WO2014193647A2 - Composés alcényles et procédés d'utilisation - Google Patents

Composés alcényles et procédés d'utilisation Download PDF

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WO2014193647A2
WO2014193647A2 PCT/US2014/037856 US2014037856W WO2014193647A2 WO 2014193647 A2 WO2014193647 A2 WO 2014193647A2 US 2014037856 W US2014037856 W US 2014037856W WO 2014193647 A2 WO2014193647 A2 WO 2014193647A2
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mmol
cancer
alkylene
cycloalkyl
independently
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PCT/US2014/037856
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English (en)
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WO2014193647A3 (fr
Inventor
Ning Xi
Xiaobo Li
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Calitor Sciences, Llc
Sunshine Lake Pharma Co., Ltd.
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Publication of WO2014193647A2 publication Critical patent/WO2014193647A2/fr
Publication of WO2014193647A3 publication Critical patent/WO2014193647A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • This invention relates to novel substituted alkenyl 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-phosphorylate tyrosine 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 et al., "Receptor tyrosine kinase inhibitors as potent weapons in war against cancers" Curr. Pharm. Des. 2009, 15, 758).
  • ALK Anaplastic lymphoma kinase
  • NPM nucleophosmin
  • ALK 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.
  • 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 et al., "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer", Nature 2007, 448, 561).
  • JAK3-STAT3 pathway and the PI3K-Akt pathway have been shown to be vital primarily for cell survival and phenotypic changes (Chiarle et al., "The anaplastic lymphoma kinase in the pathogenesis of cancer", Nat. Rev. Cancer, 2008, 8, 11; Barreca 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 In both embryos and adults, activated c-Met promotes a morphogenetic program, known as invasive growth, which induces cell spreading, the disruption of intercellular contacts, and the migration of cells towards their surroundings (Peschard et al, "From Tpr-Met to Met, tumorigenesis and tubes", Oncogene, 2007, 26, 1276; Stellrecht et al., "Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target", Cancer Letter, 2009, 280, 1). [013] A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, thyroid, colon, renal, glioblastomas, and prostate, etc.
  • 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. Thus, extensive evidence that 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 et al., "Molecular cancer therapy: can our expectation be MET", Eur. J. Cancer, 2008, 44, 641; Benedetta et al, “Targeting the c-Met Signaling Pathway in Cancer", Clin. Cancer Res., 2006, 12, 3657).
  • 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 (Alice et al, Nat. Rev. Drug Discovery, 2011, 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 improvement in potency, pharmacokinetic properties, and/or toxicity profile over certain other ALK and/or c-Met inhibitor compounds found in the art.
  • the compounds disclosed herein are inhibitors of protein tyrosine kinases.
  • the compounds disclosed herein 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 2 is independently D, F, CI, Br, I, CN, N0 2 , N3, OR a , SR a , NR a R b , (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C6)alkynyl, -(Ci-C 4 )alkylene-CN, -(Ci-C 4 )alkylene-NR a R b , -(Ci-C 4 )alkylene-OR a , (C3-C 8 )cycloalkyl, -(Ci-C 4 )alkylene-(C3-C 8 )cycloalkyl, (C 3 - C 8 )heterocyclyl, or -(Ci-C4)alkylene-(C3-C 8 )heterocyclyl; each R a and R b is independently H,
  • each of Wi and W 2 is independently CR C ; and W3 is N or
  • each of Ai, A 2 and A3 is independently H, D, CN, N3, -
  • Z is
  • each of Zi and Z 2 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R 1 groups; provided that when Z is phenyl, each R 1 is not OH.
  • each R 1 is independently D, F, CI, OR a , NR a R b , -
  • each R 2 is independently D, F, CI, OR a , NR a R b , (Ci-
  • each R a and R b is independently H, (Ci-C3)alkyl, (C3-
  • Ce)cycloalkyl, (C3-Ce)heterocyclyl, or R a and R b are taken together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic ring, and wherein each of the above substituents is optionally substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, N3, OH, NH 2 , (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
  • each R c is independently H, D, F, CI, CN, NH 2 , -
  • each R c is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, CN, N3, OH, NH 2 , (Ci- C3)alkyl, (C3-Ce)cycloalkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
  • Z is
  • Z is optionally independently substituted with 1, 2, or 3 R 1 groups; provided that when Z is phenyl, each R 1 is not OH.
  • compositions comprising a compound disclosed herein, or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, 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 adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, mas
  • 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 the method 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).
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 36 S, 18 F, and 37 C1.
  • the compounds disclosed herein that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds disclosed herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
  • the compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomers 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 (X) and (E) conformational isomers. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution), a chemical equilibrium, of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto- enol tautomerization is the intercoiiversion of penta.ne-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol -keto tautomerization.
  • a specific example of phenol-keto tautomerization is the intercoiiversion of pyridin-4-ol and pyridin-4(lH)- one tautomers.
  • any asymmetric atom (e.g., carbon or the like) of the compoimd(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the ( ?)-, (5) ⁇ or (R,S)- configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S) ⁇ configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.
