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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P37/00—Drugs for immunological or allergic disorders
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D233/22—Radicals substituted by oxygen atoms
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  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/30—Oxygen or sulfur atoms
  • C07D233/32—One oxygen atom
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • 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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  • 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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  • 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
  • C07D403/10—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 aromatic rings
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  • 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
  • C07D403/12—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 chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems

Definitions

• This invention is related to at least one compound selected from a compound of formula I
• p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level.
• MDM2 and p53 form a feedback control loop.
• MDM2 can bind p53 and inhibit its ability to transactivate p53- regulated genes.
• MDM2 mediates the ubiquitin-dependent degradation of p53.
• p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein.
• This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
• MDM2 is also a co factor for E2F, which plays a central role in cell cycle regulation.
• MDM2 The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
• EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicit . Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated.
• WO 00/78725 to Choueiry et al. report a method for making substituted amidine compounds, and indicate that imidazoline- type compounds maybe useful in the treatment of diabetes or related diseases involving impaired glucose disposal.
• the present invention provides at least one compound selected from a compound of formula I
• Xi and X 2 are halogen
• X 3 is lower alkoxy
• R is selected from the group consisting of
• Ri is selected from the group consisting of
• R 2 is selected from hydrogen, methyl and lower alkoxy
• R 3 is selected from the group consisting of heteroaryl, heterocycle, lower alkyl substituted with R 7 , aryl, lower alkoxy, and lower alkyl; i is selected from the group consisting of
• R 5 is selected from the group consisting of oxo, heteroaryl, aryl substituted by a substituent selected from lower alkoxy and fluoro,
• ⁇ is selected from the group consisting of lower alkyl substituted by -N-lower alkyl, lower alkyl substituted by heterocycle, lower alkyl substituted by heterocycle substituted by one or two substituents selected from lower alkyl, lower alkyl substituted by hydroxyl lower alkyl substituted by lower alkoxy, and oxo;
• R is selected from the group consisting of cyano, hydroxy, lower alkoxy, heteroaryl, heterocycle, heterocycle substituted by oxo,
• N-lower alkyl and aryl substituted by a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
• R 8 is selected from the group consisting of
• R 9 is selected from the group consisting of
• Rio is selected from a heterocycle, and heterocycle substituted by one or more groups selected from the group consisting of C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
• R ⁇ is selected from lower alkyl, and lower alkyl substituted by a substituent selected from the group consisting of alkoxy, heteroaryl substituted by lower alkyl, cyano, and trifluoromethyl;
• R 12 is selected from the group consisting of lower alkoxy, NH 2 ,
• R 13 is selected from the group consisting of heteroaryl, heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen, heterocycle,
• heterocycle substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen, C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, oxo, and lower alkyl substituted with -OC(O)CH 3 ;
• heterocycle lected from the group consisting of
• heterocycle substituted by one or two substituents selected from the group consisting of hydroxy, alkoxy, trifluoromethyl, C(O)-lower alkyl, C(O)-NH 2) C(O)-N-lower alkyl, lower alkyl substituted by hydroxy and oxo;
• R 17 is selected from the group consisting of
• Ri 8 is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl, heterocycle and hydroxyl;
• the present invention provides at least one compound selected from a compound of formula I
• X 3 is lower alkoxy
• R is selected from the group consisting of
• Ri is selected from the group consisting of
