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WO2013016720A2 - Nouveaux dérivés biaryl-hétérocycliques substitués en tant qu'inhibiteurs de protéine kinase pour le traitement du cancer et d'autres maladies - Google Patents

Nouveaux dérivés biaryl-hétérocycliques substitués en tant qu'inhibiteurs de protéine kinase pour le traitement du cancer et d'autres maladies Download PDF

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WO2013016720A2
WO2013016720A2 PCT/US2012/048741 US2012048741W WO2013016720A2 WO 2013016720 A2 WO2013016720 A2 WO 2013016720A2 US 2012048741 W US2012048741 W US 2012048741W WO 2013016720 A2 WO2013016720 A2 WO 2013016720A2
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substituted
compound
cancer
group
amino
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WO2013016720A3 (fr
Inventor
Magnus Pfahl
F. Javier PIEDRAFITA
Laxman Rao Cilamkoti VENKAT
Venugopal Rao VEERAMANENI
Bhaskar Venepalli
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GERINDA THERAPEUTICS Inc
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GERINDA THERAPEUTICS Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Gleevec® (Imatinib mesylate) in 2001 for the treatment of Chronic Myelogenous Leukemia (CML) represented a hallmark in cancer treatment, proving the principle of targeted drug development and encouraged further research on small molecules as novel targeted therapies.
  • Gleevec was first identified as an inhibitor of Bcr-Abl tyrosine kinase, and later found to inhibit cKIT and PDGFR as well. Inhibition of cKIT and PDGFR was the basis for the subsequent accelerated approval of Gleevec for advanced gastrointestinal tumors (GISTs).
  • GISTs advanced gastrointestinal tumors
  • Several other small molecule kinase inhibitors have since been approved for the treatment of various solid tumors, including the EGFR inhibitors Iressa® and Tarceva® and the multikinase inhibitors Nexavar® and Sutent®.
  • the inventors descibe a scaffold for small molecule kinase inhibitors that can yield highly selective inhibitors, including molecules useful for treating certain cases of Acute yelogeneous Leukemia (AML) as well as various solid tumors.
  • AML Acute yelogeneous Leukemia
  • FLT-3 FMS-like tyrosine kinase 3
  • FLT-3 is a receptor tyrosine kinase that catalyzes the phosphorylation of hydroxy groups on tyrosine residues of proteins.
  • Receptor tyrosine kinases comprise a large family of transmembrane receptors with diverse biological activity.
  • FLT-3 is a member of the Platelet Derived Growth Factor Receptor (PDGFR) tyrosine kinase subfamily and shares the structural features of KIT, FMS, and PDGFR.
  • PDGFR Platelet Derived Growth Factor Receptor
  • FLT-3 has five immunoglobulin-like domains in the extracellular region, a single transmembrane sequence, and an intracellular short juxtamembrane portion followed by the kinase domain (Blume-Jensen and Hunter, Nature, 2001, vol. 411 : 355-365). Its activation signals are transduced through phosphorylation of itself and cytoplasmic proteins in biochemical signaling pathways that promote uncontrolled cell growth and inhibit apoptosis.
  • FLT-3 Aberrant expression of FLT-3 occurs in the majority of AML patients (Birg, et al., Blood, 1992 vol. 80:2584-2593; Carow, et al. Blood, 1996, vol. 87:1089-1096). Moreover, up to 40% of AML patients have a mutated FLT-3 kinase such that the enzyme is constitutively active, resulting in the activation of downstream signaling molecules and uncontrolled growth of bone marrow stem cells.
  • ITD internal tandem duplication
  • the second type are point mutations, with mutations at residue D835 within the kinase domain occuring most frequently (-7%) (Yamamoto, et al., Blood, 2001 , vol. 97(8):2434-2439; Abu-Duhier, et al. Br J Haematol , 2001 , vol. 113(4):983-988). Both ITD and D835 mutations render FLT-3 constitutively active in the absence of FLT-3 ligand and patients carrying these mutations have a very poor prognosis (Abu-Duhier, et al., Br. J Haematol , 2000, vol. 111:190-195). Additional point mutations have been found at lower rates. This lethal blood cancer carries a grim prognosis with survival duration of five years for only 14% of patients. Consequently, there is a need for effective agents to treat both early and late stage diseases of AML.
  • the present invention relates to a novel class of kinase inhibitors that are substituted benzoxazole derivatives that inhibit FLT-3 mutants with high efficacy and specifically kill leukemic cells that carry the FLT-3 ITD mutation in vitro and in vivo.
  • these compounds efficiently inhibit the related kinase c-KIT (including Gleevec resistant mutants), and/or RET, and/or PDGFRa/ ⁇ in in vitro tests, and can therefore be expected to also be useful for treating cancers in which these kinases play a proliferative role.
  • the general chemical structures and specific examples shown in this specification cover molecules that belong to a new class of very selective kinase inhibitors that can serve as "targeted anticancer” agents and function by defined mechanisms, inhibiting specific kinases, very differently from drugs that are currently available for the treatment of myeloid leukemia and other cancers. Therefore, the heterocyclic compounds disclosed herein are useful in the treatment of diseases of uncontrolled proliferation including AML, gastrointestinal stromal cancers (GISTs), melanoma, and thyroid cancer, as well as other cancers and other diseases, including inflammation and atherosclerosis. Furthermore, these patentable new compounds are selective kinase inhibitors with good oral bioavailability.
