrogen, oxygen and sulfur Examples of all-carbon aryl groups are phenyl and naphthyl Examples of aryl group containing from one to three heteroatoms are, without limitation, pyrrole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, pyrazole, oxadiazole, thiadiazole, triazole, 5 pyridine, pyrimidine, pyridazine, indole, benzofuran, benzothiofuran, indazole, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, quinoline, isoquinoiine, quinazoiine, quinoxalines, and the like
The term "heterocyclic ring" indicates a ring system composed of 4 to 7 atoms and containing one or two heteroatoms selected from nitrogen, oxygen and sulfur The ring may also contain one or more double bonds, but does not have a completely conjugated π- electron system Examples, without limitation, of heterocyclic rings are azetidine, pyrrolidine, imidazoline, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, and the like
The term "halogen" indicates fluorine, chlorine, bromine or iodine;
The term "hydroxy" indicates an -OH group
The term "alkoxy" indicates both an -O-a)kyl and an -O-cycloalkyl group Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, t-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like
The term "amino" indicates an -NHz group;
The term "trihalomethyl" group indicates a -CX3 group wherein X is a halogen atom, as defined above
The term "nitro" indicates a -NO2 group The term "cyano" indicates a -CaN group
The term "mercapto" indicates an -SH group
The term "alkylthio" indicates both an -S-alkyl and an -S-cycloalkyl group Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like The term "acyl" indicates a -C(O)-R' group, where R1 is selected from the group consisting of hydrogen, alkyl, trihalomethyl, cycloalkyl and aryl Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like
As used herein, the term "pharmaceutically acceptable salt" indicates those salts which retain the biological effectiveness and properties of the parent compound Such salts include:
(i) acid addition salts which are obtained by reaction of a free base in the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, or perhcloric acid and the like, or with organic acids such as acetic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
(ii) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e g , an alkali metal ion or an alkaline earth ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like
DETAILED DESCRIPTION
It is an object of the present invention to provide a process for the preparation of compounds of formula (I) and the pharmaceutically acceptable salts thereof
The 4-arylpyrrole substituted 2-indolinones of formula (I) can be prepared through a process consisting of standard synthetic transformations, which are comprised within the scope of the invention, and reported for instance in Smith, Michael - March's Advanced Organic Chemistry: reactions mechanisms and structure - 5th Edition, Michael B Smith and Jerry March, John Wiley & Sons lnc , New York (NY), 2001) It is known to the skilled person that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions Protection of such reactive centers, and subsequent deprotection at the end of the synthetic transformations, can be accomplished following standard procedures described in: Green, Theodora W and Wuts, Peter G M - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons lnc . New York (NY), 1999 The compounds of this invention and the salts thereof can be prepared by and in analogy to the following processes
A compound of formula (I) can be obtained by a process which comprises converting a compound of formula (I) into another compound represented by the same formula (I) Such a conversion is illustrated by but is not limited to the following examples A compound of formula (I) can be obtained by separating a single isomer from a mixture of stereoisomers represented by the same formula (I) Said stereoisomers include diastereomers and enantiomers A compound of formula (I) can be obtained by treating another compound represented by the same formula (I), and containing a basic residue, like a primary, secondary or a tertiary amine, with an inorganic or organic acid thereby obtaining a pharmaceutically acceptable salt In a similar way, a compound of formula (I) can be obtained by treating another compound of formula (I), and containing an acidic proton, with an inorganic or organic base thereby obtaining a pharmaceutically acceptable salt
A compound of formula (I) can be obtained by treating another compound represented by formula (I) with suitable reagents in order to remove one or more protective groups introduced in one of the synthetic steps, as known to those skilled in the art
A compound of formula (I) can be obtained by treating another compound represented by formula (I) with suitable reagents in order to transform one or more functional groups into one or more new functional groups
A compound of formula (I) can be obtained by reacting a compound of formula (II)
wherein R1, R2, Ar and R4 are as defined above, with a compound of formula (III),
H2N — R3
(HI) wherein R3 is as defined above, in the presence of a suitabte condensing agent. It is intended that whenever a compound of formula (II) or (III) contains functional groups that can interfere in the condensation reaction, said functional groups be protected with suitable protecting groups before carrying out the condensation reaction A compound of formula (III) is either a commercially available amine or can be readily prepared from compounds of formula (IV),
X-R3 <IV> wherein X represents chlorine, bromine, iodine or OH by means of standard procedures that are known to those skilled in the art
A compound of formula (II) can be obtained by reacting a compound of formula (V)
wherein R4 and Ar are as defined above, with an indolin-2-one of formula (Vl),
(VI) wherein R1 and R2 are as defined above, in the presence of a proper inorganic or organic base
A compound of formula (Vl)1 wherein R1 and R2 are as defined above, is either commercially available or can be prepared from commercially available compounds by using
standard functional group transformations, and according to general procedures for the synthesis of indolin-2-ones (see, for instance: G M Karp, Preparation and reactions of indolin-2(3H)-ones A review, Organic Preparations and Procedures International 1993, vol. 25, pp 481-513)
In one experimental approach, a compound of formula (V) can be obtained from a compound of formula (VII),
(VII) wherein Ar and R4 are as defined above, R11 is selected among methyl, ethyl, tert-butyl, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, and R12 is a suitable protecting group, usually tert-butyloxycarbonyl or phenylsulphonyl or 4-methylphenylsulphonyl, by hydrolysis in the presence of an aqueous inorganic base or inorganic or organic acid
A compound of formula (VII) can be obtained from a compound of formula (VIII),
,OH Ar- BN
V0H (IX) wherein Ar is as defined above, in the presence of an organic or inorganic base and a suitable organo-palladium complex as catalyst Boronic acids of formula (IX) are either commercially available or can be prepared according to procedures reported in the literature (see, for example, T Ishiyama, M Murata and N Miyaura, Palladium(O)-cata!yzed cross- coupling reaction of alkoxydiboroπ with haloareπes: a direct procedure for arylboronic esters, Journal of Organic Chemistry 1995, vol 60, pp 7508-7510; T. Ishiyama, Y Itoh, T Kitano and N Miyaura, Synthesis of arylboroπates via the palladium(0)-catalyzed cross-coupling
reaction of tetra(alkoxo)diborons with aryl triflates, Tetrahedron Letters 1997, vol. 38, pp. 3447-3450).
A compound of formula (VIIl) can be obtained from a compound of formula (X),
A compound of formula (X) can be obtained from a compound of formula (Xl),
(XI) wherein R4, R" and R13 are as defined above, by treatment with phosphorus oxychloride (POCI3) and N,N-dimethylformamide in dichloromethane
Compounds of formula (Xl), wherein R4, Rπ and R13 are as defined above, can be prepared following literature procedures or modifications thereof As an example, a compound of formula (Xl) wherein R4 is methyl, R11 is ethyl and R13 is 0-SO2CF3, can be prepared by treatment of the compound of Formula (XII)
(XII) with trifluoromethanesulfonyl chloride in dichloromethane and in the presence of an organic base The compound of formula (XIi) can be obtained as described in A Treibs und A Ohorodnik, Eine neue synthese von β-hydroxypyrrolen, Justus Liebig Annalen der Chemie 1958, vol 611, pp.139-145
In another approach, a compound of formula (V) can be obtained from a compound of formula (XIII),
(Xiπ) wherein R4, Ar and Rt1 are as described above, by hydrolysis in the presence of an aqueous inorganic base or inorganic acid A compound of formula (V) can also be obtained from a compound of formula (XIII), wherein Ar and R4 are as defined above, and R11 is benzyl or A- methoxybenzyl, by treatment with hydrogen and a metal catalyst in a suitable organic solvent A compound of formula (XIII) can be obtained from a compound of formula (XIV) 1
(XIV) wherein R4, Ar and R11 are as described above, by treatment with phosphorus oxychloride (POCI3) and N.N-dimethylformamide in dichloromethane In another approach, a compound of formula (XIV) can be obtained by condensing a β-ketoester of formula (XV)
(XV) wherein R4 and R11 are as defined above with a 2-amino-1-aryl-ethanone derivative of formula (XVI)
(XVI) wherein Ar is as defined above, in the presence of a proper inorganic or organic base (examples of Knorr synthesis of pyrroles are reported for instance in The Chemistry of Heterocyclic Compounds, R Alan Jones, 1990, vol 48, part 1, pp 107-113, John Wiley & Sons Inc) Compounds of formula (XV), wherein R4 and R11 are as defined above, are either commercially available or can be prepared from commercially available compounds by using
staπdard procedures for the synthesis of β-ketoesters that are known to those skilled in the art
Compounds of formula (XVI), wherein Ar is as defined above, are either commercially available or can be obtained from compounds of formula (XVII)
(XVII) wherein Ar is as defined above and X represents chlorine, bromine or iodine, according to standard procedures for the conversion of α-haloketones into α-aminoketones
A compound of formula (XVII), wherein Ar is as defined above and X represents chlorine, bromine or iodine, is either commercially available or can be obtained by reaction of an aryl-methyl-ketone of formula (XVI 11)
(XVIII) wherein Ar is as defined above, with a proper halogenating agent in a suitable organic solvent
Compounds of formula (XVIII), wherein Ar is as defined above, are either commercially available or can be obtained by means of standard procedures for the synthesis of aryl-methyl-ketones that are known to those skilled in the art.
In another approach, a compound of formula (I) can be obtained by reacting a compound of formula (XIX)
(XIX) wherein R3, R4, and Ar are as defined above, with an indolln-2-one of formula (Vl), as defined above, in the presence of a proper inorganic or organic base.
Compounds of formula (XIX), as defined above, can be obtained by reacting a compound of formula (V), as defined above, with a compound of formula (III), as defined above, in the presence of a suitable condensing agent It is intended that whenever a compound of formula (III) or (V) contains functional groups that can interfere in the condensation reaction, said functional groups be protected with suitable protecting groups before carrying out the condensation reaction
The synthesis of a compound of formula (I)1 according to the synthetic processes described above, can be conducted in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques, like, for example, column chromatography, before carrying out the subsequent reaction Alternatively, two or more 5 steps of the synthetic sequence can be carried out in a so-called "one-pot° procedure, as known in the art, whereby only the compound resulting from the two or more steps is isolated and purified
The compounds described above can be prepared as exemplified in the following procedures
I O A compound of formula (I), as defined above, can be obtained by separating diastereomers or enantiomers of formula (t) In a typical procedure, diastereomers can be separated by crystallization or by standard chromatographic techniques as known to those skilled in the art Enantiomers can be separated by crystallization, by chromatography using a chiral stationary phase, or by transformation into diastereomers followed by separation
15 thereof and final conversion into the pure enantiomers (as a general reference, see: Jacques, Jean; Collet, Andre; Wilen, Samuel H , - Enantiomers, Racemates, and Resolutions, John Wiley & Sons lnc , New York (NY), 1981)
A compound of formula (I), as defined above, containing a basic or an acid group can be transformed into a pharmaceutically acceptable salt In a typical procedure, a compound of 0 formula (I) containing a basic group is dissolved in either a protic solvent, like water, methanol, ethanol or isopropanol, or an aprotic solvent, like acetonitrile, dioxane, tetrahydrofuran, or dichloromethane, or mixture thereof, and the proper amount of an inorganic or organic acid, dissolved in a suitable solvent, usually water, methanol, ethanol or isopropanol, is added at a temperature ranging from -200C to room temperature The salt is 5 usually isolated by filtration of the precipitate obtained by a) cooling; or b) addition of a precipitating solvent, usually diethyl ether or diisopropyl ether; or c) partial evaporation of the solvent In a typical procedure for a compound of formula (I) containing an acidic group, said compound is usually dissolved in a protic solvent, like water, methanol, ethanol or isopropanol, or mixtures thereof, and then treated with the proper amount of an inorganic or 0 organic base, dissolved in a suitable solvent The salt is usually isolated by filtration of the precipitate obtained in analogy to the procedure described above for a compound containing a basic group
A compound of formula (I), as defined above, can be obtained by treating a compound of formula (I), containing one or more protective groups, with suitable reagents to 5 remove one or more protective groups Reagents and procedures are known to those skilled in the art, and are reported, for instance, in: Green, Theodora W and Wuts, Peter G M - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons inc , New York
(NY)1 1999. Protective groups are usually introduced in order to mask a hydroxyl (-OH), a primary or secondary aliphatic or aromatic amine, a carboxylic acid, or any other functional group that can interfere in any of the synthetic steps for the synthesis of a compound of formula (I) A compound of formula (I) can be obtained by reacting a compound of formula (H), as defined above, with a compound of formula (III), as defined above, in the presence of a condensing agent such as N.N'-dicyclohexylcarbodiimide, N.N'-diisopropylcarbodiimide, 1- ethyl-3-(3-dimethylaminopropyl)-carbodiimide, CMbenzotriazol-i-yO-N.N.N'.N'- tetramethyluronium tetrafluoborate (TBTU), Mukayama's reagent, and other condensing agents known to those skilled in the art The reaction is usually conducted in a solvent selected from N,N-dimethylformamide, acetoπitrile, dichloromethane, tetrahydrofuran or dioxane, or mixtures thereof, in the presence of an inorganic or organic base, preferably an organic base selected from triethylamine, N.N-diisopropylethylamine or pyridine, at a temperature ranging from -100C to 40°C, and for a period of time from 1 to 48 hours. A compound of formula (III) is usually a commercially available amine or can be prepared by suitable precursors such as an alkyl or cycloalkyl halide or alcohol following standard procedures reported, for instance, in Vogel, Arthur Israel - Vogel's textbook of practical organic chemistry, 5th Ed , Longman Scientific & Technical, Longman Group UK Limited, 1989. A compound of formula (II) can be obtained by reacting a compound of formula (V), as defined above, with an indolin-2-one of formula (Vl)1 as defined above, in a suitable solvent such as ethanol, isopropanol, dioxane, or mixtures thereof, in the presence of a suitable organic or inorganic base, such as pyrrolidine or sodium hydroxide, at a temperature ranging from 80 to 100°C, and for a period of time of from 1 to 24 hours A compound of formula (V) can be prepared from a compound of formula (VII)1 as defined above, by treatment with an inorganic base, such as sodium or potassium hydroxide, in a suitable solvent, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from room temperature to reflux, and for a period of time ranging from 1 to 12 hours A compound of formula (VII) can be obtained from a compound of formula (VIII), as defined above, by treatment with a boronic acid of formula (IX), as defined above, in presence of a suitable palladium catalyst, usually 10% tetrakis(triphenylphosphine)-palladium(0), a suitable organic base, such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran or dioxane, at a temperature from 50 to 100°C, and for a period of time of from 1 to 8 hours.