• R 2 is selected from hydrogen and methyl
• R 3 is selected from the group consisting of heteroaryl, heterocycle, and
• CH 2 -R 7 is selected from the group consisting of
• R 5 is selected from the group consisting of oxo, heteroaryl, aryl substituted by a substituent selected from lower alkoxy and fluoro,
• SO -R H and lower alkyl substituted by a substituent selected from R i5 and C(O)-R ⁇ 6 ; is selected from the group consisting of lower alkyl substituted by -N-lower alkyl, lower alkyl substituted by heterocycle, lower alkyl substituted by heterocycle substituted by one or two substituents selected from lower alkyl, lower alkyl substituted by hydroxyl lower alkyl substituted by lower alkoxy, and oxo;
• R 7 is selected from the group consisting of cyano, hydroxy, lower alkoxy, heteroaryl, heterocycle, , heterecycle substituted by oxo,
• N-lower alkyl and aryl substituted by a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
• R 8 is selected from the group consisting of
• R 9 is selected from the group consisting of
• Rio is selected from a heterocycle, and heterocycle substituted by one or more groups selected from the group consisting of C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
• Rn is selected from lower alkyl, and lower alkyl substituted by a substituent selected from the group consisting of alkoxy, heteroaryl substituted by lower alkyl, cyano, and trifluoromethyl;
• R 12 is selected from the group consisting of lower alkoxy, NH 2 ,
• R 13 is selected from the group consisting of heteroaryl, heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen, heterocycle,
• heterocycle substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen, C(O)-lower alkyl, C(O)-NH 2 ,
• R 15 is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl,
• R ⁇ 6 is selected from the group consisting of lower alkoxy
• N-lower alkyl substituted by R ⁇ 8 heterocycle and heterocycle substituted by one or two substituents selected from the group consisting of hydroxy, alkoxy, trifluoromethyl, C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, lower alkyl substituted by hydroxy and oxo;
• R17 is selected from the group consisting of
• Ris is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl, heterocycle and hydroxyl;
• the two hydrogen of the imadazoline ring are in a cis configuration to each other.
• the compound may be in a racemic form and maybe optically active.
• the compound maybe an isomer.
• the present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction.
• compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide with a potency that is approximately 100 fold greater than a p53-derived peptide.
• these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in GI and G2 phase, resulting in potent antiproliferative activity against wild- type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.
• the present invention provides at least one compound selected from a compound selected from a compound of formula I
• Xi and X 2 are halogen
• X 3 is lower alkoxy
• R is selected from the group consisting of
• Ri is selected from the group consisting of N-lower alkyl, unsubstituted heterocycle and heterocycle substituted by one or more substituents selected from the group consisting of NH 2 , NH-C(O)-lower alkyl, C(O)-lower alkyl, C(O)-lower alkoxy, oxo, heterocycle, and lower alkyl substituted by hydroxy;
• R 2 is selected from hydrogen, methyl and lower alkoxy
• R 3 is selected from the group consisting of heteroaryl, heterocycle, lower alkyl substituted with R 7 , aryl, lower alkoxy, and lower alkyl;
• R4 is selected from the group consisting of
• R 5 is selected from the group consisting of oxo, heteroaryl, aryl substituted by a substituent selected from lower alkoxy and fluoro, C(S) -N-lower alkyl,
• Rg is selected from the group consisting of lower alkyl substituted by -N-lower alkyl, lower alkyl substituted by heterocycle, lower alkyl substituted by heterocycle substituted by one or two substituents selected from lower alkyl, lower alkyl substituted by hydroxyl lower alkyl substituted by lower alkoxy, and oxo;
• R 7 is selected from the group consisting of cyano, hydroxy, lower alkoxy, heteroaryl, heterocycle, heterecycle substituted by oxo,
• N-lower alkyl and aryl substituted by a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
• R 8 is selected from the group consisting of N-lower alkyl, heterocycle, heterocycle substituted by a substituent selected from the group consisting of oxo,
• R 9 is selected from the group consisting of
• Rio is selected from a heterocycle, and heterocycle substituted by one or more groups selected from the group consisting of C(O)-Iower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
