WO2013138210A1 - Composés cycliques substitués et procédés d'utilisation - Google Patents

Composés cycliques substitués et procédés d'utilisation Download PDF

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WO2013138210A1
WO2013138210A1 PCT/US2013/030096 US2013030096W WO2013138210A1 WO 2013138210 A1 WO2013138210 A1 WO 2013138210A1 US 2013030096 W US2013030096 W US 2013030096W WO 2013138210 A1 WO2013138210 A1 WO 2013138210A1
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alkylene
mmol
cancer
etoac
heterocyclyl
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PCT/US2013/030096
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Ning Xi
Tingjin WANG
Lei Yi
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Ning Xi
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to novel substituted cyclic compounds, and salts thereof, which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
  • the invention relates to compounds that inhibit the protein tyrosine kinase activity, resulting in the inhibition of inter- and/or intra-cellular signaling.
  • This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. By adding phosphate groups to substrate proteins, they direct the activity, localization and overall function of many proteins, and serve to orchestrate the activity of many cellular processes. Kinases are particularly prominent in signal transduction and co-ordination of complex functions such as the cell cycle. Of the 518 human protein kinases, 478 belong to a single superfamily whose catalytic domains are related in sequence. These can be clustered into groups, families and sub-families, of increasing sequence similarity and biochemical function.
  • a partial list of such kinases include abl, AATK, ALK, Akt, Axl, bmx, bcr-abl,
  • Receptor tyrosine kinases are a diverse group of transmembrane proteins that act as receptors for cytokines, growth factors, hormones and other signaling molecules. Receptor tyrosine kinases (RTKs) are expressed in many cell types and play important roles in a wide variety of cellular processes, including growth, differentiation and angiogenesis. Activation of the kinase is effected by binding of a ligand to the extracellular domain, which induces dimerization of the receptors. Activated receptors auto-phosphorylatetyrosine residues outside the catalytic domain via cross-phosphorylation. This auto-phosphorylation stabilizes the active receptor conformation and creates phosphotyrosine docking sites for proteins that transduce signals within the cell.
  • RTKs Receptor tyrosine kinases
  • Receptor tyrosine kinases are hyper-activated (through receptor activating mutations, gene amplification, growth factor activation, etc.) in many human solid tumors and hematological malignancies. RTK's elevated activation contributes to tumourigenesis factors such as hyperplasia, survival, invasion, metastasis and angiogenesis. Inhibition of receptor tyrosine kinases proved to be effective strategies in cancer therapy (Sharma PS; et al. "Receptor tyrosine kinase inhibitors as potent weapons in war against cancers" Curr. Pharm. Des. 2009, 15, 758).
  • ALK Anaplastic lymphoma kinase
  • NPM anaplastic large-cell lymphoma
  • ALK fusions were also found in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). Studies suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. Moreover, studies have implicated various mutations of the ALK gene in both familial and sporadic cases of neuroblastoma. ALK mutations in neuroblastoma cells results in constitutive ALK phosphorylation and attenuation. Conversely, inhibition of ALK by sRNA and small molecule ALK inhibitors resulted in profound growth inhibition in those cell lines (Palmer, R. H.; et al. "Anaplastic lymphoma kinase: signalling in development and disease" Biochem.J. 2009, 420, 345).
  • EML4-ALK fusion gene comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene were identified in NSCLC cells.
  • EML4-ALK fusion transcript was detected in approximately 3- 7% of NSCLC patients examined.
  • Experimental evidence from in vitro and in vivo studies demonstrated oncogenic transforming activity of the EML4-ALK fusion proteins and reinforced the pivotal role of EML4-ALK in the pathogenesis of NSCLC in humans (Soda, M.; et al. "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer" NaturelWl, 448, 561).
  • JAK3-STAT3 pathway and the PI3K-Akt pathway have been shown to be vital primarily for cell survival and phenotypic changes(Chiarle, R.; et al. "The anaplastic lymphoma kinase in the pathogenesis of cancer” Nat. Rev. Cancer200S, 8, 11 ; Barreca, A.; et al. "Anaplastic lymphoma kinase (ALK) in human cancer" J. Mol. Endocrinol. 2011, 47, Rl 1).
  • c-Met also referred to as hepatocyte growth factor receptor (HGFR)
  • HGFR hepatocyte growth factor receptor
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c-Met is also implicated in atherosclerosis and lung fibrosis. Invasive growth of certain cancer cells is drastically enhanced by tumor- stromal interactions involving the HGF/c-Met pathway.
  • c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met as major targets in cancer drug development (Migliore C; Giordano S. "Molecular cancer therapy: can our expectation be MET" Eur. J.
  • Crizotinib is an ATP-competitive small molecule ALK inhibitor, which also displays activity against the c-Met receptor tyrosine kinase.
