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WO2011008788A1 - Composés à substitution fluoro en tant qu'inhibiteurs de kinase et leurs méthodes d'utilisation - Google Patents

Composés à substitution fluoro en tant qu'inhibiteurs de kinase et leurs méthodes d'utilisation Download PDF

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WO2011008788A1
WO2011008788A1 PCT/US2010/041872 US2010041872W WO2011008788A1 WO 2011008788 A1 WO2011008788 A1 WO 2011008788A1 US 2010041872 W US2010041872 W US 2010041872W WO 2011008788 A1 WO2011008788 A1 WO 2011008788A1
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methyl
compound
pyridin
pyrimidin
fluoro
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Dawei Zhang
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/04—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 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates generally to the field of pharmaceutical agents and, more specifically, to pharmaceutically active compounds, pharmaceutical compositions and methods of use thereof, to treat various oncology diseases.
  • the invention also relates to intermediates and processes useful in the preparation of such compounds.
  • Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates.
  • the phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate.
  • Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue.
  • protein tyrosine kinases are enzymes, which catalyze the phosphorylation of specific tyrosine residues in cellular proteins.
  • kinases in the protein kinase family include, without limitation, AbIl (v-Abl Abelson murine leukemia viral oncogene homolog 1), Akt, Bcr-Abll, BIk, Brk, Btk, c-Kit, c-Met, c-Src, c-Fms, CDKl-10, cRafl, CSFlR, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, FIt-I, Fps, Frk, Jak, KDR, MEK, PDGFR, PIK, PKC, PYK2, Ros, Tie, Tie2, and Zap70. Due to their activity in numerous cellular processes, PTKs have emerged as important therapeutic targets.
  • AbIl v-Abl Abelson murine leukemia viral oncogene homolog 1
  • Akt Akt
  • Bcr-Abl protein In chronic myelogenous leukemia (CML), the Philadelphia chromosome leads to a fusion protein of AbI with Bcr (breakpoint cluster region), termed Bcr-Abl protein.
  • Bcr-Abl protein The Abl-part of the Bcr-Abl protein becomes a constitutively active PTK.
  • This deregulated PTK interacts with multiple cellular signaling pathways and results in transformation and deregulated proliferation of the cells [T.G. Lugo et al., Science 247, 1079-1082 (1990)].
  • GISTs gastrointestinal stromal tumors
  • c-kit which encodes a transmembrane receptor for a growth factor termed Scf (stem cell factor).
  • Scf stem cell factor
  • Mutations generally occur in the intracellular part, which acts as a PTK to activate other enzymes. Mutations make c-Kit function independent of activation by Scf, leading to a high cell division rate and possibly genomic instability.
  • the active sites of PTKs each have a binding site for ATP.
  • Individual PTKs can be inhibited by small molecule therapeutics designed to specifically fit into and occupy the active site, thereby modulating the enzyme activity of the protein.
  • small molecule therapeutics designed to specifically fit into and occupy the active site, thereby modulating the enzyme activity of the protein.
  • U.S. Patent No. 5,543,520 and 5,521,184 describes a variety of PTK inhibitors which are developed for the treatment of different types of clinical conditions. Hence, it is desirable to identify additional compounds which target one or more PTKs and can be used to treat diseases caused by over- activation of specific PTKs.
  • the compounds provided by the invention including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by general Formula I,
  • R 1 is -NHX
  • R 2 is -NHC(O)R 4 ;
  • X is a pyridine or pyrimidine ring optionally substituted independently with one or more substituents of R 5 ;
  • R 4 is a phenyl ring optionally substituted with one or more substituents of R ;
  • R 5 is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo, acetyl, benzyl, cyclopropyl, C 2- io- alkenyl, C 2 _io-alkynyl, or R is a pyridine or pyrimidine ring optionally substituted independently with one or more substituents of R 7 ;
  • R 6 is H, halo, haloalkyl, CN, NO 2 , C 1-10 -alkyl, C 2
  • R 7 is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl, tert-butyl, methylamino,
  • ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein said ring system is optionally substituted independently with 1 -5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamin
  • R 8 and R 9 taken together with the atom to which they are attached form a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and said ring optionally substituted independently with 1-5 substituents of R 7 .
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • herein provides methods for regulating the tyrosine kinase signaling transduction comprising administrating to a mammalian subject a therapeutically effective amount of a compound of Formula I.
  • methods for treating or preventing a Bcr-Abl, c-Kit, or PDGF-R mediated disorder said method comprises administrating to a mammalian subject a therapeutically effective amount of a compound of Formula I.
  • methods for treating neoplasia comprising administrating to a mammalian subject in need thereof, a therapeutically effective amount of a compound of Formula I.
  • the present invention also provides methods for making compounds of Formula I, and intermediates useful in such procedures.
  • the compounds provided by the invention are capable of modulating the tyrosine kinases enzyme such as AbI, c-Kit or PDGF-R etc.