• R ⁇ is selected from lower alkyl, and lower alkyl substituted by a substituent selected from the group consisting of alkoxy, heteroaryl substituted by lower alkyl, cyano, and trifluoromethyl;
• R12 is selected from the group consisting of lower alkoxy, NH 2 ,
• R 13 is selected from the group consisting of heteroaryl, heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen, heterocycle, heterocycle substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen, C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, oxo, and lower alkyl substituted with -OC(O)CH 3 ;
• R 14 is selected from the group consisting of trifluoromethyl, lower alkyl, aryl substituted by lower alkyl,
• R 15 is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl, N-lower alkyl, SO 2 -lower alkyl, C(O)-lower alkyl, SO 2 -NH 2 ,
• heterocycle lected from the group consisting of
• heterocycle substituted by one or two substituents selected from the group consisting of hydroxy, alkoxy, trifluoromethyl, C(O)-lower alkyl,
• Ri8 is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl, heterocycle and hydroxyl;
• the present invention provides at least one compound selected from a compound of formula I
• Xi and X 2 are halogen
• X 3 is lower alkoxy
• R is selected from the group consisting of
• Ri is selected from the group consisting of N-lower alkyl, unsubstituted heterocycle and heterocycle substituted by one or more substituents selected from the group consisting of NH 2 , NH-C(O)-lower alkyl, C(O)-lower alkyl, C(O)-lower alkoxy, oxo, heterocycle, and lower alkyl substituted by hydroxy;
• R 2 is selected from hydrogen and methyl
• R 3 is selected from the group consisting of heteroaryl, heterocycle, and
• R 4 is selected from the group consisting of
• R 5 is selected from the group consisting of oxo, heteroaryl, aryl substituted by a substituent selected from lower alkoxy and fluoro,
• Rs is selected from the group consisting of lower alkyl substituted by -N-lower alkyl, lower alkyl substituted by heterocycle, lower alkyl substituted by heterocycle substituted by one or two substituents selected from lower alkyl, lower alkyl substituted by hydroxyl lower alkyl substituted by lower alkoxy, and oxo;
• R is selected from the group consisting of cyano, hydroxy, lower alkoxy, heteroaryl, heterocycle, heterecycle substituted by oxo,
• R 8 is selected from the group consisting of
• R 9 is selected from the group consisting of
• Rio is selected from a heterocycle, and heterocycle substituted by one or more groups selected from the group consisting of C(O)-lower alkyl, C(O)-NH 2 , C(O)-N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
• R1 1 is selected from lower alkyl, and lower alkyl substituted by a substituent selected from the group consisting of alkoxy, heteroaryl substituted by lower alkyl, cyano, and trifluoromethyl;
• R 12 is selected from the group consisting of lower alkoxy, NH 2 ,
• R 13 is selected from the group consisting of heteroaryl, heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen, heterocycle, heterocycle substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen, C(O) -lower alkyl, C(O)-NH 2 ,
• R1 4 is selected from the group consisting of trifluoromethyl, lower alkyl, aryl substituted by lower alkyl,
• R 15 is selected from the group consisting of lower alkoxy, cyano, trifluoromethyl, N-lower alkyl, SO 2 -lower alkyl, C(O)-lower alkyl, SO 2 -NH 2 , SO 2 -N-lower alkyl,
• heterocycle elected from the group consisting of
• heterocycle substituted by one or two substituents selected from the group consisting of hydroxy, alkoxy, trifluoromethyl, C(O)-lower alkyl,
• lower alkyl substituted by hydroxy substituted by hydroxy
• the two hydrogen of the imadazoline ring are in a cis configuration to each other.
• the compound may be in a racemic form and may be optically active.
• the compound may be an isomer.
• Xi and X 2 are both chloro; X 3 is ethoxy or isopropoxy.
• the trifluoromethyl group is para to the imidazoline ring.
• the trifluoromethyl group is meta to the imidazoline ring.
• the R group is preferred to be C(O)-phenyl-CH 2 -R 1 , C(O)-NR 2 R 3 , C(O)- piperidine substituted by R 4 , and C(O)-piperazine substituted by R 5 , SO 2 -R 6 .
• Xi and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is para to the imidazoline ring, and R is C(O)- piperidine substituted by R 4 .
• Xi and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is para to the imidazoline ring, and R is C(O)- piperazine substituted by R 5 .
• Xi and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is meta to the imidazoline ring, and R is C(O)- iperidine substituted by R 4 .
