WO2014193647A2 - Alkenyl compounds and methods of use - Google Patents

Alkenyl compounds and methods of use Download PDF

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Publication number
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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French (fr)
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WO2014193647A3 (en
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/en
Publication of WO2014193647A3 publication Critical patent/WO2014193647A3/en

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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
    • 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.

Abstract

The present invention provides novel substituted alkenyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

Description

ALKENYL COMPOUNDS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATION
[001] This application claims the benefit of U.S. Provisional Application Serial Number
61/827,599, filed on May 26, 2013, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[002] 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. In particular, 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.
BACKGROUND OF THE INVENTION
[003] 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.
[004] A partial list of such kinases include abl, AATK, ALK, Akt, Axl, bmx, bcr-abl,
Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, MER, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, Tyro-3, tie, tie2, TRK, Yes and Zap70.
[005] Receptor tyrosine kinases (RTKs) 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.
[006] Receptor tyrosine kinases (RTKs) 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).
[007] Anaplastic lymphoma kinase (ALK), a membrane associated tyrosine kinase receptor from the insulin receptor superfamily, has been implicated in oncogenesis in several human tumors. Indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms (the most common being nucleophosmin (NPM)-ALK) in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) (Morris et al., "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma", Science, 1994, 263, 1281).
[008] ALK fusions were also found in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). Studies suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. Moreover, studies have implicated various mutations of the ALK gene in both familial and sporadic cases of neuroblastoma. ALK mutations in neuroblastoma cells results in constitutive ALK phosphorylation and attenuation. Conversely, inhibition of ALK by sRNA and small molecule ALK inhibitors resulted in profound growth inhibition in those cell lines (Palmer et al., "Anaplastic lymphoma kinase: signalling in development and disease", Biochem. J, 2009, 420, 345).
[009] More recently, various isoforms of a fusion gene comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene were identified in NSCLC cells. The 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).
[010] Fusions of ALK have clear oncogenic potential as its aberrant tyrosine kinase activity enhances cell proliferation and survival and leads to cytoskeletal rearrangements and changes in cell shape. Oncogenic ALK transformation is mediated by interactions with downstream molecules that trigger substantial intracellular signaling cascades. Similarly to most normal and oncogenic tyrosine kinases, ALK fusions activate many different pathways that are strictly interconnected and overlapping. The most relevant and better characterized pathways are reported: the Ras-extracellular signal-regulated kinase (ERK) pathway, the Janus kinase 3 (JAK3)-STAT3 pathway and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. These three pathways have many points of interaction to mediate the effects of ALK activity. Overall, the 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).
[011] The involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others has also been implicated. In a survey of a collection of human cancer cell lines, Dirks,et al. confirmed the expression of ALK transcripts in nervous system-derived lines, including retinoblastoma, and a large percentage of cell lines derived from solid cancers of ectodermal origin, including melanoma and breast carcinoma (Dirks et al., "Cancer's source in the peripheral nervous system", Nat. Med., 2008, 14, 373).
[012] c-Met, also referred to as hepatocyte growth factor receptor (HGFR), is expressed predominantly in epithelial cells but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. The natural ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF). 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). Agents targeting c-Met signaling pathway are now under clinical investigation (Joseph et al., "Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer", Clin. Cancer Res., 2009, 15, 2207; Paolo et al, "Drug development of MET inhibitors: targeting oncogene addiction and expedience", Nat. Rev. Drug Discovery, 2008, 7, 504).
[014] Many ALK and/or c-Met inhibitors are now under clinical development for the treatment of various human cancers. 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. These rearrangements of the ALK gene (EML4-ALK) constitute driver mutations that are critical for the malignant phenotype of lung adenocarcinomas that have the mutations. Thus, the inhibition of mutated kinase ALK for the treatment of cancer is validated.
[015] 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).
[016] 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).
[017] There is, therefore, still a need for effective therapies for use in proliferative disease, including treatments for primary cancers, metastatic disease, and for targeted therapies, including tyrosine kinase inhibitors, such as ALK and/or c-Met inhibitors, dual inhibitors, selective inhibitors, and for potent, orally bioavailable, and efficacious inhibitors, and for inhibitors that provide optimized dosing schedule, such as once daily oral administration.
[018] 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.
SUMMARY OF THE INVENTION
[019] Provided herein are new compounds and methods for treating cell proliferative diseases. The compounds disclosed herein are inhibitors of protein tyrosine kinases. Preferably, 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. Accordingly, provided herein are new inhibitors of protein tyrosine kinase receptor signaling, for example, ALK receptor signaling, c-Met receptor signaling.
[020] Specifically, it has been found that compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of receptor tyrosine kinases, such as ALK and/or c-Met. Accordingly, the invention provides compounds having the formula (I):
Figure imgf000006_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each of Z, Wi, W2, W3, Ai, A2 and A3 is as defined herein.
[021] In certain embodiments, each of Wi, W2 and W3 is independently N or CRC; each of Ai, A2 and A3 is independently H, D, CN, N3, -C(=0)ORa, -C(=0)NRaRb, (Ci-
C6)alkyl, -(Ci-C4)alkylene-CN, -(Ci-C4)alkylene-ORa, -(Ci-C4)alkylene-NRaRb, (C3- C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, (C3-C8)heterocyclyl, -(Ci-C4)alkylene-(C3- C8)heterocyclyl, (C6-C10)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, -C(=0)ORa, -C(=0)NRaRb, (Ci- C6)alkyl, (Ci-Ce)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, optionally substituted (C6-C10)aryl, and optionally substituted 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N;
Z is
Figure imgf000007_0001
wherein each of Zi, Z2 and Z3 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH; each R1 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, -C(=0)NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C4)alkylene-CN, -(Ci- C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-Cio)cycloalkyl, -(Ci-C4)alkylene-(C3- Cio)cycloalkyl, (C3-Cio)heterocyclyl, -(Ci-C4)alkylene-(C3-Cio)heterocyclyl, (C6-Cio)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, -(Ci-C4)alkylene-(C6-Cio)aryl, -(Ci-C4)alkylene-(5-10 membered heteroaryl), or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, (C3-C6)cycloalkyl, or (C3-C6)heterocyclyl ring, wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups. each R2 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C4)alkylene-CN, -(Ci-C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, (C3- C8)heterocyclyl, or -(Ci-C4)alkylene-(C3-C8)heterocyclyl; each Ra and Rb is independently H, (Ci-C6)aliphatic, (C3-Ce)cycloalkyl, -(Ci-C4)alkylene- (C3-C6)cycloalkyl, (C3-Ce)heterocyclyl, -(Ci-C4)alkylene-(C3-C6)heterocyclyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic ring, wherein each of the above substituents is optionally substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci- C6)alkoxy, and (Ci-C6)alkylamino; and each Rc is independently H, D, F, CI, Br, I, N3, CN, NH2, -NHS(=0)2(Ci-C6)alkyl, - N(Ra)C(=0)(Ci-C6)alkyl, -NHC(=0)NRaRb, -N[(Ci-C6)alkyl]C(=0)NRaRb, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylamino, (C3-Ce)cycloalkyl, (C3-C6)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci-Ce)alkyl, (C3- C6)cycloalkyl, (Ci-Ce)haloalkyl, (Ci-Ce)alkoxy, and (Ci-C6)alkylamino.
[022] In another embodiment, each of Wi and W2 is independently CRC; and W3 is N or
CRC.
[023] In another embodiment, each of Ai, A2 and A3 is independently H, D, CN, N3, -
C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O,
5 and N, and wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, ORa, NRaRb, - C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl.
[024] In another embodiment, Z is
Figure imgf000008_0001
(Ilia), or (Illb) wherein each of Zi and Z2 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
[025] In another embodiment, each R1 is independently D, F, CI, ORa, NRaRb, -
C(=0)NRaRb, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C2-C4)alkenyl, -(Ci-C2)alkylene-NRaRb, -(Ci- C2)alkylene-ORa, (C3-Ce)cycloalkyl, -(Ci-C2)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, - (Ci-C2)alkylene-(C3-C6)heterocyclyl, or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, (C3-Ce)cycloalkyl, or (C3-C6)heterocyclyl ring, and wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups.
[026] In another embodiment, each R2 is independently D, F, CI, ORa, NRaRb, (Ci-
C4)alkyl, (Ci-C4)haloalkyl, (C3-Ce)cycloalkyl, or (C3-C6)heterocyclyl. [027] In another embodiment, each Ra and Rb is independently H, (Ci-C3)alkyl, (C3-
Ce)cycloalkyl, (C3-Ce)heterocyclyl, or Ra and Rb 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, NH2, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
[028] In another embodiment, each Rc is independently H, D, F, CI, CN, NH2, -
NHS(=0)2(Ci-C3)alkyl, -N(Ra)C(=0)(Ci-C3)alkyl, -NHC(=0)NRaRb, -N[(Ci-
C3)alkyl]C(=0)NRaRb, (Ci-C3)alkyl, (Ci-C3)alkoxy, (Ci-C3)alkylamino, (C3-C6)cycloalkyl, or (C3-C6)heterocyclyl, and wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci- C3)alkyl, (C3-Ce)cycloalkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
[029] In another embodiment, Z is
Figure imgf000009_0001
wherein Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
[030] In another aspect, provided herein are pharmaceutical 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. In certain embodiments, the compound is an inhibitor of protein tyrosine kinase. In other embodiments, the compound is an inhibitor of ALK receptor signaling and HGF receptor signaling.
[031] In some embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent. In other embodiments, 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.
[032] In certain embodiments, 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, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof.
[033] In another aspect, provided herein are methods 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.
[034] In another aspect, 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.
[035] In some embodiments, the proliferative disorder is metastatic cancer. In other embodiments, 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. In further embodiments, the proliferative disorder is atherosclerosis or lung fibrosis.
[036] In another aspect, provided herein is 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.
[037] In some embodiments, the protein kinase is a receptor tyrosine kinase. In other embodiments, the receptor tyrosine kinase is ALK and/or c-Met.
[038] In another aspect, provided herein is a method of inhibiting protein tyrosine kinase, the method comprises contacting the kinase with the compound disclosed herein, or with the composition disclosed herein. In other embodiments, provided herein is 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. [039] In some embodiments, inhibition of receptor protein kinase activity, such as ALK and/or HGF receptor signaling, 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.