  • the FDA recently approved crizotinib (Pfizer' s Xalkori ® , originally known as PF-02341066) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in which tumor cells exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene.
  • Crizotinib is administered 250 mg twice daily. Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8 (Xalkori ® FDA-Approved Patient Labeling, Pfizer Inc. February 2012).
  • crizotinib As seen with other targeted cancer drugs, patients with ALK-positive NSCLC eventually relapse on crizotinib. The development of acquired resistance is clearly the major hurdle preventing targeted therapies such as crizotinib from having an even more substantial impact on patients (Nature Review Drug DiscoverylQW, 10, 897).
  • the present invention provides novel compounds believed to have clinical use for treatment of cancer through inhibiting ALK and/or c-Met. Preferred compounds of the present invention are also believed to provide an improvemnet in potency, pharmacokinetic properties, and/or toxicity profile over certain other ALK and/or c-Met inhibitor compounds found in the art.
  • the present invention provides new compounds and methods for treating cell proliferative diseases.
  • the compounds of the invention are inhibitors of protein tyrosine kinases.
  • the compounds of the invention are capable of inhibiting, for example, ALK (including ALK fusions such as EML4-ALK, NPM-ALK, etc.), and c-Met receptor (hepatocyte growth factor receptor) signaling.
  • ALK including ALK fusions such as EML4-ALK, NPM-ALK, etc.
  • c-Met receptor hepatocyte growth factor receptor
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z is as defined herein.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F;
  • each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N 3 , Ci_ 6 alkyl, Ci_ 6 haloalkyl, -CN, -OH, -OR a , - NR b R c , -(Ci_ 4 alkylene)-CN, -(C M alkylene)-OH, -(Ci_ 4 alkylene)-OR a or -(C ⁇ alkylene)- NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
  • R is Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 - 6 heterocyclyl, C6-ioaryl, C 1 -9 heteroaryl, -(Ci ⁇ alkylene)-(C 3 _ 6 cycloalkyl), -(Ci ⁇ alkylene)-(C 3 _ 6 heterocyclyl),
  • C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci_ 6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 6 alkylene)-(C 6 -ioaryl) and -(Ci_ 6 alkylene)-(Ci_ 9 heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H or D.
  • Z is
  • C 5 _i 2 fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , -(Ci_ 3 alkylene)- CN, -(Ci_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , - (Ci_ 3 alkylene)-CN, -(d_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
  • R is independently
  • each R b and R c is independently H, C3-6 cycloalkyl or -(Ci_ 3 alkylene)-(C 3 _ 6 cycloalkyl); or R b and R c , together with the nitrogen atom they are attached to, optionally form C3_ 6 heterocyclyl; wherein the C3_ 6 cycloalkyl, - (Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) and C3_ 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • X is independently O or NH
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(Ci_
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • each W and W is independently O, NH or N(Ci_ 3 alkyl)-;
  • each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(C 1-3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer herein is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)- OR a or -(Ci_ 3 alkylene)-NR b R c .
  • R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H or C 1-2 alkyl; or R b and
  • R c together with the nitrogen atom they are attached to, optionally form C3-6heterocyclyl; wherein the and C3- 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • compositions comprising a compound disclosed herein, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and an optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the compound is an inhibitor of protein tyrosine kinase.
  • the compound is an inhibitor of ALK receptor signaling and HGF receptor signaling.
  • the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent.
  • the therapeutic agent is a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.
  • the therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol
  • kits for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient infected with the proliferative disorder which comprises administrating a pharmaceutically effective amount of a compound disclosed herein, or the pharmaceutical composition disclosed herein to the patient.
  • provided herein is use of the compound disclosed herein, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.
  • the proliferative disorder is metastatic cancer.
  • the proliferative disorder is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma or a myeloproliferative disorder.
  • the proliferative disorder is atherosclerosis or lung fibrosis.
  • a method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.
  • the protein kinase is a receptor tyrosine kinase.
  • the receptor tyrosine kinase is ALK and/or c-Met.
  • a method of inhibiting protein tyrosine kinase comprises contacting the kinase with the compound disclosed herein, or with the composition disclosed herein.
  • a method of inhibiting ALK receptor signaling and/or HGF receptor signaling comprises contacting the receptor with the compound disclosed herein, or with the pharmaceutical composition disclosed herein.
  • inhibition of receptor protein kinase activity can be in a cell or a multicellular organism. If in a multicellular organism, the method disclosed herein may comprise administering to the organism the compound disclosed herein, or the pharmaceutical composition disclosed herein. In some embodiments, the organism is a mammal; in other embodiments, the organism is a human. In still other embodiments, the method further comprises contacting the kinase with an additional therapeutic agent.
  • a method of inhibiting proliferative activity of a cell comprising contacting the cell with an effective proliferative inhibiting amount of the compound disclosed herein or the pharmaceutical composition disclosed herein. In some embodiments, the method further comprises contacting the cell with an additional therapeutic agent.