  • a compound disclosed herein can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemat.es or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.
  • the compounds disclosed herein 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. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”. In general, the term “substituted” whether proceeded by the term “optionally” or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally 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.
  • substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic group contains 1-20 carbon atoms. In some embodiments, the aliphatic group contains 1-10 carbon atoms. In other embodiments, the aliphatic group contains 1-8 carbon atoms. In still other embodiments, aliphatic groups contain 1-6 carbon atoms. In yet other embodiments, the aliphatic group contains 1-4 carbon atoms, and in further embodiments, the aliphatic group contains 1-3 carbon atoms.
  • aliphatic group examples include linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.
  • (Ci-C6)aliphatic groups include unbranched or branched, unsubstituted or suitably substituted (Ci-Ce)alkyl, (C 2 - C 6 )alkenyl or (C2-Ce)alkynyl groups.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-8 carbon atoms. In still other embodiments, the alkyl group contains 1-6 carbon atoms. In yet other embodiments, the alkyl group contains 1-4 carbon atoms, and in further embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl group examples include methyl (Me, -CH3), ethyl
  • alk- refers to both straight chain and branched saturated carbon chain.
  • alkyl ene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkyl ene group contains 1-6 carbon atoms. In some embodiments, the alkylene group contains 1-4 carbon atoms. In other embodiments, the alkylene group contains 1-2 carbon atoms. Some non-limiting examples of the alkylene group include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • the alkenyl group contains 2 to 8 carbon atoms, more preferably, 2 to 6 carbon atoms, and most preferably 2 to 4 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 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.
  • the alkynyl group contains 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and most preferably 2 to 4 carbon atoms.
  • Some non-limiting examples of the alkynyl group include ethynyl (-C ⁇ CH), propynyl (propargyl, -CH 2 C ⁇ CH), - 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, the alkoxy group contains 1-20 carbon atoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms. In other embodiments, the alkoxy group contains 1-8 carbon atoms. In still other embodiments, the alkoxy group contains 1-6 carbon atoms. In yet other embodiments, the alkoxy group contains 1-4 carbon atoms, and in further embodiments, the alkoxy group contains 1-3 carbon atoms.
  • alkoxy group examples include methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (z ' -PrO, i- propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy ( ⁇ -BuO, z-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (n-pentoxy, O
  • carbocycle refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system.
  • carbocyclyl group include cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1- cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated ring having
  • a bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl.
  • the cycloalkyl contains 3 to 10 carbon atoms. In still other embodiments, the cycloalkyl contains 3 to 8 carbon atoms, and in yet other embodiments, the cycloalkyl contains 3 to 6 carbon atoms.
  • the cycloalkyl radical is optionally substituted independently with one or more substituents described herein.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected from heteroatoms and that is completely saturated or that contains one or more units of unsaturation, but not aromatic, having one or more point of attachment to the rest of the molecule.
  • a bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl, and one of the rings can be either a monocarbocycle or a monohetercycle.
  • One or more ring atoms are optionally substituted independently with one or more substituents described herein.
  • the "heterocycle”, “heterocyclyl”, 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 S0 2 , PO or PO2).
  • it is a monocycle having 3 to 6 ring members (2 to 5 carbon atoms and 1 to 2 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) or a bicycle having 7 to 10 ring members (4 to 9 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 S0 2 , PO or P0 2 ).
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • Some non- limiting examples of the heterocyclic ring include, 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-dio
  • 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).
  • halogen means F, CI, Br or I.
  • ⁇ 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 be attached to a methyl group to form a di-deuterated methyl (-CD 2 H), and three of deuterium atoms may be attached to a methyl group to form a tri-deuterated methyl group (-CD3).
  • N3 denotes an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, MeNs); or attached to a phenyl group to form phenyl azide (PI1N3).
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 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 one or more point of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring”. Some non-limiting examples of the aryl ring would include phenyl, naphthyl, and anthracene.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 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 to 7 ring members and that has a one or more point of attachment to the rest of the molecule.
  • a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
  • the heteroaryl radical is optionally substituted independently with one or more substituents described herein.
  • heteroaryl ring 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-
  • Carboxyalkyl denotes -CO2H.
  • 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 1 or 2 alkyl radicals of 1 to 6 carbon atoms, attached to a nitrogen atom. Even more preferred alkylamino radicals having 1 or 2 alkyl radicals of 1 to 3 carbon atoms, attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N- dimethylamino, N,N-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 1 to 6 carbon atoms and one or more amino radicals. Some non-limiting examples of such radical include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • fused bicyclic refers 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 is a carbocyclic or a heterocyclic.
  • fused bicyclic ring system examples include hexahydrofuro[3,2-3 ⁇ 4]furan, hexahydrofuro[2,3-3 ⁇ 4]furan, octahydrocyclopenta[c]pyrrole, hexahydro-lH-pyrrolizine, and octahydro-lH-pyrido[l,2-a]pyrazine.