A compound of formula (VIII) can be obtained by treatment of a compound of formula (X)1 as defined above, with di-tert-buty! dicarbonate, phβnylsuiphcnyl chloride or 4-
methylphenylsulphonyl chloride in the presence a suitable amount of a 4-dialkylaminopyridine catalyst, such as 4-dimethylaminopyridine or 4-(1-pyrrolidiπyl)pyridine, The reaction is carried out in the presence of an inorganic or organic base, such as triethylamine or diisopropylethylamine, in a solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, or dichloromethane at a temperature ranging from room temperature to reflux, and for a time ranging from 1 to 6 hours
A compound of formula (X) can be obtained from a compound of formula (Xl), as defined above, by reaction with phosphorus oxychloride (POCI3) and N,N-dimethylformamide in a solvent such as dichloromethane or dichloroethane, at a temperature ranging from 0°C to reflux, and for a period of time ranging from 1 to 12 hours
A compound of formula (Xl), wherein R4 is methyl, R11 is ethyl, and R13 is 0-SO2CF3, can be prepared by treatment of a compound of formula (XII) with trifluoromethanesulfonyl chloride in a solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane or dichloroethane, in the presence of a suitable organic base such as triethylamine, diisopropylethylamine, pyridine or collidine, at a temperature ranging from -20 to 10°C, and for a period of time of from 1 to 6 hours
In another approach, a compound of formula (V) can be obtained from a compound of formula (XIII), as defined above, by treatment with an inorganic base, such as sodium or potassium hydroxide, in a suitable solvent, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from room temperature to reflux, and for a period of time ranging from 1 to 12 hours Alternatively, a compound of formula (XIII), as defined above, can be treated with an acid like, for instance, hydrochloric or sulphuric acid, in a solvent like water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from room temperature to reflux, and for a period of time ranging from 1 to 24 hours In still another approach, a compound of formula (XIII), wherein R11 is benzyl or 4-mefhoxybenzyl, can be treated with hydrogen and a hydrogenation catalyst, or with cyclohexene or cyclohexadiene, or formic acid or ammonium formate and a hydrogenation catalyst in a suitable solvent such as water, methanol, ethanol, isopropanol, dioxane or mixtures thereof, at a temperature ranging from room temperature to reflux, and for a period of time ranging from 1 to 48 hours The hydrogenation catalyst is usually palladium on carbon
A compound of formula (XIII), as defined above, can be obtained from a compound of formula (XIV), wherein R4, Ar and R11 are as defined above, by reaction with phosphorus oxychloride (POCI3) and N,N-dimethylformamide in a solvent such as dichloromethane or dichloroethane, at a temperature ranging from 0°C to reflux, and for a period of time ranging from 1 to 12 hours
A compound of formula (XIV), as defined above, can be prepared by reacting a β- ketoester of formula (XV)1 wherein R4 and R11 are as defined above, with a 2-amino-1-aryl- ethanone of formula (XVI)1 wherein Ar is as defined above, in the presence of an organic or inorganic base, such as sodium acetate, sodium hydroxide, or potassium hydroxide in a suitable solvent such as water, ethanol, methanol or mixtures thereof, at a temperature ranging from 200C to reflux, and for a period of time of from 1 to 24 hours.
A compound of formula (XVI)1 as defined above, can be obtained from an α- haloketone of formula (XVII), wherein Ar is as defined above and X represents chlorine, bromine or iodine by using standard procedures for the conversion of α-haloketones into α- aminoketones For example a compound of formula (XVII), wherein Ar is as defined above and X represents chlorine, bromine or iodine, can be converted into a compound of formula (XX)
6O0C and for a period of time ranging from 1 hour to 5 days
In another approach a compound of formula (XVII), wherein Ar is as defined above and X represents chlorine, bromine or iodine, can be converted into a compound of formula (XXI)
(XXI) wherein Ar is as defined above, by reaction with sodium azide in a suitable solvent such as N.N-dimethylformamide, dimethylsulfoxide, acetone, terahydrofuran, 1,4-dioxane, ethanol, methanol, water or mixtures thereof at a temperature ranging from 0 to 1000C and for a period of time of from 1 to 24 hours Then, a compound of formula (XVI), as defined above, can be obtained by reduction of a compound of formula (XXI), as defined above, for instance with
hydrogen and a hydrogenation catalyst, in a suitable solvent such as water, methanol, ethanol, isopropanol, dioxane or mixtures thereof, at a temperature ranging from room temperature to reflux, and for a period of time ranging from 1 to 48 hours The hydrogenation catalyst is usually palladium on carbon. A compound of formula (XVII)1 wherein Ar is as defined above and X represents chlorine, bromine or iodine, can be prepared by halogeπation of an aryl-methyl-ketone of formula (XVIII), as defined above. For instance, a compound of formula (XVII)1 wherein Ar is as defined above and X represents bromine, can be obtained by treating a compound of formula (XVIII), as defined above, with bromine in a suitable solvent such as chloroform, tetrachloromethane, acetic acid, 1 ,4-dioxane, diethyl ether, methanol, ethanol or mixtures thereof at a temperature ranging from 00C to reflux and for a period of time of from 1 hour to 48 hours
In another approach, a compound of formula (I) can be obtained by reacting a compound of formula (XIX), as defined above, with an indolin-2-one of formula (Vl), as defined above, in a suitable solvent such as ethanol, isopropanol, dioxane, or mixtures thereof, in the presence of a suitable organic or inorganic base, such as pyrrolidine or sodium hydroxide, at a temperature ranging from 80 to 1000C, and for a period of time of from 1 to 24 hours
A compound of formula (XIX), as defined above, can be prepared by reacting a compound of formula (V), as defined above, with a compound of Formula (III), as defined above, in the presence of a condensing agent such as N.N'-dicyclohexylcarbodiimide, N1N'- diisopropylcarbodiimide, 1 -ethyl^-^-dimetriylarriinopropyO-carbodiimide, O-(benzotriazol- 1 - yl)-N,N,N',N'-tetramethyluronium tetrafluoborate, Mukayama's reagent, and other condensing agents known to those skilled in the art The reaction is usually conducted in a solvent selected from N.N-dimethylformamide, acetonitrile, dichloromethane, tetrahydrofuran or dioxane, or mixtures thereof, in the presence of an inorganic or organic base, preferably an organic base selected from triethylamine, N,N-diisopropylethylamine or pyridine, at a temperature ranging from -10°C to 400C, and for a period of time from 1 to 48 hours
The short forms and abbreviations used herein have the following meaning: "Ci" means "Curie", "DMSO" means "dimethylsulfoxide", "ID" means "identity", "KDa" means "kiloDalton", "microCi" means "microCurie", "mg" means "milligram", "microg" means "microgram", "mL° means "milliliter", "microL" means "microliter", "M" means "molar", "mM" means "millimolar", "microM" means "micromolar", and "nM" means "nanomolar"
Compounds of the present invention were tested in biochemical as well as in cell- based assays, as described below
Preparation of IGF-1R for use in biochemical assay
Cloning and Expression
Human cDNA was used as template for amplification by polymerase chain reaction (PCR) of the predicted cytoplasmic portion of IGF-1R (amino acid residues 960-1367 of precursor protein; see NCBI Entrez Protein Accession #P08069), which includes the entire kinase domain PCR was conducted using the forward primer sequence 5'- CTCGGATCCAGAAAGAGAAATAACAGCAGGCTG-3' and the reverse primer sequence 5'- CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-S". In order to facilitate subsequent cloning steps, both primers comprise a BamHI restriction endonuclease site sequence This PCR product was cloned in frame using BamHI sticky ends into a transfer vector for the baculovirus expression system, pVL1392 (Pharmiπgen), previously modified by insertion into the pVL1392 multiple cloning site of sequences encoding Glutathione S-transferase (GST) fusion protein, PreScissioπ protease cleavage site and partial MCS cassette derived from the pGex-6P plasmid (Amersham BioSciences) Insertion of the IGF-1R PCR product described above into the pGex-6P derived BamHI site of the modified pVL1392 vector results in an open reading frame corresponding to the pGEX-6P GST protein and PreScission peptide fused with the human 1GF-1R cytoplasmic domain In order to obtain fusion protein, Sf21 insect cells (Invitrogen) are cotransfected with 2 microg of purified plasmid and 1 microg of virus DNA (BaculoGoldTM Transfection Kit, Pharmingen), as described in the Baculovirus Instruction manual (Pharmingen) A first amplification of the virus is performed using 600 microL of cotransfected virus on 6 x 108 Sf21 in a monolayer culture, in 12 mL of medium (TNM-FH Grace's medium - Pharmingen) After 3 days the medium is collected, centrifuged and transferred to a sterile tube A second amplification is prepared with the same method using 2 mL on 3 x 107 cells, diluted in 40 mL of medium For the third amplification of virus, 1 mL of supernatant from the second round are used per 3 x 107 cells diluted in 40 mL of medium.
