WO2008042867A2 - Modulateurs de kinases multiples - Google Patents

Modulateurs de kinases multiples Download PDF

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WO2008042867A2
WO2008042867A2 PCT/US2007/080113 US2007080113W WO2008042867A2 WO 2008042867 A2 WO2008042867 A2 WO 2008042867A2 US 2007080113 W US2007080113 W US 2007080113W WO 2008042867 A2 WO2008042867 A2 WO 2008042867A2
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signaling
hydrogen
induces cell
induces
optionally substituted
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WO2008042867A3 (fr
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Dale E. Johnson
Jagarlapudi A. R. P. Sarma
Duvvuri Subrahmanyam
Sucha Sudarsanam
Francine Grant
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Emiliem Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • 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

Definitions

  • the invention relates to compounds and compound structures representing modulators of multiple kinases. These compounds exhibit kinase activity modulation patterns over a multiplicity of kinases contributing to various medical conditions.
  • Phosphorylation and dephosphorylation are processes by which phosphate groups are added or removed from a target molecule, typically a protein.
  • the process of reversible phosphorylation is a key feature of cellular regulation, including signal transduction, gene expression, cell cycle regulation, cytoskeletal regulation and apoptosis. See, e.g., Roberts (2003) "Protein phosphorylation” The Engineer 17:12-13; and Hunter (2000) “Signaling-2000 and beyond" Cell 100:113-127.
  • kinases add phosphate groups and phosphatases remove phosphate groups from substrates.
  • the substrates are proteins whose enzymatic activity is modulated thereby.
  • Signal transduction is one example of a process involving protein phosphorylation that is critical for cellular regulation. After an extracellular stimulatory factor (such as a ligand) binds to its recognized cell surface receptor, signal transduction is initiated, often mediated by a specific set of cellular protein kinases. These kinases subsequently phosphorylate the target molecule, resulting in an altered activity and a continued cellular response to the signal. See, e.g., Nishizuka (1986) "Studies and perspectives of protein kinase C" Science 233:305-312.
  • kinases act in signaling for a large number of biological functions. For example, in the context of cancer, kinases are largely responsible for signaling whether cells should continue to grow, remain dormant, or proceed to cell death. To stop cells from growing without control, thereby leading to tumor progression, the signaling activities of certain kinases can be inhibited.
  • the present invention provides compounds which are designed to modulate kinase targets in a selected pattern, which pattern of modulation will act synergistically in effecting modulation of signal transduction, either at a set time point, or over a temporal window. It is expected that the compounds can be applied to address various medical areas, including the oncology area, as well as many others caused by an inappropriate pattern of kinase signals. It is expected that treatments will be matched appropriately, e.g., according to tumor type, location, stage of disease, molecular definition, and others. [0011] The present invention provides structures, compounds and methods for modulating a pattern of kinase signaling useful in therapeutic applications.
  • the pattern incorporates effects on multiple kinases, in contrast to drugs designed to modulate a single kinase target.
  • the pattern will affect a plurality of kinases, e.g., a defined pattern of kinase effects.
  • An attractive pattern might be selected to selectively modulate certain kinase pathways while exhibiting minimal effect on others, and may target multiple points in a signal pathway.
  • Another attractive pattern may target modulating kinases in alternative or parallel signaling pathways, and the signal is modulated by affecting alternative signals. In another case, both strategies may be applied, depending upon the clinical context.
  • the invention further identifies chemical scaffolds and compounds capable of achieving the desired pattern of selective modulation of kinase pathways, e.g., by acting on specified kinases in the specified direction.
  • the present invention also provides methods for analyzing data and identifying important patterns of kinase inhibition useful in therapeutic applications. In some cases, the various kinases will function in the same pathways and inhibition may be at multiple points in a signal process. In other cases, the various kinases will function in alternative or parallel signaling pathways, and the signal is modulated by affecting alternative signals. And in other cases, both strategies may be applied, depending upon the clinical context.
  • the invention further identifies chemical scaffolds and compounds capable of achieving desired patterns of inhibition of kinase pathways, e.g., by acting on specified kinases.
  • the invention provides a method comprising identifying a therapeutically valuable profile inhibition of a plurality of kinases, the profile capable of being effected by a group of compounds sharing a chemical scaffold.
  • the method provides effects on one or more pathways important in development or maintenance of an oncogenic state of cells.
  • the compounds number at least 5.
  • the pathways number at least 2.
  • the pathways include cell division signal, metastasis, angiogenesis, and apoptosis.
  • Direct means of modulation may make use of antibodies which interact specifically with defined kinases, or nucleic acid sequence based methods may be used, e.g., antisense or RNAi means to modulate gene expression.
  • various combinations of structural segments are screened computationally for modulation of a plurality of kinases, preferably in patterns as described.
  • Specific attractive modulation patterns have been identified, and means to achieve such are provided.
  • the means include antibody based methods or transcription regulation methods. Both make use of sequences specific for the identified kinases, e.g., or of genetic, developmental, or resistance variants thereof.
  • Other means to achieve desired patterns of kinase modulation are effected by various small molecule scaffold structures, whether combinations or single compounds.
  • Those patterns of modulation of kinases may be effected by combinations with antibody or nucleic acid anti-sense reagents, e.g., based upon sequences of the described kinases.
  • the invention further provides structures and methods for modulating relevant patterns of kinase signaling useful in therapeutic applications.
  • the patterns incorporate effects on multiple kinases, in contrast to drugs designed to inhibit a single kinase target.
  • the pattern will affect a plurality of kinases, e.g., a defined or desired pattern of kinase effects.
  • An attractive pattern may target modulating kinases in alternative or parallel signaling pathways, and the signal is modulated by affecting alternative signals.
  • both strategies may be applied, depending upon the clinical context.
  • the invention further identifies chemical scaffolds and compounds capable of achieving the desired pattern of selective modulation of kinase pathways, e.g., by acting on specified kinases in the specified direction. In some cases, the pattern will include inhibition of various kinases with little effect on others.
  • the compound binds to the designated kinases in a pattern as described below, and/or modulates a biological activity modulated by the designated kinases in a pattern as described below.
  • the compounds further provide methods of modulating the biochemical activity of the designated kinases described in Table 1, the method comprising exposing those kinases to a compound as described herein at an effective concentration, e.g., less than about 1 mM, 100 nM, 10 nM, or 1 nM.
  • the pattern of selectivity exhibits at least about 0.5 log unit of specificity for said designated kinase effect relative to certain others.
  • the pathways include cell division signal, metastasis, angiogenesis, and apoptosis.
  • One embodiment provides a compound of Formula (I) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • X is O or NH; Z is CH or N;
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 1 substituents;
  • B is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 7 substituents;
  • R 2 and R 8 are independently selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or C 1-6 alkyl;
  • R 1 and R 7 are independently selected from hydrogen, halogen, OR 9 , Cl-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CON(R 9 ) 2 , NHR 9 , N(R ⁇ 2 , COR 9 , C0-4alkylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, CCMalkylheterocyclyl, CN, amino, NHCOR 9 , hydroxy, Cl-6alkoxy, OC(O)R 9 , -OC0-4alkylaryl, OC0-4alkylhetero
  • R 3 and R 4 are independently selected from hydrogen, halogen, CF 3 , CN, hydroxy, NO 2 , amino, NHAryl, NHR 9 , COOH, OR 9 , COOR 9 , CONHR 9 , or CON(R 9 ) 2 ; R 3 and R 4 may together form a 5-membered or 6- membered aryl or heteroaryl ring; R 5 and R 6 are independently selected from hydrogen, Cl-6 alkyl and optionally may be joined to form a 3-10 membered cycloalkyl;
  • R 9 is selected from hydrogen, Cl-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • One embodiment provides a compound selected from:
  • Another embodiment provides a compound of Formula (II) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • Y is O or NH
  • Z is CH or N
  • A is an optionally substituted heteroaryl ring having between 6 and 12 members and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 1 substituents;
  • R 7 is selected from hydrogen or Cl-6 alkyl
  • R 5 is selected from hydrogen, halogen, hydroxy, OR 8 , CN, amino, NHR 8 or Cl-6 alkyl;
  • R 1 and R 4 are independently selected from hydrogen, halogen, OR 8 , Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 8 , CON(R 8 ) 2 , NHR 8 , N(R 8 ) 2> COR 8 , C0-4alkylC3-10cycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, C0-4alkylheterocyclyl, CN, amino, NHCOR 8 , hydroxy, Cl-6alkoxy, OC(O)R 8 , -OC0-4alkylaryl, OC0-4alkylheteroaryl, -OC0
  • R 8 is selected from hydrogen, Cl -6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • One embodiment provides a compound selected from: l-(4-(oxazolo[5,4-b]pyridin-7-yloxy)phenyl)-3-(5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)urea; l-(4-(oxazolo[5,4-b]pyridin-7-yloxy)phenyl)-3-(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)urea; l-(4-(quinazolin-4-yloxy)phenyl)-3-(5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)urea; N-methyl-4-(4-(3-(5-
  • Yet another embodiment provides a compound of Formula (III) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • X is O or NH; Z is CH or N;
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 1 substituents;
  • B is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 7 substituents;
  • R 2 and R 8 are independently selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or C 1-6 alkyl;
  • R 1 and R 7 are independently selected from hydrogen, halogen, OR 9 , C 1-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CON(R 9 ) 2 , NHR 9 , N(R 9 ) 2 , COR 9 , C0-4alkylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, CO ⁇ alkylheterocyclyl, CN, amino, NHCOR 9 , hydroxy, C 1 -6alkoxy, OC(O)R 9 , -OC0-4alkylaryl,
  • OC0-4alkylheteroaryl -OC0-4alkylC3-10cycloalkyl, NHCOOR 9 , OC0-4alkylC3-10heterocycloalkyl, OC0-4alkylNR 9 , NR 9 COOR 9 , OCONR 9 , or NR 9 COR 9 ;
  • R 3 and R 4 are independently selected from hydrogen, halogen, CF 3 , CN, hydroxy, NO 2 , amino, NHAryl, NHR 9 ,
  • R 3 and R 4 may together form a 5-membered or 6- membered aryl or heteroaryl ring;
  • R 5 and R 6 are independently selected from hydrogen or C 1-6 alkyl
  • R 9 is selected from hydrogen, Cl -6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • Still another embodiment provides a compound selected from: N-(4-(6-chloropyridin-3-yl)phenyl-N'-(4-(pyridin-4-yloxy)phenyl)-sulfamide; N-(4-(6-chloropyridin-3-yl)phenyl-N'-(4-(oxazolo[5,4-b]pyridin-7-yloxy)phenyl)-sulfamide; or N-(4-(6-chloropyridin-3-yl)phenyl-N'-(4-(quinazolin-4-yloxy)phenyl)-sulfamide.