  • This invention thus also relates to the use of such compounds for the treatment of solid tumor cancers, including, but not limited to, GISTs, certain forms of medullary thyroid cancer and renal cancer, as well as other diseases.
  • Pharmaceutical compositions comprising these compounds, methods of treating diseases and methods of preparing them, are also described.
  • combination therapy refers to a therapeutic regimen that involves the provision of at least two distinct therapies to achieve an indicated therapeutic effect.
  • a combination therapy may involve the administration of two or more chemically distinct active ingredients, for example, a substituted benzoxazole derivative according to the invention and another chemotherapeutic agent.
  • Combination therapy may, alternatively, involve administration of a substituted benzoxazole derivative according to the invention with the delivery of another treatment, such as radiation therapy and/or surgery.
  • a combination therapy may involve administration of a substituted benzoxazole derivative according to the invention together with one or more other biological agents (e.g., anti-VEGF, TGF , PDGF, or bFGF agent), chemotherapeutic agents, and another treatment such as radiation and/or surgery.
  • the active ingredients may be administered as part of the same composition or as different compositions.
  • the compositions comprising the different active ingredients may be administered at the same or different times, by the same or different routes, using the same of different dosing regimens, all as the particular context requires and as determined by the attending physician.
  • the drug(s) may be delivered before or after surgery or radiation treatment.
  • “Monotherapy” refers to a treatment regimen based on the delivery of one therapeutically effective compound, whether administered as a single dose or several doses over time.
  • a “patentable” composition, process, machine, or article of manufacture according to the invention means that the subject matter satisfies all statutory requirements for patentability at the time the analysis is performed. For example, with regard to novelty, non-obviousness, or the like, if later investigation reveals that one or more claims encompass one or more embodiments that would negate novelty, non-obviousness, etc., the claim(s), being limited by definition to “patentable” embodiments, specifically exclude the unpatentable embodiment(s).
  • the claims appended hereto are to be interpreted both to provide the broadest reasonable scope, as well as to preserve their validity. Furthermore, the claims are to be interpreted in a way that (1) preserves their validity and (2) provides the broadest reasonable interpretation under the circumstances, if one or more of the statutory requirements for patentability are amended or if the standards change for assessing whether a particular statutory requirement for patentability is satisfied from the time this application is filed or issues as a patent to a time the validity of one or more of the appended claims is questioned.
  • a "plurality” means more than one.
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the agents and compounds of this invention and which are not biologically or otherwise undesirable.
  • the agents and compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of charged groups, for example, charged amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • sample-holding vessel The terms “separated,” “purified,” “isolated,” and the like mean that one or more components of a sample contained in a sample-holding vessel are or have been physically removed from, or diluted in the presence of, one or more other sample components present in the vessel.
  • Sample components that may be removed or diluted during a separating or purifying step include, chemical reaction products, unreacted chemicals, proteins, carbohydrates, lipids, and unbound molecules.
  • kits is used herein in various contexts, e.g., a particular species of chemotherapeutic agent.
  • the term refers to a population of molecules, chemically indistinguishable from each other, of the sort referred in the particular context.
  • a “subject” or “patient” refers to an animal in which treatment can be effected by molecules of the invention.
  • the animal may have, be at risk for, or be believed to have or be at risk for a disease or condition that can be treated by compositions and/or methods of the present invention.
  • Animals that can be treated in accordance with the invention include vertebrates, with mammals such as bovine, canine, equine, feline, ovine, porcine, and primate (including humans and non-human primates) animals being particularly preferred examples.
  • a “therapeutically effective amount” refers to an amount of an active ingredient, e.g., a substituted benzoxazole derivative according to the invention, sufficient to effect treatment when administered to a subject or patient.
  • a therapeutically effective amount of a composition according to the invention may be readily determined by one of ordinary skill in the art.
  • the therapeutically effective amount will vary depending upon the particular subject and condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be
  • a therapeutically effective amount of the active ingredient when administered as a monotherapy constitutes a therapeutically effective amount of the active ingredient when administered as a monotherapy (ie., a therapeutic regimen that employs only one chemical entity as the active ingredient).
  • treatment or “treating” of a disease or disorder includes preventing or protecting against the
  • therapeutic regimen means any treatment of a disease or disorder using chemotherapeutic drugs, radiation therapy, surgery, gene therapy, DNA vaccines and therapy, antisense-based therapies including siRNA therapy, anti- angiogenic therapy, immunotherapy, bone marrow transplants, aptamers and other biologies such as antibodies and antibody variants, receptor decoys and other protein-based therapeutics.
  • the present invention is directed to a patentable new class of substituted benzoxazole derivatives that exhibit protein kinase (PK) inhibition activity or modulating ability and are therefore useful in treating diseases and disorders related to abnormal PK activity.
  • PK protein kinase
  • Ri, R2, R3.R11.R12 R21 , 22 , R23 , 24 , R25 , R28 , 29 and R30 are independently or together hydrogen, alkyl, substituted alkyl, haloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyl, substituted acyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcar
  • a related aspect of the invention provide methods of synthesizing the compounds of the invention.