  • the compounds including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by general Formula I:
  • R 1 is -NHX
  • R 2 is -NHC(O)R 4 ;
  • X is a pyridine or pyrimidine ring optionally substituted independently with one or more substituents of R 5 ;
  • R 4 is a phenyl ring optionally substituted with one or more substituents of R 6 ;
  • R 5 is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo, acetyl, benzyl, cyclopropyl, C 2 _io- alkenyl, C 2 _io-alkynyl, or R 5 is a pyridine or pyrimidine ring optionally substituted independently with one or more substituents of R 7 ;
  • R 6 is H, halo, haloalkyl, CN, NO 2 , C 1-10 -alkyl,
  • R 7 is H, halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl, tert-butyl, methylamino,
  • ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein said ring system is optionally substituted independently with 1 -5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamin
  • R 8 and R 9 taken together with the atom to which they are attached form a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and said ring optionally substituted independently with 1-5 substituents of R 7 .
  • X is selected from the group consisting of: 4-(pyridin-3-yl)pyrimidin-2-yl, 4,5'-bipyrimidin-2-yl, 2,3'- bipyridin-6-yl, 3,4'-bipyridin-2'-yl; 4-(pyrimidin-5-yl)pyridin-2-yl, and 6-(pyrimidin-5- yl)pyridin-2-yl.
  • X is 4-(pyridin-3-yl)pyrimidin-2-yl.
  • X is 4,5'-bipyrimidin-2-yl.
  • R 4 is a phenyl optionally substituted with one or more substituents of R 6 .
  • R 6 is F, Cl or CF 3 .
  • R is (4-methylpiperazin-l-yl)methyl, (4-ethylpiperazin-l- yl)methyl, piperazin-1-ylmethyl or 4-methyl-lH-imidazol-l-yl.
  • the compound of Formula I is in the form of
  • the compound of Formula I is a hydrochloride, benzenesulfonate, or methanesulfonate salt. In some embodiments, the compound of Formula I is in the form of a solvate. In other embodiments, the compound of Formula I is in the form of a metabolite. In other embodiments, the compound of Formula I is in the form of a prodrug.
  • the selected compound is in the form of pharmaceutically acceptable salt.
  • the selected compound is a hydrochloride
  • the selected compound is in the form of a solvate. In other embodiments, the selected compound is in the form of a metabolite. In other embodiments, the selected compound is in the form of a prodrug.
  • compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • the compositions are for the treatment of a disease regulated by a protein kinase.
  • the pharmaceutical compositions further comprise an antineoplastic agent, an immunosuppressant, an immunostimulant, or combination thereof.
  • the pharmaceutical compositions are suitable for oral, parenteral, or intravenous administration.
  • the present invention provides methods for regulating the tyrosine kinase signaling transduction comprising administering to a mammalian subject a therapeutically effective amount of a compound of Formula I.
  • inventions provide herein methods for treating or preventing AbI, c-Kit or PDGF-R mediated disorder, said method comprises administering to a mammalian subject a therapeutically effective amount of a compound of Formula I.
  • the neoplasia is selected from leukemias, colon carcinoma, renal cell carcinoma, gastrointestinal stromal cancer, solid tumor cancer, multiple myeloma, breast cancer, pancreatic carcinoma, non-small cell lung cancer, non-Hodgkin' s lymphoma, hepatocellular carcinoma, thyroid cancer, bladder cancer, colorectal cancer, and prostate cancer.
  • the neoplasia is chronic myelogenous leukemia, or gastrointestinal stromal cancer.
  • the methods further comprising administering one or more anti-cancer agents.
  • halo when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • alkyl refers to a straight or branched chain or cyclic chain
  • hydrocarbon radical with only single carbon-carbon bonds Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted.
  • Alkyl groups are Ci-Cio.
  • alkenyl when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and ten carbon atoms.
  • alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl.
  • alkenyl and lower alkenyl embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations, as appreciated by those of ordinary skill in the art.
  • alkynyl when used alone or in combination, denotes linear, cyclic or branched radicals having at least one carbon-carbon triple bond and having two to ten carbon atoms. Examples of such radicals include, without limitation, ethynyl, propynyl
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl, bicylic aryl (e.g., naphthyl) and biaryl groups (e.g., biphenyl), all of which may be optionally substituted.
  • haloalkyl refers to a lower alkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difuoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like.
  • heteroaryl are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl N-oxide, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl,
  • the term "lower” refers to herein in connection with organic radicals or compounds respectively defines such radicals or compounds as containing up to and including 10 carbon atoms.
  • One aspect of this invention provides organic radicals or compounds as containing up to and including 6 carbon atoms.
  • Yet another aspect of the invention provides organic radicals or compounds that contain one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon.
  • a pharmaceutically acceptable when used with reference to a compound of Formula I is intended to refer to a form of the compound that is safe for administration to a subject.
  • a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound of Formula I which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.
  • FDA Food and Drug Administration
  • salts Included in the compounds of Formula I are the pharmaceutically acceptable salt forms of the free-base compounds.