  • Yet another embodiment provides a compound of Formula (IV) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • X is O or NH
  • Y is O, NH, -OCH 2 - or -CH 2 O-
  • Z is CH or N
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R' substituents;
  • R 1 and R 4 are independently selected from hydrogen, halogen, OR 9 , Cl-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CONCR 9 ) ⁇ NHR 9 , N(R 9 ) 2 , COR 9 , C0-4a!kylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, C0-4alkylheterocyclyl, CN, amino, NHCOR 9 , hydroxy, Cl-6
  • R 2 and R 3 are independently selected from hydrogen, halogen, CF 3 , CN, hydroxy, NO 2 , amino, NHAryl, NHR 9 , COOH, OR 9 , COOR 9 , CONHR 9 , or CON(R 9 ) 2 ; R 2 and R 3 may together form a 5-membered or 6- membered aryl or heteroaryl ring; R 5 is selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or Cl-6 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, Cl-6 alkyl and optionally may be joined to form a 3-10 membered cycloalkyl;
  • R 8 is selected from hydrogen or Cl-6 alkyl
  • R 9 is selected from hydrogen, Cl-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • the compound binds to the designated kinases in a particular pattern; and/or modulates a biological activity modulated by the designated kinases in such a pattern.
  • Embodiments further provide methods of modulating the biochemical activity of the designated kinases, the method comprising exposing those kinases to a compound of Claim 1 at an effective concentration, e.g., less than about 1 mM, 100 nM, 10 nM, or 1 nM.
  • the pattern of selectivity exhibits at least about 0.5 log unit of specificity for said designated kinase effect relative to certain others.
  • the pathways include cell division signal, metastasis, angiogenesis, and apoptosis.
  • Figure 1-10 illustrate embodiments according to the invention for the design of modulators of panels of multiple kinases.
  • the present invention provides structures, compounds and methods for modulating a pattern of kinase signaling useful in therapeutic applications.
  • the pattern incorporates effects on multiple kinases, in contrast to drugs designed to modulate a single kinase target.
  • the pattern will affect a plurality of kinases, e.g., a defined pattern of kinase effects.
  • An attractive pattern might be selected to selectively modulate certain kinase pathways while exhibiting minimal effect on others, and may target multiple points in a signal pathway.
  • Another attractive pattern may target modulating kinases in alternative or parallel signaling pathways, and the signal is modulated by affecting alternative signals. In another case, both strategies may be applied, depending upon the clinical context.
  • the invention further identifies chemical scaffolds and compounds capable of achieving the desired pattern of selective modulation of kinase pathways, e.g., by acting on specified kinases in the specified direction.
  • FIG. 1-10 The compound design and screening approach of the present invention are summarized in Figures 1-10. These methods are based on the identification of a set of validated kinases. Crystal structures of known kinases are solved through X-ray crystallography, NMR based methods or other protein structure elucidation methods. The binding sites of the kinases are analyzed and scaffolds of potential modulators are generated. Lead compounds are designed based on the scaffolds and tested both in silico and through experimental methods to identify lead compounds for further development. Derivatives of the lead compounds are synthesized and tested for their kinase modulatory activity across selected kinase profiles. Details of the methods and compounds described herein are set forth below.
  • a foundation of the approach is a comprehensive understanding of the signaling network of individual kinases and their roles in physiologic and pathologic conditions. This provides the basis to identify targets for pharmaceutical intervention in various human diseases and conditions.
  • the invention teaches how to identify simultaneously sets of kinases (relevant multi-kinase profiles) and chemical starting points (scaffolds) to modulate multi-kinases.
  • the invention provides processes that lead to the synthesis of kinase modulators with predetermined multi-kinase profiles in a timely manner.
  • a pathway is a series of linked biochemical steps, with a beginning and an end; activity within a pathway takes the form of flux, or flow, of molecules, e.g., substrates.
  • the network of pathways forms the biochemical repertoire or potential phenotypes of a biological system.
  • a profile is a combination of kinases that together modulate one or more biological pathways whose coordinated inhibition leads to a desired physiological effect.
  • the profile involves at least two, three, four or more target kinases. This in effect amounts to combination therapies, for example, a "cocktail" of selective drugs.
  • our combination strategy can be combined with other therapy leading to multiple therapeutic modalities.
  • the difference will preferably be a one log difference in effect on binding specificity or biological activity across the kinases, for example in terms of molar concentrations.
  • the differences for a similar effect on a plurality of kinases will typically be small at an appropriate pharmacological concentration, e.g., less than about 1.3, 1, or 0.3 log units difference in molar concentrations.
  • the differences will typically be large at an appropriate pharmacological concentration, e.g., more than about 1, 1.3, 2, 2.3, 3 or more log units difference in molar concentrations.
  • a profile which inhibits kinases A and B, but not C will preferably have similar amounts of inhibition of the A and B kinases at the appropriate pharmacological concentration, while much less (e.g., about 2 logs) less effect on kinase C.
  • the assay will have biochemical components, e.g., kinases at concentrations analogous to physiological conditions.
  • the concentrations of compound necessary to effect the desired modulatory effects on kinases may be at least about 10, 30, 100, 300, or more on different kinases.
  • kinases A and B may be effected by similar concentrations of compound, while kinase C may be unaffected until much higher concentrations of compound are reached. Conversely, the sensitivity of kinase C may low, while much lower amounts of compound may modulate kinases A and B. Additional effects of kinases D, E, and so on may also be combined into these compounds using various SAR or pharmacophore models directed to the additional kinases. Alternatively, appropriate selective entities modulating kinases D and E (but not A, B, and C) may be used in combination to extend the selectivity of the combined treatment.
  • kinase signal pathways are relevant in cell-cell interactions, in regulation of organ metabolism and physiology, and thereby aspects of organ physiology and systems biology. These may be either in the context of normal growth or development, or in abnormal contexts. In particular, many diseases or disorders may be caused by or cause aberrant interactions within an organism.
  • Kinases have been implicated in various cancer conditions, and a number of drugs have been developed which target specific kinases. See Wanebo, et al. (2006) “Targeting growth factors and angiogenesis; using small molecules in malignancy” Cancer Metastasis Rev. 25:279-92, PMID: 16770540; Adjei and Hidalgo (2005) "Intracellular signal transduction pathway proteins as targets for cancer therapy” J. Clin.
  • Protein kinases regulate multiple cellular processes that contribute to tumor development and progression, including cell growth, differentiation, migration, and programmed cell death (apoptosis). Inappropriate activity of protein kinases has been implicated in a variety of human diseases such as cancer, diabetes, and autoimmunity. In cancer model systems, perturbation of tyrosine kinase signaling can result in malignant transformation. For tumors whose growth is driven by activated kinases caused by genetic alterations, targeted drugs can potentially modulate or reverse malignant progression.
  • tyrosine kinase modulators are safe and therapeutically active in selected populations of cancer patients.
  • Several of these drugs are now part of the standard treatment regimen for specific tumor types. Modulating the abnormal activity of kinases with small molecules has demonstrated significant clinical benefit in patients, as in the case of the Bcr/Abl tyrosine kinase modulator Gleevec, the first marketed small molecule (SM) protein kinase modulator approved for treatment of chronic myelogenous leukemia (CML).
  • SM small molecule
  • CML chronic myelogenous leukemia
  • Other drugs such as Tarceva, Nexavar and Sutent, have followed the success of Gleevec. Judging from the efficacy of these drugs and results from ongoing clinical studies, protein kinases have been firmly established as targets for oncology therapeutics. The era of the so-called targeted therapies for cancer is arriving, supplanting cytotoxic drugs.
  • Protein kinases are classified according to major groups and families, which are denominated TK, TKL, STE, CMGC, CAMK, and AGC. Kinases share a catalytic domain, but otherwise have diverse domain architecture. The common catalytic domain is where ATP binds and transfer of a phosphate group to a substrate takes place.
  • Kinase assays may be performed by many standard and other methodologies, and assay services are commercially available. See Giordano and Romano (eds. 2004) Cell Cycle Control and Dvsregulation Protocols: Cvclins. Cvclin-Dependent Kinases, and Other Factors (Methods in Molecular Biology) Humana Press, ISBN: 0896039498; Terrian (ed.
  • IQ technology utilizes an iron compound that acts as a dark quencher upon specific binding to the phosphoryl group of a fluorescent dye-labeled phosphorylated peptide.
  • the binding event results in a decrease in the observed fluorescence intensity of the dye- labeled peptide after it becomes phosphorylated by the kinase.
  • Systems biology analyses and techniques are described, e.g., in Klipp, et al. (2005) Systems Biology in Practice: Concepts. Implementation and Application Wiley, ISBN: 3527310789; Kitano (ed. 2001) Foundations of Systems Biology MIT Press, ISBN: 0262112663; Bower and Bolouri (eds.
  • the human genome encodes some 518 protein kinases that share a catalytic domain conserved in structure, but which notably differ in how their catalysis is regulated.
  • the ATP binding pocket is between the two lobes of the kinase fold. This ATP binding site, together with less conserved hydrophobic surrounding pockets, has been the focus of modulator design that has exploited differences in kinase structure and pliability in order to achieve selectivity.
  • Drugs are in clinical trials that target all stages of signal transduction. These range from the receptor tyrosine kinases that initiate intracellular signaling through second-messenger generators and kinases involved in signaling cascades to the kinases that regulate the cell cycle that governs cellular fate.
  • cancer is one indication for which kinases have been validated as targets for therapeutic intervention
  • many other medical conditions will similarly be sensitive to the fundamental signal pathways regulated by these same kinases.
  • other medical conditions will be susceptible to treatment by the compounds of the invention, including inflammation, developmental abnormalities, aging processes, and the like.
  • Particular target medical conditions include those in which modulation of a process such as angiogenesis, cell cycle progression, cell division, cell growth, cell migration, cell mobility, cell motility, cell proliferation, cell survival, oncogenesis, p53 degradation, general proliferation, tumorigenesis, apoptosis, or metastasis are likely processes contributing to the symptoms or condition.
  • PK related disorder As used herein, "PK related disorder,” "PK driven disorder,” and “abnormal PK activity” all refer to a condition characterized by inappropriate; i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of one of: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation, and/or growth.
  • Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation, and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
  • the term "therapeutically effective amount” as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor; (2) modulating (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) modulating to some extent (that is, slowing to some extent, preferably stopping) tumor growth; and/or (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
  • the above-referenced protein kinase related disorder is selected from the group consisting of a receptor protein kinase related disorder, a cellular kinase disorder, and a serine-threonine kinase related disorder.
  • the protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, and glioma in a further aspect of this invention.
  • the compounds of this invention may modulate the activity of protein phosphatases which are enzymes which remove phosphate groups from phosphorylated proteins.
  • the compounds disclosed herein may also represent a new generation of therapeutic compounds for diseases and disorders associated with abnormal phosphatase activity (such as, without limitation, cell proliferation disorders and inflammatory disorders).
  • the terms defined herein with respect to PKs would be understood by one skilled in the art to have the same or similar meaning with regard to phosphatases. IV. Medicinal Chemistry
  • references on assays and approaches include Moore and Kliewer (2000) Toxicology 153: 1-10;
  • Parameters on compounds screened by in silico screening include services and software available from
  • the cytochrome P450 system is a significant component of modulating toxicity of proposed therapeutic compounds. See, e.g., Park, et al. (2005) "The role of metabolic activation in drug-induced hepatotoxicity” Ann- Rev. Pharmacology and Toxicology 45:177-202. Ann. Revs. Pr. and Coon (2005) "Cytochrome P450: Nature's Most Versatile Biological Catalyst” Ann. Rev. Pharmacology and Toxicology 45: 1-25.