• Xi and X 2 are chloro, X 3 is ethoxy or sopropoxy, the trifluoromethyl group is meta to the imidazoline ring, and R is C(O)- ?iperazine substituted by R 5 .
• R 5 is lower alkyl substituted by R 15 .
• piperazine is substituted by oxo and lower alkyl substituted by R ⁇ 5 .
• R 15 is selected from the group consisting of - SO 2 -methyl, hydroxy and lower alkoxy.
• Alkoxy denotes -O-alkyl
• Alkyl denotes a straight-chained or branched saturated aliphatic hydrocarbon.
• “Lower alkyl” groups denote C1-C6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like.
• lower alkyl is preferably C1-C4 alkyl, and more preferably C1-C3 alkyl.
• Aryl means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system.
• Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
• Cycloalkyl means a non-aromatic, partially or completely saturated monovalent cyclic hydrocarbon radical containing 3 to 8 atoms.
• Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Effective amount means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
• Halogen means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.
• Hetero atom means an atom selected from N, O and S.
• Heteroaryl means an aromatic heterocyclic ring system containing up to two rings.
• Preferred heteroaryl groups include, but are not limited to, thienyl, f ⁇ ryl, indolyl, pyrrolyl, pyridinyl, pyridine, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
• Heterocycle or “heterocyclyl” means a saturated or partially unsaturated, non- aromatic cyclic radical of 3 to 8 ring atoms in which from one to 3 ring atoms are hetero atoms selected from nitrogen, oxygen, S(O)n (where n is an integer from 0 to 2), or a combination thereof, the remaining ring atoms being C.
• heterocycles are piperidine, piperazine, pyrrolidine, morpholine, indoline, tetrahydropyranyl, thiomorpholino, pentamethylene sulfide, and pentamethylene sulfone.
• IC 50 refers to the concentration ofa particular compound required to inhibit 50% ofa specific measured activity. IC 50 can be measured, inter alia, as is described subsequently.
• Lower alkyl alone or in conjunction with another term, e.g. lower alkyl- heterocycle, denotes a straight-chain or branched saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms.
• Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like.
• Lower alkoxy refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, propyloxy or propoxy, butyloxy and the like.
• “Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid.
• esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
• “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
• Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
• Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
• Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
• “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc. means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
• substituted as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
• “Therapeutically effective amount” means an amount of at least one designated compound, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
• Compounds of the present invention as exemplified advantageously show IC50s from about 70 ⁇ M to about 100 ⁇ M.
• the compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
• a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
• the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it maybe given as continuous infusion.
• the meso- 1,2-diamines of formula 3 are known compounds and prepared according to the literature procedures (see Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40).
• the compound of formula 7 can be prepared from compound 4 by the reaction with the benzoyl chloride 5 in the presence of a base such triethylamine, then with an amine in a solvent such as dimethylformamide.
• the compound of formula 8 can be prepared from compound 4 by the reaction with the sulfonyl chloride 6 in the presence of a base such triethylamine, then with an amine in a solvent such as dimethylformamide.
• the compound of formula 4 can be converted to the compound of formula 9 using phosgene in the presence of a base such as triethylamine (scheme 2).
• a base such as triethylamine
• the compounds 10, 11, or 12 can then be obtained by the reaction of 9 with a suitable amine group (a known compounds or a compound prepared by known methods).
• R and R 5 groups of in the compounds 11 and 12 can be functionalized further as illustrated in scheme 3.
• the compound of formula 9 can react with an appropriately protected piperazine to afford a compound of formula 13 after deprotection.
• the compound of formula 9 can react with an appropriately protected piperidine to afford a compound of formula 15 after deprotection.
• a compound of formula 17 can be prepared from compound 9 by the reaction with 4-hydroxyethylpiperidine and triethylamine, followed by the conversion of the hydroxyl group to a suitable leaving group (LG) such as toluenemethylsulfonate.
• LG leaving group
• Compound 18 can be prepared from compound 17 by displacing the leaving group with an amine.