  • this invention relates to pharmaceutical compositions comprising a compound described herein in admixture with one or more pharmaceutically acceptable excipients.
  • this invention relates to the use of the compounds described herein for inhibiting uncontrolled cellular proliferation such as various forms of cancer and leukemias, as well as for treating inflammatory diseases or atherosclerosis.
  • uncontrolled cellular proliferation such as various forms of cancer and leukemias
  • methods involve administering to a mammal diagnosed as having a disease of uncontrolled cellular proliferation or a composition comprising a compound according to the invention. .
  • FIGURE 1 illustrates the effect of Compounds 1, 2, and 3 on the growth of MV4-11 cells, which carry a FLT-3 ITD mutation.
  • Cells were treated for 48 hours with increasing concentrations of compounds and the percentage of cell growth was calculated with respect to control cells grown in the presence of 0.1% solvent (DMSO).
  • DMSO 0.1% solvent
  • FIGURE 2 depicts the selectivity of Compound 1 for FLT-3 mutant cells (MV4-11).
  • leukemia (AML) cells harboring wild type FLT-3 (HL-60 and HEL 92.1.7.) were not killed by Compound 1.
  • FIGURE 3 shows the pharmacokinetic profile of Compound 1 in a rat study.
  • Three rats were given a single oral dose of 5 mg/kg of Compound 1 and blood samples were obtained at different periods of time up to 24 h.
  • Plasma concentrations of Compound 1 (in nM) are given as a function of time.
  • FIGURE 4 illustrates the efficacy of Compound 1 in inhibiting tumor growth in an athymic mouse model of AML in which MV4-11 tumors are grown subcutaneously in nude mice. Mice were given a daily dose of vehicle or 10 mg/kg. At day 21 (arrow), the dosing schedule was increased to twice daily, with an 8 hours span between doses.
  • FIGURE 5 shows that Compound 1 had no significant effect on body weight during the length of treatment (38 days), indicating no major toxicity.
  • FIGURE 6 illustrates the size (A) and weight (B) of MV4-11 tumors isolated from nude mice after 38 days of treatment with Compound 1. Tumors in animals treated with Compound 1 were clearly smaller in size and weighed an average of 44% relative to tumors isolated from vehicle-treated animals.
  • FIGURE 7 shows a representative scheme of the synthetic pathway for the compounds disclosed herein in Formula 1, wherein m is 0.
  • the present invention provides compounds that are useful, for example, to prevent, alleviate or otherwise treat cancer and in particular AML, gastro intestinal cancer - including Gleevec resistant GISTs- and certain thyroid cancer in humans and other mammals.
  • compounds of the invention have demonstrated oral bioavailability as exhibited by their high blood levels after oral dosing, either alone or in the presence of an excipient. Oral bioavailability allows oral dosing for use in chronic diseases, with the advantage of self-administration and decreased cost over other means of administration.
  • alkyl denotes a radical containing 1 to 12 carbons, straight or branched chain group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.
  • alkenyl denotes a straight or branched chain hydrocarbon radical containing 1 to 12 carbons and a carbon-carbon double bond, such as vinyl, allyl, 2- butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like.
  • alkenyl includes dienes and trienes of straight and branch chains.
  • alkynyl denotes a straight or branched chain hydrocarbon radical containing 1 to 12 carbons and a carbon-carbon triple bond such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • alkynyl includes di- and tri-ynes.
  • substituted alkyl denotes a radical containing 1 to 12 carbons of the above definitions that are substituted with one or more groups, but preferably one, two or three groups, selected from hydroxyl, holagen, cycloalkyl, amino, mono- substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more than one group is present then they may be the same or different.
  • substituted alkenyl denotes a radical containing 1 to 12 carbons of the above definitions that are substituted with one or more groups, but preferably one, two or three groups, selected from halogen, hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more than one group is present then they may be the same or different.
  • substituted alkynyl denotes a radical containing 1 to 8 carbons of the above definitions that are substituted with one or more groups, but preferably one or two groups, selected from halogen, hydroxyl, cycloalkyl, amino, mono- substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, sub- stituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy.
  • cycloalkyi denotes a cyclic alkyi moiety containing 3 to 8 carbons, wherein alkyi is defined above, to include such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.
  • substituted cycloalkyi denotes a cycloalkyi as defined above that is further substituted with one or more groups, selected from halogen, alkyi, hydroxyl, alkoxy, substituted alkoxy, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, amino, mono-substituted amino ordi-substituted amino.
  • groups selected from halogen, alkyi, hydroxyl, alkoxy, substituted alkoxy, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, amino, mono-substituted amino ordi-substituted amino.
  • cycloalkenyl denotes a radical containing 3 to 8 carbons, such as cyclopropenyl, l-cyclobutenyl, 2- cyclobutenyl, l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like.
  • substituted cycloalkenyl denotes a cycloalkenyl as defined above further substituted with one or more groups selected from halogen, alkyi, hydroxyl, alkoxy, substituted alkoxy, haloalkoxy, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted, dialkylcarboxamide, amino, mono- substituted amino or di-substituted amino.