  • Various cytochrome P450 isoforms, in decreasing order of importance, is typically P450 isoforms 3A4 » 2D6 > 2C9, 2C19 » 1 A2, 2El.
  • Such effects are not limited to drug induced effects on pharmacology, but may similarly be induced by environmental effects, e.g., diet, specific food intake, and other physiological effects, e.g., status of the immune or nervous system, presence of infectious agents, general health status, etc.
  • Xenobiotic transporters are expressed in several tissues including the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. Functional characteristics of transporters provide important information allowing improvements in drug delivery or drug design through targeting or avoiding specific transporter proteins.
  • Optimizing drugs based on transporter interaction offers the possibility of delivering a drug to a target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable.
  • the expression system of transporters is an efficient tool for screening the activity of individual transport processes.
  • the changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs.
  • ABLl GeneID 25; see MIM 189980; described functions include ATP binding, DNA binding; nucleotide binding, protein C-terminus binding, protein-tyrosine kinase activity, and transferase activity; indicated function pathways dependent upon gene include DNA damage response (signal transduction resulting in induction of apoptosis), S-phase-specific transcription in mitotic cell cycle, intracellular signaling cascade, mismatch repair, protein amino acid phosphorylation, regulation of progression through cell cycle, and regulation of transcription (DNA-dependent).
  • AKTl GeneID 207 (NCBI); see MIM 164730; described functions include ATP binding, identical protein binding, nucleotide binding; protein kinase activity, receptor signaling protein serine/threonine kinase activity, sugar porter activity, and transferase activity; indicated function pathways dependent upon gene include G-protein coupled receptor protein signaling pathway, anti-apoptosis, apoptosis, carbohydrate metabolism, glucose metabolism, glycogen biosynthesis, insulin receptor signaling pathway, insulin-like growth factor receptor signaling pathway, nitric oxide biosynthesis, protein amino acid phosphorylation, protein amino acid phosphorylation, regulation of translation, response to heat, signal transduction, and transport.
  • AURKA GeneID 6790; see MIM 164920; described functions include ATP binding, nucleotide binding, protein binding, protein binding, protein kinase activity, protein serine/threonine kinase activity, and transferase activity, indicated functional pathways dependent upon gene include cell cycle, mitosis, phosphoinositide- mediated signaling, protein amino acid phosphorylation, protein amino acid phosphorylation, regulation of protein stability, spindle organization, and biogenesis.
  • BRAF GeneID 673; see MIM 164757; described functions include ATP binding, diacylglycerol binding, metal ion binding, nucleotide binding, protein serine/threonine kinase activity, receptor signaling protein activity, transferase activity, zinc ion binding; indicated functional pathways dependent upon gene include anti-apoptosis, intracellular signaling cascade, organ morphogenesis, protein amino acid phosphorylation.
  • CDC2 GeneED 983 (NCBI); see MIM 116940; described functions include ATP binding, cyclin- dependent protein kinase activity, nucleotide binding, protein binding, and transferase activity; indicated function pathways dependent upon gene include anti-apoptosis, cell cycle, cell division, mitosis, protein amino acid phosphorylation, regulation of progression through cell cycle, and traversing start control point of mitotic cell cycle.
  • EGFR GeneID 1956 (NCBI); see MIM 131550; described functions include ATP binding, MAP/ERK kinase kinase activity, actin filament binding, double-stranded DNA binding, epidermal growth factor receptor activity, epidermal growth factor receptor activity, identical protein binding, nitric-oxide synthase regulator activity, nucleotide binding, protein heterodimerization activity, transferase activity, and transmembrane receptor activity; indicated function pathways dependent upon gene include calcium-dependent phospholipase A2 activation, cell cycle, cell proliferation, cell surface receptor linked signal transduction, cell-cell adhesion, epidermal growth factor receptor signaling pathway, negative regulation of progression through cell cycle, ossification, phospholipase C activation, positive regulation of MAPK activity, positive regulation of cell migration, positive regulation of epithelial cell proliferation, positive regulation of nitric oxide biosynthesis, positive regulation of phosphorylation, protein amino acid phosphorylation, protein insertion into membrane
  • ERBB2 GeneID 2064 (NCBI); see MIM 164870 (also designated HER2); described functions include ATP binding, ErbB-3 class receptor binding, electron carrier activity, epidermal growth factor receptor activity, epidermal growth factor receptor activity, iron ion binding, non-membrane spanning protein tyrosine kinase activity, nucleotide binding, protein heterodimerization activity, protein heterodimerization activity, protein- tyrosine kinase activity, receptor activity, receptor signaling protein tyrosine kinase activity, and transferase activity; indicated function pathways dependent upon gene include cell proliferation, electron transport, heart development, mammary gland development, nervous system development, phosphoinositide-mediated signaling, positive regulation of MAPK activity, positive regulation of epithelial cell proliferation, protein amino acid phosphorylation, protein amino acid phosphorylation, regulation of angiogenesis, transmembrane receptor protein tyrosine kinase signaling pathway, and trans
  • FRAPl GeneID 2475 (NCBI); see MIM 601231; described functions include binding, kinase activity, phosphoprotein binding, phosphotransferase activity (alcohol group as acceptor), and transferase activity, indicated function pathways dependent upon gene include cell growth, phosphorylation, protein catabolism, regulation of progression through cell cycle, regulation of translation, response to nutrient, and signal transduction.
  • JAK3 GeneID 3718 (NCBl); see MIM 600173; described functions include ATP binding, Janus kinase activity, nucleotide binding, protein binding, protein-tyrosine kinase activity, protein-tyrosine kinase activity, and transferase activity, indicated function pathways dependent upon gene include intracellular signaling cascade, mesoderm development, protein amino acid phosphorylation, and protein amino acid phosphorylation.
  • KDR GeneID 3791 (NCBI); see MIM 191306; described functions include ATP binding, nucleotide binding, receptor activity, transferase activity, vascular endothelial growth factor receptor activity; indicated functional pathways dependent upon gene include angiogenesis, cell differentiation, protein amino acid phosphorylation, and transmembrane receptor protein tyrosine kinase signaling pathway.
  • KIT GeneID 3815 (NCBI); see MIM 164920; described functions include ATP binding, nucleotide binding, receptor activity, receptor signaling protein tyrosine kinase activity, transferase activity, and vascular endothelial growth factor receptor activity; indicated functional pathways dependent upon gene include protein amino acid dephosphorylation, protein amino acid phosphorylation, signal transduction, and transmembrane receptor protein tyrosine kinase signaling pathway.
  • LCK GeneID 3932 (NCBI); see MIM 153390; described functions include ATP binding, ATPase binding, CD4 receptor binding, CD8 receptor binding, SH2 domain binding, SH2 domain binding, glycoprotein binding, nucleotide binding, phosphoinositide 3-kinase binding, protein C-terminus binding, protein kinase binding, protein serine/threonine phosphatase activity, protein-tyrosine kinase activity, protein-tyrosine kinase activity, and transferase activity; indicated functional pathways dependent upon gene include Ras protein signal transduction, T cell differentiation, caspase activation, hemopoiesis, induction of apoptosis, intracellular signaling cascade, positive regulation of T cell activation, positive regulation of T cell receptor signaling pathway, protein amino acid phosphorylation, regulation of lymphocyte activation, regulation of progression through cell cycle, release of sequestered calcium ion into cytosol, response to drug, and zinc ion homeost
  • MAP2Kl GeneID 5604 (NCBI); see MIM 176872; described functions include ATP binding, MAP kinase kinase activity, nucleotide binding, protein binding, protein serine/threonine kinase activity, protein- tyrosine kinase activity, and transferase activity; indicated functional pathways dependent upon gene include cell motility, chemotaxis, protein amino acid phosphorylation, and signal transduction.
  • MAPKl GeneID 5594 (NCBI); see MIM 176948; described functions include ATP binding, MAP kinase activity, nucleotide binding, protein serine/threonine kinase activity, and transferase activity; indicated functional pathways dependent upon gene include cell cycle, chemotaxis, induction of apoptosis, protein amino acid phosphorylation, response to stress, signal transduction, and synaptic transmission.
  • PDGFRB GeneID 5159; see MIM 173410; described functions include ATP binding, nucleotide binding, platelet activating factor receptor activity, platelet-derived growth factor receptor activity, protein binding, receptor activity, and transferase activity; indicated functional pathways dependent upon gene include vascular endothelial growth factor receptor activity, protein amino acid phosphorylation, signal transduction, and transmembrane receptor protein tyrosine kinase signaling pathway.
  • PIK3CG GeneID 5294 (NCBI); see MIM 601232; described functions include inositol or phosphatidylinositol kinase activity, phosphatidylinositol 3-kinase activity, phosphatidylinositol-4,5-bisphosphate 3-kinase activity, and transferase activity; indicated functional pathways dependent upon gene include G-protein coupled receptor protein signaling pathway.
  • SRC GeneID 6714 (NCBI); see MIM 190090; described functions include ATP binding, SH2 domain binding, SH3/SH2 adaptor activity, nucleotide binding, protein binding, protein-tyrosine kinase activity, protein- tyrosine kinase activity, and transferase activity; indicated functional pathways dependent upon gene include protein amino acid phosphorylation, protein kinase cascade, and signal complex formation.
  • Non-human species counterparts will be useful in many contexts including testing in other species and evaluation of in vitro and in vivo animal models. Other activities and pathways related to a species counterpart may often be adapted to a human counterpart.
  • Binding pockets of all known kinase crystal structures are classified and interacting residues identified.
  • binding pockets are clustered according to shape similarities.
  • a two-way clustering of kinases and IC50 of compounds are performed. In addition, clustering of compounds by themselves is performed. This yields sets of profiles for which Quantitative Structure Activity Relationship (QSAR) and Quantitative Structure Property Relationship (QSPR) are modeled.
  • QSAR Quantitative Structure Activity Relationship
  • QSPR Quantitative Structure Property Relationship
  • the binding sites of the kinases are analyzed and scaffolds of potential modulators are generated.
  • Lead compounds are designed based on the scaffolds and tested both in silico and through experimental methods to identify lead compounds for further development. Derivatives of the lead compounds are synthesized and tested for their kinase inhibitory activity across selected kinase profiles. Details of the methods and compounds described herein are set forth below.
  • a "Structure Target Activity” is generated from: (i) all known kinase modulators ; (ii) known kinase crystal structures; (iii) novel chemical scaffolds generated from analysis of kinase modulators and crystal structures; and (iv) kinase biology, which provides as the basis for selectivity based on the foregoing information.
  • the process bypasses key steps in the conventional drug discovery. The approach moves the starting point of drug discovery to the lead-optimization stage and results in both time and cost savings.
  • drug-like properties e.g., the ADMETox, and simplicity of synthesis and susceptibility to patent protection.
  • Pharmacophore models have been applied, e.g., GOLD and GLIDE, for predicting the activities against various kinases, e.g., KDR or PDGFRB.
  • animal models will further confirm appropriate response in an organismal context.
  • Table 1 lists biological pathways relevant to diseases. These pathways include kinases as important mediators.
  • Kinase refers to official gene symbol (according to Human Genome Organization, HUGO).