[040] In another aspect, provided herein is a method of inhibiting proliferative activity of a cell, wherein the method comprises 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.
[041] In another aspect, provided herein is a method of treating a cell proliferative disease in a patient, wherein the method comprises 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.
[042] In another aspect, provided herein is a method of inhibiting tumor growth in a patient, the method 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.
[043] In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).
[044] The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND GENERAL TERMINOLOGY
[045] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
[046] As used herein, the following definitions shall apply unless otherwise indicated.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in Sorrell et al., "Organic Chemistry", University Science Books, Sausalito: 1999, and Smith et al., "March's Advanced Organic Chemistry", John Wiley & Sons, New York: 2007, all of which are incorporated by reference in their entireties.
[047] As used in the specification and claims, the term "a," "an," "the" and similar terms used in the context of the present invention are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
[048] As used herein, 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.
[049] As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human.
[050] 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. Some non-limiting examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 170, 180, 31P, 32P, 36S, 18F, and 37C1.
[051] 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 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, 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.
[052] Stereochemical definitions and conventions used herein generally follow Parker et al., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes 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. For a given chemical structure, 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.
[053] Depending on the choice of the starting materials and procedures, 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.
[054] 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.
[055] Unless otherwise stated, 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.
[056] The term "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. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of 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.
[057] Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
[058] 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. In certain embodiments, 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.
[059] Accordingly, as used herein 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.
[060] 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.
[061] Any resulting 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. 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 (2nd Ed. Robert et al, Elsevier, Oxford, UK, 2012); Eliel et al, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen et al, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
[062] As described herein, 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.
[063] At various places in the present specification, 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. For example, the term "Ci-Ce alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
[064] At various places in the present specification, linking substituents are described.
Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.
[065] The term "aliphatic" or "aliphatic group" 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. Some non-limiting examples of the aliphatic group include linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. For example, (Ci-C6)aliphatic groups include unbranched or branched, unsubstituted or suitably substituted (Ci-Ce)alkyl, (C2- C6)alkenyl or (C2-Ce)alkynyl groups.
[066] The term "alkyl" or "alkyl group" 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.
[067] Some non-limiting examples of the alkyl group include methyl (Me, -CH3), ethyl
(Et, -CH2CH3), 1 -propyl (rc-Pr, n-propyl, -CH2CH2CH3), 2-propyl (z-Pr, /-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (/-Bu, /-butyl, -CH2CH(CH3)2), 2- butyl O-Bu, 5-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (/-Bu, /-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-QCF^CF^CFfeCFb), 3-methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (- C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.
[068] The prefix "alk-" refers to both straight chain and branched saturated carbon chain.
[069] The term " 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 (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.
[070] The term "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. Preferably, the alkenyl 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 alkenyl group include ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.
[071] The term "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. Preferably, 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, -CH2C≡CH), - C≡C-CH3, and the like.
[072] The term "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.
[073] Some non- limiting examples of the alkoxy group include methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (z'-PrO, i- propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (ι-BuO, z-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2- methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2- methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l- butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like. [074] The term "haloalkyl" or "haloalkoxy" refers to alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
[075] The term "carbocycle", "carbocyclyl", "carbocyclic ring" or "cycloaliphatic" 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. Some non-limiting examples of the carbocyclyl group include cycloalkyl, cycloalkenyl, and cycloalkynyl. Further non- limiting examples of the carbocyclyl group 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.
[076] The term "cycloalkyl" refers to a monovalent or multivalent saturated ring having
3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl. In some embodiments, 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.
[077] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used interchangeably herein 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. In some embodiments, 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 S02, PO or PO2). In other embodiments, 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 S02, PO or P02).
[078] 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-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, and 1,2,3,4-tetrahydro isoquinolinyl. Some non- limiting examples of the heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (=0) moieties are pyrimidindionyl and 1, 1-dioxo-thiomorpholinyl.
[079] The term "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), ΝΗ (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
[080] The term "halogen" means F, CI, Br or I.
[081] The term "Η" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
[082] The term "D" or "2H" 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 (-CDH2), two of deuterium atoms may be attached to a methyl group to form a di-deuterated methyl (-CD2H), and three of deuterium atoms may be attached to a methyl group to form a tri-deuterated methyl group (-CD3).
[083] The term "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).
[084] The term "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. The term "aryl" may be used interchangeably with the term "aryl ring". Some non-limiting examples of the aryl ring would include phenyl, naphthyl, and anthracene. The aryl radical is optionally substituted independently with one or more substituents described herein. [085] The term "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. In some embodiments, a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. The term "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.
[086] Further non-limiting examples of the 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-thienyl, 3-thienyl, pyrazolyl (e.g., 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1- isoquinolinyl, 3 -isoquinolinyl or 4-isoquinolinyl).
[087] The term "carboxy" or "carboxyl", whether used alone or with other terms, such as
"carboxyalkyl", denotes -CO2H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=0)-.
[088] The term "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.
[089] The term "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.
[090] The term "unsaturated" as used herein, means that a moiety has one or more units of unsaturation.
[091] The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.
[092] The term "fused bicyclic", "fused cyclic", "fused bicyclyl" or "fused cyclyl" 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.
Figure imgf000021_0001
Structure a Structure b Structure c
[093] Some non-limiting examples of the fused bicyclic ring system include hexahydrofuro[3,2-¾]furan, hexahydrofuro[2,3-¾]furan, octahydrocyclopenta[c]pyrrole, hexahydro-lH-pyrrolizine, and octahydro-lH-pyrido[l,2-a]pyrazine.
[094] The term "spirocyclyl", "spirocyclic", "spiro bicyclyl" or "spiro bicyclic" is used interchangeably and refers to a monovalent or multivalent ring system wherein a ring originating from a particular annular carbon of another ring. For example, as depicted in Structure d, a saturated bridged ring system (ring B and B') is termed as "fused bicyclic", whereas 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.
Figure imgf000021_0002
Structure d
[095] As described herein, a bond drawn from a substituent to the center of one ring within a ring system (as shown below) represents substitution of the substituent at any substitutable position on the rings to which it is attached. For example, Structure e represents possible substitution in any of the positions on the B ring shown in Structure f-1, f-2 and f-3.
Figure imgf000022_0001
Structure e Structure f-1 Structure f-2 Structure f-3
[096] The term "prodrug" as used herein, 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.
Other prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound. A thorough discussion of prodrugs is provided in Higuchi et al, Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium
Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987; Rautio et al, Prodrugs: Design and Clinical
Applications, Nat. Rev. Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of
Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference.
[097] 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. Accordingly, 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.
[098] 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,
66, 1-19, which is incorporated herein by reference. Some non-limiting examples of 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. Other examples of 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, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, /?-toluenesulfonate, undecanoate, valerate salts, and the like. 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. Further examples of the pharmaceutically acceptable salt include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-8 sulfonate and aryl sulfonate.
[099] A "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.
[0100] The term "pharmaceutically acceptable earlier" includes 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.
[0101] 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). In another embodiment, 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. In yet another embodiment, 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. In yet another embodiment, the term "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
[0102] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, 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). Similarly, 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. For a general description of protecting groups and their use, see Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al, Protecting Groups, Thieme, Stuttgart, 2005.
DESCRIPTION OF THE COMPOUNDS DISCLOSED HEREIN
[0103] 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):
Figure imgf000024_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each of Z, Wi, W2, W3, Ai, A2 and A3 is as defined herein.
[0104] In certain embodiments, each of Wi, W2 and W3 is independently N or CRC; each of Ai, A2 and A3 is independently H, D, CN, N3, -C(=0)ORa, -C(=0)NRaRb, (Ci- C6)alkyl, -(Ci-C4)alkylene-CN, -(Ci-C4)alkylene-ORa, -(Ci-C4)alkylene-NRaRb, (C3- C8)cycloalkyl, -(Ci-C4)alkylene-(C3-Cg)cycloalkyl, (C3-Cg)heterocyclyl, -(Ci-C4)alkylene-(C3- C8)heterocyclyl, (C6-C10)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, -C(=0)ORa, -C(=0)NRaRb, (Ci- C6)alkyl, (Ci-Ce)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, optionally substituted (C6-C10)aryl, and optionally substituted 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N;
Z is
Figure imgf000025_0001
wherein each of Zi, Z2 and Z3 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH; each R1 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, -C(=0)NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C4)alkylene-CN, -(Ci- C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-Cio)cycloalkyl, -(Ci-C4)alkylene-(C3- Cio)cycloalkyl, (C3-Cio)heterocyclyl, -(Ci-C4)alkylene-(C3-Cio)heterocyclyl, (C6-C10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, -(Ci-C4)alkylene-(C6-Cio)aryl, -(Ci-C4)alkylene-(5-10 membered heteroaryl), or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, (C3-C6)cycloalkyl, or (C3-C6)heterocyclyl ring, wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups. each R2 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C4)alkylene-CN, -(Ci-C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, (C3- C8)heterocyclyl, or -(Ci-C4)alkylene-(C3-C8)heterocyclyl; each Ra and Rb is independently H, (Ci-C6)aliphatic, (C3-Ce)cycloalkyl, -(Ci-C4)alkylene- (C3-C6)cycloalkyl, (C3-Ce)heterocyclyl, -(Ci-C4)alkylene-(C3-C6)heterocyclyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic ring, wherein each of the above substituents is optionally substituted with 1, 2, 3 or
4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci- C6)alkoxy, and (Ci-C6)alkylamino; and each Rc is independently H, D, F, CI, Br, I, N3, CN, NH2, -NHS(=0)2(Ci-C6)alkyl, - N(Ra)C(=0)(Ci-C6)alkyl, -NHC(=0)NRaRb, -N[(Ci-C6)alkyl]C(=0)NRaRb, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylamino, (C3-Ce)cycloalkyl, (C3-C6)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci-Ce)alkyl, (C3- C6)cycloalkyl, (Ci-Ce)haloalkyl, (Ci-Ce)alkoxy, and (Ci-C6)alkylamino.
[0105] In another embodiment, each of Wi and W2 is independently CRC; and W3 is N or
CRC.
[0106] In another embodiment, each of Ai, A2 and A3 is independently H, D, CN, N3, -
C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O,
5 and N, and wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, ORa, NRaRb, - C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl.