  • pharmaceutically-acceptable salts embraces salts, commonly used to form alkali metal salts and to form addition salts of free acids or free bases, which have been approved by a regulatory agency. Salts are formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula I with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound of Formula I with a base to form a salt.
  • compositions described herein, in some embodiments are formed as, and/or used as, pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or with an organic acid, such as, for example, acetic acid, propionic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic
  • salts formed when an acidic proton present in the parent compound is replaced by a metal ion e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion.
  • a metal ion e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion.
  • compounds described herein coordinate with an organic base from basic nitrogen-containing groups, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a compound of Formula I is a hydrochloric
  • derivative is broadly construed herein, and intended to encompass any salt of a compound of this invention, any ester of a compound of this invention, or any other compound, which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to modulate a kinase enzyme.
  • prodrug denotes a compound which upon
  • administration to a subject or patient is capable of providing (directly or indirectly) a compound of this invention, i. e. active ingredient, as a result of spontaneous chemical reaction (s), enzyme catalyzed chemical reaction (s), and/or metabolic chemical reaction (s), or a combination of each.
  • a "pharmaceutically-acceptable prodrug” as used herein denotes a prodrug, which is pharmaceutically acceptable.
  • Prodrugs are described in R.B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego (1992) Chapter 8: Prodrugs and Drug delivery Systems pp 352-401 ; in H.
  • the compound(s) of Formula I are used to treat a subject by administering the compound(s) as a pharmaceutical composition.
  • the compound(s) in one embodiment, can be combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.
  • excipient denotes any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active
  • composition which is typically included for formulation and/or administration purposes.
  • “Diluent” and “adjuvant” are defined hereinafter.
  • diluent refers to an agent or mixture of agents that when added to a formulation makes that formulation thinner or less concentrated and may also improve manufacturability. Diluents of the present invention can also serve other functions. For example, a diluent can also serve as a sweetener. Representative diluents include, but are not limited to, sucrose, sorbitol, xylitol, dextrose, fructose, malitol, sugar potassium, aspartame, saccharin, saccharin sodium, and mixtures thereof.
  • adjuvant refers to agents that aid or increase the action of the principle drug or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug in such a way as to enhance its effects
  • treat refers to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • the phrase "effective amount" is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • the effective amount in one embodiment, is administered in a single dosage form or in multiple dosage forms.
  • the mobile phase used a mixture of solvent A (H 2 O/0.1 % HOAc) and solvent B (ACN/0.1% HOAc) with a 9 min time period for a gradient from 10% to 90% solvent B. The gradient was followed by a 0.5 min period to return to 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) of the column.
  • solvent A H 2 O/0.1 % HOAc
  • solvent B ACN/0.1% HOAc
  • the invention further encompasses "intermediate" compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all "intermediates" included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).
  • Starting materials of the invention are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the schemes and examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary.
  • protecting groups may be used. Particularly, if one or more functional groups, for example carboxy, hydroxy, amino, or mercapto groups, are or need to be protected in preparing the compounds of the invention, because they are not intended to take part in a specific reaction or chemical transformation, various known conventional protecting groups may be used. For example, protecting groups typically utilized in the synthesis of natural and synthetic compounds, including peptides, nucleic acids, derivatives thereof and sugars, having multiple reactive centers, chiral centers and other sites potentially susceptible to the reaction reagents and/or conditions, may be used.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they readily lend themselves, i.e. without undesired secondary reactions, to removal, typically accomplished by solvolysis, reduction, photolysis or other methods of removal such as by enzyme activity, under conditions analogous to physiological conditions. It should also be appreciated that the protecting groups should not be present in the end-products. The person skilled in the art knows, or can easily establish, which protecting groups are suitable with the reactions described herein.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols R ⁇ -R 9 and X when used in the formulas depicted are to be understood to represent those groups described above in relation to Formula I unless otherwise indicated.
  • LG is a leaving atom or group including halogen atoms, e.g. bromine, iodine or chlorine atoms, and sulphonyloxy group, e.g.
  • alkylsulphonyloxy group such as trifluoromethylsulphonyloxy, and arylsulphonyloxy groups, such as /?-toluenesulphonyloxy
  • PG is a protecting group for amine
  • AIk is a lower alkyl, lower alkenyl or lower alkynyl group
  • Ar is an aryl or heteroaryl group.
  • a compound of Formula I may be prepared by reaction of an aniline intermediate (1) with a benzoic acid intermediate (2) according to Scheme 1.
  • the reaction may be performed in a solvent such as N,N-dimethylformamide (DMF), acetonitrile (CH 3 CN), or tetrahydrofuran (THF), in the presence of a carboxylic acid coupling reagent, and optionally in the presence of a base such as triethylamine (Et 3 N) or N, N-diisopropylethylamine (DIEA).
  • a solvent such as N,N-dimethylformamide (DMF), acetonitrile (CH 3 CN), or tetrahydrofuran (THF)
  • a carboxylic acid coupling reagent such as triethylamine (Et 3 N) or N, N-diisopropylethylamine (DIEA).