  • NCBI refers to unique numeric identifier for the kinase as designated by NCBI.
  • Pathway refers to specific biological pathway as it is commonly understood.
  • Class refers to specific biological function mediated by the pathway. [00111] .
  • GSK3A, GSK3B (2931, 2932) » Activation of cAMP-Dependent PKA » Induces oncogenesis MAP2K1 , MAP2K2 (5604, 5605) » Activation of cAMP-Dependent PKA » Induces cell survival
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG
  • PRKCI PRKDl
  • PRKD3 PRKCQ
  • PRKCZ (5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 23683, 5588, 5590) » Activation of PKC through GPCR » Induces cell survival
  • EPHB4 (2050 » Akt Signaling » Induces cell cycle progression EPHB4 (2050 » Akt Signaling » Inhibits apoptosis EPHB5 (2051 » Akt Signaling » Induces cell cycle progression EPHB5 (2051 » Akt Signaling » Inhibits apoptosis EPOR (2057 » Akt Signaling » Induces cell cycle progression EPOR (2057 » Akt Signaling » Inhibits apoptosis ERBB2 (2064) » Akt Signaling » Induces cell cycle progression ERBB2 (2064) » Akt Signaling » Inhibits apoptosis ERBB4 (2066) » Akt Signaling » Induces cell cycle progression ERBB4 (2066) » Akt Signaling » Inhibits apoptosis ERBB4 (2066) » Akt Signaling » Induces cell cycle progression ERBB4 (2066) » Akt Signaling » Inhibits apoptosis apoptosis ERBB4 (2066) » Akt
  • Akt Signaling Inhibits apoptosis PDKl (5163) » Akt Signaling » Induces cell cycle progression
  • Akt Signaling Inhibits apoptosis PRKDC (5591) » Akt Signaling » Induces cell cycle progression
  • CDK5 (1020) » Dopamine-DARPP32 Feedback onto cAMP Pathway » Induces cell survival PRKACA, PRKACB, PRKACG, PRKARlA, PRKARlB, PRKAR2B, PRKAR2A (5566, 5567, 5568, 5573, 5575, 5577, 5576) » Dopamine-DARPP32 Feedback onto cAMP Pathway » Induces cell survival PRKCA, PRKCBl, PRKCD, PRKCE, PRKCH, PRKCG, PRKCI, PRKDl, PRKCQ (5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 5588) » Dopamine-DARPP32 Feedback onto cAMP Pathway » Induces cell survival
  • PAK6 (56924) » FAKl Signaling » Induces cell proliferation
  • PTK2 (5747) » FAKl Signaling » Metastasis RAFl (5894) » FAKl Signaling » Induces cell proliferation
  • BTK (695) » Fas Signaling » Induces cell proliferation
  • MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6 (5604, 5605, 5606, 6416, 5608) » FLT3 Signaling » Induces cell division
  • MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6 (5604, 5605, 5606, 6416, 5608) » JAK/STAT Pathway » Induces cell division
  • PAK3 (5063) » JNK Pathway » Induces tumorigenesis
  • PAK4 (10298) » JNK Pathway » Induces cell migration
  • CDK2 (1017) » p53 Signaling » Induces cell cycle progression
  • CDK4 ( 1019) » p53 Signaling » Induces cell cycle progression
  • MAP2K1; MAP2K2; MAP2K3; MAP2K4; MAP2K5; MAP2K6 (5604; 5605; 5606; 6416; 5607; 5608) » p70S6K Signaling » Induces cell survival MAPKl; MAPK3; MAPK4; MAPK6; MAPK7; MAPK8; MAPK9; MAPKlO; MAPK14; MAPKl 1; MAPK12; MAPK13 (5594; 5595; 5596; 5597; 5598; 5599; 5601; 5602; 1432; 5600; 6300; 5603) » p70S6K Signaling » Induces cell growth
  • PRKCD (5580) » p70S6K Signaling » Induces cell growth PRKCD (5580) » p70S6K Signaling » Induces cell motility
  • PAK2 (5062) » PAK pathway » Induces cell survival
  • PAK3 (5063) » PAK pathway » Induces cell survival
  • PAK6 (56924) » PAK pathway » Induces cell survival
  • PRKCBl (5579) » PBK Signaling » Induces cell proliferation PRKCD (5580) » PBK Signaling » Induces cell growth PRKCD (5580) » PDK Signaling » Induces cell proliferation PRKCE (5581) » PBK Signaling » Induces cell growth PRKCE (5581) » PBK Signaling » Induces cell proliferation PRKCG (5582) » PBK Signaling » Induces cell growth PRKCG (5582) » PBK Signaling » Induces cell proliferation PRKCH (5583) » PBK Signaling » Induces cell growth PRKCH (5583) » PBK Signaling » Induces cell proliferation PRKCI (5584) » PBK Signaling » Induces cell growth
  • MAP2K1 » PDK Signaling in B-Lymphocyte » Induces cell growth MAP2K2 (5605) » PDK Signaling in B-Lymphocyte » Induces cell growth MAPKl (5594) » PDK Signaling in B-Lymphocyte » Induces cell growth MAPKlO (5602) » PDK Signaling in B-Lymphocyte » Induces cell growth MAPKl 1 (5600) » PBK Signaling in B-Lymphocyte » Induces cell growth MAPK12 (6300) » PBK Signaling in B-Lymphocyte » Induces cell growth MAPK 13 (5603) » PBK Signaling in B-Lymphocyte » Induces cell growth MAPK14 (1432) » PBK Signaling in B-Lymphocyte » Induces cell growth MAPK3 (5595) » PBK Signaling in B-Lymphocyte » Induces cell growth MAPK4 (5596) » PBK Signaling in B-Lymphocyte » Induces cell growth MA
  • MAPK9 (5601) » PDK Signaling in B-Lymphocyte » Induces cell growth
  • PK.3CA (5290) » PDK Signaling in B-Lymphocyte » Induces cell growth
  • PIK3CB (5291) » PDK Signaling in B-Lymphocyte » Induces cell growth
  • PIK3CG (5294) » PDK Signaling in B-Lymphocyte » Induces cell growth
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG;PRKD3; PRKDl; PRKCQ; PRKCI; PRKCZ(5578;
  • AKTl (207 » S-IP Stimulated Signaling » Inhibits apoptosis
  • MAPK6 [or ERK3] (5597) » S-IP Stimulated Signaling » Inhibits apoptosis
  • MAP2K1, MAP2K2 (5604, 5605) » TGF-Beta Pathway » Induces angiogenesis
  • MAP2K1, MAP2K2 (5604, 5605) » TGF-Beta Pathway » Induces cell growth
  • MAP2K1, MAP2K2 (5604, 5605) » TGF-Beta Pathway » Induces cell mobility
  • MAP2K1, MAP2K2 (5604, 5605) » TGF-Beta Pathway » Induces tumorigenesis MAP2K4 (6416) » TGF-Beta Pathway » Induces angiogenesis
  • MAP3K7 (6885) » TGF-Beta Pathway » Induces angiogenesis MAP3K7 (6885) » TGF-Beta Pathway » Induces cell growth
  • MAP3K1; MAP3K2; MAP3K3; MAP3K4; MAP3K5 (4214; 10746; 4215; 4216; 4217) » TNF Signaling »
  • MAPK3; MAPKl; MAPK4; MAPK6; MAPK12 (5595; 5594; 5596; 5597; 6300) » TNF Signaling » Induces cell survival
  • MAP2K1; MAP2K2; MAP2K3; MAP2K4; MAP2K5; MAP2K6 (5604; 5605; 5606; 6416; 5607; 5608) » TNF- Induced Apoptosis Implicating Sphingolipids » Induces proliferation
  • MAP3K1 (5595) » TNFRl Pathway » Induces cell survival
  • MAP3K7 (6885) » TNFRl Pathway » Induces cell survival
  • MAPK8 (5599) » TNFRl Pathway » Induces cell survival
  • PRKCI (5584) » UVC-Induced MAPK Signaling » Induces tumorigenesis PRKCQ (5588) » UVC-Induced MAPK Signaling » Induces cell proliferation
  • PRKDl (5587) » UVC-Induced MAPK Signaling » Induces cell proliferation PRKDl (5587) » UVC-Induced MAPK Signaling » Induces tumorigenesis
  • MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6 (5604, 5605, 5606, 6416, 5608) » VEGF and S-IP Signaling » Induces angiogenesis
  • MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6 (5604, 5605, 5606, 6416, 5608) » VEGF and S-IP Signaling » Induces cell proliferation
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG
  • PRKCI PRKDl
  • PRKD3 PRKCQ
  • PRKCZ (5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 23683, 5588, 5590) » VEGF and S-IP Signaling » Induces angiogenesis
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG
  • PRKCI PRKDl
  • PRKD3 PRKCQ
  • PRKCZ 5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 23683, 5588, 5590
  • VEGF Pathway Induces cell survival MAP2K1 , MAP2K2 (5604, 5605) » VEGF Pathway » Induces angiogenesis
  • MAP2K1, MAP2K2 (5604, 5605) » VEGF Pathway » Induces cell proliferation
  • MAP2K3, MAP2K6 (5595, 5608) » VEGF Pathway » Induces angiogenesis
  • MAPKAPK2, MAPKAPK3 (9261, 7867) » VEGF Pathway » Induces angiogenesis
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG
  • PRKCI PRKDl
  • PRKD3 PRKCQ
  • PRKCZ (5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 23683, 5588, 5590) » VEGF Pathway » Induces angiogenesis
  • PRKCA PRKCBl
  • PRKCD PRKCE
  • PRKCH PRKCG
  • PRKCI PRKDl
  • PRKD3 PRKCQ
  • PRKCZ (5578, 5579, 5580, 5581, 5583, 5582, 5584, 5587, 23683, 5588, 5590) » VEGF Pathway » Induces cell proliferation
  • AKTl (207), AKT2 (208), AKT3 (10000)
  • 20 AURKA (6790), CDC2 (983), CDK2 (1017), CDK5 (1020), GSK3B (2932)
  • CDK2 (1017), CDK4 (1019), EGFR (1956), HER2 (2064),
  • PK3CA FRAPl (2475), PK3CA (5290), PIK3CB (5291), PDC3CD (5293), PDC3CG (5294), PIK3CG (5294)
  • IRAKI (3654), IRAK2 (3656), IRAK3 (11213), IRAK4 (51135), MAP3K5 (4217), PIK3CA (5290),
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a physiologically acceptable carrier, diluent, or excipient; and (ii) a compound as described herein.
  • the receptor or cellular protein kinase whose catalytic activity is selectively modulated (to an appropriate amount, e.g., about 1.0, 1.3, 2, or 2.3 log units) by a compound of this invention at a pharmaceutically acceptable concentration.
  • the target kinase to be selectively inhibited is selected from the group consisting of two or more (e.g., 3, 4, or more) among ABL,
  • selected profiles may include inhibition of select subsets of specific kinases, e.g., at nanomolar range concentrations, while lack of inhibition of other select subsets of kinases at similar or higher concentration, e.g., tens, hundreds or thousands of times higher , e.g., sub or micromolar concentrations, or substantially different quantitative effects at similar concentrations.