[0107] In another embodiment, Z is
Figure imgf000026_0001
wherein each of Zi and Z2 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
[0108] In another embodiment, each R1 is independently D, F, CI, ORa, NRaRb, -
C(=0)NRaRb, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C2-C4)alkenyl, -(Ci-C2)alkylene-NRaRb, -(Ci- C2)alkylene-ORa, (C3-Ce)cycloalkyl, -(Ci-C2)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, - (Ci-C2)alkylene-(C3-C6)heterocyclyl, or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, (C3-Ce)cycloalkyl, or (C3-C6)heterocyclyl ring, and wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups.
[0109] In another embodiment, each R2 is independently D, F, CI, ORa, NRaRb, (Ci-
C4)alkyl, (Ci-C4)haloalkyl, (C3-Ce)cycloalkyl, or (C3-C6)heterocyclyl.
[0110] In another embodiment, each Ra and Rb is independently H, (Ci-C3)alkyl, (C3-
Ce)cycloalkyl, (C3-Ce)heterocyclyl, or Ra and Rb 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, NH2, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
[0111] In another embodiment, each Rc is independently H, D, F, CI, CN, NH2, -
NHS(=0)2(Ci-C3)alkyl, -N(Ra)C(=0)(Ci-C3)alkyl, -NHC(=0)NRaRb, -N[(Ci-
C3)alkyl]C(=0)NRaRb, (Ci-C3)alkyl, (Ci-C3)alkoxy, (Ci-C3)alkylamino, (C3-C6)cycloalkyl, or (C3-C6)heterocyclyl, and wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci- C3)alkyl, (C3-Ce)cycloalkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, and (Ci-C3)alkylamino.
[0112] In another embodiment, Z is
Figure imgf000027_0001
wherein Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
[0113] Some non- limiting examples of the compound disclosed herein, and their pharmaceutically acceptable salts and solvates thereof, are shown in the following:
Table 1
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000030_0002
[0114] 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.
[0115] 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).
[0116] Unless otherwise stated, all stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the invention.
[0117] In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase
"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.
[0118] 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).
[0119] 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.
COMPOSITION, FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS DISCLOSED HEREIN
[0120] According to one aspect, 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.
[0121] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, some non-limiting examples of the 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.
[0122] As described above, the pharmaceutically acceptable 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. Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds., 1988-1999, Marcel Dekker, New York, all of which are incorporated by reference in their entireties, are disclosed various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
[0123] 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; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
[0124] The compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[0125] For this purpose, 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.
[0126] The pharmaceutically acceptable 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. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.
[0127] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These 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. Such materials include cocoa butter, beeswax and polyethylene glycols.
[0128] The pharmaceutically acceptable 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.
[0129] 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. For topical applications, 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. Alternatively, 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.
[0130] For ophthalmic use, 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. Alternatively, for ophthalmic uses, 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. Such 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.
[0131] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0132] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0133] 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. In order to prolong the effect of a compound disclosed herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, dissolving or suspending the compound in an oil vehicle accomplishes delayed absorption of a parenterally administered compound form. [0134] 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.
[0135] 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.
[0136] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0137] 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.
[0138] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used include polymeric substances and waxes.
[0139] 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. Additionally, 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.
[0140] The compounds disclosed herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein 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.
[0141] The amount of the compounds disclosed herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, 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.
[0142] 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. In this instance, 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. As used herein, 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". As used herein, "additional therapeutic agents" is meant to include chemotherapeutic agents and other anti-proliferative agents.
[0143] For example, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative disease or cancer. Examples of 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 6,506,735, US 6,221,849, US 6,953,783, US 11/393,380.
[0144] In another embodiment of the present invention, for example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of 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), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (chlormethine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, etc), anti-metabolites (methotrexate, raltitrexed, pemetrexed, etc), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5- fluorouracil, cytarabine, gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone), antiangiogenic agents (avastin and others), monoclonal antibodies (Belimumab (BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gemtuzumab (MYLOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab (VECTIBIX®), ranibizumab (LUCENTIS®), rituximab (RITUXAN®), tositumomab (BEXXAR®), trastuzumab (HERCEPTIN®), kinase inhibitors (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®), and others), and agents inhibiting or activating cancer pathways such as the mTOR, HIF (hypoxia induced factor) pathways (such as everolimus and temsirolimus) and others. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglist-rame.htm, and The Merck Manual, Eighteenth Ed. 2006, the entire contents of which are hereby incorporated by reference.
[0145] In another embodiment, the compounds disclosed herein can be combined, with cytotoxic anti-cancer agents. Examples of such agents can be found in the 13th Edition of the Merck Index (2001). These 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, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
[0146] Other 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). These 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, uridine, and vinorelbine.
[0147] Other 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).
[0148] In another embodiment, 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, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607,
JNJ38877605, TKI258, GDC-0941 (Folkes et al, J. Med. Chem., 2008, 51 : 5522), BZE235, and others.
[0149] In another embodiment, 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).
[0150] In another embodiment, 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.
[0151] Those additional agents may be administered separately from the compound- containing composition, as part of a multiple dosage regimen. Alternatively, 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.
[0152] 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.
USES OF THE COMPOUNDS AND COMPOSITIONS DISCLOSED HEREIN [0153] 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.
[0154] 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. Such diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis and lung fibrosis.
[0155] The compounds disclosed herein would be useful for the treatment of 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 of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); 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).
[0156] The compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability. [0157] 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.
[0158] Besides being useful for human treatment, 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. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
[0159] Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.
[0160] 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.
[0161] 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. Examples of 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.
[0162] 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. The term "biological sample" as used herein, 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.
[0163] In certain embodiments of the present invention an "effective amount" or
"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.
[0164] 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. Vascular stents, for example, have been used to overcome restenosis (re -narrowing of the vessel wall after injury). However, 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.
[0165] 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.
GENERAL SYNTHETIC PROCEDURES
[0166] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention.
[0167] Generally, 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. For example, 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. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
[0168] In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, Shanghai Medpep. Co Ltd, Aladdin-Shanghai Jinchun Reagents, Ltd, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.
[0169] Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2CI2 and CHCI3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous Na2S04 prior use.
[0170] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. [0171] Column chromatography was conducted using a silica gel column. Silica gel (300-
400 mesh) was purchased from Qingdao Ocean Chemical Factory. lH NMR spectra were recorded with a Bruker 400 MHz spectrometer or a Bruker 600 MHz spectrometer at ambient temperature. !H NMR spectra were obtained as CDCb, DMSO-<i6, CD3OD or acetone-<i6 solutions (reported in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
[0172] Low-resolution mass spectral (MS) data were generally determined on an Agilent
6120 Quadrupole HPLC-MS (Zorbax SB-C 18, 2.1 x 30 mm, 3.5 micron, 6 minutes run, 0.6 mL/min flow rate, 5% to 95% (0.1% formic acid in CH3CN) in (0.1% formic acid in H20)) with UV detection at 210/254 nm and electrospray ionization mode (ESI).
[0173] Purities of compounds were assessed by Agilent 1260 Pre-HPLC or Calesep Pump
250 Pre-HPLC (Column NOVASEP 50/80 mm DAC) with UV detection at 210 nm/254 nm.
[0174] The following abbreviations are used throughout the specification:
ATP adenosine triphosphate
AcOH, HAc, CH3COOH acetic acid
BF3 -Et20 boron trifluoride etherate
BBr3 boron tribromide
BINAP 2,2'-bis(diphenylphosphino)-l, 1 '-binaphthyl
BOC, Boc butyloxycarbonyl
(Boc)20 Di-tert-butyl dicarbonate
BSA bovine serum albumin
CDCb chloroform deuterated
CH3COOK potassium acetate
CHCI3 chloroform
CH2CI2, DCM methylene chloride
CH3SO2CI, MsCl methanesulfonyl chloride
CS2CO3 cesium carbonate
Cu copper
Cul copper(I) iodide
DAST Diethylaminosulfur trifluoride
DBU l ,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane
DEAD dimethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIBAL diisobutylaluminum hydride
DIEA, DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMAC N,N-dimethylacetamide
DME dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
DTT DL-Dithiothreitol
EDCI 1 -(3 -dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride
EDTA Ethylene Diamine Tetraacetic Acid
EtOAc, EA ethyl acetate
EtOH, CH3CH2OH ethanol
Et20 diethyl ether
Et3N, TEA triethylamine
FBS fetal bovine serum
Fe iron
g gram
h hour
min minute
HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBr hydrobromic acid
HBTU O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HC1 hydrochloric acid
H2 hydrogen
H20 water
H202 hydrogen peroxide
HO Ac AcOH acetic acid
HO AT 1 -Hydroxy-7-azabenzotriazole
HOBt 1-hydroxybenzotriazole hydrate
HMTA Hexamethylenetetramine K2CO3 potassium carbonate
OH potassium hydroxide
LiBr Lithium bromide
LiHMDS lithium bis(trimethylsilyl)amide
L1AIH4 Lithium aluminium hydride
LDA Lithium diisopropylamide
MCPBA weta-chloroperbenzoic acid
MeCN, CH3CN acetonitrile
Me2NH HCl dimethylamine hydrochloride
Mel methyl iodide
MeOH, CH?OH methanol
MeONa, CH3ONa sodium methoxide
2-MeTHF 2-methyl tetrahydrofuran
MgS04 magnesium sulfate
MsCl methanesulfonyl chloride
MTBE methyl tert-butyl ether
mL, ml milliliter
min minute
N2 nitrogen
ft-BuOH 1-butanol
«-BuLi «-butyllithium
«-Bu4NHS04 Tetrabutylammonium Hydrogen Sulfate
NaBH4 sodium borohydride
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
NaC102 sodium chlorite
NaH sodium hydride
Na2C03 sodium carbonate
NaHC03 sodium bicarbonate
NaH2P04 sodium biphosphate
Nal sodium iodide
NaO(t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na2S04 sodium sulfate NADPH triphosphopyridine nucleotide
NBS N-Bromosuccinimide
NIS N-Iodosuccinimide
NH3 ammonia
NH3 · H2O ammonium hydroxide
NH4CI ammonium chloride
NMP N-methylpyrrolidinone
PBS phosphate buffered saline
PPh3 triphenylphosphine
P2O5 Phosphorus pentoxide
P(t-Bu)3 tri(tert-butyl)phosphine
P(0-Tol)3 Tri(o-tolyl)phosphine
Pd/C palladium on carbon
Pd2(dba)3 bis(dibenzylideneacetone) palladium
Pd(dppf)Cl2 l,l-bis(diphenylphosphino)ferrocene palladium chloride
Pd(dppf)Cl2 · CH2CI2 dichloro[ 1 , 1 'bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct
Pd(OAc)2 palladium acetate
Pd(OH)2 palladium hydroxide
Pd(PPh3)4 palladium tetrakis triphenylphosphine
Pd(PPh3)2Ck Bis(triphenylphosphine)palladium(II) chloride
PCR Polymerase Chain Reaction
PE petroleum ether (60-90 °C)
POCI3 phosphorous oxychloride
PI1SO2CI benzenesulfonyl chloride
PyBop benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
SOCb thionyl dichloride
TBAB tetrabutylammonium bromide
TBAF tetrabutyl ammonium fluoride
TBAI tetrabutylammonium iodide
f-BuOK potassium tert-butanolate
TBAHSO4 tetrabutylammonium hydrogen sulfate TBTU O-benzotriazol-l-yl-N,N,N ',Ν '-tetramethyluronium tetrafluoroborate
TFA trifluoroacetic acid
TEAC bis(tetra-ethylammonium)carbonate
THF tetrahydrofuran
μΐ^ microliter
[0175] Representative synthetic procedures for the preparation of compounds of the disclosure are outlined below in following schemes. Unless otherwise indicated, each of Wi, W2, W3, Zi, Z2, Z3, A2, A3, R1, and R2 carry the definitions set forth above in connection with formula (I). X is CI, or Br. Ry is independently H, or R1. Ring "A" is an optionally substituted N- containing heterocycyclyl.