  • the carboxylic acid coupling reagent can include coupling reagents that are conventionally used for activating and coupling carboxylic acids, including l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1- hydroxybenzotriazole (HOBt), l-hydroxy-7-aza-benzotriazole (HOAt), O-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol- 1-yl)- N,N,N',N'-tetrametriyluronium hexafluorophosphate (HATU), and (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP).
  • EDC l-ethyl-3-(3-dimethylaminopropy
  • Compounds of the formula of the benzoic acid intermediate (2) either are known compounds or may be prepared using methods analogous to those used for the preparation of the known compounds.
  • a detailed synthesis of a compound having a formula of the benzoic acid intermediate (2) wherein R 4 is 4-((4-methylpiperazin-l- yl)methyl)-3-(trifluoromethyl)phenyl can be found in Example 18 in the Compound Synthesis section (vide infra).
  • the aniline intermediate (1) may be prepared by reduction of a nitro intermediate (3), reduction of an azide intermediate (4), or deprotection of a protected aniline intermediate (5) according to Scheme 2.
  • Reduction of a nitro group to an amine group may be carried out using conventional procedures, for example by using catalytic hydrogenation in the presence of a metal catalyst such as palladium in a suitable solvent such as ethanol (EtOH), methanol (MeOH), ethyl acetate (EtOAc), tetrahydrofuran (THF), or a mixture thereof, or by using a reducing agent such as sodium hydrosulfite or sodium sulfide in a solvent such as ethanol at an elevated temperature such as the reflux temperature, or by using a reducing agent such as zinc (Zn) or iron (Fe) in a solvent such as water, ethanol (EtOH), or a mixture thereof, optionally in the presence of an inorganic acid such as hydrochloric acid or a salt such as ammonium chloride (NH 4 Cl).
  • a metal catalyst such as palladium in a suitable solvent such as ethanol (EtOH), methanol (MeOH), ethyl a
  • Reduction of an azide group to an amine group may be carried out using conventional procedures, for example by using catalytic hydrogenation as just described for the reduction of nitro group, or by using a reducing agent such as zinc (Zn) or iron (Fe) in a solvent such as water, ethanol (EtOH), or a mixture thereof, in the presence of an inorganic salt such as ammonium chloride (NH 4 Cl) at an elevated temperature such as the reflux temperature, or by using a reducing agent such as triphenylphosphine (PPh 3 ) in a solvent mixture of THF and water.
  • a reducing agent such as zinc (Zn) or iron (Fe) in a solvent such as water, ethanol (EtOH), or a mixture thereof
  • an inorganic salt such as ammonium chloride (NH 4 Cl)
  • a reducing agent such as triphenylphosphine (PPh 3 ) in a solvent mixture of THF and water.
  • Deprotection of a protected amine group may be carried out in a manner known per se and, depending on the nature of each specific protecting group, in various procedures, preferably by solvolysis or reduction.
  • Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially t-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl which is unsubstituted or substituted, for example 4-nitro- benzyloxycarbonyl, and also formyl or trityl.
  • the protected aniline intermediate (5) maybe prepared by a reaction between an aniline intermediate (6) and a heteroaryl intermediate (7) according to Scheme 3.
  • the reaction in Scheme 3 may be a displacement reaction performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example a ketone such as acetone, an alcohol such as ethanol or 2-ethoxyethanol or an aromatic hydrocarbon such as toluene, optionally in the presence of a base, for example an organic amine such as pyridine or triethylamine or an inorganic base, for example a hydride such as sodium hydride, an alkoxide such as potassium t- butoxide, or a carbonate such as potassium carbonate, or an acid, for example an inorganic acid such as hydrochloric acid.
  • a solvent for example a ketone such as acetone
  • an alcohol such as ethanol or 2-ethoxyethanol or an aromatic hydrocarbon such as toluene
  • a base for example an organic amine such as pyridine or triethylamine or an inorganic base
  • a hydride such as sodium hydride
  • reaction in Scheme 3 may be a palladium-catalyzed amination of aryl halides and sulfonates with aniline derivatives in accordance with standard practices [see, for example, B.H. Yang et al., J. Organomet. Chem. 576, 125-146 (1999); J.F. Hartwig et al., J. Org. Chem. 64, 5575-5580 (1999); J.P. Wolfe et al., J. Org. Chem. 65, 1158-1174(2003); M.S. Driver et al., J. Am. Chem. Soc. 118, 7217-7218 (J. Am. Chem.
  • the heteroaryl intermediate (7) is a heteroaryl compound bearing a leaving atom or group including halogen atoms, e.g. bromine, iodine or chlorine atoms, and sulphonyloxy group, e.g. alkylsulphonyloxy group such as trifluoromethylsulphonyloxy, and arylsulphonyloxy groups, such as /7-toluenesulphonyloxy.
  • Compounds of the formula of the heteroaryl intermediate (7) either are known compounds or may be prepared using methods analogous to those used for the preparation of the known compounds.