Protein expression is performed in H5 insect cells infected with 14 mL virus / 1 x 109 insect cells (MOI = 1 5) for 65 h with shaking at 27°C Cells are harvested by centrifugation at 1200xg for 10 minutes Protein Purification
Cells were resuspended in phosphate buffered saline solution (PBS), 20 mM dithiothreito! (DTT), 02% CHAPS, 20% glycerol, 1 mM OVA, "Complete" protease inhibitor cocktail (1 tablet/ 50 mL buffer; Roche Diagnostics, Milan, Italy) and lysed by liquid extrusion with a Gaulin homogenizer (Niro Soavi, Italy) The lysate was centrifuged at 14000xg for 45 minutes and the supernatant was loaded onto a column containing 10 mL Glutathione Sepharose (Amersham Biosciences) The column was first washed with PBS buffer for 5 column volumes, then with 100 mM Tris pH 8 0, 20% glycerol for 5 column volumes, and
lastly eluted with 10 mM glutathione in 100 mM Tris pH 8 O1 20% glycerol Fractions of 10 mL were collected, and protein-rich fractions were pooled Typically, 20 mg of fusion protein were recovered from 1 x 10θ cells, and this was typically >85% pure as judged by SDS-PAGE followed by Coomassie staining Purified protein was stored at -800C prior to its use in biochemical assays
Inhibition assay for IGF-1 R kinase activity
The inhibitory activity of putative kinase inhibitors and the potency of selected compounds was determined using a Scintillation Proximity Assay (SPA) in 96 well microtiter plate format The assay is based on the ability of streptavidin-coated SPA beads to capture a biotinylated peptide containing a site that can be phosphorylated by IGF-1 R kinase When a radioactively labeled phosphate moiety is transferred by the kinase to the biotinylated peptide, this stimulates light emission by the bead, which is measured in a scintillation counter
The buffers/components used in the assay were as follows Kinase Buffer (buffer KB) was composed of 50 mM HEPES, 3 mM MnCI2, 1 mM DTT, 3 microM Na3VO4, pH 7 9 Enzyme Buffer (buffer EB) was composed of buffer KB containing 06 mg/mL BSA (bovine serum albumin) SPA scintillation beads (Product Code Number RPNQ0007, Amersham Biosciences, Piscataway, NJ USA) were prepared as a 10 mg/mL suspension in PBS containing 32 mM EDTA1 500 microM unlabeled ATP, and 0 1% Triton X-100 This preparation is referred to below as "SPA bead suspension" On the day of assay, IGF-IR was pre-phosphorylated in order to linearize reaction kinetics To achieve this, the desired quantity of enzyme was incubated for 30 min at 28°C at a concentration of 1050 nM enzyme in buffer EB containing 100 microM unlabeled ATP After preincubation, and immediately before assay, this pre-phosphorylated IGF-1 R kinase preparation was diluted to an enzyme concentration of 60 nM by addition of 165 volumes of buffer KB This diluted prephosphorylated enzyme is referred to below as "enzyme mix"
The substrate used in the assay was a carboxy-terminally biotinylated peptide of the following sequence: KKKSPGEYVNIEFGGGGGK-biotin The peptide was obtained in batches of >95% peptide purity from American Peptide Company, lnc (Sunnyvale, CA, USA)
"ATP Mix", referred to below, consisted of buffer KB containing 6 nM 33Py-ATP (gamma phosphate-labeled, Redivue™ Code Number AH9968, 1000-3000Ci/mmole, Amersham
Biosciences Piscataway, NJ, USA), 18 microM unlabeled ATP, and 30 microM biotinylated substrate peptide. This solution contained these components at 3X their final reaction concentration Compounds to be tested were prepared in 100% DMSO at appropriate concentrations These preparations were then diluted 33-fold using buffer KB, so as to obtain compound at 3X the desired final assay concentration in buffer KB containing 3% DMSO
This 3X preparation is referred to below as "compound working solution"
Kinase reaction: Reactions were performed in 96-wetl U-bottom microtiter plates (such as Product #650101, Greiner Bio-One, Kremsmuenster, Austria) in a final reaction volume of 30 microL To each test well were added 10 microL of "compound working solution- containing appropriate dilution of compound, followed by 10 microL "ATP Mix" and 10 microL "Enzyme Mix", thus starting the reaction Well content was immediately mixed by pipetting, and reactions were incubated for 60 minutes at room temperature After incubation, reactions were stopped by adding 100 microL/well °SPA bead suspension" Wells were incubated a further 15 minutes at room temperature, then 110 microL were withdrawn from each well and transferred to separate wells of 96-well opaque scintillation counting plates (such as OptiPlate™-96. PerkinElmer LAS1 lnc Boston, MA, USA), each containing 100 microL/well 5M CsCI After 4 hours resting at room temperature to allow SPA bead floatation, these plates were read using a scintillation counter (Packard TopCount NXT, PerkinElmer LAS1 lnc Boston, MA, USA) in order to quantitate the light emitted from each well (proportional to the amount of phosphate incorporated into the substrate peptide during kinase reaction) Many of the steps described above, such as those involving compound dilution, addition of mixes to the reaction, and transfer of completed reaction to counting plates can be automated using robotized pipetting stations (such as Multimek and Biomek liquid handlers, Beckman Coulter lnc , Fullerton, CA, USA), and a dilution curve of a known kinase inhibitor such as staurosporine can be routinely included as a positive control for IGF-1R inhibition Results: data were analyzed using the "Assay Explorer" software package (Elsevier
MDL1 San Leandro, CA 94577) For single compound concentrations, inhibitory activity wss typically expressed as % inhibition obtained in presence of compound, compared to total activity of enzyme obtained when inhibitor is omitted
Compounds showing desired inhibition can be further analyzed in order to study the potency of the inhibitor through IC50 calculation In this case, inhibition data obtained using serial dilutions of the inhibitor can be fitted by nonlinear regression using the following equation:
where vb is the baseline velocity, v is the observed reaction velocity, vo is the velocity in the absence of inhibitors, and [I] is the inhibitor concentration
Western blot analysis of receptor phosphorylation following stimulation with IGF-1 in MCF-7 human breast cancer cells
MCF-7 cells (ATCC# HTB-22) were seeded in 12-we!l tissue culture plates at 2x105 cells/well in E-MEM medium (MEM+ Earle's BSS+ 2 mM glutamine + 0.1 mM non-essential amino acids) + 10% FCS, and incubated overnight at 37°C, 5% CO2, 100% relative humidity Cells were then starved by replacing E-MEM + 10% FCS with E-MEM + 0 1% BSA, and incubating overnight After this incubation, wells were treated with desired concentrations of compound for 1 hour at 37βC, and were then stimulated with 10 nM recombinant human IGF- t (Invitrogen, Carlsbad, CA1 USA) for 10 minutes at 37°C Cells were then washed with PBS and lysed in 100 microL/well cell lysis buffer (M-PER Mammalian Protein Extraction Reagent [Product #78501, Pierce, Rockford, IL, USA] + 10 mM EDTA + Protease inhibitor cocktail [Sigma-Aldrich product #P8340] + phosphatase inhibitor cocktail [Sigma-Aldrich products #P2850 + #P5726]) Cell lysates were cleared by centrifugation at 10,000xg for 5 minutes, and 10 microg/lane of cleared lysate protein were run on NuPAGE gels (NuPAGE 4-12% 10- lane Bis-Tris gels, Invitrogen) with MOPS running buffer, then transferred onto Hybond-ECL nitrocellulose filters (Amersham Biosciences, Little Chalfoπt, Buckinghamshire, UK) using Mini PROTEAN Il chambers (Bio-Rad Laboratories, Hercules, CA, USA) Filters bearing transferred protein were incubated for 1 hour in blocking buffer (TBS + 5% BSA + 0 15% Tween 20), and probed for 2 hours in the same buffer containing 1/1000 rabbit anti-phospho IGF- 1 R TyM 131/lnsR Tyr 1146 antibody (product #3021 , Cell Signaling Technology, Beverly, MA, USA) for the detection of phosphorylated IGF-1R, or 1/1000 dilution of rabbit IGF-IrB(H- 60) antibody (product #sc-9038, Santa Cruz Biotechnology, lnc , Santa Cruz, CA, USA) for detecting total IGF-1R U chain In either case, filters were then washed for 30 minutes with several changes of TBS + 0 15% Tween 20, and incubated for 1 hour in washing buffer containing 1/5000 dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham, product #NA934), then were washed again and developed using the ECL chemiluminescence system (Amersham) according to manufacturer's recommendations Unless otherwise stated, reagents used were from Sigma-Aldrich, St Louis, MO, USA
Growth factor Induced Sβ ribosomal protein phosphorylation in primary human fibroblasts.
Phosphorylation of S6 ribosomal protein in response to growth factor stimulation of normal human dermal fibroblasts (NHDF) was used to assess compound potency in inhibiting IGF-I induced signal transduction in cells, and selectivity towards EGF and PDGF stimulus NHDF cells obtained from PromoCell (Heidelberg, Germany), were maintained at 37°C in a humidified atmosphere with 5% CO2 in complete Fibroblast Growth Medium (PromoCell) For assay, NHDF were seeded in 384-well tissue culture plates (clear- and flat-bottomed black plates; Matrix Technologies fnc , Hudson, NH, USA) at a density of 5000 cells/well in serum-
free medium containing 0 1% bovine serum albumin (BSA) and incubated for 5 days. Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invitrogen Corp , CA, USA), 10 nM EGF (Gibco BRL1 USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany) Cells were then fixed in PBS/37% paraformaldehyde for 20 minutes at room temperature, washed X2 with PBS, and permeabilized with PBS/0 3% Triton X-100 for 15 minutes Wells were then saturated with PBS/1% non-fat dry milk (Bio-Rad Laboratories, Hercules, CA1 USA) for 1 hour, and then probed for 1 hour at 37°C with anti-phospho-S6 (Ser 235/236) antibody (Cell Signaling Technology, Beverly, MA, USA, cat #2211) at 1/200 dilution in PBS/1% milk/03% Tween 20 Wells were then washed twice with PBS, and incubated for 1 hour at 370C with PBS/1% milk/0 3% Tween 20 + 1 microg/mL DAPI (4,6-diamidino-2-phenylindote) + 1/500 Goat anti- rabbit Cy5™-conjugated secondary antibody (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK) Wells were then washed X2 with PBS, and and 40 microL PBS are left in each well for immunofluorescence analysis Fluorescence images in the DAPI and Cy 5™ channels were automatically acquired, stored and analysed using a Cellomics ArrayScan™ IV instrument (Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm was used to quantify cytoplasmic fluorescence associated with phospho-S6 (Cy5™ signal parameter: "Mean Lyso Mass-pH") for each cell in 10 fields/well, and eventually expressed as a mean population value Unless otherwise stated, reagents were obtained from Sigma- Aldrich, St Louis, MO1 USA
Inhibition assay for cKit kinase activity
The inhibitory activity of putative kinase inhibitors and the potency of selected compounds were determined using a Dowex Assay in 384 well microtiter plate format At the end of the kinase reaction, un-reacted ATP was captured by an excess of ion exchange Dowex resin The resin was allowed to settle down at the bottom of the reaction plate by gravity Supernatant was subsequently withdrawn and transferred into a counting plate, then evaluated by β-counting
The buffers/components used in the assay were as follows Kinase Buffer (buffer KB) was composed of 50 mM HEPES, 5 mM MgCI2 1 5 mM MnCI2, 10 mM DTT, 3 microM Na3VO4, pH 7 9 Enzyme Buffer (buffer EB) was composed of buffer KB containing 02 mg/mL BSA (bovine serum albumin) Dowex beads (SIGMA, custom prepared resin DOWEX 1x8 200-400 mesh, 2 5 Kg) were prepared by diluting 500 g of wet resin to 2 L with 150 mM sodium formate, pH 3 00 The resin was allowed to settle down (some hours) and then the supernatant was discarded After three washes as above over a couple of days, the resin was allowed to settle and two volumes (with respect to the resin volume) of 150 mM sodium formate buffer were added The washed resin was stable for more than one week' the stock
resiπ was kept at 4°C before use This preparation is referred to below as "dowex resin suspension"
On the day of the assay, c-kit kinase was pre-phosphorylated in order to linearize reaction kinetics To achieve this, the desired quantity of enzyme was incubated for 60 min at S 28°C at a concentration of 4500 nM enzyme in buffer EB containing 300 microM unlabeled ATP After incubation, and immediately before assay, this pre-phosphorylated c-kit kinase preparation was diluted to an enzyme concentration of 12 nM by addition of buffer KB This diluted enzyme is referred to below as "enzyme mix"
The substrate used in the assay was a peptide of the following sequence: K V V E E I0 N G N N Y V Y I D P T Q L P Y D H K W E F P R N R The peptide was obtained in batches of >95% peptide purity from American Peptide Company, lnc (Sunnyvale, CA, USA). "ATP
Mix", referred to below, consisted of buffer KB containing 264 nM 33Py-ATP (gamma phosphate-labeled, Redivue™ Code Number AH9968, 1000-3000Ci/mmole, Amersham Biosciences, Piscataway, NJ1 USA), 132 microM unlabeled ATP, and 7 5 microM substrate S peptide This solution contained these components at 3X their final reaction concentration Compounds to be tested were prepared in 100% DMSO at appropriate concentrations These preparations were then diluted 33-fold using buffer KB, so as to obtain compound at 3X the desired final assay concentration in buffer KB containing 3% DMSO This 3X preparation is referred to below as "compound working solution" 0 Inhibition assay for PDGFR1 kinase activity
The inhibitory activity of putative kinase inhibitors and the potency of selected compounds were determined using a Dowex Assay in 384 well microtiter plate format At the end of the kinase reaction, un-reacted ATP was captured by an excess of ion exchange
Dowex resin The resin was allowed to settle down at the bottom of the reaction plate by5 gravity Supernatant was subsequently withdrawn and transferred into a counting plate, then evaluated by β-countiπg
The buffers/components used in the assay were as follows Kinase Buffer (buffer KB) was composed of 50 mM HEPES, 5 mM MnCI2 1 mM MnCI2, 1 mM DTT1 3 microM Na3VO4, pH 7 5 Enzyme Buffer (buffer EB) was composed of buffer KB containing 0 2 mg/mL BSA0 (bovine serum albumin) Dowex beads (SIGMA, custom prepared resin DOWEX Jx8200-400 mesh, 2 5 Kg) were prepared by diluting 500 g of wet resin to 2 L with 150 mM sodium formate, pH 300 The resin was allowed to settle down (some hours) and then the supernatant was discarded After three washes as above over a couple of days, the resin was allowed to settle and two volumes (with respect to the resin volume) of 150 mM sodium5 formate buffer are added The washed resin was stable for more than one week; the stock
resin is kept at 4°C before use This preparation is referred to below as "dowex resin suspension"
On the day of the assay, PDGFRI was pre-phosphorylated in order to linearize reaction kinetics. To achieve this, the desired quantity of enzyme was incubated for 40 min at 28°C at a concentration of 850 nM enzyme in buffer EB containing 200 microM unlabeled ATP After incubation, and immediately before assay, this pre-phosphorylated PDGFR 1 kinase preparation was diluted to an enzyme concentration of 18 nM by addition of buffer KB This diluted pre-phosphorylated enzyme is referred to below as "enzyme mix"
The substrate used in the assay was bovine myelin basic protein (mbp) from Sigma "ATP Mix", referred to below, consisted of buffer KB containing 2 5 nM 33Py-ATP (gamma phosphate-labeled, Redivue™ Code Number AH9968, 1000-3000Ci/mmole, Amersham Biosciences, Piscataway, NJ, USA), 30 microM unlabeled ATP, and 24 microM mbp This solution contained these components at 3X their final reaction concentration. Compounds to be tested were prepared in 100% DMSO at appropriate concentrations. These preparations were then diluted 33-fold using buffer KB, so as to obtain compound at 3X the desired final assay concentration in buffer KB containing 3% DMSO. This 3X preparation is referred to below as "compound working solution"
Kinase reaction: Reactions were performed in 384-well U-bottom microtiter plates (Greiner Bio-One, Kremsmuenster, Austria) in a final reaction volume of 30 microL To each test well were added 10 microL of "compound working solution" containing appropriate dilution of compound, followed by 10 microL "ATP Mix" and 10 microL "Enzyme Mix", thus starting the reaction Well content was immediately mixed by pipetting, and reactions were incubated for 60 minutes at room temperature After incubation, reactions were stopped by adding 70 microL/well "dowex resin suspension11 Three cycles of mixing were done immediately after the addition of the resin Plates were allowed to rest for about 1 hour and then 20 microL were withdrawn from each well and transferred to separate wells of 384-well opaque scintillation counting plates (such as OptiPlate™-384, PerkinElmer LAS, Iπc Boston. MA, USA), with 70 microL/well of Microscint 40 (Perkin-Elmer) After 5 min of orbital shaking, plates were read using a scintillation counter (Packard TopCount NXT, PerkinElmer LAS, Inc., Boston, MA, USA) in order to quantitate the amount of phosphate incorporated into the substrate peptide during kinase reaction
Many of the steps described above, such as those involving compound dilution, addition of mixes to the reaction, and transfer of completed reaction to counting plates can be automated using robotized pipetting stations (such as Multimek and Biomek liquid handlers, Beckman Coulter Iπc , Fullerton, CA1 USA), and a dilution curve of a known kinase inhibitor
such as slaurosporine can be routinely included as a positive control for kinase activity inhibition.