Scheme 1
Figure imgf000050_0001
[0176] Some compounds with general structures as defined in Formula (I) can be prepared in a general method illustrated in Scheme 1. Compound (1) is converted to boronic ester (or acid) (3) under standard conditions known to those skilled in the art such as, but not limited to, treatment with Bis(pinacolato)diboron (2) in the presence of Pd catalysis.
[0177] The synthesis of the desired kinase inhibitors (14) was also demonstrated in
Scheme 1. Bicyclic heteroaromatic (4) is first reacted with dimethylamine hydrochloride and paraformaldehyde, followed by treating with HMTA (7) at refluxed temperature to give aldehyde (8). Compound (8) is protected with a suitable group such as, but not limited to, PhSC , in the presence of PhS02Cl and base such as NaOH, Et3N, or pyridine in an aprotic solvent (for example, CH2CI2, CHCI3, etc.). Compound (10) is then reacted with Wittig reagent (triphenyl phosphonium ylide) (11), followd by deprotection of the amino group under standard conditions known to those skilled in the art such as, but not limited to, treatment with aqueous base to give compound (13). The desired kinase inhibitors (14) are obtained by the coupling of bromo compound (13) with the boronic ester (3) in the presence of an appropriate Pd catalyst.
Scheme 2
Figure imgf000051_0001
[0178] The compounds disclosed herein may be prepared by the method as described in
Scheme 2. Treatment of boronic ester (3) with bicyclic heteroaromatic (4) under Suzuki conditions gives compound (15). The subsequent iodination of (15) with N-iodosuccinimide at rt affords iodo compound (16), which is further protected with a suitable group such as, but not limited to, PhS02, in the presence of PhS02Cl and base such as NaOH, Et3N, or pyridine in an aprotic solvent (for example, CH2C12, CHC , etc.). Compound (17) is reacted with Pinacol vinylboronate (18) to furnish vinyl compound (19). Vinyl compound (19) is treated with bromo compound (20) under Heck conditions, follow by deprotection of the amino group with aqueous base to give the desired kinase inhibitors (21).
Scheme 3
Figure imgf000051_0002
{10) 123) (24)
[0179] The compounds disclosed herein may be also prepared by the method as described in Scheme 3. Aldehyde (10) is reacted with compound (22), follow by deprotection of the amino group with aqueous base to provide nitrile (23). Coupling of (23) with boronic ester (3) in the presence of an appropriate Pd catalyst furnishes the desired kinase inhibitors (24). Scheme 4
Figure imgf000052_0001
[0180] Scheme 4 shows another method to prepare the kinase inhibitors disclosed herein.
Thus, 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).
Figure imgf000052_0002
[0181] Kinase inhibitors (27) and (28) can also be prepared according to the general methods as described in Schemes 1 and 3.
[0182] In the following examples, if only one regioisomer (Z or E) is indicated in the product, it means that the said regioisomer is greater than 95% (by HPLC or !H NMR) in the product.
EXAMPLES
Example 1 (iT)-3-(2,6-dichlorostyryl)-5-(l-(piperi
pyridine
Figure imgf000052_0003
Step 1) tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate
[0183] To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (7.94 g, 39.45 mmol) in DCM (100 mL) was added Et3N (8.6 mL, 59.18 mmol) slowly at 0 °C, followed by the addition of MsCl (3.7 mL, 47.34 mmol) and a solution of DMAP (48.0 mg, 0.390 mmol) in DCM (3 mL). The mixture was stirred at rt for 1 hour, then quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (11.11 g, 100%).
MS (ESI, pos. ion) m/z: 302.0 (M+23).
Step 2) tert-butyl 4-(4-iodo-lH-pyrazol-l-yl)piperidine-l -carboxylate
[0184] To a stirred solution of 4-iodo-lH-pyrazole (8.98 g, 46.28 mmol) in DCM (160 mL) was added NaH (1.67 g, 55.53 mmol, 80% NaH/mineral oil) portion-wise at 0 °C. The mixture was stirred at 0 °C for 1 hour, then tert-butyl 4-((methylsulfonyl)oxy)piperidine-l- carboxylate (14.22 g, 50.90 mmol) was added. The resulted mixture was stirred at 100 °C for 15 hours, then cooled to rt, quenched with H20 (30 mL) and concentrated in vacuo. The residue was diluted with H20 (150 mL), and the mixture was extracted with EtOAc (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (12.25 g, 70.2%>).
MS (ESI, pos. ion) m/z: 322.0 (M-56+1).
Step 3) tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl) piperidine- 1 -carboxylate
[0185] To a solution of tert-butyl 4-(4-iodo-lH-pyrazol-l-yl)piperidine-l -carboxylate
(1.00 g, 2.650 mmol) in DMSO (11 mL) were added 4,4,4,,4,,5,5,5*,5*-octamethyl-2,2,-bi(l,3,2- dioxaborolane) (942.5 mg, 3.710 mmol) and CH3COOK (1.04 g, 10.60 mmol) sequentially. The mixture was degassed and charged with N2 several times, then Pd(PPh3)2Cl2 (93.0 mg, 0.130 mmol) was added. The resulted mixture was stirred at 80 °C for 2 hours, then cooled to rt, and filtered through a pad of celite. The filtrate was washed with brine (100 mL x 3), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (878.6 mg, 87.9%).
MS (ESI, pos. ion) m/z: 378.0 (M+l).
Step 4) 1 -(5 -bromo- 1 H-pyrrolo[2,3 -b]pyridin-3 -yl)-N,N-dimethylmethanamine
[0186] A mixture of 5-bromo-lH-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol),
Me2NH HCl (8.9 g, 110 mmol) and paraformaldehyde in n-BuOH (400 mL) was refluxed for 40 minutes. After the removal of the solvent, the residue was diluted with water (200 mL), and then conc.HCl (16 mL) was added dropwise, followed by the addition of ether (150 mL). Filtered, and the filtrate was extracted with ether (150 mL x 2). The combined organic phases were basied with solid K2CO3 to pH=12, then cooled in an ice bath. Filtered, and the filter cake was washed successively with ice-cold water (50 mL x 3) and ice-cold ether (50 mL x 3), then dried in a vacuum oven overnight to give the title compound as a creamy white solid (19.5 g, 75%).
Step 5) 5-bromo-lH-pyrrolo[2,3-blpyridine-3-carbaldehyde
[0187] To a refluxing solution of ΗΜΤΑ (10.7 g, 76.8 mmol) in propionic acid (38 mL,
66%) was added l-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (19.5 g, 76.8 mmol). The mixture was refluxed for 2.5 hours, then cooled to rt, and poured into water (250 mL). The resulted suspension was cooled in an ice bath, and filtered. The filter cake was washed with ice-cold water (50 mL) and dried in vacuo overnight to give the title compound as a white solid (12.45 g, 75%).
MS (ESI, pos. ion) m/z: 225.0 (M+l);
lU NMR (400 MHz, DMSO-t ί): δ 8.45-8.48 (m, 1H), 8.52-8.54 (m, 1H), 8.54-8.57 (m, 1H), 9.93 (s, 1H), 12.5-13.4 (br, 1H);
13C NMR (100 MHz, DMSO- ¼): δ 113.7, 115.9, 118.2, 130.9, 139.7, 145.0, 147.7, 185.5. Step 6) (E)-5-bromo-3-(2,6-dichlorostyryl)-lH-pyrrolo[2J-blpyridine
[0188] To a refluxing solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde
(2.54 g, 11.3 mmol) and (2,6-dichlorobenzyl)triphenylphosphonium chloride (5.17 g, 11.3 mmol) in EtOH (30 mL) was added a fresh prepared solution of CH3ONa (621 mg, 87.0 mmol) in MeOH (15 mL) slowly over 1.5 hours under N2 atmosphere. The mixture was continued refluxing and stirring for another 1 hour. After the removal of the solvent, the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1), followed by stirring in a co-solvent EtOAc/PE (1/1, 10 mL) for 30 minutes, and then filtered to give the title compound as a white solid (200 mg, 4.8%).
MS (ESI, pos. ion) m/z: 367.0 (M +1);
!H NMR (400 MHz, DMSO-t ί): δ 7.04 (d, J = 16.8 Hz, 1H), 7.26 (d, J = 16.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.96 (s, 1H), 8.36 (d, J= 1.7 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H);
13C NMR (100 MHz, DMSO- ¼): δ 111.5, 111.6, 118.6, 118.8, 128.5, 128.8, 129.6, 129.8, 133.3, 134.7, 143.3, 147.3.