  • spirocyclyl refers to a monovalent or multivalent ring system wherein a ring originating from a particular annular carbon of another ring.
  • a saturated bridged ring system (ring B and B') is termed as "fused bicyclic"
  • ring A and ring B share an atom between the two saturated ring system, which terms as a "spirocyclyl” or "spiro bicyclyl”.
  • Each cyclic ring in a spirocyclyl is a carbocyclic or a heterocyclic.
  • 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 e represents possible substitution in any of the positions on the B ring shown in Structure f-1, f-2 and f-3.
  • 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 disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein 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 "metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolite 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.
  • the invention includes metabolites of compounds disclosed herein, 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.
  • a "pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein.
  • the pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharm. Sci., 1977,
  • the pharmaceutically acceptable salt include 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.
  • the pharmaceutically acceptable salt 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, pect
  • 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 dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • compositions 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.
  • 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 disclosed herein.
  • solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • compositions include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, p. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • preservatives e.g., antibacterial agents, antifungal agents
  • isotonic agents e.g., absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • the term “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • the term “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • the term “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • 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, t-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 -CH2CH2S02Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxy-methy-1, 2-(p-toluenesulfonyl) ethyl, 2-(p- nitrophenylsulfenyl)-ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • the present invention provides alkenyl 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/or c-Met receptor. More specifically, the present invention rovides a compound of Formula (I):
  • each R 2 is independently D, F, CI, Br, I, CN, N0 2 , N 3 , OR a , SR a , NR a R b , (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C6)alkynyl, -(Ci-C 4 )alkylene-CN, -(Ci-C 4 )alkylene-NR a R b , -(Ci-C 4 )alkylene-OR a , (C 3 -C 8 )cycloalkyl, -(Ci-C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 - C 8 )heterocyclyl, or -(Ci-C 4 )alkylene-(C3-C 8 )heterocyclyl; each R a and R
  • each of Wi and W 2 is independently CR C ; and W3 is N or
  • each of Ai, A 2 and A3 is independently H, D, CN, N3, -
  • Z is
  • each of Zi and Z 2 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R 1 groups; provided that when Z is phenyl, each R 1 is not OH.
  • each R 1 is independently D, F, CI, OR a , NR a R b , -
  • each R 2 is independently D, F, CI, OR a , NR a R b , (Ci-
  • C 4 )alkyl (Ci-C 4 )haloalkyl, (C3-Ce)cycloalkyl, or (C3-C6)heterocyclyl.
  • each R a and R b is independently H, (Ci-C3)alkyl, (C3-
  • Ce)cycloalkyl, (C3-Ce)heterocyclyl, or R a and R b are taken together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic ring, and wherein each of the above substituents is optionally substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, N3, OH, NH 2 , (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
  • each R c is independently H, D, F, CI, CN, NH 2 , -
  • each R c is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, CN, N3, OH, NH 2 , (Ci- C3)alkyl, (C3-Ce)cycloalkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
  • Z is
  • Z is optionally independently substituted with 1, 2, or 3 R 1 groups; provided that when Z is phenyl, each R 1 is not OH.
  • the present invention also comprises the use of a compound disclosed herein, 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 disclosed herein are useful in the manufacture of an anti-cancer medicament.
  • the compounds disclosed herein 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 disclosed herein 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 disclosed herein is such that is effective to detectably inhibit a protein kinase in a biological sample or in a patient.
  • certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives 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 disclosed herein 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 non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include 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; talc
  • compositions disclosed herein 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, intraarticular, 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. These 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 disclosed herein 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 disclosed herein 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 in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • the 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 disclosed herein 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., antiemetics
  • the compounds disclosed herein can be combined, with cytotoxic anti-cancer agents.
  • cytotoxic anti-cancer agents 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, procarbamate, asparaginase, bleomycin, carboplatin, car
  • cytotoxic drugs suitable for use with the compounds disclosed herein 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,
  • cytotoxic anti-cancer agents suitable for use in combination with the compounds disclosed herein also include newly discovered cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al, J. Clin. Oncol, 2003, 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. Oncol, 2003, 21(4), 646-651
  • the compounds disclosed herein can be combined with other signal transduction inhibitors.
  • Some non-limiting examples of such agents include antibody therapies such as trastuzumab (HERCEPTIN ® ), cetuximab (ERBITUX ® ), ipilimumab (YERVOY ® ) and pertuzumab.
  • Some non-limiting examples of such therapies also include 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, brivanib, canert
  • the compounds disclosed herein can be combined with inhibitors of histone deacetylase.
  • Some non-limiting examples of such agents include 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 On
  • the compounds disclosed herein 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 disclosed herein 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 disclosed herein is such that is effective to detectably inhibit a protein kinase, such as ALK and c-Met inhibitory activity.
  • the compounds disclosed herein are useful in therapy as antineoplastic agents or to minimize deleterious effects of ALK and c-Met signaling.