  • a method of treating a cell proliferative disease in a patient comprising administering to the patient in need of such treatment an effective therapeutic amount of the compound disclosed herein or the pharmaceutical composition disclose herein. In other embodiments, the method further comprises administering an additional therapeutic agent.
  • a method of inhibiting tumor growth in a patient comprises administering to the patient in need thereof an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering an additional therapeutic agent.
  • provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”.
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • D denotes a single deuterium atom.
  • One of this radical may be attached, for example, to a methyl group to form a mono-deuterated methyl group (-CDH 2 ), two of deuterium atoms may attached to a methyl group to form a di-deuterated methyl (-CD 2 H), and three of deuterium atoms may attached to a methyl group to form a tri-deuterated methyl group (-CD 3 ).
  • N 3 denotes an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, Me s); or attached to a phenyl group to form phenyl azide (PI1N 3 ).
  • halogen means F, CI, Br or I.
  • alkyl or "alkyl group” as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twenty carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, alkyl groups contain 1-10 carbon atoms. In other embodiments, alkyl groups contain 1-6 carbon atoms. In still other embodiments, alkyl groups contain 1-3 carbon atoms, and in yet other embodiments, alkyl groups contain 1-2 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl (Me, -CH 3 ), ethyl
  • alkyl and the prefix “alk-” as used herein, are inclusive of both straight chain and branched saturated carbon chain.
  • alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, alkylene groups include 1-10 carbon atoms. In some embodiments, alkyl groups contain 1-6 carbon atoms. In other embodiments, alkyl groups contain 1-4 carbon atoms. In still other embodiments, alkyl groups contain 1-3 carbon atoms. Examples of alkylene radicals include, but are not limited to,methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ⁇ CH), 2-propynyl (propargyl, -CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon atom through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1-20 carbon atoms. In some embodiments, alkoxy groups contain 1-10 carbon atoms. In other embodiments, alkoxy groups contain 1-8 carbon atoms. In still other embodiments, alkoxy groups contain 1-6 carbon atoms, and in yet other embodiments, alkoxy groups contain 1-4 carbon atoms.
  • alkoxy radicals include, but are not limited to, methoxy (MeO, -
  • alkylamino embraces “N-alkylamino” and “N,N-dialkylamino” where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, ⁇ , ⁇ -diethylamino, and the like.
  • aminoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • Carbocycle refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic ring system.
  • Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated ring having
  • a cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments, a cycloalkyl contains 3 to 6 carbon atoms.
  • the cycloalkyl radicals are optionally substituted independently with one or more substituents described herein.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR (as in N- substituted pyrrolidinyl).
  • heterocycle refers to a monocyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • One or more ring atoms are optionally substituted independently with one or more substituents described herein.
  • the "heterocycle”, “heterocyclyl”, “heterocyclic ring'Or “heterocyclic” group is a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, PO or PO2, with the proviso that when the ring is a 3-membered ring, there is only one heteroatm).
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homo-piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxo
  • the heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
  • aryl and "aryl ring” interchangeably used herein, refer to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3-7 ring members and that has a single point of attachment to the rest of the molecule.
  • aryl rings would include phenyl, naphthyl, anthracene, and the like.
  • heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5-7 ring members and that has a single point of attachment to the rest of the molecule.
  • heteroaryl include the following monocycles: 2-furanyl, 3- furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3- pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5- tetrazolyl), triazolyl (e.g., 2- triazolyl and 5-triazolyl), 2-thienyl
  • arylamino denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the arylamino radicals may be further substituted on the aryl ring portion of the radical.
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO 2 H.
  • fused bicyclic “fused bicyclic”, “fused cyclic”, “fused bicyclyl” or “fused cyclyl” refer to saturated bridged ring system which has a C-C bond shared between two five-membered rings (Structure a), two six-membered rings (Structure b) and one five-membered ring and one six-membered ring (Structure c), as depicted in Structures a-c.
  • Each cyclic ring in a fused bicyclyl can be either a carbocyclic or a heterocyclic.
  • fused bicyclyl examples include hexahydrofuro[2,3-b]furan-
  • a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the rings to which it is attached.
  • Structure d represents possible substitution in any of the positions on the B ring shown in Structure e.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • prodrug represents a compound that is transformed in vivo into a compound of formula (I). Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
  • Prodrugs of the compounds of the invention may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (d-C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the invention that contains an OH group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • phosphates such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is incorporated herein by reference.
  • a "metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s).
  • a "pharmaceutically acceptable salt” as used herein refers to organic or inorganic salts of a compound of the invention.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J.
  • salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_4 alkyl)4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate and aryl sulfonate.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, i-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a "carboxy- protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include -CH 2 CH 2 SO 2 PI1, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxy-methy-1, 2-(p-toluenesulfonyl) ethyl, 2-(p- nitrophenylsulfenyl)-ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and P. J. Kocienski,Protecting Groups, Thieme, Stuttgart, 2005.
  • the present invention provides pyridine compounds, salts, and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions and disorders modulated by receptor tyrosine kinases, especially ALK and c-Met receptor. More specifically, the present invention provides a compound of Formula (I):
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z is as defined herein.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F;
  • each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N 3 , Ci_ 6 alkyl, Ci_ 6 haloalkyl, -CN, -OH, -OR a , - NR b R c , -(Ci_ 4 alkylene)-CN, -(C M alkylene)-OH, -(Ci_ 4 alkylene)-OR a and -(Ci_ 4 alkylene)- NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
  • R is Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 - 6 heterocyclyl, C6-ioaryl, Ci_ 9 heteroaryl, -(Ci_ 4 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci ⁇ alkylene)-(C 3 _ 6 heterocyclyl), -(Ci- 4 alkylene)- (C6-ioaryl) or Ci- 6 alkynyl, C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci ⁇ alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 4 alkylene)-(C 3 - 6 cycloalkyl), -(Ci_ 4 alkylene)-(C 6 -ioaryl) and -(Ci ⁇ alkylene)-(Ci_ 9 heteroaryl
  • each R b and R c is independently H, Ci- 6 alkyl, C 3 _ 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci_ 9 heteroaryl, -(Ci_ 6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 6 alkylene)-(C 3 _ 6 heterocyclyl), -(Ci- 6 alkylene)- (C6-ioaryl) or -(Ci_ 6 alkylene)-(Ci_ 9 heteroaryl); or R b and R c , together with the nitrogen atom they are attached to, optionally form C 3 _ 6 heterocyclyl; wherein the Ci- 6 alkynyl, C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci- 6 alkylene)-(C 3 _ 6 cycloal
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H or D.
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , - (Ci_ 3 alkylene)-CN, -(Ci_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a and -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
  • R is independently Ci_ 3 alkyl, Ci_ 3 alkenyl, Ci_ 3 alkynyl, C 3 _
  • Ci_ 3 alkyl, Ci_ 3 alkenyl, Ci_ 3 alkynyl, C 3 _ 6 cycloalkyl and -(Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H, Ci_ 3 alkyl, C 3 _
  • Ci_ 3 alkyl, C 3 _ 6 cycloalkyl, - (Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) and C 3 _ 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • X is independently O or NH
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, C 1-3 haloalkyl, -OH, -OR , -NR b R c , -(C 1-3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , provided that when n is 1, 2 or 3, the said Z is not substituted with one hydroxyl (OH) group, the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • each W and W is independently O, NH or N(Ci_ 3 alkyl)-;
  • each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(d_ 3 alkylene)- OH, -(C 1 _ 3 alkylene)-OR a or -(d_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(Ci_
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, d_ 3 haloalkyl, -OR a , -NR b R c , -(d_ 3 alkylene)-OH, -(Ci -3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR a , -NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)- OR a and -(Ci_ 3 alkylene)-NR b R c .
  • R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H or C 1-2 alkyl; or R b and R c , together with the nitrogen atom they are attached to, optionally form C3- 6 heterocyclyl; wherein the and C3- 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • the present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of a hyperproliferative disease state and/or an angiogenesis mediated disease state, including those described previously.
  • the compounds of the present invention are useful in the manufacture of an anti-cancer medicament.
  • the compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of protein kinases.
  • the present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a method of treating hyperproliferating and angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula (I).
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the compounds of the invention also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula (I).
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid, hydrobro
  • the invention features pharmaceutical compositions that include a compound of formula (I), a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the compositions of the invention is such that is effective to detectably inhibit a protein kinase in a biological sample or in a patient.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin;
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
  • suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the low intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adj
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • dissolving or suspending the compound in an oil vehicle accomplishes delayed absorption of a parenterally administered compound form.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polythylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain pacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • compositions should be formulated so that a dosage of between 0.01 - 200 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • Compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents where the combination causes no unacceptable adverse effects. This may be of particular relevance for the treatment of hyper-proliferative diseases such as cancer.
  • the compound of this invention can be combined with known cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents, as well as with admixtures and combinations thereof.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated”.
  • additional therapeutic agents is meant to include chemotherapeutic agents and other anti-proliferative agents.
  • chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative disease or cancer.