Step 7) ( E)-ter 't-butyl 4-(4-(3-(2,6-dichlorostyryl)-lH-pyrrolo[23-b]pyridin-5-yl)-lH-pyrazol-l- vDpiperidine- 1 -carboxylate [0189] To a stirred solution of (E)-5-bromo-3-(2,6-dichlorostyryl)-lH-pyrrolo[2,3- b]pyridine (310 mg, 0.84 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (477 mg, 1.26 mmol) in DME (20 mL) was added a solution of Na2C03 (268 mg, 2.52 mmol) in H20 (3 mL). The solution was degassed and charged with nitrogen for three times. Then Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was added. The solution was degassed and charged with nitrogen for three times again, then stirred and refluxed overnight. After cooling to rt, the mixture was diluted with EtOAc (20 mL), and filtered through a CELITE® pad. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a white solid (300 mg, 66%).
MS (ESI, pos. ion) m/z: 538.0 (M+l);
!H NMR (400 MHz, CD3OD): δ 1.50 (s, 9H), 1.90-2.10 (m, 2H), 2.16-2.28 (m, 2H), 2.96 (br, 2H), 4.19-4.31 (m, 1H), 4.31-4.42 (m, 1H), 7.08-7.21 (m, 2H), 7.34-7.42 (m, 3H), 7.55 (s, 1H), 7.86 (s, 1H), 7.90 (s, 1H), 8.40 (d, J= 1.6 Hz, 1H), 8.43 (d, J= 1.4 Hz, 1H);
13C NMPv (100 MHz, CD3OD): δ 28.5, 32.7, 59.8, 80.8, 113.6, 119.1, 120.1 , 121.2, 122.0, 124.8, 126.3, 128.0, 129.1, 130.2, 132.4, 132.9, 134.6, 135.3, 136.8, 141.2, 148.2, 155.4.
Step 8) (E)-3-(2,6-dichlorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridine
[0190] To a solution of (E)-tert-buty\ 4-(4-(3-(2,6-dichlorostyryl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (200 mg, 0.37 mmol) in CH2C12 (25 mL) was added a solution of HC1 in EtOAc (7.4 mL, 7.4 mmol, 1 M) slowly at 0 °C. The mixture was warmed up to rt and stirred overnight, then filtered, and the solid was dissolved in water (200 mL). The resulted mixture was adjusted to PH=10 with saturated Na2C03 aqueous solution, and extracted with CH2C12 (100 mL x 4). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2Cl2/MeOH/Et3N (v/v/v) = 100/10/0.5) to give the title compound as a white solid (130 mg, 80%).
MS (ESI, pos. ion) m/z: 438.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 1.75-1.91 (m, 2H), 2.02 (d, J = 11.3 Hz, 2H), 2.56-2.71 (m, 2H), 3.07 (d, J = 12.4 Hz, 2H), 3.19 (s, 1H), 4.12-4.30 (m, 1H), 7.14 (d, J = 16.8 Hz, 1H), 7.23- 7.35 (m, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 8.01 (s, 1H), 8.36 (s, 1H), 8.50 (s, 1H), 8.61 (s, 1H), 11.8-12.4 (br, 1H); 13C NMR (100 MHz, DMSO-Λ): δ 33.4, 40.1, 59.2, 111.9, 117.4, 118.1, 119.6, 121.8, 123.9, 124.7, 127.9, 128.4, 128.9, 130.5, 133.5, 135.2, 135.6, 141.2, 148.1. -3-(2-chlorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1
Figure imgf000056_0001
Step 1) 5-bromo-l-(phenylsulfonyl)-lH-pytTolor2,3-b1pyridine-3-carbaldehyde
[0191] To a suspension of 5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (5.0 g,
22.2 mmol) in CH2CI2 (130 mL) was added benzenesulfonyl chloride (5.0 mL, 39.0 mmol), tetra-n-butylammonium hydrogen sulphate (0.98 g, 2.89 mmol) and NaOH aqueous solution (4.2 mL, 50%). The mixture was stirred at rt for 2 hours, then poured into water (500 mL), and extracted with CH2CI2 (200 mL x 3). The combined organic phases were washed with saturated NaHCC"3 aqueous solution (150 mL x 2), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was washed with ether (150 mL x 3), and then filtered to give the title compound as a white solid (6.78 g, 84%).
MS (ESI, pos. ion) m/z: 365.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 7.62-7.71 (m, 2H), 7.75-7.83 (m, 1H), 8.16-8.24 (m, 2H), 8.52 (d, J= 2.2 Hz, 1H), 8.57 (d, J= 2.2 Hz, 1H), 9.03 (s, 1H), 10.03 (s, 1H).
Step 2) (Z)-5-bromo-3-(2-chlorostyryl)-lH-pyrrolo[2,3-blpyridine (2a)
(E)-5-bromo-3-(2-chlorostyryl)- lH-pyrrolo[2,3-blpyridine (2b)
Figure imgf000056_0002
[0192] To a suspension of (2-chlorobenzyl)triphenylphosphonium chloride (2.28 g, 6.57 mmol) in dry THF (100 mL) was added n-BuLi (2.63 mL, 2.5 M) dropwise at -10 °C. The mixture was warmed up to rt and stirred further for 3.5 hours. Then a solution of 5-bromo-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.0 g, 5.5 mmol) in THF (80 mL) was added and the mixture was stirred at rt for 12 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was dissolved in ethanol (220 mL), and then NaOH aqueous solution (110 mL, 10%) was added. The mixture was stirred and refluxed for 40 minutes, then concentrated in vacuo, and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound (2a) (Z)-5-bromo-3-(2-chlorostyryl)-lH- pyrrolo[2,3-b]pyridine as a pale yellow solid (525 mg, 28.7%) and (2b) (E)-5-bromo-3-(2- chlorostyryl)-lH-pyrrolo[2,3-b] pyridine as a pale yellow solid (810 mg, 44.3%).
The title compound (2a) (Z)-5-bromo-3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridine:
MS (ESI, pos. ion) m/z: 335.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 6.52 (d, J = 11.9 Hz, 1H), 6.91 (dd, J = 11.9, 0.6 Hz, 1H), 7.16-7.24 (m, 1H), 7.25-7.37 (m, 3H), 7.44 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.0, 1.1 Hz, 1H), 8.22 (d, J= 2.2 Hz, 1H), 12.00 (s, 1H);
13C NMR (100 MHz, DMSO-Λ): δ 110.0, 110.8, 119.5, 123.2, 123.3, 127.1, 127.7, 129.0, 129.4, 129.7, 130.6, 132.4, 136.9, 142.8, 146.6.
The title compound (2b) (E)-5-bromo-3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridine:
MS (ESI, pos. ion) m/z: 335.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 7.22-7.28 (m, 1H), 7.30 (d, J = 16.5 Hz, 1H), 7.34-7.40 (m, 1H), 7.44-7.49 (m, 1H), 7.48 (d, J = 16.5 Hz, 1H), 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.97 (s, 1H), 8.35 (d, J= 2.2 Hz, 1H), 8.52 (d, J= 2.2 Hz, 1H), 12.20 (s, 1H);
13C NMR (100 MHz, DMSO-Λ): δ 111.5, 112.1, 119.3, 120.1, 124.2, 126.1, 127.4, 127.8, 128.1, 129.6, 131.4, 135.5, 143.2, 147.3.
Step 3) ( E)-ter 't-butyl 4-(4-(3-(2-chlorostyryl)-lH-pyrrolo[2J-blpyridin-5-yl)-lH-pyrazol-l-yl) piperidine- 1 -carboxylate
[0193] The title compound was prepared according to the procedure as described in
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 Na2C03 (617 mg, 5.82 mmol) in water (4.6 mL) and Pd(PPh3)2Cl2 (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%).
MS (ESI, pos. ion) m/z: 504.0 (M+l);
¾ NMR (400 MHz, CDC13): δ 1.49 (s, 9H), 1.90-2.10 (m, 2H), 2.14-2.27 (m, 2H), 2.80-3.10 (m,
2H), 4.20-4.45 (m, 3H), 7.14-7.21 (m, 1H), 7.24-7.32 (m, 2H), 7.41 (dd, J = 8.0, 1.2 Hz, 1H), 7.48-7.57 (m, 2H), 7.72 (dd, J = 7.7, 1.5 Hz, 1H), 7.75 (d, J = 0.3 Hz, 1H), 7.88 (d, J = 0.6 Hz, 1H), 8.38 (d, J= 1.9 Hz, 1H), 8.52 (d, J= 1.9 Hz, 1H), 10.2 (s, 1H);
13C NMR (100 MHz, CDCb): δ 28.5, 29.7, 32.5, 59.6, 80.0, 114.1, 118.3, 120.8, 122.2, 122.3, 123.6, 123.7, 125.5, 125.7, 127.0, 127.9, 129.8, 132.8, 136.0, 136.6, 141.7, 148.4, 154.6.
Step 4) (E)-3-(2-chlorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[23
[0194] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using {E)-tert- vXy\ 4-(4-(3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridin-5- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (440 mg, 0.873 mmol) and a solution of HC1 in EtOAc (6 mL, 24 mmol, 4M). The crude product was washed with EtOAc (6 mL), and filtered to give the title compound as an off white solid (230 mg, 65%).
MS (ESI, pos. ion) m/z: 404.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 1.76-1.90 (m, 2H), 1.94-2.06 (m, 2H), 2.55-2.67 (m, 2H), 3.00-3.10 (m, 2H), 4.10-4.30 (m, 1H), 7.20-7.30 (m, 1H), 7.32-7.52 (m, 4H), 7.86 (s, 1H), 7.87 (dd, J= 8.0, 1.5 Hz, 1H), 7.94 (s, 1H), 8.29 (s, 1H), 8.44 (d, J= 2.0 Hz, 1H), 8.56 (d, J= 2.0 Hz, 1H), 11.94 (s, 1H);
13C NMR (100 MHz, DMSO-Λ): δ 33.5, 45.0, 59.2, 112.2, 117.6, 119.5, 121.6, 123.4, 124.4, 124.8, 125.9, 126.6, 127.3, 127.9, 129.5, 131.3, 135.3, 135.8, 141.1, 147.7.
Example 3 ( ^-3-(2-chlorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridine
Figure imgf000058_0001
Step 1) (Z)-tert-butyl 4-(4-(3-(2-chlorostyryl)-lH-pyrrolor2,3-b1pyridin-5-yl)-lH-pyrazol-l-yl) piperidine- 1 -carboxylate
[0195] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using (Z)-5-bromo-3-(2-chlorostyryl)-lH-pyrrolo[2,3-b]pyridine (400 mg, 1.20 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l -carboxylate (678 mg, 1.80 mmol), a solution of Na2C03 (382 mg, 3.6 mmol) in water (2.8 mL), and Pd(PPh3)2Cl2 (84 mg, 0.12 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a white solid (460 mg, 76%).