  • the cycloalkenyl is substituted with more than one group, they may be the same or different.
  • alkoxy denotes a radical alkyi, defined above, attached directly to an oxygen such as, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy and the like.
  • substituted alkoxy denotes a radical alkoxy of the above definition that is substituted with one or more groups, but preferably one or two groups, selected from, hydroxyl, cycloalkyi, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted
  • dialkylcarboxamide alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy.
  • mono-substituted amino denotes an amino substituted with one group selected from alkyi, substituted alkyi or arylalkyi wherein the terms have the same defini- tions found throughout.
  • di-substituted amino denotes an amino sub- stituted with two radicals that may be same or different selected from aryl, substituted aryl, alkyi, substituted alkyi or arylalkyi wherein the terms have the same definitions found throughout. Some examples include dimethylamino, methylethylamino, diethylamino and the like.
  • haloalkyl denotes a radical alkyi, defined above, substituted with one or more halogens, preferably fluorine, such as a trifiuoromethyl, pentafluoroethyl and the like.
  • haloalkoxy denotes a haloalkyl as defined above, that is directly attached to an oxygen to form trifluoromethoxy, pentafluoroethoxy and the like.
  • acyl denotes a radical containing 1 to 8 carbons such as formyl, acetyl, propionyl, butanoyl, iso- le butanoyl, pentanoyl. hexanoyl, heptanoyl, benzoyl and the like.
  • acyloxy denotes a radical containing 1 to 8 carbons of an acyl group defined above directly attached to an oxygen such as acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.
  • aryl denotes an aromatic ring radical containing 6 to 10 carbons that include phenyl and naphthyl.
  • substituted aryl denotes an aromatic radical as defined above that is substituted with one or more selected from hydroxyl, cycloalkyi, aryl, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino, 1 mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted I dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, alkylthio, I alkoxy, substituted alkoxy or haloalkoxy, wherein the terms are defined herein.
  • halo or “halogen” refers to a fluoro, chloro, bromo or iodo group.
  • thioalkyl denotes a sulfide radical containing 1 to 8 carbons, linear or branched. Examples include methyl sulfide, ethyl sulfide, isopropyl sulfide and the like.
  • thiohaloalkyl denotes a thioalkyl radical substituted with one or more halogens. Examples include trifluoromethylthio, 1,1-difluoroethylthio, 2,2,2- trifluoroethylthio and the like.
  • alkyl ester refers to an alkyl ester of a carboxylic acid, wherein alkyl has the same definition as found above. Examples include carbomethoxy, carboethoxy, carboisopropoxy and the like.
  • alkylcarboxamide denotes a single alkyl group attached to the amine of an amide, wherein alkyl has the same definition as found above. Examples include N-methylcarboxamide, N-ethylcarboxamide, N-isopropylcarboxamide and the like.
  • substituted alkylcarboxamide denotes a single “substituted alkyl” group, as defined above, attached to the amine of an amide.
  • dialkylcarboxamide denotes two alkyl or arylalkyl groups that are the same or different attached to the amine of an amide, wherein alkyl has the same definition as found above.
  • Examples of a dialkylcarboxamide include N,N - dimethylcarboxamide, N -methyl-N -ethyl carboxamide and the like.
  • dialkylcarboxamide denotes two alkyl groups attached to the amine of an amide, where one or both groups are a "substituted alkyl", as defined above. It is understood that these groups may be the same or different. Examples include N,N-dibenzylcarboxamide, N-benzyl-N-methylcarboxamide and the like.
  • alkylamide denotes an acyl radical attached to an amine or monoalkylamine, wherein the term acyl has the same definition as found above.
  • alkylamide include acetamido, propionamido and the like.
  • arylalkyl defines an alkylene, such as -CH2- for example, which is substituted with an aryl group that may be substituted or unsubstituted as defined above.
  • alkylene such as -CH2- for example
  • arylalkyl examples include benzyl, phenethylene and the like.
  • an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- repeat units in the polyester, regardless of whether ethylene glycol is used to prepare the polyester.
  • any variable, moiety, group, or the like occurs more than one time in any variable or structure of compound of the invention, its definition at each occurrence is independent of its definition at every other occurrence. All percentages, ratios, and proportions used herein are by weight unless otherwise specified. Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only, and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • the compounds of the invention are patentable compounds of formula I having any combination of the values, specific values, more specific values, and preferred values described herein.
  • W is (a) or (b) or (c) or (d)
  • D and E are together or independently -CR30-, or -N-;
  • Ar is formula (e), or ( f) or (g) or (h)
  • n 0 to 1
  • Ri R2 f3 ⁇ 4,Rii ,Ri2 R21 R22,R23, 24,R25, R28, 29 and R30 are independently or together hydrogen, alkyl, substituted alkyl, haloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyl, substituted acyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcar
  • A is -CR21 R22-, -NR23-, -0-, or -S- ;
  • B is -OR24,-SR25, -NR28R29;
  • D and E are together or independently -CR30-, or -N-.
  • Preferred heterobicyclic residues may be selected from
  • compounds of formula (1 ) disclosed herein may exist in the form of tautomers (1 ) and (2), which are within the scope of the invention.