  • the compounds disclosed herein 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 disclosed herein 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 lymphocytic 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, myelodysplasia syndrome and promyelocytic leukemia); tumors
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, 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.
  • 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;
  • the compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability.
  • the compounds disclosed herein are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.
  • the compounds disclosed herein are also useful in the reduction of blood flow in a tumor in a subject.
  • the compounds disclosed herein are also useful in the reduction of metastasis of a tumor in a subject.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • the treatment method that includes administering a compound or composition disclosed herein 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 disclosed herein 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 disclosed herein 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 disclosed herein, 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 disclosed herein.
  • 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 disclosed herein, 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 disclosed herein, 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 disclosed herein.
  • Scheme 4 shows another method to prepare the kinase inhibitors disclosed herein.
  • iodo compound (17) compound is reacted with Vinyl compound (25) under Heck conditions, follow by deprotection of the amino group with aqueous base to give the desired kinase inhibitors (26).
  • Kinase inhibitors (27) and (28) can also be prepared according to the general methods as described in Schemes 1 and 3.
  • Step 2) tert-butyl 4-(4-iodo-lH-pyrazol-l-yl)piperidine-l -carboxylate
  • Step 4) 1 -(5 -bromo- 1 H-pyrrolo[2,3 -b]pyridin-3 -yl)-N,N-dimethylmethanamine
  • Example 1 Step 7 by using (E)-5-bromo-3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridine (648 mg, 1.94 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l -carboxylate (1099 mg, 2.91 mmol), a solution of Na 2 C0 3 (617 mg, 5.82 mmol) in water (4.6 mL) and Pd(PPh 3 ) 2 Cl 2 (136 mg, 0.194 mmol). The crude compound was purified by a silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give the title compound as a white solid (670 mg, 69%).
  • Step 1) (Z)-tert-butyl 4-(4-(3-(2-chlorostyryl)-lH-pyrrolor2,3-b1pyridin-5-yl)-lH-pyrazol-l-yl) piperidine- 1 -carboxylate
  • Step 2) (Z)-3-(2-chlorostyryl)-5-(l -(piperidin-4-yl)- lH-pyrazol-4-yl)- lH-pyrrolo[23-b]pyridine
  • Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridin-5- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (330 mg, 0.655 mmol) and a solution of HC1 in EtOAc (3.5 mL, 14 mmol, 4 M). The crude product was washed with EtOAc (6 mL) and filtered to give the title compound as an off-white solid (150 mg, 57%).
  • Step 3 (EVfe -butyl 4-(4-(3-(2-chloro-4-fluorostyrvn-lH-pyrrolor2,3-blpyridin-5-vn-lH- pyrazol- 1 -yDpiperidine- 1 -carboxylate
  • Step 1) (Z)-tert-butyl 4-(4-(3-(2-chloro-4-fiuorostyrvn-lH-pyrrolor2,3-blpyridin-5-vn-lH- p yrazol- 1 -vDpiperidine- 1 -carboxylate
  • Step 2) (z ⁇ -3-(2-chloro-4-fluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3- blpyridine
  • Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (342 mg, 0.66 mmol) and a solution of HC1 in EtOAc (6.4 mL, 26.2 mmol, 4.1M). The crude product was stirred with EtOAc (5 mL) at refluxing temperature to give the title compound as a pale yellow solid (103 mg, 37%).
  • the mixture was microwaved at 150 °C for 1 hour, then cooled to rt, poured into water (50 mL) and the resulted mixture was extracted with CH2CI2 (50 mL x 4). The combined organic layers were dried over anhydrous Na 2 S04, and concentrated in vacuo. The crude product was used in next step without further purification.
  • Example 1 Step 8 by using ⁇ E)-tert- vXy ⁇ 4-(4-(3-(2-(2,6-dichloro-3-fluorophenyl)prop-l-en-l- yl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (91 mg, 0.18 mmol) and a solution of HC1 in EtOAc (1 mL, 4 mmol, 4 M). The crude product was purified by a silica gel column chromatography (DCM/CH 3 OH (v/v) 15/1) to give the title compound as a white solid (68 mg, 80%).
  • Example 1 Step 8 by using (E)-tert-butyl 4-(4-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (500.0 mg, 0.874 mmol) and a solution of HCl in EtOAc (4.4 mL, 17.60 mmol, 4 M). The crude product was washed with EtOAc (10 mL) several times and filtered to give the title compound as a yellow solid (300.0 mg, 72.7%).
  • Step 1) tert-butyl 4-(4-(lH-pyrrolor2,3-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
  • Example 1 Step 7 by using tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate (11.3 g, 30 mmol), 5-bromo-lH-pyrrolo[2,3-b]pyridine (4.93 g, 25 mmol), a solution of Na 2 C0 3 (8.0 g, 75 mmol) in water (63 mL) and Pd(PPh 3 ) 2 Cl 2 (1.8 g, 2.5 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give the title compound as a white solid (4.8 g, 52%).