  • chemotherapeutic agents or other antiproliferative agents include HDAC inhibitors including, but are not limited to, SAHA, MS-275, MGO 103, and those described in WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agents including, but not limited to, 5-aza-dC, Vidaza and Decitabine and those described in US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,73
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • known chemotherapeutic agents include, but are not limited to, for example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention and include surgery, radiotherapy (in but a few examples, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, taxanes (paclitaxel, taxotere), platinum derivatives (cisplatin, carboplatin, oxaliplatin), biologic response modifiers (interferons, interleukins), tumor necrosis factor (TNF, TRAIL receptor targeting agents, to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antieme
  • the compounds of the present invention can be combined, with cytotoxic anti-cancer agents.
  • cytotoxic anti-cancer agents examples include, by no way of limitation, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, proc
  • cytotoxic drugs suitable for use with the compounds of the invention include, but are not limited to, those compounds acknowledged to be used in the treatment of neoplastic diseases, such as those for example in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill).
  • agents include, by no way of limitation, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2,2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, P
  • cytotoxic anti -cancer agents suitable for use in combination with the compounds of the invention also include newly discovered cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology2003, 21(4), 646-651), tositumomab (Bexxar ® ), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3181), and the inhibitors of the kinesin spindle protein Eg5 (Wood, et al. Curr. Opin.Pharmacol.2001, 1, 370-377).
  • cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology2003, 21(4),
  • the compounds of the present invention can be combined with other signal transduction inhibitors.
  • examples of such agents include, by no way of limitation, antibody therapies such as trastuzumab (Herceptin ® ), cetuximab (Erbitux ® ), ipilimumab (Yervoy ® ) and pertuzumab.
  • Examples of such therapies also include, by no way of limitation, small-molecule kinase inhibitors such as imatinib (Gleevec ® ), sunitinib (Sutent ® ), sorafenib (Nexavar ® ), erlotinib (Tarceva ® ), gefitinib (Iressa ® ), dasatinib (Sprycel ® ), nilotinib (Tasigna ® ), lapatinib (Tykerb ® ), crizotinib (Xalkori ® ), ruxolitinib (Jakafi ® ), vemurafenib (Zelboraf ® ), vandetanib (Caprelsa ® ), pazopanib (Votrient ® ), afatinib, alisertib, amuvatinib, axitinib, bosutinib
  • the compounds of the present invention can be combined with inhibitors of histone deacetylase.
  • examples of such agents include, by no way of limitation, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryan, et al. Proceedings of the American Association of Cancer Research 2004, 45, abstract 2452), FR-901228 (Piekarz, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3028) and MGCDOl 03 (US 6,897,220).
  • SAHA suberoylanilide hydroxamic acid
  • LAQ-824 Ottmann, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3024
  • LBH-589 Beck, et al. Proceedings of the American Society for Clinical
  • the compounds of the present invention can be combined with other anti-cancer agents such as proteasome inhibitors, and m-TOR inhibitors. These include, by no way of limitation, bortezomib, and CCI-779 (Wu, et al. Proceedings of the American Association of Cancer Research 2004, 45, abstract 3849).
  • the compounds of the present invention can be combined with other anti-cancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.
  • those additional agents may be administered separately from the compound- containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with the compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another which would result in the desired activity of the agents.
  • the amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Normally, the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically.
  • the invention features pharmaceutical compositions that include a compound of formula (I), or a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the compositions of the invention is such that is effective to detectably inhibit a protein kinase, such as ALK and c-Met inhibitory activity.
  • the compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious effects of ALK and c-Met signaling.
  • Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of proliferative diseases, condition, or disorder in a patient by administering to the patient a compound or a composition of the invention in an effective amount.
  • diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis and lung fibrosis.
  • neoplasm including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of lymphoid lineage (including acute and chronic myelogenous
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
  • the compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis.
  • the compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability.
  • the compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
  • the compounds of the present invention are also useful in the reduction of blood flow in a tumor in a subject.
  • the compounds of the present invention are also useful in the reduction of metastasis of a tumor in a subject.
  • the compounds of the present invention include the pharmaceutically acceptable derivatives thereof.
  • the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.
  • the treatment method that includes administering a compound or composition of the invention can further include administering to the patient an additional therapeutic agent (combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an antiinflammatory agent, wherein the additional therapeutic agent is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition of the invention as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the additional therapeutic agent may be administered at the same time as a compound of the invention or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
  • the invention also features a method of inhibiting the growth of a cell that expresses ALK or c-Met, that includes contacting the cell with a compound or composition of the invention, thereby causing inhibition of growth of the cell.
  • a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell, or a leukemia cell.
  • the invention provides a method of inhibiting ALK or c-Met kinase activity in a biological sample that includes contacting the biological sample with a compound or composition of the invention.
  • biological sample means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of kinase activity, particularly ALK or c-Met kinase activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • an “effective dose” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • a compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
  • the compounds of this invention or pharmaceutical compositions thereof may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of this invention.
  • Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121, the contents of each of which are incorporated by reference herein.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics into the composition.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the compounds may also be coated on implantable medical devices, such as beads, or co- formulated with a polymer or other molecule, to provide a "drug depot" thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
  • the compounds in this invention may be prepared by methods described herein, wherein the substituents are as defined for formula(I), above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Persons skilled in the art will recognize that the chemical reactions described herein may be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention.
  • the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
  • MS data were generally determined on an Agilent 1200 Series LCMS (Zorbax SB-C18, 2.1 x 30 mm, 4 micorn, 10 minutes run, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 0)) with UV detection at 210/254 nm and a low resonance electrospray mode (ESI).
  • Agilent 1200 Series LCMS Zorbax SB-C18, 2.1 x 30 mm, 4 micorn, 10 minutes run, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 0)
  • UV detection at 210/254 nm
  • ESI low resonance electrospray mode
  • the desired kinase inhibitor (7) disclosed hererin can be prepared in a method illustrated in Scheme 1.
  • (R)-aryl alcohol (1) and substituted fluoropyridine (2) is treated with a base such as NaH in aprotic solvent such as THF to give the coupled compound (3).
  • the nitro group in (3) is then reduced to an amine (4) under acidic conditions using a reducing agent such as Fe powder.
  • Subsequent regio-selective bromination of the pyridine ring can be accomplished with the aid of N-bromo-succinimide to furnish compound (5).
  • Final coupling of (5) with compound (6) in the presence of a suitable Pd catalyst affords the desired kinase inhibitor (7).
  • kinase inhibtor (7) in this invention may be synthesized through the procedure depicted in Scheme 2.
  • the intermediate (5) and (Boc) 2 0 is treated with a base such as a 2 C0 3 , aHC0 3 or Et 3 N to give N-protected compound (8).
  • Compound (8) is then coupled with bis(pinacolato)diboronwith the aid of an appropriate Pd catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2 or Pd(PPh 3 ) 2 Cl 2 in an aprotic solvent (for example, DMSO, DMF or dioxane) to afford a boronic acid derivative (9).
  • an aprotic solvent for example, DMSO, DMF or dioxane
  • the preferred bases for the coupling reaction include NaHC(3 ⁇ 4, KHC0 3 , Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , and others.
  • the reaction is preferably performed in a mixed solvent such as DME/H 0, dioxane/H 0, at a temperature ranging from 70 °C to 100 °C.
  • Boc- group and other PG group are all removed under acidic conditions, for example, trifluoroacetic acid (TFA) in DCM, or HCl in ethyl acetate or ethyl ether to afford the desired kinase inhibitor (7).
  • TFA trifluoroacetic acid
  • Step 9) N,N-bis(tert-butoxycarboxyl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- fluorotetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 10 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l -(4-fluorotetrahvdrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Step 1 4-iodo- 1 -(4-((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3 -yl)- 1 H-pyrazole
  • Step 2 N.N-bis(ter/-butoxycarbonyl)-3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- ((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 3) 4-(4-(6-amino-5-((R)-l -(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- !H-pyrazol- 1 - yl)tetrahydrofuran-3 -ol
  • Step 2) l-(tert-butoxycarbonyl)-2,5-dihvdro-lH-pyrrole
  • Step 6) 1 -( 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3 -yl)-4-iodo- 1 H-pyrazole
  • Step 7) 1 -(1 -(ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl- 1 ,3 ,2- dioxaborolan-2-yl)- IH-pyrazole
  • Step 8) 5-(l -(1 -( ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)- lH-pyrazol-4-yl)-3-( (R)- 1 -(2.6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 9) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-fluoropyrrolidin-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Step 1) 1 -CI -( ' ter?-butoxycarbonyl -4-( ' ( ' tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-3 -yl)-4-iodo- lH-pyrazole
  • Step 2 N.N-bisCter/-butoxycarbonyl)-5 -C 1 -C 1 -Cter/-butoxycarbonyl)-4-CCtetrahydro-2H-pyran-2- yl)oxy)pyrrolidin-3 -yl)- lH-pyrazol-4-yl)-3 -((R)- 1 -C2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin- 2 -amine
  • Step 3 4-(4-(6-amino-5-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l- yl)pyrroridin-3-ol
  • Step 2) ⁇ ((Syi-l-ftert-butoxycarbonyD-S-faethoxycarbonyDpyrrolidin-S-yD ⁇ -iodo-lH- pyrazole
  • Step 5 C( ' 2S)-4-( ' 4-( ' 6-amino-5-( ' ( ' R)-l-( ' 2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)- 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol
  • Step 6 ((2S)-4-(4-(6-amino-5-( ' ( ' R)-l-( ' 2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)pyrrolidin-2-yl)methanol
  • Step 2) (SV 1 -( 1 -(tert-butoxycarbonyl)pyrrolidin-3 -yl -4-iodo- 1 H-pyrazole
  • Step 5 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-3-yl)-lH- pyrazol-4- yl)pyridin-2-amine
  • Example 7 3- /?)-1- 2,6- ⁇ € ⁇ -3- ⁇ 6 ⁇ 1)6 ⁇ )-5- 1- 4,4-( ⁇ 6 ⁇ 1 ⁇ 6 ⁇ 3 ⁇ -2- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 4) l-((4,4-dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)- lH-pyrazole
  • Step 5 3-((R)- 1 -(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l -((4.4-dimethyloxetan-2-yl)methyl)- 1 H-pyrazol-4-yl)pyridin-2-amine
  • Step 2) l-(tert-butoxycarboxyl)-3-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol
  • Step 2) (S)- 1 -(( 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
  • Example 6 Step 2 by using a suspension of 4-iodo-lH-pyrazole(840mg, 7.4mmol), (5)-(l-(tert- butoxycarbonyl)pyrrolidin-2-yl)methyl methanesulfonate(1.4g) and NaH(320mg, 12mmol, 90% dispersion in mineral oil)in DMF (20 mL).