• a compound of formula 21 (W can be any suitable group as defined in R5) can be prepared by alkylation of an appropriately protected compound of formula 19 with WX (X could be any suitable leaving group such as Cl, Br, I) using conventional methods (scheme IV).
• the amide anion is generated by a base such as sodium hydride. The reaction typically is carried out in dimethylformamide.
• a compound of formula 24 (W can be any suitable group as defined in R5) can be prepared by reacting of an appropriately protected compound of formula 19 with WX (X could be any suitable leaving group such as Cl, Br, I), epoxide, or alkene using conventional methods (scheme V).
• the compounds synthesized in these examples are racemic.
• the enantiomers of the compounds of interest can be separated using chiral column chromatography (e.g. ChiralPak ® AD, ChiralPak ® OD, etc).
• ChiralPak ® AD ChiralPak ® AD
• ChiralPak ® OD ChiralPak ® OD
• One enanatiomer is shown to be more potent in our in vitro assay than the other.
• Example 2 In an analogous manner as described in example 1, there were obtained: 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-trifluoromethyl-phenyl)-4,5- dihydro- lH-imidazole
• reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water.
• the vial was agitated and centrifuged.
• the organic layer was transferred to a 4 mL vial and concentrated in vacuo to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl- phenyl)-4,5-dihydro-imidazol-l-yl]-[4-(propane-2-sulfonyl)-piperazin-l-yl]- methanone.
• LR-MS (M+H) + 697.4.
• RECT1F1ED SHEET (RULE 91) ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-l-yl]-[4-(morpholine-4- sulfonyl)-piperazin-l-yl]-methanone (9.0 mg).
• LR-MS 740.2 [(M+H) + ].
• 2-Bromopropionitrile (10 uL, 0.120 mmol) was added to a mixture of [4,5-bis-(4- chloro -phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol- 1 -yl] - [piperazin-l-yl]-methanone hydrochloride and diisopropylethylamine (42 uL, 0.240 mmol) in dimethylformamide (1.0 mL). The reaction was stirred at room temperature overnight.
• Methyl vinyl sulfone (11 uL, 0.125 mmol) was added to a mixture of [4,5-bis-(4- chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol- 1 -yl] - [piperazin-l-yl]-methanone (40 mg, 0.064 mmol, example 8A), and diisopropylethylamine (35 uL, 0.205 mmol) in anhydrous dimethylformamide (1.0 mL). The reaction was stirred overnight.
• Triethylamine (0.170, 1.2 mmol) and 4-(hydroxymethyl)piperidine (0.50 g, 4.4 mmol) were added. After 1 h, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate.
• Piperazine-2-one (21 mg, 0.21 mmol) was added to a solution £4,5-bis-(4-chloro- phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-l-yl]-[4- bromomethyl-piperidin-1-yl] -methanone (48 mg, 0.07 mmol) in anhydrous dimethylformamide (2.0 mL). The mixture was stirred overnight at 70 °C. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride.
• Morpholine (19 uL, 0.22 mmol) was added to a solution of [4,5-bis-(4-chloro- phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-l-yl]- [ vinyl] sulfone (40 mg, 0.07 mmol) in benzene (2.0 mL). The mixture was stirred overnight at 50 °C.
• Piperidine-l,4-dicarboxylic acid 4-amide l-( ⁇ l-[4,5-bis-(4-chloro-phenyl)-2-(2- ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazoIe-l-carbonyl]-piperidin-4-yl ⁇ - amide) was prepared in an analogous manner as described in example 11.
• Example 243 In Vitro Assay The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2- interacting region of p53 (Lane et al.). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu) -labeled anti-GST antibody and streptavidin- conjugated Allophycocyanin (APC).
• FRET fluorescence resonance energy transfer
• Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well.
• BSA bovine serum albumin
• DTT dithiothreitol
• TBS Tris-borate saline
• IC 5 os showing biological activity that applies to compounds of the subject matter of this invention ranges from about 0.020 uM to about 5 uM. Specific data for some examples are as follows:

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