  • Step 2) tert-butyl 4-(4-(3-iodo-lH-pyrrolo[2J-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
  • Example 2 Step 1 by using tert-butyl 4-(4-(3-iodo-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l- yl)piperidine-l -carboxylate (4.93 g, 10 mmol), PhS0 2 Cl (2 mL, 15 mmol), rc-Bu 4 NHS0 4 (0.44 g, 1.3 mmol) and NaOH aqueous solution (1.9 mL, 50%).
  • Example 1 Step 8 by using ⁇ E)-tert- vXy ⁇ 4-(4-(3-(2,5-dichlorostyryl)-lH-pyrrolo[2,3-b]pyridin- 5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (160 mg, 0.30 mmol) and a solution of HC1 in EtOAc (5 mL, 10 mmol, 2 M). The crude product was purified by a silica gel column chromatography (DCM/MeOH/NH 4 OH (v/v/v) 8/1/0.02) to give the title compound as a yellow solid (60 mg, 46.1%).
  • Step 1) (Z)-tert-butyl 4-(4-(3-(2-chloro-6-methylstyryl)-l-(phenylsulfonyl)-lH-pytTolor2,3-b1 pyridin-5-yl)- lH-pyrazol- 1 -vDpiperidine- 1 -carboxylate (la)
  • Step 2 (Z)-fert-butyl 4-(4-(3-(2-chloro-6-methylstyryl)-lH-pyrrolor2,3-blpyridin-5-yl)-lH- p yrazol- 1 -vDpiperidine- 1 -carboxylate (2a)
  • Example 9 Step 5 by using tert-butyl 4-(4-(l-(phenylsulfonyl)-3-vinyl-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (198 mg, 0.95 mmol), 2-bromo-l,4- difluorobenzene (500 mg, 0.9 mmol), Pd(OAc) 2 (4 mg, 0.018 mmol), PPh 3 (9 mg, 0.036 mmol), K 2 C0 3 (310 mg, 2.25 mmol) and TBAI (0.09 mmol, 33 mg).
  • Step 2) ( E)-ter 't-butyl 4-(4-(3-(2,5-difluorostyryl)-lH-pyrrolo[23-blpyridin-5-yl)-lH-pyrazol-l- vDpiperidine- 1 -carboxylate
  • Example 1 Step 8 by using ⁇ E)-tert-bvXy ⁇ 4-(4-(3-(2,5-difluorostyryl)-lH-pyrrolo[2,3-b]pyridin- 5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (240 mg, 0.47 mmol), and a solution of HC1 in EtOAc (5 mL, 10 mmol, 2 M). The crude product was purified by a silica gel column chromatography (CH 2 Cl 2 /MeOH/NH 4 OH (v/v/v) 8/1/0.02) to give the title compound as a yellow solid (85 mg, 44.2%).
  • Step 1) ( E)-ter 't-butyl 4-(4-(3-(2-chloro-6-(trifluoromethyl)styryl)-lH-pyrrolo[2J-blpyridin-5- vD- 1 H-p yrazol- 1 -vDpiperidine- 1 -carboxylate
  • Step 2) (E)-3-(2-chloro-6-(trifluoromethyl)styryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine
  • Step 3 (EVfert-butyl 4-(4-(3-(2,6-dichloro-3-fluorostyrvn-lH-pyrrolor2,3-blpyridin-5-vn-lH- pyrazol- 1 -yDpiperidine- 1 -carboxylate
  • Step 2) (Z)-tert- vXy ⁇ 4-(4-(3-(2-(2-chlorophenyl)-2-cyanovinyl)-lH-pyrrolo[23-blpyridin-5-yl)- lH-pyrazol- 1 -vDpiperidine- 1 -carboxylate
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2- chlorophenyl)acrylonitrile (359 mg, 1.0 mmol), tert- vXy ⁇ 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (566 mg, 1.5 mmol), a solution of Na 2 C0 3 (318 mg, 3.0 mmol) in water (2.5 mL) and Pd(PPh 3 ) 2 Cl 2 (70 mg, 0.1 mmol). The crude product was purified by a silica gel column chromatography (EtOAc/PE (v/v) 3/2) to give the title compound as a yellow solid (360 mg, 68%).
  • Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-(2-chlorophenyl)-2-cyanovinyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (265 mg, 0.5 mmol) and a solution of HCl in EtOAc (3.5 mL, 10.5 mmol, 3 M). The crude product was washed with EtOAc (5 mL), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (192 mg, 89%).
  • Step 2 (Z)-tert-butyl 4-(4-(3-(2-(2-chloro-6-fluorophenyl)-2-cvanovinyl)-lH-pyrrolor2,3- blpyridin-5-yl)-lH-pyrazol- 1 -yPpiperidine- 1 -carboxylate
  • Step 3 ( )-2-(2-chloro-6-fluorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-blpyridin-3-yl)acrylonitrile
  • Example 14 Step 1 by using 2-phenylacetonitrile (1.12 g, 9.6 mmol), t-BuOK (1.08 g, 9.6 mmol), a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.92 g, 8.0 mmol) in DMF (60 mL), EtOH (60 mL) and NaOH aqueous solution (30 mL, 10%). The crude product was washed with MeOH (3 mL), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (375 mg, 14%).