  • the compounds disclosed herein may also include salts of the compounds.
  • salt refers to a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group.
  • Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts.
  • Preferred anionic salts include the halides (such as, for example, chloride salts).
  • one or more compounds disclosed herein may include salts formed by reaction of a nitrogen contained within the compound, such as an amine, aniline, substituted aniline, pyridyl and the like, with an acid, such as HCI, carboxylic acid and the like. Therefore, all possible salt forms in relationship to the tautomers and a salt formed from the reaction between a nitrogen and acid are within the scope of the invention. When intended for administration to a subject, such salts should be appropriate for such use.
  • pharmaceutically acceptable means suitable for use in humans, whereas “veterinarily acceptable” means suitable for use in non-human animals, particularly non-human mammals.
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are not biologically or otherwise undesirable.
  • the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • pharmaceutically acceptable salts see, e.g., Berge, et al. ((1977) J. Pharm. Sci, vol. 66, 1).
  • non-toxic pharmaceutically acceptable salts non-toxic salts formed with nontoxic, pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, fumaric, methanesulfonic, trifluoromethanesulfonic, and toluenesulfonic acid and the like.
  • Salts also include those from inorganic bases, such as ammonia, sodium hydroxide, potassium hydroxide, and hydrazine.
  • Suitable organic bases include methylamine, ethylamine, propylamine, dimethylamine, diethylamine, diethanolamine, trimethylamine, triethylamine, triethanolamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine, and guanidine.
  • the present invention also includes other forms of the compounds of the invention, including prodrug forms.
  • a "prodrug” is a compound that contains one or more functional groups that can be removed or modified in vivo to result in a molecule that can exhibit therapeutic utility in vivo. [Magnus, if you are aware of any prodrug example sof the compounds of the invention, it may be useful to provide an exemplary structure after the structures for compounds 1-10.]
  • the present invention provides, but is not limited to, the specific compounds set forth in the Examples as well as those set forth below, and a pharmaceutically acceptable salt thereof: m is 0:
  • the compounds of the invention can be synthesized by any suitable method.
  • a representative scheme of the synthetic pathway in the production of the compounds of the invention is shown in FIG. 7, and is described below.
  • Coupling reaction such as that described for the formation of Biaryl (XXIV) may be conducted using boronic esters, such as where RI5 together with the boron form a pinacol borate ester (formation of pinacol esters: Ishiyama, et al., J. Org. Chem., 1995, vol. 60,7508-7510, Ishiyama, et al., Tetrahedron Letters, 1997, vol.
  • Some embodiments of the invention provide a process for the preparation of a compound of the Formula (XXII):
  • W is (a),(b),(c),or (d)
  • B is -OR 2 4,-SR 25 -NR28R29;
  • D and E are together or independently -CR30-, or -N-;
  • Ar is formula (e) or (f) or (g) or (h)
  • Ri, R2, R3, R21, 22 , 23 , 24 , 25 , R28 , R29 an d R30 are independently or together hydrogen, alkyl, substituted alkyl, haloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyl, substituted acyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkyl
  • R1 is linear alkyi chain or branched alkyi chain or cyclic alkyi group 6
  • the product is of the formula (XXI).
  • One embodiment of the invention relates to the processes for making compounds of Formula I, which comprises coupling two aromatic rings to give a biaryl wherein one of the aryl rings contains a carbonyl moiety, preferably an aldehyde.
  • the resulting biaryl aldehyde can be converted to biaryl acid and condense with amines in presence of coupling reagents
  • Coupling of two aryl rings may be conducted using an aryl boronic acid or esters with an aryl halide (such as, iodo, bromo, or chloro), triflate or diazonium tetrafluoroborate; as described respectively in Suzuki, Pure & Applied Chem., 66:213-222 (1994), Miyaura and Suzuki, Chem. Rev. 95:2457-2483 (1995), Watanabe, Miyaura and Suzuki, Syn- lett. 207-210 (1992), Littke and Fu,Angew. Chem. Int.
  • an aryl halide such as, iodo, bromo, or chloro
  • triflate or diazonium tetrafluoroborate as described respectively in Suzuki, Pure & Applied Chem., 66:213-222 (1994), Miyaura and Suzuki, Chem. Rev. 95:2457-2483 (1995), Watanabe, Miyaura and Suzuki,
  • precursors such as (X), (XX) and (XXX) may be employed:
  • (X) is either a triflate, a halide (such as, iodo, bromo, or chloro), or diazonium tet- rafluoroborate or hydrogen and R15 is either alkyl or hydrogen .
  • a halide such as, iodo, bromo, or chloro
  • R15 is either alkyl or hydrogen .
  • the coupling groups may be reversed.
  • the boronic ester may be prepared from an aryl halide by conversion into the corresponding aryl lithium, followed by treatment with a trialkyl borate.
  • the boronic ester is hydrolyzed to the boronic acid.
  • the coupling reaction may also be conducted between an arylzinc halide and an aryl halide or triflate. Alternately, the coupling reaction may also be executed using an aryl trialkyltin derivative and an aryl halide or triflate.
  • These coupling methods are reviewed by Stanforth, Tetrahedron 65 54:263-303 (1998) and incorporated herein by reference. In general, the utilization of a specific coupling procedure is selected with respect to available precursors, chemoselectivity, regioselectivity and steric considerations.