MS (ESI, pos. ion) m/z: 504.0 (M+l); ¾ NMR (400 MHz, CDCb): δ 1.50 (s, 9H), 1.86-2.03 (m, 2H), 2.10-2.22 (m, 2H), 2.80-3.05 (m, 2H), 4.20-4.43 (m, 3H), 6.65 (d, J = 11.9 Hz, 1H), 6.86 (d, J = 12.2 Hz, 1H), 7.04 (td, J = 7.6, 0.9 Hz, 1H), 7.15-7.23 (m, 2H), 7.29-7.34 (m, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.0, 1.1 Hz, 1H), 7.51 (s, 1H), 7.59 (s, 1H), 8.38 (s, 1H), 9.82 (s, 1H);
13C NMR (100 MHz, CDCb): δ 28.4, 29.7, 32.5, 59.5, 78.0, 1 1 1.9, 1 18.6, 120.7, 121.3, 122.9, 123.3, 124.7, 125.6, 125.8, 126.5, 128.4, 129.4, 131.0, 133.6, 136.4, 137.5, 141.1 , 147.5, 154.6.
Step 2) (Z)-3-(2-chlorostyryl)-5-(l -(piperidin-4-yl)- lH-pyrazol-4-yl)- lH-pyrrolo[23-b]pyridine
[0196] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 404.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 2.13-2.31 (m, 4H), 2.44-2.60 (m, 2H), 2.98-3.12 (m, 2H), 4.45-4.62 (m, 1H), 7.20-7.30 (m, 1H), 7.32-7.41 (m, 2H), 7.44-7.54 (m, 2H), 7.81-7.92 (m, 2H), 8.01 (s, 1H), 8.32 (s, 1H), 8.47 (d, J= 1.8 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 12.02 (s, 1H).
Example 4 (E)-3-(2-chloro-4-fluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolor2,3-b1pyridine
Figure imgf000059_0001
Step 1) (2-chloro-4-fluorobenzyl)triphenylphosphonium bromide
[0197] A mixture of l-(bromomethyl)-2-chloro-4-fluorobenzene (2.24 g, 10 mmol) and triphenylphosphine (2.86 g, 1 1 mmol) in toluene (12 mL) was refluxed with vigorous stirring for 12 hours, then cooled to rt, and filtered. The solid was washed with PE (10 mL) to give the title compound as white powder (4.60 g, 95%>). The crude product was used in the next step without further purification.
Step 2) (z^-5-bromo-3-(2-chloro-4-fluorostwl)-lH-pyrrolo[2,3-b]pyridine (2a)
(E)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3-b]pyridine (2b)
Figure imgf000060_0001
[0198] To a suspension of (2-chloro-4-fluorobenzyl)triphenylphosphonium bromide (2.43 g, 5.0 mmol) in dry THF (20 mL) was added n-BuLi (2.5 mL, 6.0 mmol, 2.5 M in hexane) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 20 minutes, then a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.83 g, 5.0 mmol) in dry THF (80 mL) was added . The mixture was stirred at 0 °C for 30 minutes, the cooling bath was removed and the mixture was stirred at rt for another 8 hours. The reaction was quenched with water (20 mL), concentrated in vacuo, and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was dissolved in EtOH (240 mL), and then NaOH aqueous solution (120 mL, 2.5 M) was added. The resulted mixture was refluxed for 3 hours, then concentrated in vacuo, and the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound (2a) (Z)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3-b]pyridine as a white solid (650 mg, 37%) and (2b) (E)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3- b]pyridine as a white solid (735 mg, 42%).
The title compound (2a) (Z)-5-bromo-3-(2-chloro-4-fiuorostyryl)-lH-pyrrolo[2,3-b]pyridine: MS (ESI, pos. ion) m/z: 351.0 (M+l);
lU NMR (400 MHz, DMSO-t ί): δ 12.02 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.34-7.30 (m, 2H), 7.10 (td, J = 8.5, 2.6 Hz, 1H), 6.92 (d, J = 11.9 Hz, 1H), 6.46 (d, J= 11.9 Hz, 1H).
The title compound (2b) (E)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3-b]pyridine: MS (ESI, pos. ion) m/z: 351.0 (M+l);
lU NMR (400 MHz, OMSO-de): δ 12.20 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 7.96 (s, 1H), 7.93 (dd, J= 8.9, 6.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.30-7.22 (m, 2H).
Step 3) (EVfe -butyl 4-(4-(3-(2-chloro-4-fluorostyrvn-lH-pyrrolor2,3-blpyridin-5-vn-lH- pyrazol- 1 -yDpiperidine- 1 -carboxylate
[0199] The title compound was prepared according to the procedure as described in Example 1 Step 7 by using (E)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3-b]pyridine (352 mg, 1.0 mmol), tert-butyl 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 Na2C03 (318 mg, 3.0 mmol) in water (3 mL) and Pd(PPli3)2Cl2 (70 mg, 0.1 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 (450 mg, 86%).
MS (ESI, pos. ion) m/z: 522.0 (M+l);
lU NMR (400 MHz, DMSO-Λ): δ 11.93 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.91 (dd, J = 8.8, 6.3 Hz, 1H), 7.85 (s, 1H), 7.48-7.41 (m, 2H), 7.32-7.25 (m, 2H), 4.45-4.35 (m, 1H), 4.08-4.04 (m, 2H), 2.95 (s, 2H), 2.09-2.06 (m, 2H), 1.89- 1.79 (m, 2H), 1.43 (s, 9H).
Step 4) (E)-3-(2-chloro-4-fluorostwl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridine
[0200] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using {E)-tert-bvXy\ 4-(4-(3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (250 mg, 0.48 mmol) and a solution of HC1 in EtOAc (4.6 mL, 18.9 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 (139 mg, 69%).
MS (ESI, pos. ion) m/z: 422.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 11.93 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 7.94 (d, J= 0.5 Hz, 1H), 7.91 (dd, J= 8.9, 6.3 Hz, 1H), 7.85 (s, 1H), 7.48-7.41 (m, 2H), 7.32-7.25 (m, 2H), 4.24-4.19 (m, 1H), 3.06-3.04 (m, 2H), 2.68-2.55 (m, 2H), 2.01-1.99 (m, 2H), 1.88-1.78 (m, 2H).
Example 5 (Z)-3-(2-chloro-4-fluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolor2,3-b1pyridine
Figure imgf000061_0001
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
[0201] The title compound was prepared according to the procedure as described in Example 1 Step 7 by using (Z)-5-bromo-3-(2-chloro-4-fluorostyryl)-lH-pyrrolo[2,3-b]pyridine (352 mg, 1.0 mmol), tert-butyl 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 Na2C03 (318 mg, 3.0 mmol) in water (3 mL) and Pd(PPli3)2Cl2 (70 mg, 0.1 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 (476 mg, 91%).
MS (ESI, pos. ion) m/z: 522.0 (M+l);
lU NMR (400 MHz, DMSO-Λ): δ 11.75 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.21 (s, 1H), 7.13-7.11 (m, 1H), 6.95 (d, J = 11.96 Hz, 1H), 6.44 (d, J = 12.0 Hz, 1H), 4.41-4.33 (m, 1H), 4.08-4.04 (m, 2H), 2.95 (s, 2H), 2.07-2.04 (m, 2H), 1.85-1.75 (m, 2H), 1.43 (s, 9H).
Step 2) (z^-3-(2-chloro-4-fluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3- blpyridine
[0202] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 422.0 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 11.90 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.91 (dd, J = 8.8, 6.3 Hz, 1H), 7.85 (s, 1H), 7.48-7.41 (m, 1H), 7.32-7.25 (m, 1H), 4.24-4.19 (m, 1H), 3.06-3.03 (m, 2H), 2.63-2.56 (m, 2H), 2.03-1.98 (m, 2H), 1.87-1.77 (m, 2H).
Example 6 (Z)-2-(2,6-dichlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b1pyridin-3-yl)acrylonitrile (2a)
(E)-2-(2,6-dichlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridin-3-yl)acrylonitrile (2b)
Figure imgf000062_0001
Step 1) (Z)-3-(5-bromo- 1 -(phenylsulfonyO- lH-pyrrolo[2,3-blpyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (la)
(E)-3-(5-bromo-l-(phenylsulfonyl)-lH-pytTolor2,3-b1pyridin-3-yl)-2-(2,6- dichlorophenyDacrylonitrile (lb)
Figure imgf000063_0001
[0203] To a solution of 2-(2,6-dichlorophenyl)acetonitrile (3.06 g, 16.4 mmol) in DMF
(60 mL) was added t-BuOK (1.84 g, 16.4 mmol). The mixture was heated to 50 °C and stirred further for 50 minutes, then a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridine-3-carbaldehyde (5 g, 13.7 mmol) in DMF (100 mL) was added slowly over 1.5 hours. The reaction was stirred at 50 °C overnight, then cooled to rt, quenched with water (20 mL), and concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and water (100 mL), and the resulted mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound (a mixturte of la and lb) as a yellowish solid (1.26 g, 24%).
MS (ESI, pos. ion) m/z: 392.0 (M-140+1).
Step 2) (2r)-2-(2,6-dichlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3- blpyridin-3-yl)acrylonitrile (2a)
(E)-2-(2,6-dichlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b1pyridin-3-yl)acrylonitrile (2b)
Figure imgf000063_0002
2a 2b
[0204] To a mixed solution of CH3CN (5 mL) and Na2C03 aqueous solution (5 mL, 2 M) were added 3-(5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl) acrylonitrile (a mixture of la and lb) (680 mg, 1.73 mmol), tert-butyl 4-(4- (4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (849 mg, 2.25 mmol) and Pd(PPh3)2Cl2 (84 mg, 0.12 mmol). 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 Na2S04, and concentrated in vacuo. The crude product was used in next step without further purification.