  • Step 2) (Z)-tert- vXy ⁇ 4-(4-(3-(2-cyano-2-phenylvinyl)-lH-pyrrolo[2J-blpyridin-5-yl)-lH- p yrazol- 1 -vDpiperidine- 1 -carboxylate
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacrylonitrile (353 mg, 1.1 mmol), tert- vXy ⁇ 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l -carboxylate (619 mg, 1.6 mmol), a solution of Na 2 C03 (350 mg, 3.3 mmol) in water (3 mL) and Pd(PPh 3 ) 2 Cl 2 (77 mg, 0.11 mmol). The crude product was purified by a silica gel column chromatography (EtOAc/PE (v/v) 1/1) to give the title compound as a yellow solid (360 mg, 67%).
  • Example 1 Step 7 by using 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(5-chloro-2- (trifluoromethyl)phenyl) acrylonitrile (500 mg, 1.2 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (679 mg, 1.8 mmol), a solution of Na 2 C0 3 (382 mg, 3.6 mmol) in water (3.0 mL) and Pd(PPh 3 ) 2 Cl 2 (84 mg, 0.12 mmol). The crude product was purified by a preparative thin-layer chromatography (DCM/MeOH (v/v) 25/1) to give the title compound as a yellow solid (360 mg, 68%).
  • DCM/MeOH (v/v)
  • Step 3 (z ⁇ -2-(5-chloro-2-(trifluoromethyl)phenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile
  • Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-(5-chloro-2-(trifluoromethyl)phenyl)-2- cyanovinyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)- lH-pyrazol-1 -yl)piperidine- 1 -carboxylate (265 mg, 0.5 mmol) and a solution of HCl in EtOAc (3.5 mL, 10.5 mmol, 3 M). The crude product was washed with EtOAc (3 mL), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (192 mg, 89%).
  • Step 1) (Z)-3-(5-bromo-lH-pyrrolo[2J-blpyridin-3-yl)-2-(2,6-dichlorophenyl)acrylonitri [0248]
  • the title compound was prepared according to the procedure as described in
  • Example 14 Step 1 by using 2-(2,6-dichlorophenyl)acetonitrile (446.5 mg, 2.400 mmol), t- BuOK (269.3 g, 2.400 mmol), a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridine-3-carbaldehyde (730.4 g, 2.000 mmol) in DMF (20 mL), EtOH (50 mL) and NaOH aqueous solution (10 mL, 10%). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) 2/1) to give the title compound as a yellow solid (280.0 mg, 35.6%).
  • Step 2 (z)-2-(2,6-dichlorophenyl)-3-(5-(2-(piperazin-l-yl)pyridin-4-yl)-lH-pyrrolor2,3-b1 p yridin-3 - yl)acrylonitrile
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (157 mg, 0.4 mmol), l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-2-yl)piperazine (174 mg, 0.6 mmol), a solution of CS2CO3 (391 mg, 1.2 mmol) in water (2 mL), and Pd(dppf)Ci2-CH2Ci2 (66 mg, 0.08 mmol).
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (118 mg, 0.3 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amine (99 mg, 0.45 mmol), a solution of CS2CO3 (293 mg, 0.9 mmol) in water (1.5 mL), and Pd(dppf)Cl2-CH2Ci2 (25 mg, 0.03 mmol).
  • Step 2) (3-hydroxypyrrolidin-l-yl)(4-(4 ⁇ ,5,5-tetramethyl-13,2-dioxaborolan-2-yl)phenyl) methanone
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (157 mg, 0.4 mmol), (3-hydroxypyrrolidin-l-yl)(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanone (190 mg, 0.6 mmol), a solution of Cs 2 C0 3 (391 mg, 1.2 mmol) in water (2 mL), and Pd(dppf)Cl 2 -CH 2 Cl 2 (33 mg, 0.04 mmol).
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (314 mg, 0.8 mmol), (6-methoxypyridin-3-yl)boronic acid (183 mg, 1.2 mmol), a solution of Cs 2 CC"3 (782 mg, 2.4 mmol) in water (4.0 mL), and Pd(dppf)Cl 2 -CH 2 Cl 2 (65 mg, 0.08 mmol).
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (150.0 mg, 0.38 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl) piperazine (165.5 mg, 0.57 mmol), a solution of CS2CO3 (373.0 mg, 1.14 mmol) in water (4 mL), and Pd(dppf)Cl2-CH2Cl2 (62 mg, 0.076 mmol).
  • Step 2) 1 -(tetrahydro-2H-pyran-4-yl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1H- pyrazole
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (197 mg, 0.5 mmol), l-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (209 mg, 0.75 mmol), a solution of CS2CO3 (489 mg, 1.5 mmol) in water (5 mL), and Pd(dppf)Cl2-CH 2 Ci2 (41 mg, 0.05 mmol).