  • the aniline intermediate (6) maybe prepared by an analogous reaction described for the synthesis of intermediate (1) from intermediates 3-5 in Scheme 2 (vide supra).
  • a detailed synthesis of a compound having a formula of aniline intermediate (6) wherein PG is ethoxycarbonyl can be found in Example 10 in the Compound Synthesis section (vide infra).
  • an benzoyl chloride intermediate (8) can react with intermediate (1) to form a compound of Formula I according to Scheme 4:
  • the reaction may be performed in a solvent such as N,N-dimethylformamide (DMF), acetonitrile (CH 3 CN), pyridine, or tetrahydrofuran (THF), and optionally in the presence of a base such as triethylamine (Et 3 N) or N, N-diisopropylethylamine (DIEA).
  • a base such as triethylamine (Et 3 N) or N, N-diisopropylethylamine (DIEA).
  • Et 3 N triethylamine
  • DIEA N, N-diisopropylethylamine
  • intermediate (2) can be converted to intermediate (8) by a reaction of intermediate (2) with reagent e.g. oxalyl chloride or thionyl chloride, in a solvent e.g. dichloromethane, optionally with catalytic amount of N,N-dimethylformamide, at ambient temperature or at elevated temperature e.g. the reflux temperature.
  • reagent e.g. oxalyl chloride or thionyl chloride
  • solvent e.g. dichloromethane
  • the heteroaryl intermediate (7) which bears a leaving atom or group, can react with an aniline intermediate (9) to form a compound of Formula I according to Scheme 5:
  • reaction in Scheme 5 may be a displacement reaction or a palladium- catalyzed amination of aryl halides and sulfonates with aniline derivatives in accordance with the standard practices described for the synthesis of protected aniline intermediate (5) in Scheme 3.
  • the aniline intermediate (9) may be prepared from a nitro intermediate (10) by an analogous reduction described for the synthesis of the aniline intermediate (1) from the nitro intermediate (3) in Scheme 2 (vide supra).
  • the nitro intermediate (10) may be prepared from an aniline intermediate (11) by an analogous coupling reaction described for the synthesis of Formula I from the aniline intermediate (1) in Schemes 1 and 3 (vide supra).
  • the aniline intermediate (11) may be prepared from a protected aniline intermediate (12) by an analogous deprotection described for the synthesis of the aniline intermediate (1) from the protected aniline intermediate (5) in Scheme 2 (vide supra).
  • Deprotection of a protected amine group may be carried out in a manner known per se and, depending on the nature of each specific protecting group, in various procedures, preferably by solvolysis or reduction.
  • Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially t-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl which is unsubstituted or substituted, for example 4-nitro- benzyloxycarbonyl, and also formyl or trityl.
  • Compounds of Formula I may also be prepared by interconversion of other compounds of Formula I and it is to be understood that the invention extends to such interconversion processes.
  • standard substitution approaches employing for example alkylation, arylation, acylations, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substituents to and/or extend existing substituents in compounds of Formula I.
  • existing substituents in compounds of Formula I may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of Formula I.
  • alkylation or arylation of a compound of Formula I may be achieved by reaction of the compound with a reagent AIk-LG or Ar-LG, wherein AIk is a lower alkyl group; Ar is an aryl or heteroaryl group.
  • the alkylation or arylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. cesium carbonate or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as N,N-dimethylformamide or an ether such as tetrahydrofuran, at around 0 0 C to around 40 0 C.
  • a base e.g. an inorganic base such as a carbonate, e.g. cesium carbonate or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as N,N-dimethylformamide or an ether such as tetrahydrofuran, at around 0 0 C to
  • the leaving group LG may be alternatively part of the compound of Formula I and the reaction performed with an appropriate nucleophilic reagent in a solvent such as an alcohol, e.g. ethanol, at an elevated temperature, e.g. the reflux temperature.
  • a solvent such as an alcohol, e.g. ethanol
  • I may be acylated or thioacylated.
  • the reaction may be performed for example with an acyl halide or anhydride in the presence of a base such as a tertiary amine, e.g.
  • triethylamine in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, or an alcohol, e.g. methanol, at ambient temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0 0 C.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, or an alcohol, e.g. methanol
  • Formula I may be formylated, for example by reaction of the compound with a mixed anhydride HC(O)OC(O)CH 3 or with a mixture of formic acid and acetic anhydride.
  • Formula I may be sulphonated, for example by reaction of the compound with a reagent
  • Alk-S(O) 2 -LG, or Ar-S(O) 2 -LG in the presence of a base for example an inorganic base such as sodium hydride, in a in a dipolar aprotic solvent such as N,N-dimethylformamide, at ambient temperature.
  • a base for example an inorganic base such as sodium hydride, in a in a dipolar aprotic solvent such as N,N-dimethylformamide, at ambient temperature.