  • the acid compounds (XXII) can be coupled with cyclic amine in presence of coupling reagents, DCC, HOBT, EDC.HCI or HATU and tertiary amine as the base
  • the coupling can be carried out using combination of EDC.HCI and HOBT, or HATU.
  • the compounds of the present invention have been found to be potent compounds in a number of biological assays, both in vitro and in vivo, that correlate to, or are representative of, human diseases.
  • the compounds that inhibit FLT-3 kinase are cytotoxic to leukemic cells.
  • Compound 1 has a highly specific kinase binding profile when tested against approximately 442 different kinases, including mutated kinases as for instance in the case of FLT3 and KIT (see Table 1), as measured using the Ambit kinase screening platform (Fabian, et al., Nature Biotechnology, 2005, vol. 23:329- 336).
  • Table 3 depicts the binding constants (Kd) for Compound 1 with the most relevant kinases. Of note is a Kd value of 28 nM observed with FLT-3 ITD mutant that is most frequently found in AML patients.
  • the selective biological response of inhibition of FLT-3 was tested in a cell proliferation assay with MV4-11 cells.
  • human AML cells which express FLT-3 ITD mutant, were aliquoted into 96-well plates each with different concentrations of Compound 1 , 2, or 3.
  • Cell proliferation assays using 3-4,5-dimethylthiazol-2,5-diphenyltetrazoilum (MTT) were conducted to measure inhibition of cell proliferation and cell killing of the human AML cell line MV4-11.
  • Compounds 1 , 2, and 3 dramatically inhibited cellular proliferation (cell growth below 100%) at low concentrations and killed (growth percentage shown as negative values) MV4-11 cells at concentrations of 1 ⁇ or higher ( Figure 1).
  • Table 4 illustrates that compounds 1 , 2, and 3 do not inhibit the growth of any leukemia cells containing wild type FLT-3 and only a few cancer cell lines were dramatically affected by a high concentration (10 ⁇ ) of the compounds. Thus, only Caki-1 renal cancer cells and KM-12 colon carcinoma cells were most significantly growth inhibited by compounds 1, 2, and 3. These compounds inhibited MV4-11 cells with IC50 values between 0.2 and 0.45 ⁇ , whereas KM-12 cells were inhibited with IC50 values between 1.1 and 1.5 ⁇ (see Table 5, below).
  • Compound 1 is a selective FLT-3 inhibitor with potent cell killing effects on FLT-3 ITD mutant MV4-11 cells.
  • a single oral dose of 5 mg/Kg of Compound 1 was given to 3 rats. Blood samples were removed at various time points for analysis of drug levels.
  • the single oral dose of compound 1 produced plasma drug concentration of about 1 ⁇ within 1 hour and reached a maximal concentration (C ma x) of 1.4 ⁇ within 2 hours and an overall peak that extended for 8 hours (see Figure 3).
  • C ma x maximal concentration
  • the maintenance of high plasma drug levels for several hours and good bioavailability suggest that compound 1 could be administered orally twice a day for a more effective dosing.
  • a subcutaneous tumor xenograft model was used to assess the effects of Compound 1 in vivo.
  • Athymic nude mice injected with cells expressing constitutively activated FLT-3 (FLT-3 ITD) is a proven model of leukemia (O'Farrell, et al., Blood, 2003, vol. 101 : 3597-3605). These mice typically sicken and die within a few weeks following subcutaneous injection of MV4-11 cells, with large spleens full of leukemic cells.
  • MV4-11 a human leukemia cell line that expresses a FLT-3-ITD mutation were harvested during exponential growth and were resuspended in matrigel (BD Biosciences, Bedford, MA).
  • Athymic nude mice were injected with 5 x 10 6 MV4-11 cells near the hind flank on day 0.
  • the therapeutic effects of daily oral administration of Compound 1 were evaluated in this animal model.
  • One group of mice was treated with 10 mg/kg of Compound 1 administered orally once a day and a second group was treated with vehicle (placebo).
  • Tumor volumes were measured twice/week using vernier caliper for the duration of treatment and volumes were calculated as ellipsoid volumes (Tomayko and Reynolds, Cancer Chemother Pharmacol,, 1989, vol. 24(3): 148-154).
  • Figure 4 demonstrates that Compound 1 significantly inhibited tumor growth in this model. Because the pharmacokinetic profile observed in Figure 3 demonstrates that compound 1 is cleared from the system soon after 8 h, we increased the dosing schedule of compound 1 to twice daily after day 21 (as indicated with an arrow in Figure 4). Figure 5 shows that body weight was not significantly affected by compound 1. Overall, a dramatic effect of tumor growth inhibition was observed with Compound 1, with no overt signs of toxicity.
  • a preferred embodiment of the invention relates to the use of the compounds disclosed herein.
  • the compounds disclosed herein may be either used singularly or plurally, and pharmaceutical compositions thereof for the treatment of mammalian diseases, particularly those related to humans.
  • Compounds disclosed herein and compositions thereof may be administered by various methods including, for example, orally, enterally, parentally, topically, nasally, vaginally, ophthalinically, sublingually or by inhalation for the treatment of leukemic and other cancers including A L and certain solid tumors.