  • Step 2) l-(tetrahvdrofuran-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
  • Example 1 Step 3 by 4-iodo-l-(tetrahydrofuran-3-yl)-lH-pyrazole (528 mg, 2.0 mmol), Bis(pinacolato)diboron (762 mg, 3.0 mmol), CH3COOK (784 mg, 8.0 mmol), and Pd(dppf)Cl2-CH 2 Cl2 (164 mg, 0.2 mmol).
  • Step 1 7-methoxy-3 -(4,4 ,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)quinoline
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (200 mg, 0.51 mmol), 7-methoxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (435 mg, 1.53 mmol), a solution of CS2CO3 (497 mg, 1.53 mmol) in ⁇ 2 ⁇ (0.5 mL), and Pd(dppf)Cl2-CH2Cb (41.4 mg, 0.05 mmol).
  • Step 2 tert-butyl (l-(4-(4 ⁇ ,5,5-tetramethyl-13,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3- vDcarbamate
  • tert-butyl (l-(4-bromobenzoyl)pyrrolidin-3-yl)carbamate (1.50 g, 4.06 mmol)
  • Bis(pinacolato)diboron (1.24 g, 4.87 mmol)
  • CH 3 COOK 1.20 g, 12.19 mmol
  • Pd(dppf)Ci2-CH 2 Ci2 0.662 g (0.812 mmol) under N 2 atmosphere.
  • Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (300 mg, 0.76 mmol), tert- vXy ⁇ (l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) benzoyl)pyrrolidin-3-yl)carbamate (953 mg, 2.29 mmol), a solution of K2CO3 (210 mg, 1.53 mmol) in H 2 0 (0.5 mL) and Pd(PPh 3 ) 4 (175 mg, 0.154 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) 20/1) to give the title compound as a yellow solid (154 mg, 33%).
  • DCM/MeOH (v/v) 20/1
  • Example 1 Step 8 by using ⁇ Z)-tert- vXy ⁇ (l-(4-(3-(2-cyano-2-(2,6-dichlorophenyl)vinyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)benzoyl)pyrrolidin-3-yl)carbamate (154 mg, 0.25 mmol) and a solution of HC1 in EtOAc (28 mmol, 7 mL, 4 M). The crude product was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) 100/10/1) to give the title compound as a yellow solid (50 mg, 39%).
  • Step 2 tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate
  • Step 3) fert-butyl 3-(4-iodo-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate [0272]
  • 4-iodo-lH-pyrazole (4.08 g, 21.00 mmol) in DMF (320 mL) was added NaH (0.79 g, 26.25 mmol) portion-wise at 4 °C.
  • the mixture was stirred at 4 °C for 1 hour, then tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (4.64 g, 17.50 mmol) was added.
  • Step 5 ( )-tert-butyl 3-(4-(3-(2-cyano-2-(2,6-dichlorophenyl)vinyl)-lH-pyrrolo[2J-b]pyridin- 5-yiy lH-pyrazol- 1 -yDpyrrolidine- 1 -carboxylate
  • Step 6 ( ⁇ -2-(2,6-dichlorophenyl)-3-(5-(l-(pwolidin-3-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridin-3 -yDacrylonitrile
  • Step 2) l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
  • Example 1 Step 7 by using 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(5-chloro-2- (trif uoromethyl) phenyl)acrylonitrile (300 mg, 0.70 mmol), l-methyl-4-(4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (219 mg, 1.05 mmol), a solution of CS2CO3 (456 mg, 1.4 mmol) in ⁇ 2 ⁇ (4 mL), and Pd(dppf)Cb'CH2Cb (57 mg, 10 mmol%>).
  • Step 1 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole
  • Step 2) (Z)-3-(5-(lH-pyrazol-4-vn-lH-pyrrolor2,3-blpyridin-3-vn-2-(5-chloro-2-
  • Example 1 Step 7 by using 3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(5-chloro-2- (trifluoromethyl) phenyl)acrylonitrile (300 mg, 0.7 mmol), 4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (409 mg, 2.1 1 mmol), a solution of CS2CO3 (458 mg, 1.41 mmol) in ⁇ 2 ⁇ (2 mL), and Pd(dppf)Ci2-CH2Ci2 (1 14 mg, 20 mmol%).
  • Example 1 Step 7 by using 5-bromo-3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2,3- b]pyridine (161 mg, 0.4 mmol), 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-amine (132 mg, 0.6 mmol), a solution of CS2CO3 (391 mg, 1.2 mmol) in water (2 mL), and Pd(dppf)Cl2-CH2Cb (33 mg, 0.04 mmol).
  • Step 1) (E)-tert-butyl 6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pytTolor2,3-b1pyridin-5-yl)- 3,4-dihydroisoquinoline-2(lH)-carboxylate
  • Example 1 Step 7 by using 5-bromo-3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2,3- b]pyridine (161 mg, 0.4 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (216 mg, 0.6 mmol), a solution of CS2CO3 (391 mg, 1.2 mmol) in water (2 mL), and Pd(dppf)Cl2-CH2Cb (33 mg, 0.04 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) 2/1) to give the title compound as a white solid (160 mg, 73%).