  • Step 4) 5-q -((YSV 1 -( ' tert-butoxycarbonvnpyrrolidin-2-vnmethvn- lH-pyrazol-4-vn-3 -((TO- 1 - (2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 5 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-2-yl methyl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Example 6 Step 5 by using a solution of 5-(l-(((5)-l-(?ert-butoxycarbonyl)pyrrolidin-2- yl)methyl)- lH-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine (160mg, 0.29mmol) and HCl (5 mL, 1 M in EtOAc)in EtOAc to afford the title compound as a yellow solid(60mg, 46%).
  • Step4) 1 -(((2 S)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
  • Step 5 l-(((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-(4.4.5.5-tetramethyl- 1.3-dioxolan-2-yl)-lH-pyrazole
  • Step6)5 ( 1 -(((2 S)- 1 -(tert-butoxycarbonyl -4-fluoropyrrolidin-2-yl methyl - 1 H-pyrazol-4-yl - 3 - ((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-2-amine
  • Step3 ((2S -l-(tert-butoxycarboxyl -4-((tetrahydro-2H-pyran-2-yl oxy pyrrolidin-2-yl methyl methanesulfonate
  • Step4) l-(((2S)-l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yl)methyl)-4-iodo- lH-pyrazole
  • Step 1) 1 -(((2S)- 1 -( ' tert-butoxycarbonyl -4-( ' ( ' tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-2- yl)methyl)-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazole
  • Step 2) 5-(l-(((2S)- l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yPmethyl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine
  • Example 13 4- 6-amino-5- J R)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH- Pyrazol-l-yl)tetrahvdro-2H-pyran-3-ol (13 a) and
  • Step l) l -(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate
  • MsCl 8.6 g, 59 mmol
  • the reaction was stirred at rt for 2 h. then diluted with DCM (100 mL), and washed with saturated aqueous a 2 CO 3 (250 mL) followed by brine (250 mL).
  • the organic phase was dried over anhydrous a 2 S0 4 , and concentrated in vacuoto obtain the crude compound as yellow oil (14 g, 97 %), which was used for the next step without further purification.
  • Step 2) l-(tert-butoxycarboxyl)-L2,3,6-tetrahvdropyridine
  • Step 6) 1 -(tert-butoxycarboxyl)-3 -((tetrahydro-2H-pyran-2-yl)oxy)- 1 ,2,3 ,6-tetrahydropyridine
  • Step 9) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -one
  • Step 10) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -ol
  • Step 12 l-(tert-butoxycarbonyl)-3-fluoro-5-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -vDpiperidine
  • Step 13) 5-(1-(1 -(tert-butoxycarbonyl)-5-fruoropiperidin-3 -yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2 ,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 14 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(5-fluoropiperidin-3-yl)- 1H- pyrazol-4-yl)pyridin-2-amine
  • Step 1)1 -(ter/-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- !H-pyrazol- l-yl)piperidin-3-ol
  • Step 7) 5-q -(2.2 -dideuteropiperidin-4-yl - 1 H-pyrazol-4-ylV 3 -(YRV 1 -(2.6-dichloro-3 - fluorophenyl)ethoxy)pyridin-2-amine
  • Step 1) l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)piperidin-3-ol(17.1 a)
  • Step 2) 1 -(tert-butoxycarbonyl)-4-(4-iodo- 1 H-pyrazol- 1 -yl)-3 -((tetrahydro-2H-pyran-2- yl)oxy)piperidine
  • Step 3 l-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(4-(4.4.5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine
  • Step 4) 5-( 1 -(1 -(tert-butoxycarbonyl)-3 -((tetrahvdro-2H-pyran-2-yl)oxy)piperidin-4-yl)- 1 H- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 7) 3 -((R)- 1 -(2.6-dichloro-3 -fluorophenyl)ethoxy)-5-( 1 -((3 S.4RV3 -fluoropiperidin-4-yl)- 1 H- pyrazol-4-yl)pyridin-2-amine(l 7 a)
  • Step 1) 1 -(tert-butoxycarbonyl)-3 -(4-iodo- 1 H-pyrazol- 1 -yl)-4-((tetrahydro-2H-pyran-2- yl)oxy)piperidine
  • Step 2) 1 -(tert-butoxycarbonyl)-4-((tetrahvdro-2H-pyran-2-yl)oxy)-3 -(4-(4 ,4,5 ,5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-l H-pyrazol- 1-vDpiperi dine [0277]
  • the title compound was prepared according to the procedure described in Example 17 Step 3 by using a suspension of l-(tert-butoxycarbonyl)-3-(4-iodo-lH-pyrazol-l- yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine (0.6 g, 1.25 mmol), bis(pinacolato)diboron (0.9 g, 3.8 mmol), KOAc(0.25 g, 2.5 mmol) and Pd(dppf)Cl 2 -CH 2 Cl 2 (0.1 g, 0.125 mmol)