  • Routes of administration and dosages known in the art may be found in comprehensive medicinal chemistry, volume S, Hanscb, C. Pergamon Press, 1990 [Magnus, this citation needs to be completed].
  • compositions may also be used as regulator in diseases of uncontrolled proliferation.
  • a representative but non-limiting list of cancers is myeloid leukemia, GISTs, medullar thyroid cancer, renal cancer, lymphoma, Hodgkin's disease, bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung cancers such as small cell lung cancer and non-small cell lung cancer, myeloma, neuroblastoma glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, colon cancer, cervical carcinoma, breast cancer, and skin cancer.
  • the compounds described herein may be administered as pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition.
  • compositions comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together without more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the composition and not overly deleterious to the recipient thereof.
  • compositions include those suitable for oral, enteral, parental (including intramuscular, subcutaneous and intravenous), topical, nasal, vaginal, ophthalinical, sublingually or by inhalation administration.
  • the compositions may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi- solid carrier, finely divided solid carrier or combination thereof, and then, if necessary, shaping the product into the desired delivery system.
  • compositions suitable for oral administration may be presented in a discrete unit dosage form; such as hard or soft gelatin capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art, e.g., with enteric coatings.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solution, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or one or more preservative.
  • the compounds may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-does containers with an added preservative.
  • the composition may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the com- pounds may be formulated as ointments, creams or lotion, or as the active ingredient of a transdermal patch. Suitable transdermal delivery systems are disclosed, for example, in Fisher, et al. (U.S. Pat. No.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition or suitable thickening and/or gelling agents.
  • Lotion may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active ingredient may also be delivered via iontophoresis, e.g., as disclosed in U.S. Pat. Nos.4,140,122, 4383,529, or 4,051 ,842.
  • compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the above-described compositions may be adapted to provide sustained release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic
  • compositions according to the invention may also contain other adjuvants such as flavorings, coloring, antimicrobial agents, or preservatives.
  • adjuvants such as flavorings, coloring, antimicrobial agents, or preservatives.
  • amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a model organism such as an athymic nude mouse
  • another mammal such as a human.
  • a suitable dose will, in alternative embodiments, typically be in the range of from about 0.5 to about 100 mg/kg/day, from about 1 to about 75 mg/kg of body weight per day, from about 3 to about 50 mg per kilogram body weight of the recipient per day, or in the range of 6 to 90 mg/kg/day.
  • the compound is conveniently administered in unit dosage form; for example, in alternative embodiments, containing 0.5 to 5000 mg, 5 to 750 mg, most conveniently, or 10 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient may be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ , about: 1 to 50 ⁇ , or about 2 to about 30 ⁇ . This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.5-500 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredients.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • kinases were tested at 10 ⁇ against a panel of 442 kinases. This collection of kinases included the most common FLT-3, cKIT, and RET mutations found in cancer patients. Kinase assays and binding constant measurements were done as described in Fabian et al (A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnology, 2005, 23:329-336). Briefly, the human kinases are tagged with T7 bacteriophage DNA, which is combined with immobilized active-site directed ligand and the free test compounds. The amount of T7- tagged protein bound to the solid support via the immobilized ligand is measured via quantitative PCR of the DNA tag.
  • Table 2 illustrates the selectivity score for compound 1. This score represents a quantitative measure of compound selectivity and is calculated taking into account the total number of distinct kinases, not considering mutant forms. For example compound 1 inhibits 24 kinases out of 386 by 90% or more and therefore the S(10) value is 0.062 (or 6.2% of all kinases). Nine (9) kinases are inhibited by 99% or more, which translates into a S(1 ) of 0.023.
  • PDGFR mutations have also been found in GISTs (Heinrich et al, PDGRFA activating mutations in gastrointestinal stromal tumors; Science, 2003, 299:708-710), whereas RET activating mutants are found in patients with medullary thyroid carcinoma (Phay and Shah, Targeting RET receptor tyrosine kinase activation in cancer; Clin Cancer Res, 2010, 16:5936-5941).
  • the biological response of FLT-3 inhibition was tested in a cell proliferation assay with the human A L cell line MV4- 11.
  • This cell line carries the most frequent human FLT-3 mutation, FLT-3 ITD and does not express wild type FLT-3.
  • the selectivity of cell killing was tested by comparing the effect of compounds on the V4-11 cell line with their effects on the proliferation of two other leukemia cells bearing wild type FLT-3 (HL-60 and HEL 92.1.7).
  • Cell proliferation was measured using 34,5-dimethylthiazol-2,5- diphenyltetrazoilum (MTT) assay. Briefly, cells were aliquoted into 96 well plates.
  • MV4- 11, HL-60, and HEL 92.1.7 cells were grown in RPMI medium containing 4500 mg/L glucose; 4 mM L-glutamine; 10 U/ml Pen-G; 10 mcg/ml and 10% heat-inactivated fetal bovine serum (FBS).
  • FBS heat-inactivated fetal bovine serum
  • Cells were seeded at 40,000 cells/well in 96-well tissue culture plates and maintained at 5% CO2 and 37°C. Cells were treated with test compounds or vehicle for two days. The percentage of surviving cells and cell proliferation were then measured colorimetrically.