[0205] The crude product was dissolved in CH2CI2 (40 mL), then a solution of HC1 in
EtOAc (12 mL, 3M) was added. The mixture was stirred at rt for 5 hours, then filtered, and the filter cake was dissolved in water (100 mL). The resulted mixture was adjusted to pH=10 with saturated Na2C03 aqueous solution and extracted with CH2CI2 (200 mL x 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2CI2/CH3OH/NH3 H2O (v/v/v) = 200/20/1) to give the title compound (a mixture of 2a and 2b) as an off-white solid (350 mg, 44%).
MS (ESI, pos. ion) m/z: 463.0 (M+l).
Example 7 (E)-3-(2-(2,6-dichloro-3-fluorophenyl)prop-l-en-l-yl)-5-(l-(piperidin-4-yl)-lH- pyrazol-4-yl)-lH-pyrrolor2,3-b1pyridine
Figure imgf000064_0001
Step 1) l-(2,6-dichloro-3-fluorophenyl)ethanol
[0206] To a solution of l-(2,6-dichloro-3-fluorophenyl)ethanone (5.0 g, 24.1 mmol) in methanol (40 mL) was added NaBH4 (1.36 g, 36.2 mmol) in two portions at 0 °C. The mixture was warmed to rt and stirred further for 12 hours. After the removal of the solvent, the residue was diluted with water (50 mL), and the resulted mixture was extracted with CH2CI2 (100 mL x 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give the product as colorless liquid (4.7 lg, 93%). The crude product was used in the next step without further purification.
Step 2) 2-(l-bromoethyl)-l,3-dichloro-4-fluorobenzene
[0207] A solution of Phosphorus tribromide (2.3 mL) in anhydrous DCM (50 mL) was cooled in ice water for 20 minutes. The cooled solution was then added to a mixture of l-(2- chloro-3,6-difluorophenyl)ethanol (4.7 lg, 22.4mmol) and methylene chloride (50 mL). The resulted mixture was stirred at rt for 2 hours, then poured into H20 (100 mL) and extracted with
DCM (100 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/5) to give the title compound as colorless liquid (2.1g, 35%).
!H NMR (400 MHz, CDC ): δ 2.15-2.16 (d, J = 4.7 Hz, 3H), 5.93-6.01 (m, 1H), 7.03-7.07 (m, 1H), 7.26-7.30 (m, 1H).
Step 3) (l-(2,6-dichloro-3-fluorophenyl)ethyl)triphenylphosphonium bromide
[0208] To a solution of triphenylphosphine (2.62 g, 10 mmol) in dry toluene (7 mL) was added 2-(l-bromoethyl)-l,3-dichloro-4-fluorobenzene (2.71 g, 10 mmol). The mixture was micro waved and stirred at 180 °C for 1 hour, then cooled to rt, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/2) to give the title compound as a yellow solid (2.9 g, 52%).
Step 4) (E)-5-bromo-3-(2-(2,6-dichloro-3-fluorophenyl)prop-l-en-l-yl)-lH-pyrrolo[2,3- blpyridine
[0209] To a suspension of (l-(2,6-dichloro-3-fluorophenyl)ethyl)triphenylphosphonium bromide (1.68 g, 3.15 mmol) in dry THF (4 mL) was added n-BuLi (1.8 mL, 2.5 M in hexane) at -10 °C under nitrogen atmosphere. The mixture was stirred at -10 °C for 30 minutes, then a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.05 g, 2.9 mmol) in dry THF (45 mL) was added. The mixture was stirred at -10 °C for 30 minutes, then warmed to rt and stirred further for 12 hours. The mixture was quenched with water (80 mL), concentrated in vacuo, and the residue was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04, concentrated in vacuo, and the residue was diluted with NaOH aqueous solution (60 mL, 10%>) and EtOH (120 mL). The mixture was stirred and refluxed for 1 hour, then concentrated in vacuo, and the residue was extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/1) to give the title compound as a white solid (610 mg, 48%).
MS (ESI, pos. ion) m/z: 400.2 (M+l);
'H NMR (400 MHz, CDCb): δ 8.37 (d, J= 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.46 (d, J= 2.5 Hz, 1H), 6.97-7.04 (m, 1H), 6.60 (s, 1H), 5.52-5.58 (m, 1H), 5.34 (s, 1H), 3.48 (s, 3H).
Step 5) (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- 1 -vDpiperidine- 1 -carboxylate
[0210] To a suspension of (E)-5-bromo-3-(2-(2,6-dichloro-3-fluorophenyl)prop-l-en-l- yl)-lH- pyrrolo[2,3-b]pyridine (200 mg, 0.5 mmol) in CH3CN/H20 (1/1, 4 mL) were added tert- butyl 4-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazol- 1 -yl)piperidine- 1 - carboxylate (280 mg, 0.75 mmol), Na2C03 (318 mg, 3.0 mmol), and Pd(PPh3)2Cl2 (50 mg, 0.05 mmol). The mixture was micro waved and stirred at 150 °C for 1 hour, then cooled to rt, and concentrated in vacuo to give the title compound as a brown solid (91 mg, 37%) for the next step without further purification.
Step 6) (E)-3-(2-(2,6-dichloro-3-fluorophenyl)prop-l-en-l-yl)-5-(l-(piperidin-4-yl)-lH-pyrazol- 4-yl)-lH-pwolo[2,3-b]pyridine
[0211] The title compound was prepared according to the procedure as described in
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/CH3OH (v/v) = 15/1) to give the title compound as a white solid (68 mg, 80%).
HPLC: 91.1%;
MS (ESI, pos. ion) m/z: 471.2 (M+l);
!H NMR (400 MHz, DMSO-Λ): δ 11.90 (s, 1H), 8.56 (s, 1H), 8.29-8.30 (m, 2H), 8.02 (s, 1H), 7.75 (s, 1H), 7.53-7.56 (dd, J = 5.0, 8.9 Hz, 1H), 7.37-7.42 (m, 1H), 6.77-6.80 (d, J = 11.0 Hz, 1H), 5.31-5.34 (d, J = 11.1 Hz, 1H), 4.46 (s, 1H), 3.98-3.99 (d, J = 4.5 Hz, 2H), 3.03 (s, 3H), 2.49-2.50 (m, 2H), 2.13-2.20 (m, 2H), 1.14-1.23 (m, 2H).
Example 8 (E)-3-(5-chloro-2-(trifluoromethyl)styryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine
Figure imgf000066_0001
Step 1) (5-chloro-2-(trifluoromethyl)benzyl)triphenylphosphonium bromide
[0212] A mixture of 2-(bromomethyl)-4-chloro-l-(trifluoromethyl)benzene (1.00 g, 3.657 mmol) and PPh3 (1.10 g, 4.022 mmol) in toluene (10 mL) was stirred at 1 10 °C overnight, then cooled to rt, and filtered. The filter cake was washed with toluene (20 mL) and dried in vacuo to give the title compound as a white solid (1.95g, 99.5%>).
Step 2) (E)-5-bromo-3-(5-chloro-2-(trifluoromethyl)styryl)- lH-pyrrolo[2,3-b]pyridine
[0213] To a solution of (5-chloro-2-(trifluoromethyl)benzyl)triphenylphosphonium bromide (1.80 g, 3.286 mmol) in anhydrous THF (56 mL) was added n-BuLi (1.4 mL, 3.286 mmol) at -10 °C and the mixture was stirred at 0 °C for 3.5 hours. Then a solution of 5-bromo-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.00 g, 2.738 mmol) in anhydrous THF (44 mL) was added. The mixture was stirred at rt overnight, then quenched with water (10 mL), and concentrated in vacuo. The residue was washed with water (100 mL), and the resulted mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated in vacuo, and the residue was dissolved in EtOH (108 mL). Then NaOH aqueous solution (56 mL, 10%) was added and the resulted mixture was refluxed for 40 minutes. The mixture was concentrated in vacuo, and the residue was washed with water (100 mL). The resulted mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (792.8 mg, 72.1%).
MS (ESI, pos. ion) m/z: 401.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 12.32 (s, 1H), 8.49 (d, J= 2.16 Hz, 1H), 8.36 (d, J= 2.12 Hz, 1H), 8.13 (d, J= 1.12 Hz, 1H), 8.00 (s, 1H), 7.74 (d, J= 8.52 Hz, 1H), 7.70 (d, J= 16.2 Hz, 1H), 7.49-7.47 (dd, J= 8.52, 1.12 Hz, 1H), 7.17 (d, J= 16.2 Hz, 1H).
Step 3) ( E)-ter 't-butyl 4-(4-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2J-blpyridin-5- vD- 1 H-p yrazol- 1 -vDpiperidine- 1 -carboxylate
[0214] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using (E)-5-bromo-3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2,3- b]pyridine (500.0 mg, 1.245 mmol), tert- vXy\ 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (704.6 mg, 1.867 mmol), a solution of Na2C03 (395.9 mg, 3.735 mmol) in water (30 mL), and Pd(PPh3)2Cl2 (43.7 mg, 0.062 mmol). The crude product was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 2/1) to give the title compound as a yellow solid (560.0 mg, 78.7%).
MS (ESI, pos. ion) m/z: 572.0 (M+l);
lH NMR (400 MHz, DMSO-t ί): δ 12.05 (s, 1H), 8.58 (d, J= 1.16 Hz, 1H), 8.39 (d, J= 1.88 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 1.36 Hz, 1H), 7.91 (s, 1H), 7.88 (d, J = 2.64 Hz, 1H), 7.75 (d, J = 8.56 Hz, 1H), 7.67 (d, J = 16.16 Hz, 1H), 7.49-7.47 (dd, J = 8.56, 1.48 Hz, 1H), 7.26 (d, J = 16.16 Hz, 1H), 4.44-4.39 (m, 1H), 4.08-4.01 (m, 2H), 3.10-2.80 (m, 2H), 2.10-2.07 (m, 2H), 1.89-1.79 (m, 2H), 1.43 (s, 9H).
Step 4) (iT)-3-(5-chloro-2-(trifluoromethyl¼
pyrrolo[2,3-blpyridine [0215] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 472.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 12.06 (br, 1H), 8.57 (d, J = 1.96 Hz, 1H), 8.39 (d, J= 2.04 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J= 1.32 Hz, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.75 (d, J= 8.52 Hz, 1H), 7.67 (d, J = 16.08 Hz, 1H), 7.48-7.46 (dd, J = 8.52, 1.40 Hz, 1H), 7.25 (d, J = 16.12 Hz, 1H), 4.25-4.19 (m, 1H), 3.07-3.04 (m, 2H), 2.63-2.57 (m, 2H), 2.02-1.98 (m, 2H), 1.87-1.77 (m, 2H).