  • an alcohol -OH group in compounds of Formula I may be converted to a corresponding -OAIk or -OAr group by coupling with a reagent AIkOH or
  • triphenylphosphine and an activator such as diethyl-, diisopropyl-, or
  • amines of Formula I may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohydride or sodium borohydride, in a solvent such as dichloromethane, in the presence of an acid such as acetic acid at around ambient temperature.
  • a borohydride for example sodium triacetoxyborohydride or sodium borohydride
  • an aminosulphonylamino group (- ⁇ HSO 2 ⁇ H 2 ) in compounds of Formula I may be obtained by reaction of a corresponding amine with sulphamide in the presence of an organic base such as pyridine at an elevated
  • the compounds in one embodiment also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • the compounds of the invention are modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • a compound of the invention is modified to incorporate a hydrophobic group or "greasy" moiety in an attempt to enhance the passage of the compound through a hydrophobic membrane, such as a cell wall.
  • N-(4-methyl-3,5-dinitrophenyl)carbamate (12.0 g, 44.6 mmol, 1.00 equiv) in EtOH (100 mL). This was followed by the addition of a solution of Na 2 S- 9H 2 O (20.0 g, 83.3 mmol, 1.87 equiv) in H 2 O (50 mL). The resulting solution was stirred for 18 hrs at room temperature. The resulting solution was extracted with 300 mL of ethyl acetate. The organic layer was washed with 2x200 mL of H 2 O, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • N-(3-amino-4-methyl-5-nitrophenyl)carbamate (8.50 g, 35.6 mmol, 1.00 equiv) in HF (70% in pyridine, 40 mL), followed by the addition of a solution of NaNO 2 (3.0 g) in H 2 O (10 mL) dropwise with stirring at 0 0 C. After stirred for 1 hr at 0 0 C in an ice/salt bath, the reaction mixture solution was transferred to an 80-mL sealed tube and stirred for an additional hour at 80 0 C in an oil bath. The reaction mixture was cooled and quenched by the addition of 100 mL of Na 2 CO 3 solution, followed by extraction with 2x300 mL of ethyl acetate.
  • H-NMR-PH-NC-LX-006-O 400MHz, CD 3 OD, / ⁇ m: 9.29(1H, s), 8.63(1H, s), 8.57(1H, s), 8.5O(1H, m), 8.28(1H, s), 8.18(1H, m), 8.00(2H, m), 7.55(1H, d), 7.40(2H, m), 3.86(2H, m), 3.48(2H, m), 3.00(3H, m), 2.92(4H, m), 2.51(2H, m), 2.21(3H, m).
  • the Z'-LYTETM biochemical assay employs a fluorescence-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage.
  • the kinase transfers the gamma-phosphate of ATP to a single tyrosine, serine or threonine residue in a synthetic FRET-peptide.
  • a site-specific protease recognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylation of FRET-peptides suppresses cleavage by the Development Reagent.
  • Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved, phosphorylated FRET-peptides maintain FRET.
  • a ratiometric method which calculates the ratio (the Emission Ratio) of donor emission to acceptor emission after excitation of the donor fluorophore at 400 nm, is used to quantitate reaction progress. Both cleaved and uncleaved FRET-peptides contribute to the fluorescence signals and therefore to the Emission Ratio. The extent of phosphorylation of the FRET-peptide can be calculated from the Emission Ratio.
  • the Emission Ratio will remain low if the FRET-peptide is phosphorylated (i.e., no kinase inhibition) and will be high if the FRET-peptide is non-phosphorylated (i.e., kinase inhibition).
  • test compounds are screened in 1% DMSO (final) in the well. For 10 points titrations, 3-fold serial dilutions are conducted from a 10 ⁇ M starting
  • All Peptide/Kinase Mixtures are diluted to a 2x working concentration in the appropriate Kinase Buffer.
  • All ATP Solutions are diluted to a 4x working concentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA). ATP Km apparent is previously determined using a Z'-LYTE assay.
  • the Development Reagent is diluted in Development Buffer.
  • the present invention provides compounds which are capable of modulating one or more signal transduction pathways comprising, but not limited to, Bcr- AbI, c-Kit or PDGF-R, which are important signaling molecules involved in the regulation of a number of key cellular processes, including cell growth, cell survival and invasion.
  • modulate it is meant that the functional activity (or a component) of the pathway is changed in comparison to its normal activity in the absence of the compound. This effect includes any quality or degree of modulation, including, increasing, agonizing, augmenting, enhancing, facilitating, stimulating, decreasing, blocking, inhibiting, reducing, diminishing, antagonizing, etc.
  • the compounds of the present invention can also modulate one or more of the following processes, including, but not limited to, e.g., cell growth (including, e.g., differentiation, cell survival, and/or proliferation), tumor cell growth (including, e.g., differentiation, cell survival, and/or proliferation), tumor regression, endothelial cell growth (including, e.g., differentiation, cell survival, and/or proliferation) etc.
  • cell growth including, e.g., differentiation, cell survival, and/or proliferation
  • tumor cell growth including, e.g., differentiation, cell survival, and/or proliferation
  • tumor regression including, e.g., endothelial cell growth (including, e.g., differentiation, cell survival, and/or proliferation) etc.