  • the assay is based on the cleavage of the yellow tetrazolium salt MTT to purple formazan crystals by dehydrogenase activity in active mitochondria. Therefore, this conversion only occurs in living cells with intact/functional mitochondria.
  • the formazan crystals formed are solubilized and the resulting colored solution is quantified using a scanning multiwell
  • spectrophotometer at 595 nm. Briefly, 10 ⁇ of 5 mg/ml MTT dye are added to each well and incubated for 4 hours and the reaction was stopped by adding 100 ⁇ /well of solubilization solution, consisting of 10% Sodium Dodecyl Sulfate (SDS) and 10 mM HCI. To determine cell growth, the MTT colorimetric reaction (readings at 595 nm) was also taken at time 0 in a duplicate plate and the difference between 48 h and time 0 was normalized to 100% as percentage control growth. Cell killing by test compounds is thus visualized as negative growth values in such representation.
  • solubilization solution consisting of 10% Sodium Dodecyl Sulfate (SDS) and 10 mM HCI.
  • the NCI60 Human Tumor Cell Line anticancer drug screen has been used to evaluate the growth inhibitory activity of Compounds 1-3 against a panel of 60 cancer cell lines representing nine distinct tumor types, including leukemia, lung, colon, CNS, prostate, breast, ovarian, renal, and melanoma (Shoemaker,R.H. The NCI60 human tumour cell line anticancer drug screen. Nat Rev. Cancer, 2006; 6, 813-823). In a typical screen, anticancer drugs are initially tested at a single concentration of 10 ⁇ .
  • a single oral dose of 5 mg/Kg of compound 1 was given to 3 Sprague Dawley rats. Blood samples were removed at various time points (0.5, 1 , 1.5, 2, 4, 6, 8, and 24 hours) for analysis of drug levels in plasma.
  • Figure 3 demonstrates that Compound 1 showed good bioavailability.
  • the single dose of 5 mg/Kg of Compound 1 administration produced plasma drug concentration above 1 ⁇ within 1.5 hours and reached a maximal concentration (Cmax) of 627 ⁇ 106 ng/L (1.39 ⁇ 0.24 ⁇ ) at 2 h, with an overall peak that extended over 6 hours.
  • the half time of compound 1 was 2.02 h and the mean residence time [ RT(0- ⁇ )] was 4.23 h.
  • the maximum accumulated amount [AUC(0- ⁇ )] of compound 1 was 3245 ⁇ 360 ng/L*h (7.19 ⁇ 0.8 ⁇ ).
  • Compound 1 was below detection limits at the 24 h time point.
  • the maintenance of high plasma drug levels for several hours and good oral bioavailability suggest that compound 1 could be administered orally once a day, although a twice daily dosing could also be more beneficial.
  • Example 5 Oral administration of compound 1 in the treatment of AML tumors in an animal model
  • a subcutaneous tumor xenograft model was used to assess the anticancer activity of compound 1 in vivo.
  • MV4-11 cells were harvested during exponential growth and were resuspended in Matrigel (BD Biosciences, Bedford, MA).
  • Athymic nude mice were injected with 10 million MV4-11 cells near the hind flank.
  • mice were allocated into two separate groups of 10 animals per group.
  • One group received vehicle (control group); the second group received a single oral daily dose of 10 mg/kg compound 1 (treatment group).
  • Figure 4 illustrates that Compound 1 significantly inhibited the growth of MV4-11 tumors in nude mice.
  • Figure 5 demonstrates that Compound 1 had no significant effect on body weight, suggesting the lack of major toxicity. This was corroborated by daily observations of the animals. The experiment was ended and animals were sacrificed when tumor volume reached an average size over 1500 mm 3 and tumor burden in the control untreated group was affecting the quality of life. Tumors were isolated and weighted.
  • Figure 6 illustrates that tumors in the drug treated group were significantly smaller compared to tumors in the vehicle control group.
  • the average weight of tumors in compound 1 -treated animals was about 40% that of vehicle-treated group.
  • This experiment demonstrates that compound 1 efficiently inhibits tumor growth in a MV4-11 xenograft model with no overt signs of toxicity. Improved efficacy could be obtained with enhanced doses of compound 1 and/or additional dosing schedules from the beginning of treatment.

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Abstract

La présente invention concerne une nouvelle classe brevetable de composés dérivés de benzoxazole substitués qui présentent une activité inhibitrice ou une capacité de modulation de protéine kinase (PK), ainsi que des compositions et procédés d'utilisation de tels composés, par exemple, pour prévenir ou traiter diverses maladies et divers troubles chez des êtres humains et des animaux non humains.
PCT/US2012/048741 2011-07-28 2012-07-28 Nouveaux dérivés biaryl-hétérocycliques substitués en tant qu'inhibiteurs de protéine kinase pour le traitement du cancer et d'autres maladies Ceased WO2013016720A2 (fr)

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WO2018136661A1 (fr) 2017-01-18 2018-07-26 Andrews Steven W Composés de pyrazolo[1,5-a]pyrazine substitués utilisés en tant qu'inhibiteurs de la kinase ret
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
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