Results: data were analyzed using the "Assay Explorer" software package (Elsevier MDL1 San Leandro, CA 94577) For single compound concentrations, inhibitory activity was typically expressed as % inhibition obtained in presence of compound, compared to total activity of enzyme obtained when inhibitor is omitted
Compounds showing desired inhibition can be further analyzed in order to study the potency of the inhibitor through IC50 calculation In this case, inhibition data obtained using serial dilutions of the inhibitor can be fitted by nonlinear regression using the following equation:
where vb is the baseline velocity, v is the observed reaction velocity, vo is the velocity in the absence of inhibitors, and [I] is the inhibitor concentration
Biochemical and cell-based assay data for representative compounds are reported in Table 1
Table 1
The same compounds were tested for inhibition of IGF 1 -induced IGF 1 R phosphorylation in MCF-7 cells Treatment of starved MCF7 cells with 10 nM IGFI induced receptor auto-phosphorylation Incubation of cells with increasing concentrations of compounds from Examples 37, 85, and 17 prior to treatment with IGFI resulted in inhibition of IGF1 -induced IGF 1 R auto-phosphorylation
The compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with, for example, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase ( inhibitors, topoisomerase Il inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal
antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.
Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate
The compounds of formula (I) of the present invention, suitable for administration to a mammal, e g to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, and conditions of the patient and administration route
For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily The compounds of the invention can be administered in a variety of dosage forms, e g , orally, in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectalty in the form suppositories; parenterally, e g , intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.
The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a- pharmaceutically acceptable excipient, which may be a carrier or a diluent The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form
For example, the solid oral forms may contain, together with the active compound, diluents, e g , lactose, dextrose saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e g , silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e g , starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e g , starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes
The liquid dispersions for oral administration may be, e g , syrups, emulsions and suspensions As an example the syrups may contain, as a carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol
The suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol
The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e g , sterile water, olive oil, ethyl oleate, glycols, e g , propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
The solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e g , cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin
With the aim to better illustrate the present invention, without posing any limitation to it, the following examples are now given Experimental Section
General purification and analytical methods
Flash Chromatography was performed on silica gel (Merck grade 9395, 60A) HPLC was performed on Waters X Terra RP 18 (4,6 x 50 mm, 3 5 μm) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and Micromass mod ZQ single quadrupole mass spectrometer, equipped with an electrospray (ESI) ion source Mobile phase A was ammonium acetate 5 mM buffer (pH 5 5 with acetic acid/acetonitrile 95:5), and Mobile phase B was water-acetonitrile (5:95) Gradient from 10 to 90% B in 8 minutes, hold 90% B 2 minutes UV detection at 220 nm and 254 nm Flow rate 1 mL/min Injection volume 10 DL Full scan, mass range from 100 to 800 amu Capillary voltage was 2 5 KV; source temperature was 12O0C; cone was 10 V Mass is given as m/z ratio
IH-NMR spectrometry was performed on a Mercury VX 400 operating at 40045 MHz equipped with a 5 mm double resonance probe [1H (15N-31P) IDJ3FG Varian]
Preparation 1 i-p-t∑-methoxypheπyO-Σ-oxo-βthyll-S.δJ-triaza-i-azoπia-tricycloIS.S.I.I'S.T'Jdecaπe chloride (XX)
A mixture of 2-bromo-1-(2-methoxyphenyl)-ethanone (11 15 g, 48 5 mmol) and hexamethylenetetramine (747 g, 53 3 mmol) in diethyl ether (200 mL) was stirred at room temperature overnight The precipitated white solid was filtered, washed with diethyl ether and dried in vacuo affording the title compound that was used as such for the next step (172 g)
Preparatlon 2
2-amino-1-(2-methoxyphenyl)-ethaπone hydrochloride (XVI)
A mixture of 1-[2-(2-methoxypheπyl)-2-oxo-ethyl]-3,5,7-triaza-1-azonia- tricyclo[3 3 1 r3,7*]decane chloride, ethanol (100 mL) and 37% hydrochloric acid (50 mL), was stirred at room temperature for 2 days The solvent was then removed under reduced pressure to give 19 g of a mixture of ammonium chloride and the title compound that was used as such for the next step ESI(+) MS: m/z 166 (M+H) 1 H-NMR (400 MHz), δ (ppm, DMSO-ctø: 8 14 (bs, 3H)1 7 86 (dd, 1H1 J1=I 71 Hz1 J2=793 Hz) 771 (m, 1H)1 7 30 (d. IH1 J=7 93 Hz)1 7 14 (m, 1H), 3 95 (q, 2H)1 4 36 (m, 2H)1 397 (s, 3H) Preparation 3 ethyl 4-(2-mθthoxyphenyl)-2-methyl-1H-pyrro!e-3-carboxylate (XIV)
A mixture of 2-amino-1-(2-methoxyphenyl)-ethanone hydrochloride (55% purity, 18 5 g, 50 5 mmol), ethyl acetoacetate (66 mL, 50 5 mmol) and sodium acetate (41 4 g, 505 mmol) in water (300 mL) was heated at 800C for 2 hours The reaction mixture was cooled at room temperature and extracted with 2 x 100 mL ethyl acetate (AcOEt); the organic phase was separated, washed with water (2 x 100 mL), satured sodium chloride solution, dried on anhydrous Na2SO4, filtered, and evaporated to dryness The crude residue was chromatographed on silica gel, using dichloromethaπe-diethyl ether 20:1 as eluant, to give 4 6 g of the title compound as orange solid ESI(+) MS: m/z 260 (M+H) 1 H-NMR (400 MHz), δ (ppm, DMSO-Cf6): 11 14 (bs, 1H), 721 (m, 1H), 7 10 (dd, 1H, J1=I 71 Hz1 J2=732 Hz) 6 92 (d, 1H1 J=829 Hz), 6 88 (m, 1H), 655 (d, 1H1 J=244 Hz), 3 93 (q, 2H, J=7 07 HH), 364 (s, 3H), 240 (S, 3H), 097 (t, 3H, J=707 Hz) Preparation 4 ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl-1 H-pyrrole-3-carboxylate (XIII) To a solution of anhydrous N,N-dimethylformamide (1 54 mL, 19 9 mmol) in anhydrous dichlorome thane (10 mL), under argon, at room temperature, phosphorus(lll) oxychloride (1 83 mL, 19 9 mmol) was added The mixture was stirred for few minutes then ethyl 4-(2-methoxyphenyl)-2-methyl-1H-pyrro!e-3-carboxylate (4 3 g, 166 mmol) was added The solution was refluxed for 1 h, and then evaporated to dryness The crude was stirred at room temperature for 24 h with a mixture of ethanol (5 mL), 2 N sodium hydroxide (100 mL) and water (100 mL) The mixture was then extracted with AcOEt (2 x 100 mL); the organic phase was separated, washed with water (2 x 100 mL), satured sodium chloride solution, dried on anhydrous Na2SO4, filtered, and evaporated to dryness to give the title compound (3 0 g) ESI(+) MS: m/z 288 (M+H); 286 (M-H) 1 H-NMR (400 MHz), δ (ppm, DMSO-Cf6):
1243 (bs, 1H), 909 (S1 1H)1 7.37 (m, 1H), 7 21 (dd, 1 H, J1=I 71 Hz1 J2=744 Hz) 7 06 (d, 1H1 J=7 93 Hz), δ 98 (m, 1 H)1 395 (q, 2H). 368 (s, 3H), 248 (s, 3H), 095 (t, 3H, J=7 07 Hz)
Preparation 5 ethyl 2-methyl-4-trifluoromethanesulfonyloxy-1 H-pyrrole-3-carboxylate (Xl)
To a solution of ethyl 4-hydroxy-2-methyl-1 H-pyrrole-3-carboxylate (0.1 g. 059 mmol) and 2,4,6-collidine (93 5 microL, 0 71 mmol) in anhydrous dichloromethane (2 mL), at 00C, was added dropwise a solution of triflic anhydride (116 5 microL, 071 mmol) in anhydrous dichloromethane (2 mL) The mixture was stirred at 00C for 15 min then washed with water, saturated sodium chloride solution, dried on anhydrous Na2SO4, filtered and evaporated to dryness The crude residue was chromatographed on silica gel, using n-exaπe-AcOEt 1:1 as eluant, to give 142 mg of the title compound ESI(+) MS: m/z 302 (M+H) 1 H-NMR (400 MHz), δ (ppm, DMSO-d6): 1 1 67 (bs, 1H), 6 95 (d, 1H, J=2 34 Hz), 4 16 (q, 2H, J=7 15 Hz)1 2 37 (S, 3H), 1 24 (t, 3H, J=7 15 Hz) Preparation 6 ethyl 5-f ormyl-2-methyl-4-trifluorornethanesulfonyloxy -1 H-pyrrole-3-carboxylate (X)
To a solution of anhydrous N,N-dimethylformamide (31 microL, 0 399 mmol) in anhydrous dichloromethane (4 mL), under argon, at room temperature, phosphorus(lll) oxychlorjde (365 microL, 0399 mmol) was added The mixture was stirred for few minutes then ethyl 2-methyl-4-trifluoromethanesulfonyloxy-1 H-pyrrole-3-carboxylate (0 1 g, 0 332 mmol) was added The solution was refluxed for 8 h, and then the cold mixture was diluted with dichloromethane, added of a satured solution of sodium acetate and vigorously stirred at room temperature for 30 min The organic phase was separated, washed with water (3x20 mL), dried on anhydrous Na2SO4, filtered, and evaporated to dryness The crude residue was chromatographed on silica gel, using π-exane-AcOEt 7:3 as eluant, to give 80 mg of the title compound ESI(+) MS: m/z 330 (M+H) 1 H-NMR (400 MHz), δ (ppm, DMSO-d6): 1304 (bs, 1H), 9.53 (s, 1H), 423 (q, 2H, J=748 Hz), 2 97 (s, 3H), 1 24 (t, 3H, J=7.48 Hz) Preparation 7
1-tert-butyl 3-ethyl 2-methyl-4-trifluoromethanesulfonyloxy-1H- pyrrole-1,3- dicarboxylate
To a solution of ethyl 2-methyl-4-trifluoromethaπesulfonyIoxy-1H-pyrrole-3- carboxylate (02 g, 0664 mmol) in acetonitrile (2 mL), at room temperature, were added di- tert-butyl dicarbonate (0 145 g, 0664 mmol), triethylamiπe (906 microL, 0664 mmol) and a catalytic amount of dimethylaminopyridine (0 01 g) The mixture was stirred at room temperature for 30 min then diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried on anhydrous Na2SO4, filtered and evaporated to dryness The crude residue was chromatographed on silica gel, using π-exane-AcOEt 8:2 as eluant, to give 210 mg of the title compound. ESI(+) MS: m/z 402 (M+H) IH-NMR (400 MHz), δ (ppm, DMSO- dβ): 745 (s, 1 H), 423 (q, 2H, J=6 75 Hz), 268 (s, 3H), 1 55 (s, 9H)1 1 26 (t, 3H, J=6 75 Hz)