  • the compounds of the present invention can be used to treat and/or prevent any diseases or conditions involving one or more cellular signal transduction pathways comprising Bcr-Abl, c-Kit or PDGF-R.
  • the term "treating" is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder.
  • the present invention relates to methods of treating and/or preventing diseases and conditions; and/or modulating one or more of the pathways, polypeptides, genes, diseases, conditions, etc., associated with Bcr-Abl, c-Kit or PDGF-R.
  • Methods include modulating tumor cell proliferation, including inhibiting cell proliferation.
  • the latter indicates that the growth and/or differentiation of tumor cells is reduced, decreased, diminished, slowed, etc.
  • Bcr-Abl, c-Kit or PDGF-R kinases play a key role in the activation of the cytoplasmic signaling cascade involved in cell proliferation, differentiation, and apoptosis. Any amount of inhibition is considered therapeutic.
  • Any tumor or cancer can be treated, including, but not limited to, cancers having one or more mutations in Bcr-Abl, c-Kit or PDGF-R, as well as any upstream or downstream members of the signaling pathways of which they are a part.
  • a cancer can be treated with a compound of the present invention irrespective of the mechanism which is responsible for its therapeutic effect.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • compounds of the present invention can also cause tumor regression, e.g., a decrease in the size of a tumor or in the extent of cancer in the body.
  • the invention also provides methods for treating, preventing, modulating, etc., diseases and conditions in mammals comprising administering a compound of this invention with another modulator of the signal transduction pathway comprising, but not limited to Bcr-Abl, c-Kit or PDGF-R. These can be present in the same composition or in separate formulations or dosage units. Administration can be the same or different routes, and can be simultaneous, sequential, etc.
  • Optional anti-hyper-proliferative agents which can be added to the composition include, but are not limited to, compounds listed on the cancer chemotherapy drug regimens in the 14th Edition of the Merck Index (2006), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin etc.
  • composition of the invention include, but are not limited to, those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman 's The
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Ed., Mack
  • compositions that include a compound of Formula I and at least one pharmaceutically acceptable inactive ingredient.
  • the compounds described herein are administered as pharmaceutical compositions in which compounds of Formula I are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include other medicinal or pharmaceutical agents, carriers, adjuvants, preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers.
  • the pharmaceutical compositions include other therapeutically valuable substances.
  • a pharmaceutical composition refers to a mixture of a compound of Formula I with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions described herein which include a compound of Formula I are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • aqueous oral dispersions liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations
  • All formulations for oral administration are in dosages suitable for such administration.
  • dosage units are tablets or capsules.
  • these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg.
  • the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder, a capsule, solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, beads, pellets, granules.
  • the pharmaceutical formulation is in the form of a powder.
  • the pharmaceutical formulation is in the form of a tablet.
  • pharmaceutical formulations of the compounds of Formula I are in the form of a capsule.
  • additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
  • the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
  • a capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule.
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents sprinkled on food prior to eating.
  • the particles of the compound of Formula I and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
  • the pharmaceutical solid oral dosage forms are formulated to provide a controlled release of the compound of Formula I.
  • Controlled release refers to the release of the compound of Formula I from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • immediate release compositions controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
  • Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
  • liquid formulation dosage forms for oral administration are in the form of aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).
  • the liquid dosage forms include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (T) at least one sweetening agent, and (g) at least one flavoring agent.
  • the aqueous dispersions can further include a crystalline inhibitor.
  • a compound of Formula I is formulated into a
  • formulations suitable for intramuscular, subcutaneous, or intravenous injections include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are known.
  • Parenteral injections may involve bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • the daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
  • a method of manufacturing a medicament for the treatment of cancers comprising combining an amount of a compound according to Formula I with a pharmaceutically acceptable carrier to manufacture the medicament.
  • the compounds of the invention can be dosed or administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or in conjunction with other agents.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound of Formula I is co-administered with a second therapeutic agent, wherein the compound of Formula I and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). In one embodiment, one of the therapeutic agents is given in multiple doses, and in another, two (or more if present) are given as multiple doses. In some embodiments of non-simultaneous administration, the timing between the multiple doses varies from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.

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Abstract

La présente invention concerne de nouveaux composés de formule I et leurs sels et solvates pharmaceutiquement acceptables qui possèdent une activité inhibitrice de kinase. La présente invention concerne en outre des compositions pharmaceutiques contenant ces composés ainsi que des méthodes de traitement et de prévention d'un trouble médié par Bcr-Abl, c-Kit ou le PDGF-R pour lequel un ou plusieurs inhibiteurs de kinase sont indiqués, y compris une néoplasie telle que la leucémie chronique myélogène ou des tumeurs du stroma gastro-intestinal. La présente invention a également pour objet des procédés de fabrication des composés de formule I, y compris leurs sels et solvates et des compositions pharmaceutiques contenant ces composés.