  • a protein kinase natural binding partner can bind to a protein kinase's intracellular region with high affinity. High affinity represents an equilibrium binding constant on the order of 10E-6 M or less.
  • a natural binding partner can also transiently interact with a protein kinase intracellular region and chemically modify it.
  • Protein kinase natural binding partners are chosen from a group that includes, but is not limited to, SRC homology 2 (SH2) or 3 (SH3) domains, other phosphoryl tyrosine binding (PTB) domains, guanine nucleotide exchange factors, protein phosphatases, and other protein kinases.
  • the compounds of the invention preferably modulate the activity of the protein kinase in vitro. These compounds preferably show positive results in one or more in vitro assays for an activity described.
  • the invention also features a method of identifying compounds that modulate the function of protein kinase, comprising the following steps: (a) contacting cells expressing the protein kinase with the compound; and (b) monitoring an effect upon the cells.
  • the effect upon the cells is preferably a change or an absence of a change in cell phenotype, more preferably it is a change or an absence of a change in cell proliferation or other physiological response, and even more preferably it is a change or absence of a change in the catalytic activity of the protein kinase.
  • the invention features a method for identifying the compounds of the invention, comprising the following steps: (a) lysing the cells to render a lysate comprising protein kinase; (b) adsorbing the protein kinase to an antibody; (c)incubating the adsorbed protein kinase with a substrate or substrates; and (d) adsorbing the substrate or substrates to a solid support or antibody; where the step of monitoring the effect on the cells comprises measuring the phosphate concentration of the substrate or substrates.
  • the invention features a method for treating a disease related to unregulated kinase signal transduction, where the method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein.
  • the invention also features a method of regulating kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound of the invention as described herein.
  • the invention features a method of preventing or treating an abnormal condition in an organism, where the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a protein kinase and a binding partner, e.g., substrate homolog, where the method comprises the following steps: (a) administering a compound of the invention as described herein; and (b) promoting or disrupting the abnormal interaction.
  • the organism is preferably a mammal and the abnormal condition is preferably cancer or other proliferative condition.
  • Compounds synthesized will be purified for testing in biochemical assays.
  • the assays may measure the binding capability to the designated target, compound to target binding "on-off ' kinetic rates, substrate site occupancy or competitive interaction, biologically relevant concentrations at the reactive site, "optimal biological concentrations to elicit the desired pharmacological effect", the ability to modulate the natural enzymatic reaction catalyzed by the kinase, and other such parameters.
  • Assays will be preferably evaluated in conditions similar to those found physiologically, e.g., temperature, concentration of targets, ion and salt concentrations, pH, and the like. The extent of kinase effect is determined and compared to the selectivity profile desired to confirm whether the structures have a profile of selective effects as described.
  • the correlation of structural features of the compounds is compared to the measured effect on the enzymes to determine whether the structural features of compounds match the predicted pattern of kinase effects.
  • the modulation of the panel of kinases is compared to the predicted to establish the accuracy of the algorithms used to validate particular pharmacophore models.
  • the models are further used to design additional variant structures which retain the desired pattern of modulation of kinase activity while minimizing the negative pharmacological problems.
  • the cycles of activity testing and correlation to structural features of structurally similar compounds are repeated to refine the predictive methods to prioritize the likelihood of compounds in exhibiting balance of properties of enzyme interaction and pharmacology.
  • the compounds may also be used in animal model systems to evaluate relevance of animal test systems and their relationship to corresponding human conditions.
  • QSAR and QSPR models generated are applied to scaffolds to create multiple compounds with desired binding pattern characteristics for kinase profiles.
  • Compounds are synthesized and purified using appropriate technologies. Binding pattern characteristics of compounds from these steps are confirmed using a panel of kinases and their variants (including common or relevant mutants and splice variants). In the context, e.g., of oncology, mutants and splice variants can play a role in resistance selection and ultimate drug efficacy and toxicity in a clinical setting.
  • synthesized compounds are screened against a panel of kinases, or variants thereof, found among kinases listed in selected kinase profiles. These include, for example, ABLl, ABLl E255K, ABLl G250E, ABLl T315I, ABLl Y253F, ABL2 (Arg), AKTl (PKB alpha), AKT2 (PKB beta), AKT3 (PKB gamma), AURKA (Aurora A), AURKB (Aurora B), AURKC (Aurora C), BRAF, BRAF V599E, CSNK2A1 (CK2 alpha 1), CSNK2A2 (CK2 alpha 2), EGFR (ErbBl), ERBB2 (HER2), FGFRl, FGFR2, FGFR3, FGFR3 K650E, FGFR4, FLTl (VEGFRl), FLT3, FLT3 D835Y, FLT4 (VEGFR3),
  • Pattern of inhibition of compounds is matched to a desired profile, which may be inhibition or lack of inhibition of a designated kinase recited in a profile.
  • a desired profile which may be inhibition or lack of inhibition of a designated kinase recited in a profile.
  • synthesized compounds are specific structures exhibiting desired modulation patterns, e.g., of inhibition and lack of inhibition. Data collected, both lack of inhibition and inhibition indicates that the design process described herein provides a tool that allows design of novel compounds and prediction of their activity or lack of activity across panel of kinases or kinase profile.
  • analogs of compounds can be synthesized, e.g. as described, and evaluated for structure activity relationship leading to desired patterns of inhibition. Patterns of inhibition will be useful in a therapeutic context, using a described compound with another compatible entity providing a desired pattern of kinase modulation.
  • Goal Identification of lead structures modulating a profile of multiple kinase targets.
  • Ring system A was selected from the group of 79 in table 7a;
  • Ring system B was selected from the group of 32 in table 7b;
  • L is a linker selected from the group of 24 shown in table 7c;
  • Xi is a functional group selected from the group of 13 shown in table 7d; Ri is functional group or ring system.
  • a total of 57,600 possible scaffolds were generated in silico from combinatorial assortment of 24 linkers, 79 ring system A fragments, and 32 ring system B fragments and some examples are shown in table 7e.
  • one embodiment provides a compound of Formula (I) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • X is O or NH;
  • Z is CH or N;
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 1 substituents;
  • B is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 7 substituents;
  • R 2 and R 8 are independently selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or C 1-6 alkyl;
  • R 1 and R 7 are independently selected from hydrogen, halogen, OR 9 , C 1-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CON(R 9 ) 2 , NHR 9 , N(R 9 ) 2 , COR 9 , C0-4alkylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, CO ⁇ alkylheterocyclyl, CN, amino, NHCOR 9 , hydroxy, Cl-6alkoxy, OC(O)R 9 , -OC0-4alkylaryl,
  • OC0-4alkylheteroaryl -OC0-4alkylC3-10cycloalkyl, NHCOOR 9 , OC0-4alkylC3-10heterocycloalkyl, OC0-4alkylNR 9 , NR 9 COOR 9 , OCONR 9 , or NR 9 COR 9 ;
  • R 3 and R 4 are independently selected from hydrogen, halogen, CF 3 , CN, hydroxy, NO 2 , amino, NHAryl, NHR 9 ,
  • R 3 and R 4 may together form a 5-membered or 6- membered aryl or heteroaryl ring;
  • R 5 and R 6 are independently selected from hydrogen, Cl-6 alkyl and optionally may be joined to form a 3-10 membered cycloalkyl;
  • R 9 is selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • Another embodiment provides a compound of Formula (II) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • A is an optionally substituted heteroaryl ring having between 6 and 12 members and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1 -3 R 1 substituents; R 7 is selected from hydrogen or C 1 -6 al kyl ;
  • R 5 is selected from hydrogen, halogen, hydroxy, OR 8 , CN, amino, NHR 8 or C 1-6 alkyl;
  • R 1 and R 4 are independently selected from hydrogen, halogen, OR 8 , C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 8 , CON(R 8 ) 2 , NHR 8 , N(R 8 ) 2 , COR 8 , C0-4alkylC3-10cycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, CCMalkylheterocyclyl, CN, amino, NHCOR 8 , hydroxy, Cl - ⁇ alkoxy, OC(O)R 8 , -OC0-4alkylaryl, OC0-4alkylheteroaryl, -OCO ⁇ alkylCS-lOcycloalkyl, NHCOOR 8 , OC0-4alkylC3-10he
  • R 8 is selected from hydrogen, C 1-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • Illustrative structures according to Formula II include:
  • Yet another embodiment provides a compound of Formula (III) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • X is O or NH; Z is CH or N;
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 1 substituents;
  • B is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R 7 substituents;
  • R 2 and R 8 are independently selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or Cl-6 alkyl;
  • R 1 and R 7 are independently selected from hydrogen, halogen, OR 9 , Cl-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, OCF 3 , nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CON(R 9 ) 2 , NHR 9 , N(R 9 ) 2 , COR 9 , C0-4alkylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl, C0-4alkylheterocyclyl, CN, amino, NHCOR 9 , hydroxy, Cl-6alkoxy, OC(O)R 9 , -OC0-4alkylaryl, OC0-4alkylheteroaryl, -OC0-4alkylC3-10cycloalkyl, NHCOOR 9 , OC0-4alkylC3-10
  • R 5 and R 6 are independently selected from hydrogen or Cl-6 alkyl
  • R 9 is selected from hydrogen, Cl-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • Yet another embodiment provides a compound of Formula (IV) or pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof:
  • Y is O, NH, -OCH 2 - or -CH 2 O- Z is CH or N;
  • A is an optionally substituted aryl or optionally substituted heteroaryl ring, having 5 or 6 members, and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen or sulfur; said ring being monocyclic or polycyclic, optionally substituted with 1-3 R' substituents;
  • R 1 and R 4 are independently selected from hydrogen, halogen, OR 9 , Cl-6 alkyl, C2-6 alkenyl, C2-C6 alkynyl,
  • OCF 3 nitro, CF 3 , CN, aryl, heteroaryl, COOR 9 , CON(R 9 ) 2> NHR 9 , N(R 9 ) 2 , COR 9 , C0-4alkylC3- lOcycloalkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C2-4alkenylaryl, C2-4alkynylaryl,
  • C0-4alkylheterocyclyl CN, amino, NHCOR 9 , hydroxy, Cl-6alkoxy, OC(O)R 9 , -OC0-4alkylaryl, OCO ⁇ alkylheteroaryl, -OC0-4alkylC3-10cycloalkyl, NHCOOR 9 , OC0-4alkylC3-10heterocycloalkyl, OC0-4alkylNR 9 , OCONR 9 , or NR 9 COR 9 ;
  • R 2 and R 3 are independently selected from hydrogen, halogen, CF 3 , CN, hydroxy, NO 2 , amino, NHAryl, NHR 9 , COOH, OR 9 , COOR 9 , CONHR 9 , or CON(R 9 ) 2 ; R 2 and R 3 may together form a 5-membered or 6- membered aryl or heteroaryl ring;
  • R 5 is selected from hydrogen, halogen, hydroxy, OR 9 , CN, amino, NHR 9 or Cl-6 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, Cl-6 alkyl and optionally may be joined to form a 3-10 membered cycloalkyl;
  • R 8 is selected from hydrogen or Cl-6 alkyl
  • R 9 is selected from hydrogen, Cl-6 alkyl, C2-6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • Structures of Formula IV include:
  • Cell lines and other cellular systems appropriate for testing the effect of modulators in a cell context include, e.g., 32D cell line; 3T3 cell line; 3T3 Ll cell line; 4Tl cell line; A2780 cell line; A375 cell line; A43 cell line; A431 cell line; A459 cell line; A549 cell line; Aortic smooth muscle cells; ARH-77 cell line; B cells; B 16 cell line; Ba/F3 cell line; Ba/F3-TEL-FGFR3 cell line; BALB/c3T3 cell line; BALB/MK cell line; BT-20 cell line; BT-474 tumor cell line; BT-549 cell line; BxPC3 cell line; C26 cell line; C6 cell line; CaCo-2 cell line; CaIu- 3 cell line; CCRF-CEM cell line; CHO cell line; CHO-HIRc cells; COLO 201 cell line; COLO 205 cell line; Diploid fibroblast cells; DLD-I cell line; D
  • the effect of a compound on the plurality of kinases desired in the pattern is evaluated in a cell.