  • Step 2) (E)-6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolor2,3-b1pyridin-5-yl)-l, 2,3,4- tetrahvdroisoquinoline
  • Step 1) fert-butyl 4-(4-(lH-pyrazolo[3,4-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate [0292]
  • the title compound was prepared according to the procedure as described in
  • Step 2) tert-butyl 4-(4-(3-iodo-lH-pyrazolor3,4-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
  • 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.
  • 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.
  • the mobile phase was 5mM ammonia acetate, 0.1% MeOH in water (A) : 5mM ammonia acetate, 0.1% MeOH in acetonitrile (B) (70:30, v/v).
  • the flow rate was 0.6 mL/min. Column was maintained at ambient temperature. 20 of the samples were injected.
  • Human or rat liver microsomes incubations were conducted in duplicate in polypropylene tubes.
  • the typical incubation mixtures consisted of human liver microsomes (0.5 mg protein/mL), compounds of interest (5 ⁇ ) and NADPH (1.0 mM) in a total volume of 200 ⁇ ⁇ potassium phosphate buffer (PBS, 100 mM, pH7.4).
  • PBS potassium phosphate buffer
  • Compounds were dissolved in DMSO and diluted with PBS such that the final concentration of DMSO was 0.05%.
  • the enzymatic reactions were commenced with the addition of protein after a 3 -min preincubation and incubated in a water bath open to the air at 37 °C. Reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) by adding equal volume of ice-cold acetonitrile.
  • the samples were stored at -80 °C until LC/MS/MS assays.

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Abstract

La présente invention concerne de nouveaux composés alcényles substitués, des sels et des formulations pharmaceutiquement acceptables de ceux-ci utiles pour moduler l'activité de la protéine tyrosine kinase, ainsi que pour moduler des activités cellulaires comme la prolifération, la différenciation, l'apoptose, la migration et l'invasion. L'invention concerne en outre des compositions pharmaceutiquement acceptables comprenant de tels composés ainsi que des procédés d'utilisation des compositions dans le traitement de troubles hyperprolifératifs chez des mammifères, notamment les êtres humains.
PCT/US2014/037856 2013-05-26 2014-05-13 Composés alcényles et procédés d'utilisation WO2014193647A2 (fr)

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CN106831720A (zh) * 2017-01-21 2017-06-13 河北科技大学 双‑4‑(1h‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的合成方法及其应用
WO2019125015A1 (fr) * 2017-12-20 2019-06-27 한국원자력의학원 Utilisation pour la protection ou l'atténuation des lésions dues aux rayonnements et pour la prévention ou le traitement d'une fibrose pulmonaire
CN110698506A (zh) * 2019-11-27 2020-01-17 怀化旺达生物科技有限公司 一种吡唑-4-硼酸频哪醇酯的合成方法
JP2020520352A (ja) * 2017-08-11 2020-07-09 エルジー・ケム・リミテッド ハロゲン置換のスチレンモノマーの製造方法
US10899764B2 (en) 2015-04-21 2021-01-26 Jiangsu Hengrui Medicine Co., Ltd. Imidazo isoindole derivative, preparation method therefor and medical use thereof
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10899764B2 (en) 2015-04-21 2021-01-26 Jiangsu Hengrui Medicine Co., Ltd. Imidazo isoindole derivative, preparation method therefor and medical use thereof
CN106188116A (zh) * 2016-07-14 2016-12-07 沧州普瑞东方科技有限公司 一种合成吡唑‑4‑硼酸频那醇酯的方法
CN106188116B (zh) * 2016-07-14 2018-02-06 沧州普瑞东方科技有限公司 一种合成吡唑‑4‑硼酸频那醇酯的方法
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN106831720A (zh) * 2017-01-21 2017-06-13 河北科技大学 双‑4‑(1h‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的合成方法及其应用
CN106831720B (zh) * 2017-01-21 2019-04-16 河北科技大学 双-4-(1h-吡唑-1-基)哌啶-1-甲酸叔丁酯的合成方法及其应用
JP2020520352A (ja) * 2017-08-11 2020-07-09 エルジー・ケム・リミテッド ハロゲン置換のスチレンモノマーの製造方法
US10988424B2 (en) 2017-08-11 2021-04-27 Lg Chem, Ltd. Method for preparing halogen-substituted styrene monomer
WO2019125015A1 (fr) * 2017-12-20 2019-06-27 한국원자력의학원 Utilisation pour la protection ou l'atténuation des lésions dues aux rayonnements et pour la prévention ou le traitement d'une fibrose pulmonaire
CN111971046A (zh) * 2017-12-20 2020-11-20 韩国原子力医学院 用于防护或减轻辐射损伤以及用于预防或治疗肺纤维化的用途
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
CN110698506A (zh) * 2019-11-27 2020-01-17 怀化旺达生物科技有限公司 一种吡唑-4-硼酸频哪醇酯的合成方法

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