PCT/US2010/041872 2009-07-14 2010-07-13 Composés à substitution fluoro en tant qu'inhibiteurs de kinase et leurs méthodes d'utilisation Ceased WO2011008788A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171641A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité abl1, abl2 et bcr-abl1
US8829195B2 (en) 2012-05-15 2014-09-09 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
WO2015150555A1 (fr) 2014-04-03 2015-10-08 Janssen Pharmaceutica Nv Dérivés de pyrimidine macrocycliques
US9278981B2 (en) 2012-05-15 2016-03-08 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9340537B2 (en) 2012-05-15 2016-05-17 Novatis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9750008B2 (en) 2012-08-03 2017-08-29 Telefonaktiebolaget L M Ericsson (Publ) Quasi co-located antenna ports for channel estimation

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106187995A (zh) * 2015-05-05 2016-12-07 天津国际生物医药联合研究院 含酰胺键杂环类化合物及其制备方法和应用
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CN108383718A (zh) * 2018-04-28 2018-08-10 江苏八巨药业有限公司 一种2，4，5-三氟苯乙酸的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224967A1 (en) * 2003-05-02 2004-11-11 Chen Guoqing P Phenylaminopyrimidine derivatives and methods of use
WO2005113494A2 (fr) * 2004-05-07 2005-12-01 Amgen Inc. Modulateurs de proteines kinases et procede d'utilisation
WO2006021458A2 (fr) * 2004-08-27 2006-03-02 Gpc Biotech Ag Derives de pyrimidine
WO2006079791A1 (fr) * 2005-01-25 2006-08-03 Astrazeneca Ab Composes chimiques
US20080293940A1 (en) * 2003-12-25 2008-11-27 Tetsuo Asaki Amide Derivative and Medicine
US20080300268A1 (en) * 2007-06-04 2008-12-04 Avila Therapeutics, Inc. Heterocyclic compounds and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224967A1 (en) * 2003-05-02 2004-11-11 Chen Guoqing P Phenylaminopyrimidine derivatives and methods of use
US20080293940A1 (en) * 2003-12-25 2008-11-27 Tetsuo Asaki Amide Derivative and Medicine
WO2005113494A2 (fr) * 2004-05-07 2005-12-01 Amgen Inc. Modulateurs de proteines kinases et procede d'utilisation
WO2006021458A2 (fr) * 2004-08-27 2006-03-02 Gpc Biotech Ag Derives de pyrimidine
WO2006079791A1 (fr) * 2005-01-25 2006-08-03 Astrazeneca Ab Composes chimiques
US20080300268A1 (en) * 2007-06-04 2008-12-04 Avila Therapeutics, Inc. Heterocyclic compounds and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ASAKI, T. ET AL.: "Design and synthesis of 3-substituted benzamide derivatives as Bcr- Abl kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, 2006, pages 1421 - 1425, XP025106368, DOI: doi:10.1016/j.bmcl.2005.11.042 *

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US9896444B2 (en) 2012-05-15 2018-02-20 Novartis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
CN104334529B (zh) * 2012-05-15 2017-03-15 诺华股份有限公司 用于抑制abl1、abl2和bcr‑abl1的活性的化合物和组合物
CN104334529A (zh) * 2012-05-15 2015-02-04 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的化合物和组合物
JP2015520157A (ja) * 2012-05-15 2015-07-16 ノバルティス アーゲー Ａｂｌ１、ａｂｌ２およびｂｃｒ−ａｂｌ１の活性を阻害するための化合物および組成物
WO2013171641A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité abl1, abl2 et bcr-abl1
US9278981B2 (en) 2012-05-15 2016-03-08 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9315489B2 (en) 2012-05-15 2016-04-19 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9340537B2 (en) 2012-05-15 2016-05-17 Novatis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US8829195B2 (en) 2012-05-15 2014-09-09 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
EA026559B1 (ru) * 2012-05-15 2017-04-28 Новартис Аг Соединения и композиции для ингибирования активности abl1, abl2 и bcr-abl1
US9458112B2 (en) 2012-05-15 2016-10-04 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9750008B2 (en) 2012-08-03 2017-08-29 Telefonaktiebolaget L M Ericsson (Publ) Quasi co-located antenna ports for channel estimation
US10178661B2 (en) 2012-08-03 2019-01-08 Telefonaktiebolaget L M Ericsson (Publ) Quasi co-located antenna ports for channel estimation
US10785761B2 (en) 2012-08-03 2020-09-22 Telefonaktiebolaget Lm Ericsson (Publ) Quasi co-located antenna ports for channel estimation
US11937249B2 (en) 2012-08-03 2024-03-19 Telefonaktiebolaget Lm Ericsson (Publ) Quasi co-located antenna ports for channel estimation
WO2015150555A1 (fr) 2014-04-03 2015-10-08 Janssen Pharmaceutica Nv Dérivés de pyrimidine macrocycliques
US10017509B2 (en) 2014-04-03 2018-07-10 Janssen Pharmaceutica Nv Macrocylic pyrimidine derivatives

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