  • Step 3) 5-(l-(l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-3-yl)-lH- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 5 3-( ' ( ' R -l-( ' 2,6-dichloro-3-fluorophenyl ethoxy -5-( ' l-( ' ( ' hexahvdrofuror2,3-/?1 furan-3- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 4) l-((3a5',65',6aR)-6-((tetrahvdro-2H-pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-4- (4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)- lH-pyrazole
  • Step 5 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((3a .65'.6aR)-6-((tetra- hydro-2H- pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 6 (3 ,3a5',6ay)-6-(4-(6-amino-5-((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-3-yl)- lH-pyrazol-l-yl)hexahydrofuro[3.2-/?]furan-3-ol
  • Example 23 4- g)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- (octahvdrocvclopenta[clpyrrol-5-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 2) 2,2'-(l-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid
  • Step 9) 4-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(octahvdrocyclopentarc1 pyrrol-5- yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • the LC/MS/MS system used in the analysis consists of an Agilent 1200 Series vacuum degasser, binary pump, well-plate autosampler, thermostattedcolumn compartment, the Agilent G6430 TripleQuadrupole Mass Spectrometer with an electrosprayionization (ESI) source.Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.
  • an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis.
  • An ESI source was used on the LC/MS/MS spectrometer.
  • the analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution.

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

Abstract

la présente invention concerne de nouveaux composés cycliques substitués, des sels pharmaceutiquement acceptables et des formulations les comprenant utiles dans la modulation de l'activité de la protéine tyrosine kinase, et dans la modulation des activités cellulaires telles que la prolifération, la différenciation, l'apoptose, la migration et l'invasion. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant ces composés et des procédés d'utilisation des compositions dans le traitement de troubles d'hyperprolifération chez les mammifères, notamment chez les humains.
PCT/US2013/030096 2012-03-14 2013-03-11 Composés cycliques substitués et procédés d'utilisation WO2013138210A1 (fr)

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WO2016004873A1 (fr) * 2014-07-08 2016-01-14 上海宣创生物科技有限公司 Forme cristalline d'un mésylate de dérivés nicotinamide, procédé de préparation associé, et application associée
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CN106478651A (zh) * 2015-08-31 2017-03-08 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2017048675A1 (fr) * 2015-09-17 2017-03-23 Sunshine Lake Pharma Co., Ltd. Composés hétéroaryle substitués et leurs méthodes d'utilisation
CN104557869B (zh) * 2013-10-25 2017-09-26 正大天晴药业集团股份有限公司 一种吡啶胺化合物富马酸盐的晶型
WO2018124001A1 (fr) 2016-12-27 2018-07-05 国立研究開発法人理化学研究所 Composé inhibiteur de signal bmp
US10053477B2 (en) 2014-07-04 2018-08-21 Qilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide
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CN110016013A (zh) * 2019-05-22 2019-07-16 北京凯恩梅格医药科技有限公司 一种新型的c-Met/HDAC双靶点抑制剂及其合成方法与应用
CN110128411A (zh) * 2019-05-22 2019-08-16 北京凯恩梅格医药科技有限公司 一种c-Met/HDAC双靶点抑制剂及其合成方法与应用
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US11453621B2 (en) 2015-12-11 2022-09-27 Electrophoretics Limited Isobaric mass labels having n',n'-dimeihyl piperazine-2-carboxylic acid reporter moieties

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US10053477B2 (en) 2014-07-04 2018-08-21 Qilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide
WO2016004873A1 (fr) * 2014-07-08 2016-01-14 上海宣创生物科技有限公司 Forme cristalline d'un mésylate de dérivés nicotinamide, procédé de préparation associé, et application associée
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