Preparation 8
1 -tert-butyl 3-βthyl 5-formyl-2-methyl-4-trifluoromethanesuIfonyloxy-1 H-pyrrole-1 ,3- dicarboxylate (VIIl)
The title compound can be obtained by reaction of ethyl 5-formyl-2-methyl-4- trifluorornethanesulfonyloxy-IH-pyrrole-S-carboxylate with di-tert-butyl dicarbonate ((BoC)2O] according to the following procedure To a solution of ethyl 5-formyl-2-methyl-4- trifluoromethanesulfonyloxy-1 H-pyrrole-3-carboxylate (0 1 g, 0 304 mmol) in anhydrous dichloromethane (2 mL), at room temperature, were added di-tert-butyl dicarbonate (0 1 g, 0.456 mmol), triethylamine (41.5 microL, 0 304 mmol) and a catalytic amount of dimethylaminopyrldine (0 01 g) The mixture was stirred at room temperature for 1h then diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried on anhydrous Na2SO4, filtered and evaporated to dryness. The crude residue was chromatographed on silica gel, using n-exane-AcOEt 9:1 as eluant, to give 62 mg of the title compound. In another approach, the title compound can be obtained from 1 -tert-butyl 3-ethyl 2- mehyl-4-trifluoromethanesu!fonyloxy-1H-pyrrole-1,3-dicarboxylate according to the following procedure: POCI3 (1 2 eq ) was added dropwise to a solution of N.N-dimethylformamide ( 1 .2 eq) in dichloromethane (5 mL) at O0C The solution was stirred at room temperature for 30 min The solution was then cooled at 00C and a solution of the pyrrole (1 eq.) in dichloromethane (10 mL) was added drowise The mixture was refluxed until completion of the reaction The cooled reaction mixture was diluted with ethyl acetate (30 mL), added of IN NaOH (10 mL), and vigorously stirred at room temperature until completion. The organic phase was separated, washed with water (3x20 mL), dried on anhydrous Na2SO4, filtered, and evaporated to dryness to give the expected product ESI(+) MS: m/z 452 (M+Na), 330 (M-Boc+H); ESI(-) MS: m/z 428 (M-H). IH-NMR (400 MHz), δ (ppm. DMSO-d6): 9 83 (s, 1H), 4.27 (q, 2H, J=7 07 Hz), 266 (s, 3H), 1 59 (s, 9H)1 1 28 (t, 3H, J=7 07 Hz) Preparation 9
1 -tert-butyl 3-ethyl 4-[4-(dimethylamino)phenyl]-5-formyl-2-methyl-1 H-pyrrole-1 ,3- dicarboxylate (VII) To stirred dioxane (2 mL) at room temperature, under argon, were added 1 -tert-butyl
3-ethyl 5-formyl-2-methyl-4-trifluoromethanesulfonyloxy-1 H-pyrrole-1, 3-dicarboxylate (80 mg, 0 19 mmol), 4-dimethylaminophenylboronic acid (40 mg, 0.24 mmol), triethylamine (66 microL, 049 mmol) and palladium-tetrakis-triphenylphosphine (22 mg, 0 019 mmol) The solution was heated at 900C for 3 hours The cooled reaction mixture was diluted with AcOEt (30 mL), washed with water (2x20 mL), then with saturated sodium chloride solution (20 mL), dried on anhydrous Na2SO4, filtered and evaporated to dryness. The crude residue was chromatographed on silica gel, using n-exane-AcOEt 2:8 as eluant, to give the desired
product (32 mg) ESI(+) MS: m/z 401 (M+H); ESI(-) MS: m/z 399 (M-H). 1 H-NMR (400 MHz), δ (ppm. DMSO-dβ): 9.20 (bs, IH), 7 19 (d, 2H1 J=8.50 Hz)1 672 (d, 2H. J=8 50 Hz), 4 04 (q. 2H1 J=707 Hz), 2 92 (s, 3H)1 2.51 (s, 3H)1 1 56 (S1 9H), 1 04 (t, 3H, J=7.07 Hz)
By applying a procedure analogous to the one described above, the following compounds were obtained:
Preparation 32
5-formyl-4-(2-methoxy phenyl)-2-mβthyl-1 H-py rrole-3-carboxylic acid (V) The title compound can be obtained by hydrolysis of ethyl 5-formyl-4-(2- methoxyphenyl)-2-methyl-1H-pyrrote-3-carboxylate according to the following procedure: A mixture of 5-formyl-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate (3 g, 104 mmol), ethanol (20 mL) and 20% aqueous sodium hydroxide (200 mL) was stirred at 80°C for 9 h The reaction was cooled at room temperature, acidified with 37% hydrochloric acid (100 mL) and extracted with ethyl acetate (2 x 100 mL) The organic phase was separated, washed with water (2 x 100 mL), satured sodium chloride solution, dried on anhydrous Na2SO4, filtered, and evaporated to dryness The crude residue was chromatσgraphed on silica gel, using dlchloromethane-AcOEt 1:1 as eluant, to give the title compound as white solid (2 16 g)
In another approach, the title compound can be obtained starting from 1-tert-butyl 3- ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-1 ,3-dicarboxylate according to the following procedure: A mixture of 1-tert-butyl 3-ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl- 1H-pyrrole-1,3-dicarboxylate (75 3 mg, 0 194 mmol ) in ethanol (1 mL) and 20% KOH (10 mL) was refiuxed for 1h The cooled reaction mixture was acidified to pH 3 with 2N HCI1 and extracted with AcOEt (3x15 mL) The organic phases were combined, washed with water (2x15 mL), dried on anhydrous Na2SCi1 filtered and evaporated to dryness to give 59 mg (85% yield) of the desired product as white solid ESI(+) MS: m/z 519 (2M+H), 260 (M+H); ESI(-) MS: m/z 517 (2M-H). 258 (M-H) 1 H-NMR (400 MHz), δ (ppm, DMSO-d6): 1231 (bs, IH), 1 1 69 (bs, 1H), 9 01 (s, IH), 730 (dt, IH. J=744 Hz and J=I 83 Hz), 7 17 (dd, IH, J=744 Hz and J=1.71 Hz), 7 00 (dd, 1H, J=744 Hz and J=1 09 Hz)1 6 92 (dt, 1H1 J=744 Hz and J=1 09 Hz), 3 75 (s, 3H), 245 (s, 3H)
By applying a procedure analogous to the one described above, the following compounds were obtained:
Preparation 42
4-{2-methoxyphenyl)-2-methyl-S-[(Z)-(2-oxo-1,2-dihydro-3H-iπdol-3-ylidenβ)methyl]-1H- pyrrole-3-carboxylic acid (II)
A mixture of 1,3-dihydro-indol-2-one (252 mg, 0 189 mmol ), 5-formyl-4-(2- methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (49 mg, 0 189 mmol ) and pyrrolidine (37 microL) in ethanol (4 mL) was refluxed for Ih The mixture was concentrated and the residue acidified with 2N HCI The precipitated formed was collected, washed with water, and then dried in a vacuum oven to give 65 mg (yield 92%) of the desired product as yellow solid ESI(+) MS: m/z 749 (2M+H), 375 (M+H); ESI(-) MS. m/z 747 (2M-H), 373 (M-H) 1 H-NMR (400 MHz)1 δ (ppm, DMSO-de): 1384 (bs, 1H)1 11 75 (bs, 1H)1 11 00 (bs, 1H), 740 (dt, 1H, J=8 30 Hz and J=1 83 Hz)1 7 17 (dd, 1H, J=7 56 Hz and J=1 83 Hz), 7 14 (d. 2H, J=7 56 Hz), 7 10 (d, 1H1 J=8 30 Hz)1 7 04 (t, 1H, J=8 30 Hz)1 699 (s. 1H)1 694 (t. 1H1 J=756 Hz)1 690 (d, 1 H1 J=7 56 Hz)1 3 70 (s, 3H), 261 (s, 3H)
By applying a procedure analogous to the one described above, the following compounds were obtained
Example 1
N-[(2R)-2,3-dihydroxypropyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dlhydro-3H-indol-3- ylidenβ)methylJ-4-phenyl-1H-pyrrole-3-carboxamfde (I)
A mixture of 2-methyl-5-[(Z)-(2-oxo-l,2-dihydro-3H-iπdol-3-yl(deπe)metriyl]-4-plienyl-
1 H-pyrrole-3-carboxylic acid (500 mg, 1 45mmol.), O-(benzotriazol-1-yl)-N,N,N\N'- tetramethyluronium tetrafluoborate (TBTU1 1 39 g, 435 mmol ), triethylamiπe (1 02 mL, 435 mmol) and (R)-3-amino-1,2-propandiol (396 mg, 4 35 mmol ) in dichloromethane (20 mL) was stirred at room temperature for 8h The reaction mixture was treated with 2N HCI, and extracted with AcOEt (4x20 mL) The organic phases were combined, washed with water (2x15 mL), dried on anhydrous Na2SO4, filtered and evaporated to dryness The crude residue was chromatographed on silica gel, using dichloromethane-ethanol 20:1 as eluant, to give 240 mg (40% yield) of the desired product as yellow solid 1 H-NMR (400 MHz), δ (ppm, DMSOd6): 1386 (bs, 1H), 11 02 (bs, 1H), 7.56-739 (m, 5H), 727-724 (d, 1H, J=762 Hz)1 723-7 19 (m. 1H), 722 (s, IH)1 7 19-7 15 (td, 1H, J=1 06 Hz, J=762 Hz), 7 00-696 (td, 1H, J=O 76 Hz1 J=746 Hz), 6 95-6.92 (d, IH, J=7 76 Hz)1 4 92-3 98 (m, 2H), 3 57-2 97 (m, 5H),
2 57-2 51 (m, 3H) [α]D= -4 5 (20 mg/mL, DMF)
By applying a procedure analogous to the one described above, the following compounds were obtained
1 1 1
1
1
1
1
Ex 1
1 1 1
1
1
Example 82
N-[2-(diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dJhydro-3H- indol-3-ylidene)methyl]-1H~pyrrole-3-carboxamlde (I)
A solution of N-[2-(diethylamino)ethyl]-4-{2-rπethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo- 1.2-dihydro-3H-iπdol-3-ylidene)methylJ-1H-pyrrole-3-carboxamide (37 mg, 0078 mmol ) in dichloromethane (4 mL) under argon, was cooled at 00C and added dropwise of a solution of 1M BBr3 in dichloromethane (048 mL, 048 mmol ) The reaction mixture was stirred at room temperature for 5 hours, then diluted with AcOEt (20 mL), basified with 1N Na2CO3 and extracted with AcOEt (2x15 mL) The organic phases were combined, washed with water (3x20 mL), dried on anhydrous Na2SO4, filtered and evaporated to dryness The crude residue was chromatographed on silica gel, using dichloromethane-methanol 9:1 as eluant, to give 34 mg (95% yield) of the desired product as yellow solid ESI(+) MS: m/z 459 (M+H); ESI(-) MS: m/z 915 (2M-H)1 457 (M-H)
IH-NMR (400 MHz), δ (ppm, DMSO-d6): 1375(bs, 1H), 1094(bs, 1H), 965 (bs, 1H). 786- 666 (m. 10H)1 386-2 24 (m, 11H), 1 43-0 57 (m, 6H)
By applying a procedure analogous to the one described above, the following compounds were obtained:
82
88
62
82
Example 92
N-[2-(diθthylamino)ethyl]-5-[(Z)-(5-hydroxy-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-2-methyl-4-phenyl-1H-pyrrole-3-carboxam!de (I)
By applying a procedure analogous to the one described above, the following compounds were obtained:
Example 94
4-(2-aminophenyl)-N-[2-(diethylamlno)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- iπdol-3-ylidene)methyl]-1H-pyrroIe-3-carboxamide
To a solution of N-[2-(diethylamino)ethyl]-2-methyl-4-(2-nitrophenyl)-5-((Z)-(2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide (88 mg, 0.18 mmol) in N1N- dimethylformamide (2 mL) was added SnCI2 2H2O (406 mg, ! 8 mmo!) The solution was
stirred at room temperature for 24 hours. The reaction mixture was then basified with saturated NaHCO3 solution, diluted with water (30 mL) and extracted with AcOEt (2x50 mL) The organic phases were evaporated to dryness and the crude residue was chromatographed on silica gel, using dichloromethane-methanol-30%aq NM4OH 100:10:0 5 as eluant, to give 35 mg (43% yield) of the desired product as yellow solid. ESI(+) MS: m/z 458 (M+H); ESI(-) MS: m/z 456 (M-H) IH-NMR (400 MHz), δ (ppm, DMSO-dB): 1380 (bs, 1H)1 10.97(bs, 1H), 7 37-647 (m, 10H), 503-4 61 (m, 2H), 4.02-203 (m, 11H)1 1.36-064 (m, 6H)