  • the effects may be using kinase-specific reagents compatible with a selected cell line, or by evaluating multiple kinases in that cell line.
  • Antibody reagents may be useful to allow simultaneous measurement of the impact of the compound on the different kinases together.
  • prostate cancer mouse models at /prostate_models/rnouse_rninireview ; gastrointestinal cancer animal models at /gastro_models ; hematopoietic cancer models at /hema_models ; lung cancer models at /lung_models ; mammary gland cancer models at /mammary_models ; ovarian cancer models at /ovarian_models/animal_models ; skin cancer models at
  • bladder cancer models bladder cancer models; cervical cancer models; endometrial cancer models; gastrointestinal cancer models; genitourinary cancer models; head and neck cancer models; hematopoietic cancer models; kidney cancer models; lung cancer models; mammary gland cancer models; melanoma models; myeloma models; nervous system cancer models; oral cancer models; ovarian cancer models; pancreatic cancer models; prostate cancer models; sarcoma cancer models; and skin cancer models.
  • Other disease models, or counterparts in other species may be found by search in the PubMed and patent literature databases.
  • DC Structures Exhibiting Desired Pattern of Kinase Modulation
  • the tables below disclose a selected profile desired for therapeutic compound(s) useful for treating various cancers, as well as other medical conditions. These conditions typically share mechanisms or effects with cancer, development, aging, and other similar cell processes. These compounds are lead compounds around which synthesis and further activity testing will generate a structure activity relationship dataset. This SAR can be used to generate various predictive pharmacophore models based on structural and other features for predicting similar variant structure compounds which may possess advantageous pharmacological features while retaining the desired pattern of kinase effect. Of particular importance in the selection of useful variants will be those optimized for adsorption, distribution, metabolism, excretion, toxicity, and manufacturability.
  • Tables 3a, 4a, 5a and 6a disclose selected profiles desired for therapeutic compounds useful for treating various cancers, as well as other medical conditions. These conditions typically share mechanisms or effects with cancer, development, aging, and other similar cell processes. These compounds are lead compounds around which synthesis and further activity testing will generate a structure activity relationship dataset. This SAR can be used to generate various predictive pharmacophore models based on structural and other features for predicting similar variant structure compounds which may possess advantageous pharmacological features while retaining the desired pattern of kinase effect. Of particular importance in the selection of useful variants will be those optimized for adsorption, distribution, metabolism, excretion, toxicity, and manufacturability.
  • Profile One Table 3a Profile one description: compounds selected to have the combination of high binding affinity and ability to inhibit the kinases KDR and PDGFR-B while having minimal binding affinity and ability to modulate the kinase KIT.
  • the targets are preferably human, but the combination is relevant for other species, typically mammals.
  • Six lead structures are provided.
  • the predicted ICso's derived from the KDR and PDGFR-B pharmacophore models are given in Table 3b.
  • Indications for use of compounds which exhibit a profile one modulation pattern include hepatocellular carcinoma, anti-angiogenesis, chronic obstructive pulmonary disease, thyroid tumor, T-cell lymphoma, colorectal cancer, renal cell carcinoma, myeloid leukemia cells, gastrointestinal stromal carcinoma, non-Hodgkin lymphoma, juvenile hemangiomas, and similar neoplastic conditions.
  • Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, anorexia, macular degeneration, diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, scleroderma, cardiofaciocutaneous syndrome, chronic myeloid leukemia, androgen independent prostate cancer cells, head and neck squamous cell carcinoma, cervical cancer, and similar neoplastic conditions.
  • Profile Two Table 4a Profile 2 description: compounds selected to have the combination of high binding affinity and ability to inhibit the kinases BRAF (wild type and V600E variant), KDR and PDGFR-B while having minimal binding affinity and ability to modulate the kinase KIT.
  • the targets are preferably human, but the combination is relevant for other species, typically mammals.
  • Nine lead structures are provided.
  • the predicted IC 50 1 S derived from the BRAF, KDR, PDGFR-B and KIT pharmacophore models are given in Table 4b.
  • Indications for use of compounds exhibiting a profile two modulation pattern include hepatocellular carcinoma, anti-angiogenesis, chronic obstructive pulmonary disease, thyroid tumor, T-cell lymphoma, colorectal cancer, renal cell carcinoma, myeloid leukemia cells, gastrointestinal stromal carcinoma, non-Hodgkin lymphoma, juvenile hemangiomas, melanoma, thyroid carcinoma, neuroendocrine gastroenteropancreatic tumors, lymphoblastic leukemia and similar neoplastic conditions.
  • Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, scleroderma, cardiofaciocutaneous syndrome.
  • Table 4a Profile Two Inhibitors of BRAF, KDR, PDGFR-B but not KIT
  • Profile Three Table 5a Profile three description: compounds selected to have the combination of high binding affinity and ability to inhibit the kinases AURORA, KDR, and PDGFR-B, while having minimal binding affinity and ability to modulate the kinase KIT.
  • the targets are preferably human, but the combination is relevant for other species, typically mammals.
  • Six lead structures are provided.
  • the predicted IC 50 's derived from the AURORA, KDR, PDGFR-B and KIT pharmacophore models are given in Table 5b.
  • Indications for use of compounds exhibiting a profile three modulation pattern include hepatocellular carcinoma, anti-angiogenesis, chronic obstructive pulmonary disease, thyroid tumor, T-cell lymphoma, colorectal cancer, renal cell carcinoma, myeloid leukemia cells, gastrointestinal stromal carcinoma, non-Hodgkin lymphoma, juvenile hemangiomas, esophageal squamous cell carcinoma, breast carcinoma, glioma, laryngeal carcinoma, ovarian cancer, prostate cancer, and similar neoplastic conditions.
  • Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, scleroderma, and cardiofaciocutaneous syndrome.
  • Profile Four Table 6a Profile four description: compounds selected to have the combination of high binding affinity and ability to inhibit the kinases PI3K and mTOR (FRAPl), while having minimal binding affinity and ability to modulate the kinase KIT.
  • the targets are preferably human, but the combination is relevant for other species, typically mammals.
  • Six lead structures are provided.
  • the predicted IC 50 's derived from the PI3K, mTOR (FRAPl) and KIT pharmacophore models are given in Table 6b.
  • Indications for use of compounds exhibiting a profile four modulation pattern include chronic myeloid leukemia, androgen independent prostate cancer cells, head and neck squamous cell carcinoma, cervical cancer, and similar neoplastic conditions. Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, and anorexia. Table 6a. Profile Four Inhibitors of PI3K and mTOR (FRAPl) but not KIT
  • Reagents a) 4-chbroqulnazollne, CS2CO3, DMF. 150C b) NaBH4, MeOH, OC c) SOCI2 d) Na2SO3, " IHRwaler, reflux e) CI2. H2O 0 ArNH2, Pr2NEt DCM
  • Phenol 1 may be contacted with an equivalent of 4-chloroquinazoline in the presence of a base such as potassium carbonate, sodium carbonate or cesium carbonate, in a solvent such as N.N-dimethylformamide or dimethylsulfoxide at temperatures ranging from 100 0 C to 160 0 C and may lead to aryloxy 2.
  • a base such as potassium carbonate, sodium carbonate or cesium carbonate
  • a solvent such as N.N-dimethylformamide or dimethylsulfoxide
  • Transformation into 4 may take place using neat thionyl chloride at temperatures ranging from 0 0 C to 60 0 C.
  • the resulting optionally substituted 4 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification.
  • Formation of the sulfonic acid 5 may take place in a protic solvent such as water, or a combination of water- tetrahydrofuran, at temperatures ranging from 20 0 C to 90 0 C, with a stoichiometric amount or excess of sodium sulfate.
  • Sulfonyl chloride 6 may be obtained by treatment of 5 with a chlorinating agent such as phosphorus pentachloride or phosphorus oxide trichloride, at temperatures ranging from 0 0 C to 60 0 C, for 1 to 12 hours.
  • sulfonyl chloride 6 Treatment of sulfonyl chloride 6 with an appropriately substituted aniline will provide sulfonamide 7 in the presence of a tertiary base such as triethylamine or Hunig's base, in a solvent system such as dichloromethane or the like, at temperatures ranging from 15 0 C to 40 0 C. Upon completion of the reaction, 7 is recovered by conventional methods including neutralization, extraction, chromatography and the like.
  • boronic acid 8 may be used in a Suzuki coupling with commercially available 4- bromoaniline to afford biaryl 9, in the presence of a base such as potassium carbonate or cesium carbonate, in a solvent such as dioxane, dimethoxyethane or tetrahydrofuran, at temperatures ranging from 25 0 C to 90 0 C, for 1 to 12 hours, with a source of palladium (0) such as for example Pd 2 (dba) 3 .
  • iodo pyridine 10 may be coupled to commercially available 4-aminophenyl boronic acid via a Suzuki coupling using conditions described above to provide biaryl 9.
  • the resulting optionally substituted 9 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification.
  • Sulfonamide 11 can be prepared as described in Scheme 1-2 and can be transformed into 12 through the use of a stoichiometric equivalent of a reducing agent such as tin chloride (II) in a protic solvent such as ethanol or the like. Alternatively, this reduction could take place with zinc powder in a solvent such as acetic acid.
  • the resulting optionally substituted 12 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without isolation.
  • Ring formation from 12 into 13 can take place with the use of a stoichiometric equivalent or slight excess of trimethyl orthoformate or the like, in a solvent system such as N,N-dimethylformamide or dimethylsulfoxide, for 1 to 12 hours, at temperatures ranging from 25 0 C to 100 0 C.
  • a solvent system such as N,N-dimethylformamide or dimethylsulfoxide
  • Reagents a) s-BuLi/HCON(M ⁇ )2 b) NBS, CCW c) NaN3, DMF d)TrtNCS, PPti3, dioxane 100C e) HO, dioxane
  • An aryl bromide or heteroaryl bromide 1 can be converted to a corresponding methyl ketone 2 by treatment with 1 to 2 equivalents of sec-butyl lithium (sec-BuLi) or n-BuLi at temperatures ranging from -80 0 C to -50 0 C, for about 1 to 5 hours, in a solvent such as dry ethyl ether, followed by addition of 1 to 2 equivalents of N,N-dimethylacetamide, and gradual increase of the temperature to 0 0 C.