By applying a procedure analogous to the one described above, the following compounds were obtained:
Example 101
5-[({5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2-methyl-4-phenyl-1H- pyrrol-3-yl}carbonyI)amino]pentanoic acid (I)
A mixture of methyl 5-[({5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-y!ideπe)methyl]- 2-methyl-4-phenyl-1H-pyrrol-3-yl}carbonyl)amino]pentanoate (38 mg, 0 08 mmol), eihanoi (5
mL) and 1N NaOH (1 mL, 1 mmol) was stirred at room temperature for 2 hours. The ethanol was removed under reduced pressure and the residue diluted with H2O (10 mL). The resulting solution was brought to acidic pH with 1N HCI and the precipitated solid filtered, washed with water and dried in oven at 400C. The title compound (26 mg, 70% yield) was obtained as orange solid IH-NMR (400 MHz), δ (ppm, DMSO-dβ): 13.92 (bs, 1H)1 11.95 (bs, 1H)1 10.99 (bs, 1H), 7.47-6 83 (m. 10H), 3 07-304 (m, 2H), 241 (s, 3H)1 2.14-2.05 (m, 2H)1 1.38-1.32 (m, 4H). Preparation 67 N-[2-(diethylamino)ethyl]-5-foπnyl-4-(2-methoxyphenyl)-2-methyl-1H-pyrτole-3- carboxamide (XIX)
A mixture of 5-formyl-4-(2-methoxyρheny|)-2-methyl-1H-pyrrole-3-carboxylic acid (200 mg, 073 mmol), triethylamine (021 mL, 1 54 mmol), 2-(diethylamino)ethylamiπe (0.12 mL, 085 mmol) and TBTU (372 mg, 1 16 mmol) in dry dichloromethane (15 mL) was stirred at room temperature for 1 5 hours The reaction mixture was washed with a saturated solution of sodium hydrogeπocarbonate, with water and with brine, dried over sodium sulfate and evaporated to dryness The residue was purified by flash chromatography on silica gel with dichloromethane-methanot-30% aq NH4OH 90:10:0 5 as the eluant affording 78 mg of the title compound as brown solid IH-NMR (400 MHz)1 δ (ppm, DMSO-dβ): 12 19 (bs. 1H)1 904 (S1 IH), 7.41 (m, 1H), 726 (dd, J=1 7 Hz1 J=74 Hz, 1H), 7 10 (dd, J=085 Hz, J=8.4 Hz, 1H), 7 02 (m, 1H)1 649 (bt, 1H), 3.71 (s, 3H), 3.10 (m, 2H), 242 (s, 3H), 2.37-225 (m, 6H), 084 (t, J=7 1 Hz, 6H) Preparation 68
N-I2-{diethyJamino)ethylJ-5-formyl-4-(2-hydroxyphenyl)-2-mβthyl-1H-pyrrole-3- carboxamide (XIX) A solution of N-[2-(diethylamino)ethyl]-5-formy!-4-(2-methoxyphenyl)-2-methyl-1H- pyrrole-3-carboxamide (78 mg, 022 mmol) in dry dichloromethane (3 mL) at 00C, under argon, was treated with a solution of 1M BBr3 in dichloromethane (1 1 mL, 1 1 mmol) The mixture was warmed to room temperature and stirred for 3 hours A saturated solution of sodium hydrogenocarbonatθ was then added and the mixture extracted with ethyl acetate The organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness affording a red solid (65 mg) that was used as such for the next step.
Example 102
Preparation of 5-{(Z)-[5-(benzyIoxy)-2-oxo-1 ,2-dihydro-3H-indol-3-ylldene]methyl}-N-[2-
(diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-methy|-1H-pyrrolβ-3-carboxamidθ (l)
021 mmol) and pyrrolidine (0 016 mL, 0.19 mmol) in ethanol (5 mL) was stirred at reflux for
1 5 hours The reaction mixture was then cooled at room temperature, diluted with water and extracted with ethyl acetate The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel with dichloromethane-methanol-aq 30% NH4OH 100:10:0 5 as the eluant affording 62 mg of the title compound as orange solid. 1 H-NMR (400 MHz), δ (ppm, DMSO-dβ): 13-85 <bs, 1H), 1079 (bs, 1H), 7 45-728 (m, 7H), 7 13 (m, IH), 7 03-694 (m, 3H), 6 90-6.78 (m, 3H)1 6 74 (m, IH), 503 (S, 2H)1 325-3 10 (m, 2H), 2.55 (s, 3H)1 250-2.30 (m, 6H), 0.89 (m, 6H) Example 103
Preparation of 5-[(Z)-(5-amf no-2-oxo-1 ,2-dihydro-3H-indol-3-ylidenε)methyl]-N-[2- (dIethylamlno)ethyl]-4-(2-methoxyphenyI)-2-methyl-1H-pyrrole-3-carboxam(de (I)
To a solution of tert-butyl (3Z)-3-{[4-({[2-(diethylamino)ethyl]arnino}carbonyl)-3-{2- methoxyphenyl)-5-methyl-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5- ylcarbamate (122 mg, 021 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 45 minutes, diluted with dichloromethane (50 mL), washed with IN NaOH (30 mL), water (2x30 mL) and brine (30 mL), dried over sodium sulfate and evaporated to dryness affording the title compound as red solid (77 mg) 1 H-NMR (400 MHz), δ (ppm, DMSO-Cf5): 13.90 (s, 1H), 1052 (s, 1H), 7 47 (m, IH), 722 (m, JH), 7 16 (m, 1H), 7 10 (m, 1H)1 681 (s, IH), 6.58 (m, 1H), 6.47 (bs, 1H). 643- 6 36 (m, 2H), 470 (bs, 2H)1 372 (s, 3H), 3 13 (bs, 2H), 2.52 (s. 3H), 2.35 (m, 6H), 0.87 (bt, 6H)
Example 104
5-[(2)-(5-amino-2-oxo-1)2-dihydro-3H-indol-3-ylidβne)mβthyl]-N-t2-(d[βthylamino)ethyl]- 4-(2-hydroxyphenyl)-2-methyl-1 H-pyrrole-3-carboxamide (I)
(diethylamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-1 H-pyrrole-3-carboxamide (66 mg, 0 136 mmol) in dichloromethane (5 mL) was cooled at 0°C and treated with a solution of 1M BBr3 in dichloromethane (1.4 mL, 1 4 mmol) The mixture was warmed to room temperature and stirred for 4 hours, then quenched with a saturated solution of sodium hydrogenocarfaoπate and extracted with ethyl acetate The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness The residue was purified by flash chromatography on silica gel with dichloromethane-methanol-aq 30% NH4OH 90:10:0 1 as the eluant affording the title compound as orange solid (45 mg) 1 H-NMR (400 MHz), δ (ppm, DWISO- d6): 1394 (s, 1H), 10.52 (s, 1H)1 7 31 (m. IH), 7 13 (m, IH), 700 (m, IH). 696 (m, 1H). 6.82 (S1 1 H), 675 (bs, 1 H). 6 58 (m, 1 H), 642-636 (m. 2H). 471 (bs, 2H), 3 15 (m, 2H)1 2 54 (s, 3H), 236 (m 6H), 087 (bt, 6H)
Claims
1. A compound of formula (I):
or a pharmaceutical acceptable salt thereof, wherein
Ar is aryl;
R1 is selected from the group consisting of hydrogen, halogen, -OH, alkoxy, -NH2, -NHCOR10, -NHSO2R10, and -SO2NHR10; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl;
R3 is selected from the group consisting of hydrogen, cycloalkyl, and -(CH2Jn-CH(R5)- (CH2)mRβ;
R4 is selected from the group consisting of hydrogen, methyl, and ethyl;
R5 is selected from the group consisting of hydrogen, -OH, -NH2, alkyl, and alkoxy; Rβ is selected from the group consisting of hydrogen, -OH, -NR7R8, -COR9, and aryl, or R5 and Rβ may combine to form a heterocyclic ring;
R7 and Rβ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy, cycloalky, -COR9 and aryl, or optionally R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring or an aryl ring; Rβ is selected from the group consisting of -OH, alkoxy, -NH2, and
-NR7R";
R10 is selected from the group consisting of alkyl, cycloalkyl, and aryl;
R14 is hydrogen, or R14 and R3 together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted with alkyl, wherein said alkyl may be optionally substituted with a heterocyclic ring;
R1S is independently selected from the group consisting of hydrogen, halogen, -OH1 -CN, -NO2, -NH2, -SH, alkyl optionally substituted with hydroxy or 1 to 3 fluorines, alkylthio, alkoxy optionally substituted with phenyl or 1 to 5 fluorines, -C(O)R9. -C(O)R", and -SO2-aikyi. or optionally when p is 2, then both R15substituents, together with two adjacent atoms from Ar to which they are attached, form a heterocyclic ring fused to Ar;
RIβ is selected from the group consisting of hydrogen, alky!, trihalomethyl, cycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, -SH, alkyl, trihaloalkyl, alkoxy, alkylthio, -CN, acyl,
-NO2, -NR7R8, and -SO2-alkyl; n and m are independently 0, 1, 2 or 3; p is 0, 1 , 2, or 3; with the proviso that when π is 0 then R5 is selected from hydrogen and alkyl, and when m is Q then onty one of R5 and Rβ may be -OH or -NH2; and with the proviso that when R1 is bromine, R2 is hydrogen, R4 is methyl, Ar is phenyl, then R3 is not 2-dimethylamlnoethyl, 3-diethylaminopropy) or2-(pyrrolidin-1-yl)ethyl. with the proviso that if R* is hydrogen, methylaminosulphonyl or benzyl-sulphonyl, than Ar-/R15}p is not 4-cholorophenyl or 2,4-difluorophenyl; with the proviso that the compounds 4-(4-chlorophenyl)-N-[2-(dfethylamino)ethylJ-2- methyl-5-((Z)-{5-[(methylamino)sulfonyl]-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene}methyl)- 1 H- ρyrrole-3-carboxamide,
N-[2-(diethylamino)ethylH-(2,4-difluorophenyl)-2-methyl-5-((Z)-{5- [(methylamino)sulfonyl]-2-oxo- 1 ,2-dihydro-3H-indol-3-ylidene}methyl)-1 H-pyrrole-3- carboxamide, and
4-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(4-methyl-2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyl]- 1H-pyrrole-3-carboxamide are excluded
2 A compound of formula (I), according to claim 1 , or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of hydrogen, fluorine, -OH, alkoxy, -NH2, -NHCOR10, -NHSO2R10, and -SO2NHR10; R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl;
R3 is selected from the group consisting of hydrogen and -(CH2)n-CH(R5MCH2)mRβ;
R* is methyl or ethyl;
R5 is selected from the group consisting of hydrogen and -OH; R8 is selected from the group consisting of -OH, -NR7R8, and aryl;
R7 and R8 are independently selected from hydrogen and alkyl, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring; R10 is selected from alky), cycloalkyl, and aryl; and R14 is hydrogen
3 A compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of hydrogen, fluorine, -OH, alkoxy, -NH2, -NHCORf0, -NHSO2R'0, and -SO2NHR10;
R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl; R3 is -(CH2)n-CH(R5)-(CH2)π,Rβ; R4 is methyl;
R5 is selected from the group consisting of hydrogen and OH; Rβ is selected from the group consisting of -OH, -NR7R8, and aryl; R7 and R8 are Independently selected from hydrogen and alkyl, or R7 and Rβ may combine to form a saturated or unsaturated heterocyclic ring; R10 is selected from alkyi, cycloalkyl and aryl;
R14 is hydrogen; and n and m are independently selected from O1 1 or 2
4 A compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of fluorine, alkoxy, -NH2, -NHSO2R10 and - SO2NHR10;
R2 is selected from the group consisting of hydrogen, methyl and hydroxyethyl;
R3 is -(CH2)n-CH(R5)-(CH2)mRβ; R4 is methyl;
R5 is selected from the group consisting of hydrogen, and -OH;
Rβ is selected from the group consisting of -OH, -NR7R8, and aryl;
R7 and R8 are independently selected from hydrogen and an alkyl group, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring; R10 is selected from alkyl and aryl;