  • sec-butyl lithium sec-butyl lithium
  • n-BuLi sec-butyl lithium
  • Methyl ketone 2 may be converted to an alpha bromo ketone 3 upon treatment with 1 to 1.5 equivalents of N- bromosuccinimide (NBS), in a solvent such as carbon tetrachloride (CCl 4 ), for 5 to 12 hours at temperatures ranging from 20 0 C to 55 0 C.
  • NBS N- bromosuccinimide
  • CCl 4 carbon tetrachloride
  • the acyl azide 4 can be prepared under conventional methods by contacting 3 with a stoichiometric equivalent or a slight excess of sodium azide in an anhydrous solvent such as N,N- dimethylformamide (DMF) or the like, at temperatures ranging from 25 0 C to 90 0 C, for 2 to 7 hours.
  • the resulting optionally substituted 4 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification or isolation.
  • Construction of the amino oxazole ring 5 takes place by mixing 4 with a stoichiometric amount of commercially available tritylisothiocyanate, in the presence of reducing agent triphenylphosphine, in a solvent such as dioxane or tetrahydrofuran (THF), at temperatures ranging from 20 0 C to 100 0 C for 1 to 12 hours. Removal of the protecting group under standard conditions such as treatment with a saturated solution of HCl (g) in dioxane at room temperature leads to the desired substituted amino oxazole 6.
  • SCHEME 2-2 SCHEME 2-2
  • Reagents 1) KOH, AgNO 3 , H 2 O b) Br 2 , CCI 4 c) ArB(OH) 2 , Pd(O), aq. K 2 CO 3 , PhH Or ArSnBu 3 , Pd(O), LiCI, DMF d)TFA, CH 2 CI 2
  • carboxylic acid 7 may be converted to the corresponding silver salt by treatment with a stoichiometric amount of potassium hydroxide (KOH) or the like, and silver nitrate (AgNO 3 ) preferably in a solvent such as water.
  • KOH potassium hydroxide
  • AgNO 3 silver nitrate
  • Bromooxazole 8 is obtained by directly heating the above silver salt in the presence of a stoichiometric amount of bromine (Br 2 ), at temperatures ranging from 30 °C to 75 0 C, in solvents such as carbon tetrachloride (CCl 4 ) for 2 to 8 hours.
  • Br 2 bromine
  • CCl 4 carbon tetrachloride
  • a palladium (O) catalyst such as tetrakistriphenylphosphine palladium (O) or the like
  • a deoxygenated solvent such as benzene, dimethoxyethane (DME), dioxane and the like
  • a palladium (O) catalyst such as tetrakistriphenylphosphine palladium (0) or the like in a deoxygenated solvent such as dimethoxyethane, N,N-dirnethylformamide
  • Reagents a) 1 - HSR 1 , HATU, ET3N, CH3CN 2- AB(OH)2. CuTc b) TFA, DCM
  • Boc-glycine 10 may be transformed into the corresponding aryl or heteroaryl ketone 11 via a Liebeskind-Srogl coupling using conditions described in J. Am. Chem. Soc. 2000, 122, 11260- 11261.
  • Deprotection under acidic conditions such as trifluoroacetic acid (TFA) in dichloromethane (DCM) at temperatures ranging from 0 0 C to 40 0 C, for 1 to 12 hours, leads to amino ketone 12 in quantitative yield.
  • Ketone 12 can then be treated with commercially available tritylisothiocyanate as shown in Scheme 2-1 using steps d and e to give 6.
  • Reagents a) 4-chloro quinazoline, KOtBu, K2CO3, DMF, 8OC or quinazo.n-4-ylboronlc acid, Cu(OAC)2, DME, K2CO3.
  • 4-nitro phenol 13 can be contacted with commercially available 4- chloroquinazoline in the presence of a base such as potassium tert-butoxide or the like (KOtBu) and a freshly ground base such as potassium carbonate (K 2 CO 3 ) or cesium carbonate (Cs 2 CO 3 ), in a solvent such as N,N- dimethylformamide (DMF) or tetrahydrofuran (THF), at temperatures ranging from 30 0 C to 80 0 C, for a period of 1 to 9 hours and obtain aryloxy 14.
  • a base such as potassium tert-butoxide or the like (KOtBu) and a freshly ground base such as potassium carbonate (K 2 CO 3 ) or cesium carbonate (Cs 2 CO 3 )
  • a solvent such as N,N- dimethylformamide (DMF) or tetrahydrofuran (THF)
  • Reagents a) 4-hydroxy quinazoline,Cu(OAC)2, DME, K2CO3, RT
  • Reagents a) phosgene, EON. CH2CI2 b) 6. Et3N, CH3CN c) p-NO2 phenyl chloroformate, Et3N, CH2CI2 d) 6, DIEA, CH2CI2
  • Aniline 14 may be reacted with a stoichiometric amount to a slight excess of phosgene in the presence of a tertiary base such as triethylamine (Et 3 N) or Hunig's base (DIEA), in a solvent such as dichloromethane or the like, at temperatures ranging from 0 0 C to 25 0 C, to lead isocyanate 15.
  • a tertiary base such as triethylamine (Et 3 N) or Hunig's base (DIEA)
  • Et 3 N triethylamine
  • DIEA Hunig's base
  • the resulting optionally substituted 15 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification.
  • Condensation of 14 with 6 takes place in a solvent such as dichloromethane, N,N-dimethylformamide, or acetonitrile, in the presence of a stoichiometric amount of tertiary base such as triethylamine or Hunig's base, at room temperature for 1 to 12 hours, and leads to urea 16.
  • a solvent such as dichloromethane, N,N-dimethylformamide, or acetonitrile
  • aniline 14 can be activated to its corresponding 4-nitrophenyl carbamate 17 by contact with a stoichiometric amount to slight excess of 4-nitrophenyl chloroformate or other phenyl chloroformate, in the presence of a base such as triethylamine or Hunig's base, in a solvent such as dichloromethane, at temperatures ranging from 0 0 C to 55 0 C, for 1 to 12 hours.
  • the resulting optionally substituted 17 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification.
  • Nitro pyridone 18 can be reduced to the corresponding aniline 19 using a reducing agent such as tin chloride in a solvent such as ethanol or the like, for 1 to 12 hours.
  • a reducing agent such as tin chloride in a solvent such as ethanol or the like
  • other reducing agents such as zinc powder or iron could be used instead of tin chloride.
  • Cyclization of 19 into oxazole 20 can be obtained with one stoichiometric equivalent of trimethylorthoformate in a solvent system such as N,N-dimethylformamide of the like, at temperatures ranging from 20 0 C to 90 0 C, for 1 to 12 hours.
  • the resulting optionally substituted 17 can be recovered by conventional methods such as neutralization, chromatography, filtration, crystallization and the like or can be used in the next step without purification.
  • Reagents a) 2-bramoethanol, chlorosulfonyl isocyanate, Et 3 N, DCM b)4-(quinazolin-4-yloxy)aniline, Et 3 N, CH 3 CN.
  • the burgundy colored solution was flushed with nitrogen and then sealed with the cap.
  • the reaction mixture was heated to 100 0 C for 18 hours with very vigorous stirring.
  • the reaction mixture was cooled to room temperature and filtered through a short pad of silica gel washing with ethyl acetate.
  • the mixture was dried over sodium sulfate, filtered and the solvent concentrated in vacuo affording a yellow semisolid material. This was then pre- absorbed onto silica gel and applied to a 70 g Biotage column packed with silica gel which had been preconditioned with 3:7 ethyl acetatexhloroform. The column was eluted with the same solvent system.
  • Step A Synthesis of N-[4-(6-Chloro-3-pyridinyl)phenyI]-2-oxo-l,3-oxazolidine-3-sulfonamide (22). Chlorosulfonyl isocyanate (0.17 mL, 1.9 mmole) was dissolved in dry dichloromethane (6 mL) in a dry flask under a nitrogen stream.
  • Step B Synthesis of N-[4-(6-Chloro-3-pyridinyl)phenyl]-N'-[4-(4-quinazolinyIoxy)phenyl]sulfamide (23).
  • Compound 22 (90.2 mg, 0.255 mmole) and 4-(4-quinazolinyloxy)aniline hydrochloride (63 mg, 0.23 mmole) were taken up into 4 mL of acetonitrile. Triethylamine (0.081 mL, 0.58 mmole) was added and the reaction mixture was heated to 8O 0 C for 3 hours.
  • Reagents a) cyanoaceticacid, EDC, DMAP, DCM b) hydroxylamine hydrochloride, Et 3 N c) Iron, hydrochloric acid d) 2-bromo-1-(pyridin-3-yl)ethanone, NaHCO 3 , H 2 O, THF.
  • the hot reaction mixture was filtered through Celite ® 545, washed with ethanol (20 mL), and the solvent concentrated in vacuo. The residue was taken up in water (50 mL) and then acidified to pH 4 with 10% hydrochloric acid. The aqueous layer was extracted with ether (50 mL), ethyl acetate (50 inL), toluene (50 mL) and then was brought to pH 9 using sodium bicarbonate. The aqueous layer was extracted with methylene chloride (5 x 40 mL) and the combined organic layers were stripped to a dark solid.
  • 3-Bromoacetylpyridine hydrobromide (32.9 mg, 0.12 mmole) was taken up in a 2:1 mixture of tetrahydrofiiran: water (1.5 mL) and was added in portions over a 35 minute period to the bicarbonate mixture. After 5 hours, the reaction mixture was removed from the oil bath and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (3 x 10 mL) and 0. IN hydrochloric acid (30 mL). The organic layer was dried over sodium sulfate, filtered and the solvent concentrated in vacuo affording a dark brown solid (50 mg).
  • the methods of the invention are advantageous in conditions involving immunosuppression, autoimmune conditions, inflammatory conditions, cerebral vasospasm, diabetic retinopathy, rheumatoid arthritis, or neurodegeneration.
  • Drugs that modulate kinase activities will be combined with companion efficacy and safety biomarkers for efficient and accelerated clinical development in targeted patient populations.
  • Biomarkers are objective, measurable biochemical parameters that faithfully reflect the status of a critical pathway to a disease or a critical pathway that predisposes to a disease.
  • Biomarkers in ultimate or proximal critical pathways can be direct measures of the progression or reversal of a fundamental underlying disease process.
  • a clinical development strategy will be focused on developing kinase modulator drugs, e.g., in the oncology arena, and establishing proprietary biomarkers that identify patients most likely to respond to treatment and those at risk for adverse drug reactions.
  • biomarker strategy By incorporating a biomarker strategy at the beginning, the drug candidates will be favorably positioned. This strategy increases the likelihood of drug development success and reduces the drug failure rate common within the industry.
  • Biomarkers have enormous potential to predict who will develop cancer and/or to detect the disease at an early stage. The anticipated benefit in this setting is based on the assumption that interventions exist that either prevent cancer in high-risk individuals or more effectively eradicate cancer when individuals are diagnosed at a time of low tumor burden.
  • Biomarkers can guide treatment decisions.
  • Biomarkers provide an opportunity to identify subpopulations of patients who are most likely to respond to a given therapy. This application will allow more informed decisions about modifying and adapting treatment protocols to subpopulations and also help guide patient enrollment into clinical trials.
  • Cancer biomarkers exist in many different forms, including physiologic (patient performance status), images (mammograms), specific molecules (prostate-specific antigen, PSA), genetic alterations (BRCA mutations), gene or protein expression profiles (serum protein electrophoresis for detection of monoclonal gammopathies), and cell-based markers (circulating tumor cells), among others.
  • physiologic patient performance status
  • images mammograms
  • specific molecules prostate-specific antigen, PSA
  • BRCA mutations genetic alterations
  • gene or protein expression profiles gene or protein electrophoresis for detection of monoclonal gammopathies
  • cell-based markers circulating tumor cells
  • biomarker hypothesis states that changes in levels of blood or tissue proteins, individually or multiplexed, are highly and specifically characteristic of disease states and therapeutic outcomes.
  • the basis of this hypothesis is that biological systems are adaptive and that challenges to homeostasis affect characteristic levels of proteins.
  • Biomarker development occurs in a multi-step process of discovery, followed by replication in independent cohorts, validation of diagnostic sensitivity and specificity, and, finally, translation into a clinical diagnostic test or surrogate endpoint in a clinical study.
  • Candidate biomarkers are triaged at each stage of development.
  • a biomarker can be a single protein, such as prostate-specific antigen, a panel of proteins or genes or a combination of one or more proteins, genes, and other clinical measures, together with an algorithm that integrates these into an individual profile.
  • these compounds will comprise significant therapeutic application.
  • these compounds should modulate appropriate kinase signaling and the biological effects associated therewith. More specifically, these compounds should selectively modulate cell proliferation and/or differentiation and/or promote apoptosis especially of cancer and other neoplastic cells. Pathways affected by the inhibition of the various kinases should be as indicated.
  • Description of formulation and compounding include, e.g., Johnston (2005) Compounding: The Pharmacy Technician Series Prentice Hall, ISBN: 0131147609; Rowe, et al. (eds.
  • the compounds produced according to the invention will be used to treat conditions wherein the pattern of inhibition of the various kinase signaling pathways is therapeutically beneficial.
  • This will include conditions that involve abnormal cell growth and/or differentiation such as cancers and other neoplastic conditions.
  • the subject compounds may be used to treat other conditions involving abnormal cell proliferation and/or differentiation such as neoplastic conditions and disorders.
  • the selected indication is often cancer, especially cancers involving abnormal levels of expression of the relevant kinase(s) or close relatives, cancers that express variant or mutant relatives, or cancers which comprise genetic translocation or deletion of the kinase(s).
  • the subject therapies will comprise administration of at least one compound according to the invention in an amount sufficient to elicit a therapeutic response, e.g., inhibition of one or more of tumor cell proliferation, differentiation, metastasis, mutagenesis, or promotion of apoptosis.
  • the compound may be administered alone, or may be targeted by various means, including liposomes, targeted liposomes, antibody targeting mechanisms, localized activation methods, targeting conjugates, conjugates with site activatable active components, and the like.
  • One embodiment provides a method of treating an indication selected from hepatocellular carcinoma, anti-angiogenesis, chronic obstructive pulmonary disease, thyroid tumor, T-cell lymphoma, colorectal cancer, renal cell carcinoma, myeloid leukemia cells, gastrointestinal stromal carcinoma, non-Hodgkin lymphoma, juvenile hemangiomas, and similar neoplastic conditions.
  • Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, anorexia, macular degeneration, diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, scleroderma, cardiofaciocutaneous syndrome, chronic myeloid leukemia, androgen independent prostate cancer cells, head and neck squamous cell carcinoma, cervical cancer, and similar neoplastic conditions; the method comprising administering to a subject a compound of Formula I or a compound of Formula in.
  • Another embodiment provides a method of treating an indication selected from hepatocellular carcinoma, anti-angiogenesis, chronic obstructive pulmonary disease, thyroid tumor, T-cell lymphoma, colorectal cancer, renal cell carcinoma, myeloid leukemia cells, gastrointestinal stromal carcinoma, non-Hodgkin lymphoma, juvenile hemangiomas, melanoma, thyroid carcinoma, neuroendocrine gastroenteropancreatic tumors, lymphoblastic leukemia and similar neoplastic conditions.
  • Additional medical indications for use include autoimmune conditions, rheumatoid arthritis, inflammatory diseases, dermatological conditions, macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, scleroderma, cardiofaciocutaneous syndrome; the method comprising administering to a subject a compound of Formula II or a compound of Formula FV.
  • the invention described herein includes a pharmaceutical composition which is comprised of a compound of the indicated formulae, including a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier.
  • the terms “pharmaceutically acceptable salts” and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • pharmaceutical chemist i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also of interest in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, and flowability of the resulting bulk drug.
  • a compound When a compound is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • Pharmaceutically acceptable salts also include acid addition salts.
  • the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, pers
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heterocyle, Rl, etc.
  • its definition on each occurence is independent of its definition at every other occurrence, unless otherwise stated.
  • a therapeutically effective dose of a kinase modulator is administered to a patient.
  • therapeutically effective dose herein is meant a dose that produces effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using acceptable techniques (e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery, Lippincott, Williams & Wilkins Publishers, ISBN:0683305727; Lieberman (1992) Pharmaceutical Dosage Forms (vols.
  • a "patient” for the purposes of the present invention includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, preferably a primate, and in one embodiment the patient is human.
  • the administration of the modulators of the present invention can be done in a variety of ways, either systemic or local, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, intraocularly, or directly onto a mucosal surface.
  • the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
  • the subject compounds will be typically be administered in a pharmaceutically acceptable formulation or composition.
  • compositions include injectable solutions, tablets, milk, or suspensions, creams, oil-in-water and water-in-oil emulsions, microcapsules, and microvesicles.
  • the pharmaceutical compositions are in a water soluble form, such as being present as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts of interest include the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the pharmaceutical compositions may also include one or more of the following: carrier proteins such as serum albumin; buffers; fillers such as microcrystalline cellulose, lactose, corn and other starches; binding agents; sweeteners and other flavoring agents; coloring agents; and polyethylene glycol.
  • carrier proteins such as serum albumin
  • buffers such as microcrystalline cellulose, lactose, corn and other starches
  • binding agents such as microcrystalline cellulose, lactose, corn and other starches
  • binding agents such as microcrystalline cellulose, lactose, corn and other starches
  • binding agents such as microcrystalline cellulose, lactose, corn and other starches
  • binding agents such as microcrystalline cellulose, lactose, corn and other starches
  • sweeteners and other flavoring agents such as microcrystalline cellulose, lactose, corn and other starches
  • oral solid dosage forms include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500 mg.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • unit dosage forms suitable for oral administration include, but are not limited to, powder, tablets, pills, capsules and lozenges.
  • kinase modulators e.g., small organic molecules, etc.
  • This is typically accomplished either by complexing the molecule(s) with a composition to render it resistant to acidic and enzymatic hydrolysis, or by packaging the molecule(s) in an appropriately resistant carrier, such as a liposome or a protection barrier.
  • Means of protecting agents from digestion are well known in the art.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
  • a typical pharmaceutical composition for intravenous administration would be about 0.1 to 10 mg per patient per day. Dosages from 0.1 up to about 100 mg per patient per day may be used, particularly when the drug is administered to a secluded site and not into the blood stream, such as into a body cavity or into a lumen of an organ. Substantially higher dosages are possible in direct or topical administration. Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art, e.g., Remington's Pharmaceutical Science and Goodman and Gillman, The Pharmacological Basis of Therapeutics, supra.
  • compositions will typically comprise conventional pharmaceutical excipients and carriers used in drug formulations, e.g., water, saline solutions, such as phosphate buffered saline, buffers, and surfactants.
  • saline solutions such as phosphate buffered saline, buffers, and surfactants.
  • the subject compounds may be free or entrapped in microcapsules, in colloidal drug delivery systems such as liposomes, microemulsions, and macroemulsions.
  • solid formulations containing the subject compounds such as tablets, and capsule formulations, may be prepared.
  • Suitable examples thereof include semipermeable materials of solid hydrophobic polymers containing the subject compound which may be in the form of shaped articles, e.g., films or microcapsules, as well as various other polymers and copolymers known in the art.
  • the dosage effective amount of compounds according to the invention will vary depending upon factors including the particular compound, toxicity, and inhibitory activity, the condition treated, and whether the compound is administered alone or with other therapies. Typically a dosage effective amount will range from about 0.0001 mg/kg to 1500 mg/kg, more preferably 1 to 1000 mg/kg, more preferably from about 1 to 150 mg/kg of body weight, and most preferably about 50 to 100 mg/kg of body weight.
  • the subjects treated will typically comprise warm blooded species, such as mammals, and most preferably will be primate subjects, e.g., human cancer subjects.
  • the compounds of the invention may be used alone or in combination. Additionally, the treated compounds may be utilized with other types of treatments, e.g., cancer treatments. For example, the subject compounds may be used with other chemo- or other therapies, e.g., tamoxifen, taxol, methotrexate, biologicals, such as antibodies, growth factors, lymphokines, or radiation, RNAi, etc. Combination therapies may result in synergistic results.
  • chemo- or other therapies e.g., tamoxifen, taxol, methotrexate
  • biologicals such as antibodies, growth factors, lymphokines, or radiation, RNAi, etc.
  • Combination therapies may result in synergistic results.
  • dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
  • An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
  • An example of a suitable parenteral dosage range is often from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
  • An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
  • An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
  • compositions containing kinase modulators can be administered for therapeutic or prophylactic treatments. In therapeutic applications, compositions are administered to a patient suffering from a disease (e.g., a cancer) in an amount sufficient to cure or at least partially delay or arrest the disease and its complications.
  • a disease e.g., a cancer
  • a therapeutically effective dose An amount adequate to accomplish this is defined as a "therapeutically effective dose.” Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's health. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the agents of this invention to effectively treat the patient.
  • An amount of modulator that is capable of preventing or slowing the development of cancer in a mammal is referred to as a "prophylactically effective dose.” The particular dose required for a prophylactic treatment will depend upon the medical condition and history of the mammal, the particular cancer being prevented, as well as other factors such as age, weight, gender, administration route, efficiency, etc.
  • Such prophylactic treatments may be used, e.g., in a mammal who has previously had cancer to prevent a recurrence of the cancer, or in a mammal who is suspected of having a significant likelihood of developing cancer.
  • the compounds may be administered using targeted adjuncts; delivery systems; antibody linkages, localized activation, and other means to provide localized effect.
  • the present kinase-modulating compounds can be administered alone or in combination with additional modulating compounds or with other therapeutic agent, e.g., other anti-cancer agents or treatments.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des structures de composés destinées à moduler diverses kinases sélectionnées par la régulation des voies de signalisation de kinases correspondantes. Ces voies sont aptes à réguler des fonctions biologiques. Ces composés, et des variants similaires, peuvent être utiles dans des méthodes thérapeutiques ou diagnostiques liées à ces kinases. La présente invention permet en particulier d'améliorer les effets sur les voies fonctionnelles à médiation de kinases, par la modulation de combinaisons choisies de kinases.
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US86659406P 2006-11-20 2006-11-20
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US86658806P 2006-11-20 2006-11-20
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