R14 is hydrogen; and n and m are independently selected from O or 1
5 A compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof, wherein Ar is aryl;
R1 is selected from the group consisting of fluorine, alkoxy, -NHSO2R10, and SO2NHR10; R2 is selected from the group consisting of hydrogen, methyl, and hydroxyethyl;
R3 is -(CH2)n-CH(R5)-(CHz)mRβ;
R4 is methyl;
R5 is selected from the group consisting of hydrogen and -OH; R6 is -NR7R8;
R7 and R8 are independently selected from hydrogen and an alkyl group, or R7 and RB may combine to form a saturated or unsaturated heterocyclic ring;
R10 is selected from alkyl and aryl;
R14 is hydrogen; and n and m are independently selected from 0 or 1
6 A compound of formula (I), according to claim 1 , or pharmaceutically acceptable salt thereof, wherein
Ar is phenyl or thiophene; fC is selected from the group consisting of hydrogen, F, Cl, -OH, -OCH3, -NH2, -O-CH2-phenyl. -SOrN(H)(CH3), -N-SO2-phenyl, -N-C(O)-phenyl, -N-C(O)-OC(CH3J3;
R2 is selected from the group consisting of hydrogen, methyl, and -CH2CH2OH;
R3 is selected from the group consisting of hydrogen, cycloalkyl, and -(CHz)n-CH(R5)- (CH2)π,Rβ;
R4 is -CH3;
R5 is selected from the group consisting of hydrogen, -OH, -NH2, alkyl, and alkoxy;
Rβ is selected from the group consisting of hydrogen, -OH, -NR7R8, -CORB, and aryl, or R5 and R6 may combine to form a heterocyclic ring; R7 and R8 are independently selected from the group consisting of H1 alkyl, alkoxy, cycloalky, -COR9 and aryl, or R7 and R8 may combine to form a saturated or unsaturated heterocyclic ring, wherein said heterocyclic ring is selected from morpholine, N-methylpiperazione, and 4- hydroxypiperidine; R9 is selected from the group consisting of -OH, alkoxy, -NH2, and -NR7R8;
R14 is hydrogen, or R3 and R14 together with the nitrogen to which they are attached form pyrrolidine ring substituted with methyl, wherein said methyl is substituted with another pyrrolidine ring;
R15 is independently selected from the group consisting of H, F, Cl, Br1 -OH, -CN. -NO2. -NH2, -CH3, CH(CH3J2 -CF3 -OCH3, -OCF3, -OCH2CH3, -CHCH3CH3, -CH2OH, - CH2CH2OH, -C(O)CH3, -O-CH2-phenyl, and -SO2CH3; or. when n is 2 and Ar is phenyl, both R1S substituents together form a methylenedioxy group such that the 2 Rιs substituents together with Ar form methylenedioxyphenyl; and p is O, 1, or2.
7. The compound of claim 6, or pharmaceutically acceptable salt thereof, wherein
Ar is phenyl;
R1 is selected from the group consisting of hydrogen, F, Cl, -OH, -OCH3, -NH2;
R2 is hydrogen; R3 is -(CHz)n-CH(R5MCH2),^6;
R5 is selected from the group consisting of hydrogen and -OH;
R6 is -NR7R8;
R7 and Rβ are independently selected from the group consisting of H, alkyl, alkoxy, -COR9; R9 is selected from the group consisting of -OH1 alkoxy, -NH∑;
R14 is hydrogen
R15 is independently selected from the group consisting of H, F, Cl, Br, -OH, -NO2, -NH2, -CH3, -OCH3, -OCF3; and n and m are independently selected from 1 or 2; and p is 0, 1, or 2
8 A compound of formula (I), according to claim 1 , or pharmaceutically acceptable salt thereof, selected from the group consisting of
N-[2-(diethylamiπo)ethyl]-2-methyμ5-[(2)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide; N-[2-(isopropylamlno)ethyll-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl-1H-pyrrole-3-carboxarnide;
N-(2,3-dihydroxypropyl)-2-methyl-5-[(Z)-(2-oxo-1l2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[(2R)-2,3-dihydroxypropyl]-2-methyl-5-((Z)-(2-oxo-1>2-dihydro-3H-indol-3- ylidene)melhyl]-4-phenyI- 1 H-pyrrole-3-carboxamide;
2-methyl-N-(3-moφholin-4-ylpropyl)-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyf]-4-phenyl- 1 H-pyrrole-3-carboxamide;
2-methyl-N-(3-(4-methylpiperazin- 1 -yl)propy!]-5-{(Z)-(2-oxo- 1 ,2-dihydro-3H-indol-3- y lidene)methyl]-4-pheny I- 1 H-pyrrole-3-carboxamide; N-t2-(diethylamino)ethyl]-2-methyl-5-l(Z)-(2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamIde; N-P-tdiethylaminoiethylH-H-tdimethylaminoJphenyll^-πiethyl-S-KZJ-tZ-oxo- 1 ,2- dihydro-3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamtde carboκamide;
N-[2-{diethylamino)ethyll-2-methyl-4-[4-(methylsulfonyl)phenyll-5-{(Z)-{2-oxo-t,2- dihydro-3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyll-4-(4-isopropylphenyl)-2-methyl-5-l(ZH2-oxo- 1 ,2-dihydro-
3 H-iπdol-3-ylidenβ)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethylh2-methyi-5H(Z)-{2-oxo-1,2-dihydr<>-3H-indol-3- ylidene)methyt]-4-[3-{trifluoronrielhyl)phenyl]-1H-pyrrole-3-carboxamide;
4-(3-acetylpheπyl)-N-[2-(diethylamiπo)ethyl]-2-methyl-5-t(ZH2-oxo-1l2-dihydro-3H- iπdol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-{4-(bβnzyloxy)phenyl]-N-[2-(diethylannino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyll-1H-pyrrole-3-carboxamide;
4-(4-cyanophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(ZH2-oxo-1,2-dihydro-3H- indol-S-ylideneimethyll-IH-pyrrole-S-carboxamide; 4-(4-ch)orophenyl)-N-[2-(diethylamino)ethylJ-2-methyl-5-[(Z)-(2-oxo- 1 ,2-dihydro-3H- iπdol-3-yIidβne)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethy!amino)ethyl]-2-methyl-4-(3-nitrophenyl)-5-[(Z)-(2-oxo-1r2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-{2-(diethylamino)ethyll-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- y lidene)methyl]-4-[3-(trifluoromethoxy)pheπyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethylH-(3-fluorophenyl)-2-methyl-5-[(Z)-(2-oxo-1>2-dihydro-3H- indol-3-ylidene)methyl]-1H-pyrrole~3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(3-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole^3-carboxamide; N-[2-{diethylamino)ethylJ-2-methyl-4-{3-methylphenyl)-5-KZ)-(2-oχo- 1 ,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-{2-(diethylamino)ethyll-4-(3-ethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-t2-{diethylamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-5-{(Z)-(2-oxo-1 ,2-dihydro-3H- indol-3-yltdene)methyl]-1 H-pyσofe-3-carboxamide;
N-[2-(isopropylamino)ethyl]-4-(2-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylideπe)methyl]-1H-pyrrole-3-carboxamide;
4-(2-methoxyphenyl)-2-methyl-N-(2-moφholin-4-ylethyl)-5-{(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylideπe)methyI]- 1 H-pyrrole-3-carboxamide; N-[(2R)-2,3-dihydroxypropyl]-4-(2-methoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-
3H-indol-3-ylideπe)methyl]- 1 H-pyrrole-3-carboxamide; N-[2-(diethylaπiino)ethyl]-4-(2-fluorophenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-2-methyl-4-(2-nitrophenyl)-5-[(Z)-(2-oxo-1l2-dihydro-3H- indol-3-ylideπe)methyl]- 1 H-pyrrole-3-carboxamide; 4-( 1 ,3-benzodioxol-5-yl)-N-l2-(diethylamino)ethyl]-2-methyl-5-[(2)-(2-oxo-1 ,2-dihydro-
3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-(2-(dlethylamino)ethylI-4-(2,4-difIuorophenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl)-4-(2,4-dimethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 l2-dihydro- 3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-(2-(diethylamino)ethyll-4-(2,5-dimethoxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydra- 3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
N-[2-(diethyIamino)e{hyll-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H-indol-3- y!idene)methylH-trιien-3-yl-1H-pyrro)e-3-carboxamide; N-[2-(diethylamino)ethyll-2-meihyl-5-KZ)-(2-oxo- 1 ,2-dihydro-3H-indol-3- ylidene)methyl]-4-thien-2-yl-i H-pyrrole-3-carboxamide;
4-(5-chlorothien-2-yl)-N-[2-(diethylamiπo)ethyl]-2-methyl-5-[(Z)-(2-oxo-1l2-dihydro-3H- indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-(5-acεtylthien-2-yl)-N-[2-{diethylamino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1 ,2-dihydro-3H- iπdol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
5-KZH5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (isopropylamino)ethyl]-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide;
N-(2,3-dihydroxypropyl)-5-[(Z)-{5-fluoro-2-oxo-1,2-dihydro-3H-iπdol-3-ylidene)methylJ- 2-methyl-4-phenyl- 1 H-pyrrole-3-carboxamide; S-[(ZH5-fluoro-2-oxo- 1 ,2-dihydro-3H-lndol-3-ylidene)methyπ-2-methyl-N-l3-(4- methy Ipiperazin- 1 -y l)propyll-4-phenyl- 1 H-pyrrole-3-carboxamide;
5-{(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2-methyl-N-(3- morpholin-4-ylpropyl)-4-phenyl-1 H-pyrrole-3-carboxamide;
Methyl δ-IUδ^^-fS-fluoro^-oxo-i ^-dihydro-SH-indol-S-ylideneJmethylJ^-methyM- phenyl- 1 H-pyrrol-3-yl}carbonyl)amino]pentanoate;
5-[(Z)-(5-fIuoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(4- hydroxypiperidin-1-yl)ethyl]-2-methyl-4-phenyl-1 H-pyrroIe-3-carboxamide;
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-(4- hydroxycyclohexyl)-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyll-5-[(Z)-(5-f»uoro-2-oxo-1,2-dihydro-3H-iπdol-3- ylidene)methyl)-4-(4-fluoropheπyl)-2-methyl-1 H-pyrrole-3-carboxamide; 5-l(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidβnβ)methylH-(4-fluorophenyl)-N-(2- (isopropylam<πo)ethyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
N-[3-(diethylamino)-2-hydroxypropyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-(4-fluorophenyl)-2-methyl- 1 H-pyrrole-3-carboxamide; N-p-idiethylaminoJethyll-δ-KZJ-fS-fluoro-Σ-oxo-i^-dihydro-SH-indol-S- ylidene)methyl]-4-(4-methoxyphenyl)-2-methyH H-pyrrole-3-carboxamide;
4-(4-chlorophenyl)-N-[2-(diethylamiπo)ethyl]-5-l(ZH5-fluoro-2-oxo-1,2-<lihydro-3H- indol-3-ylidene)methyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
4-(4-cyanophenyl)-N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1 ,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethylJ-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-(2-methoxyphenyl)-2-methyH H-pyrrole-3-carboxamide;
N'[2-(diethylamino)ethylH-(2,4-difluorophenyl)-5-[{Z)-(5-fluoro-2-oxo-112-dihydro-3H- indol-3-y lidene)methyl}-2-methyl- 1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1 ,2-dihydro-3H-indol-3- ylideπe)methyl]-2-methyl-4-phenyl-1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(4-fluorophenyl)-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide;
4-{4-chlorophenyl)-N-[2-(diethylamino)ethyl]-5-[(ZH5-methoxy-2-oxo-1 l2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl-1 H-pyrrole-3-carboxamide;
N-f2-(diethylamino)ethyπ-5-t(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-3H-indo!-3- ylidene)methyl]-2-methyl-4-(2-nitrophenyl)-1 H-pyrrole-3-carboxamide; N-f2-(diethylamiπo)ethylJ-4-(2,4-difluorophenyl)-5-[(Z)-(5-methoxy-2-oxo-1,2-dihydro-
3H-indol-3-ylideπe)methyl]-2-methyl- 1 H-pyrrole-3-carboxamide;
S-KZJ-CS-chloro-Σ-oxo-I .Σ-dihydro-SH-indol-S-ylideneJmethylJ-N-p- (diethylamino)ethyl)-2-methyl-4-phenyl-1H-pyrro]e-3-carboxamide;
5-f(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-4-(4-chlorophenyl)-N-[2- (drethylamiπo)ethyf]-2-methyl-1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-chloro-2-oxo-1,2-dihydrc-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-4-(2,4-difluorophenyl)-2-methyl-1 H-pyrrole-3-carboxamide;
N-[2-(isopropylamino)ethyl3-2-methyl-5-((Z)-{5-{(methylamino)sulfonyl]-2-oxo-1 ,2- dihydro-3H-indol-3-ylidene}methyl)-4-phenyl-1H-pyrrole-3-carboxamide; N-[3-(diethylamino)-2-hydroxypropyl]-2-methyl-5-((ZH5-[{methylamino)sulfoπyl]-2- oxo-1,2-dihydro-3H-iπdol-3-ylideπe}methyl)-4-phenyl-1 H-pyrrole-3-carboxamide; 4-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-((Z)-{5- [(methylamino)sulfonylJ-2-oxo-1,2-dihydro-3H-indol-3-ylidene}melhyl)-1H-pyrrole-3- carboxamide;
N-[2-(diethylamino)elhylH-(2,4-di(luorophenyl)-2-methyl-5-((Z)-{5- [(methylamJno)sulfony(|-2-oxo-1 ,2-dihydro-3H-indol-3-ylidene}methyl)-1 H-pyrrole-3- carboxamide;
N-|2-(diethylamino)ethyl]-4-[3-(hydroxymethyl)phenyl]-2-methyl-5-[(Z)-(2-oxo-1>2- dihydro-3H-indol-3-ylidene)methyl]-iH-pyrrole-3-carboxarnide;
5-{(Z)-[4-(2-hydroxyethyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidenelmethyl}-2-methyl-4- phenyl- 1 H-pyrrole-3-carboxamide);
N-p^diethylaminoJethyll-δ-^ZJ^^-hydroxyethyO^-oxo-i ^-dihydro-SH-indol-S- ylidene]methyI)-2-mβthyl-4-phenyl- 1 H-pyrrole-3-carboxamide;
N-[2-(diethytamino)ethyl]-2-methyt-5-HZ)-(4-methyl-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-phenyl- 1 H-pyrrole-3-carboxamide; N-[2-{diethylamino)ethylJ-4-(4-f(uorophenyl)-2-methyl-5-[(Z)-(4-methyl-2-oxo- 1 ,2- dihydro-3H-indol-3-ylideπe)methylJ- 1 H-pyrrole-3-carboxamide;
4-<4-chlorophenyl)-N-[2-(diethylamino)ethyl]-2-methyl-5-[(Z)-(4-methyl-2-oxo-1,2- dihydro-3H-indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-{2-(diethylamino)ethylH-(2,4-difluorophenyl)-2-methyl-5-[(ZH4-methyl-2-oxo-1 l2- dihydro-3H-indol-3-ylidene)methylj- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyl]-4-(4-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- iπdol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-{2-{diethylamiπo)ethylJ-4-(3-hydroxypheπyl)-2-methyl-5-[(Z)-(2oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide; N-[2-{diethylamino)ethyll-4-(2-hydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1 l2-dihydro-3H- indol-3-ylidene)methy I)- 1 H-pyrrole-3-carboxamide;
4-(2-hydroxyphenyl)-N-[2-(isopropylamino)ethyi]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylideπe)methyf|- 1 H-pyrrole-3-carboxamide;
N-[(2R)-2,3-dihydroxypropyl]-4-(2-hydroxyphenyl)-2-methyl-5-{(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyl]-1 H-pyrrole-3-carboxamide;
4-(2-hydroxyphenyl)-2-methyl-N-(2-moφholin-4-ylethyl)-5-t(Z)-(2-oxo-112-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
N-[2-(diethylamino)ethyri-4-(2,4-dihydroxyphenyl)-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyt]-1 H-pyrrole-3-carboxamide; N-{2-(diethy]amiπo)ethyq-5-{(Z)-(5-fluoro-2-oxo- 1 ,2-dihydro-3H-indol-3- ylidene)methyl]-4-(2-hydroxyphenyl)-2-methyl-1 H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethylh5-[(Z)-(5-hydroxy-2-oxo- 1 ,2-dihydro-3H-indol-3- ylidene)methylj-2-methyl-4-phenyl- 1 H-py rrole-3-carboxamide;
N-fa^diethylaminoJethylhδ-ltZJ-tδ-hydroxy^-oxo-I.Z-dihydrD-SH-indol-a- ylidene)methyt]-4-(2-hydroxyphenyl)-2-methyl- 1 H-pyrro!e-3-carboxamlde; ^(S-aminophenylJ-N^-^diethylaminoJethyl^-methyl-δ-lCZJ^-oxo-i.a-dihydro-SH- indol-S-ylideneJmethyll-IH-pyrrole-S-carboxamide;
4-(3-aminophenyl)-N-l2-{isopropylamino)elhyl]-2-methyl-5-{(Z)-(2-oxo-1,2-dihydro-3H- indoI-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
4-(3-aminophenyl)-N-t(2R)-2,3-dihydroxypropyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro- 3H-indol-3-ylidene)methyl]-1H-pyrrole-3-carboxamide;
4-(2-aminophenyl)-N-{2-(diethy!amino)ethyl]-2-methyl-5-[(Z)-(2-oxo-1,2-dihydro-3H- indol-3-ylidene)methy IJ- 1 H-pyrro!e-3-carboxamide;
4-(3-aminophβnyl)-N-l2-(diethylamino)ethyl]-5-I(Z)-{5-methoxy-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2-methyl- 1 H-ρyrrole-3-carboxamide; 4-(2-aminopheπyl)-N-[2-{dtethylamiπo)ethyl}-5-[(Z)-(5-methoxy-2-oxo- 1 ,2-dthydro-3H- indol-3-ylidene)methyl]-2-methyl-1H-pyπrole-3-carboxamide;
4-(3-aminophenyl)-N-{2-(diethylamino)ethyl]-5-{(ZH4-(2-hydroxyethyl)-2-oxo-1,2- dihydro-3H-indol-3-ylidenelmethy!}-2-methyl-1H-pyrrote-3-carboxamtde;
S-[({5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)mβthyl]-2-methyl-4-phβnyl- 1H-pyrrol-3-yl}carbonyl)amino}pentanoic acid;
4-(2-fluoropheπy1)-N-{2-(isopropylamino)ethyl]-2-mβthyl-5-[(Z)-(2-oxo-1 l2-dihydro-3H- indol-3-ylidene)methyl]- 1 H-pyrrole-3-carboxamide;
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indoJ-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-2-methyl-4-phenyl-1H-pyrrole-3-carboxamide; S-[(Z)-(5-Λuoro-2H3Xo-1,2-dihydro-3HHndol-3-ylidene)methyl]-N-[3-(1H-imidazol-1- yl)propyll-2-melhyl-4-phenyl-1 H-pyrrole-3-carboxamide carboxamide;
N-[3-(diethylamino)-2-hydroxypropy1]-5-[(Z)-{5-fluoiO-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl]-4-{4-bromophenyl)-2-methy!-1H-pyrrole-3-carboxamide;
N-t3-(diethylamino)-2-hydroxypropyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3- ylidene)methyl)-4-(4-methoxyphenyl)-2-methyl-1 H-pyrτole-3-carboxamide;
4-(4-bromophenyl)-N-[2-(diethylamino)βthyl]-5-[(ZH5-fIuoro-2-oxo-1,2-dihydro-3H- iπdol-3-ylidene)methyll-2-methyl-1H-pyrrole-3-carboxamide;
N-[2-(diethylamino)e*yl]-5-[(Z)-(5-fluoro-2-oxo-r,2-dihydro-3H-indol-3- ylidene)rnethyl]-4-(3-rnethoxyphenyl)-2-rnethyl-1H-pyrrole-3-carboxamide; 5-{(Z)-l5-(ben2yloxy)-2-oxo-1.2-dihydro-3H-indol-3-ylidenelmethyl}-N-t2-
(diethylamino)ethyl]-2-methyl-4-phenyl-1H-pyσole-3-carboxamide; N-[2-(diethylamino)ethyl]-4-(2-fτ»ethoxyphenyF)-2-mβthyl-5-((Z)-{2-oxθ'5- [(phenylsulfonyJ)aminoJ- 1.2-dihydro-3H-indol-3-ylidene}methyl)- 1 H-pyrrofe-3-carboxamide;
5-{(Z)-[5-(benzoylamino)-2-oxo-1,2-dihydro-3H-lndol-3-ylidene]methyl}-N-[2- (diethylamino)ethylH-(2-methoxyphenyl)-2-methyI-1H-pyrrole-3-carboxamide; tert-butyKSZJ-S^Jit-røa-tdiethylamiπoJethylJaminolcarbonyO-S^-methoxypheπylJ-S- methyl-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-iH-indol-5-ylcarbamatβ;
N-[2-(diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-methyl-5-((Z)-{2-oxo-5- t(phenylsulfoπyl)aminol- 1 ,2-dihydro-3H-indol-3-ylidene}methyl)- 1 H-pyrrole-3-carboxamide; δ^CZJ-IS-tbenzoylaminoJ^-oxo-i^-dihydro-SH-indol-S-ylidenelmethyll-N^- (diethylamino)ethyl]-4-(2-hydroxyphenyl)-2-methyl-1 H-pyrrote-3-carboxam»de;
5-{(2)-[5-<benzyloxy)-2-oxo-1,2-dihydro-3H-indol-3-ylidenelmethyl}-N-[2- (diethylamino)elhyl]-4-{2-hydroxyphenyI)-2-methyl-1H-pyrrolβ-3-carboxamtde;
5-{(ZH5-amino-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2- (diethylamino)ethyl]-4-(2-methoxyphenyl)-2-niethyl-1H-pyrrote-3-carboxamide; and 5-[(Z)-(5-amino-2-oxo-1 ,2-dihydro-3H-indol-3-y)ideπe)methvf]-N-f2-
(diethylamino)ethyl]-4-(2-hydrσxypheny l)-2-methyl- 1 H-pyrrole-3-carboxamide .
9 A method for treating a disease caused by, or associated with, dysregulated protein kinase activity, particularly IGF-IR kinase activity, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof
10 A method to treat a disease caused by or associated with dysregulated protein Kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies, diabetic retinopathies, neonatal retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neointimal formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia induced tissue damage, obesity, and metabolic disorders in which elevated IGF levels or 1GF-1R activity are implicated, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof
1 1 A method to treat a disease selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthomas, thyroid follicular cancer, and Kaposi's sarcoma, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof
12. A method to a disease selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, ctear cell renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and medulloblastoma, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof.
13 A method to treat ceil proliferative disorders selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, post-surgical stenosis and restenosis, comprising administering to a mammal in need thereof an effective amount a compound of formula (I), according to claim 1 , or pharmaceutically acceptable salt thereof
14. A method of promoting tumor angiogenesis or metastasis inhibition, comprising administering to a mammal in need thereof an effective amount a compound of formula (I}, according to claim 1, or pharmaceutically acceptable salt thereof
15 A method for synthesizing a compound for formula (I), according to claim t, prepared through a process consisting of standard synthetic transformations.
16 A pharmaceutical composition comprising of one or more compounds of formula (I), according to claim 1, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipieπt, carrier or diluent
17 A pharmaceutical composition comprising a compound of formula (I), according to claim 1, or pharmaceutically acceptable salt thereof, in combination with one or more chemotherapeutic agents or radiotherapy selected from the group consisting of antiestrogens, antiandrogens, aromatase inhibitors, topolsomerase I inhibitors, topoisomerase Il inhibitors, agents that target microtubules, piatin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, kinase inhibitors, anti-angiogenic agents, inhibitors of klnesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, famesyl transferase inhibitors, and inhibitors of hypoxic response
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