Example 9 (iT)-3-(2,5-dichlorostyryO-5-(l-(piperi
pyridine
Figure imgf000068_0001
Step 1) tert-butyl 4-(4-(lH-pyrrolor2,3-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
[0216] The title compound was prepared according to the procedure as described in
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 Na2C03 (8.0 g, 75 mmol) in water (63 mL) and Pd(PPh3)2Cl2 (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%).
MS (ESI, pos. ion) m/z: 368.0 (M+l);
lH NMR (400 MHz, DMSO-de): δ 11.56 (s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.46-7.42 (m, 1H), 6.41 (dd, J= 1.8, 3.4 Hz, 1H), 4.45-4.30 (m, 1H), 4.12-3.98 (m, 2H), 3.02-2.80 (br, 2H), 2.10-2.00 (m, 2H), 1.88-1.72 (m, 2H), 1.42 (s, 9H).
Step 2) tert-butyl 4-(4-(3-iodo-lH-pyrrolo[2J-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
[0217] To a solution of tert-butyl 4-(4-(lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (4.4 g, 12 mmol) in acetone (250 mL) was added NIS (3.3 g, 14.4 mmol). The mixture was stirred at rt for 2 hours, then concentrated to 50 mL. The resulted precipitate was collected by filtration and washed with ice-cold acetone (20 mL) to give the title compound as a pale pink solid (5.3 g, 90%).
MS (ESI, pos. ion) m/z: 494.0 (M+l).
¾ NMR (400 MHz, DMSO- e): δ 12.04 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 4.44-4.32 (m, 1H), 4.15-3.97 (m, 2H), 3.03-2.83 (br, 2H), 2.10-2.00 (m, 2H), 1.88-1.72 (m, 2H), 1.43 (s, 9H).
Step 3) tert-butyl 4-(4-(3-iodo-l-(phenylsulfonyl)-lH-pyrrolor2,3-b1pyridin-5-yl)-lH-pyrazol-l- yDpiperidine- 1 -carboxylate
[0218] The title compound was prepared according to the procedure as described in
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), PhS02Cl (2 mL, 15 mmol), rc-Bu4NHS04 (0.44 g, 1.3 mmol) and NaOH aqueous solution (1.9 mL, 50%). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) =100/1) to give the title compound as a white solid (6.1 g, 96%).
MS (ESI, pos. ion) m/z: 634.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 8.69 (d, J= 2.0 Hz, 1H), 8.48 (s, 1H), 8.17-8.12 (m, 3H), 8.05 (d, J= 0.4 Hz, 1H), 7.91 (d, J= 2.1 Hz, 1H), 7.77-7.71 (m, 1H), 7.68-7.65 (m, 2H), 4.45-4.32 (m, 1H), 4.20-4.00 (m, 2H), 3.05-2.85 (br, 2H), 2.10-2.00 (m, 2H), 1.88-1.72 (m, 2H), 1.43 (s, 9H).
Step 4) tert-butyl 4-(4-(l-(phenylsulfonyl)-3-vinyl-lH-pyrrolo[23-blpyridin-5-yl)-lH-pyrazol- 1 -vDpiperidine- 1 -carboxylate
[0219] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using tert-butyl 4-(4-(3-iodo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin- 5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (6.34 g, 10 mmol), Pinacol vinylboronate (2.00 g, 13 mmol), a solution of NaHC03 (4.2 g, 50 mmol) in water (60 mL) and Pd(dppf)Cl2-CH2Cl2 (817 mg, 1 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 pink solid (5.3 g, 97%>).
MS (ESI, pos. ion) m/z: 534.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 8.68 (d, J = 2.0 Hz, 1H), 8.50-8.40 (m, 2H), 8.15-8.05 (m, 3H), 7.78-7.68 (m, 1H), 7.68-7.59 (m, 2H), 6.86 (dd, J= 11.6, 18.0 Hz, 1H), 6.04 (d, J= 18.0 Hz, 1H), 5.41 (d, J = 11.9 Hz, 1H), 4.42-4.33 (m, 1H), 4.10-4.00 (m, 2H), 3.05-2.85 (br, 2H), 2.10- 2.00 (m, 2H), 1.88-1.72 (m, 2H), 1.42 (s, 9H). Step 5) ( E)-ter 't-butyl 4-(4-(3-(2,5-dichlorostyryl)-lH-pw
vDpiperidine- 1 -carboxylate
[0220] A mixture of tert-butyl 4-(4-(l-(phenylsulfonyl)-3-vinyl-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (205 mg, 0.95mmol), 2-bromo-l ,4- dichlorobenzene (500 mg, 0.9 mmol), Pd(OAc)2 (4 mg, 0.018 mmol), PPh3 (9 mg, 0.036 mmol) and K2C03 (310 mg, 2.25 mmol), TBAI (0.09 mmol, 33 mg) in anhydrous DMF (5 mL) was microwaved and stirred at 170 °C for 1 hour. After cooling to rt, the mixture was washed with water (15 mL), and extracted with EtOAc (lOmL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (160 mg, 32%).
MS (ESI, pos. ion) m/z: 538.0 (M+l).
Step 6) (E)-3-(2,5-dichlorostyryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[2 pyridine
[0221] The title compound was prepared according to the procedure as described in
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/NH4OH (v/v/v) = 8/1/0.02) to give the title compound as a yellow solid (60 mg, 46.1%).
MS (ESI, pos. ion) m/z: 438.0 (M+l);
!H NMR (400 MHz, CDC13): δ 8.56 (d, J = 19.2 Hz, 1H), 8.46 (d, J = 19.6 Hz, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 16.4 Hz, 1H), 7.28 (d, J = 16.4 Hz, 2H), 7.30 (m, 1H), 8.56 (d, J = 7.50 Hz, 1H), 7.27 (m, 1H), 3.25-3.23 (m, 2H), 2.67-2.51 (m, 2H), 2.06- 2.05 (m, 1H), 1.89-1.86 (m, 2H).
Example 10 (z^-3-(2-chloro-6-methylstyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b1pyridine (3a)
(E)-3 -(2-chloro-6-methylstyryl)-5 -( 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl)- 1 H- pyrrolo[2,3-b]pyridine (3b)
Figure imgf000071_0001
3a
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)
(E)-tert- vXy\ 4-(4-(3-(2-chloro-6-methylstyryl)-l-(phenylsulfonyl)-lH-pyrrolo[2,3-bl pyridin-5-yl)- lH-pyrazol- 1 -vDpiperidine- 1 -carboxylate (lb)
Figure imgf000071_0002
[0222] The title compound was prepared according to the procedure as described in
Example 9 Step 5 by using 2-bromo-l-chloro-3-methylbenzene (40 mg, 0.19 mmol), tert-butyl 4-(4-( 1 -(phenylsulfonyl)-3 -vinyl- 1 H-pyrro^
carboxylate (100 mg, 0.18 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), PPh3 (3 mg, 0.04 mmol), K2C03 (62 mg,0.45 mmol), and TBAB (5 mg, O.Olmmol). The crude product (a mixture of la and lb) as a brown solid was used in the next step without further purification.
MS (ESI, pos. ion) m/z: 658.2 (M+l).
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)
(E)-tert-bvA.y\ 4-(4-(3-(2-chloro-6-methylstyryl)- lH-pyrrolo[23-b]pyridin-5-yD- 1H- pyrazol- 1 -yDpiperidine- 1 -carboxylate (2b)
Figure imgf000071_0003
[0223] To a solution of tert-butyl 4-(4-(3-(2-chloro-6-methylstyryl)-l-(phenylsulfonyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (a mixture of la and lb) (329 mg, 0.5 mmol) in EtOH (20 mL) was added NaOH aqueous solution (10 mL, 10%). The mixture was stirred at 100 °C for 1.5 hours, then cooled to rt, and concentrated in vacuo. The residue was washed with water (50 mL), and the resulted mixture was extracted with DCM (100 mL x 3). The combined organic extracts were dried over anhydrous Na2S04, and concentrated in vacuo to give the crude product (201 mg, 64%, a mixture of 2a and 2b) for the next step without further purification.
MS (ESI, pos. ion) m/z: 518.2 (M+l).
Step 3) (z^-3-(2-chloro-6-methylstwl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridine (3a)
(E)-3-(2-chloro-6-methylstyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pw
pyridine (3b)
Figure imgf000072_0001
[0224] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using tert- vXy\ 4-(4-(3-(2-chloro-6-methylstyryl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (a mixture of 2a and 2b) (201 mg, 0.39 mmol), and a solution of HC1 in EtOAc (1.0 mL, 4 mmol, 4M). The crude product was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/1) to give the title compound (a mixture of 3a and 3b) as a white solid (E/Z=3/l, 113 mg, 70%).
HPLC: 93.2%;
MS (ESI, pos. ion) m/z: 418.1 (M+l);
Compound (3b): !H NMR (400 MHz, DMSO-Λ): δ 11.8 (s, 1H), 8.55-8.56 (d, J = 1.7 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.75-7.76 (m, 1H), 7.33-7.35 (d, J = 7.3 Hz, 1H), 7.24-7.26 (d, J= 7.24 Hz, 1H), 7.14-7.18 (m, 1H), 7.11 (s, 1H), 7.01 (m, 1H), 4.17-4.24 (m, 2H), 3.08 (s, 3H), 2.49-2.50 (m, 2H),1.98-2.02 (m, 2H), 1.81-1.84 (m, 2H), 1.14-1.23 (m, 1H).
Exam le 11 (E)-3-(2,5-difluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrroloL
Figure imgf000072_0002
Stepl) (E)-tert-butyl 4-(4-(3-(2,5-difluorostyryl)-l-(phenylsulfonyl)-lH-pwolor2,3-b1pyridin-5- vD- 1 H-p yrazol- 1 -vDpiperidine- 1 -carboxylate [0225] The title compound was prepared according to the procedure as described in
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), PPh3 (9 mg, 0.036 mmol), K2C03 (310 mg, 2.25 mmol) and TBAI (0.09 mmol, 33 mg). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a yellow solid (540 mg, 93%).
MS (ESI, pos. ion) m/z: 646.0 (M+l).
Step 2) ( E)-ter 't-butyl 4-(4-(3-(2,5-difluorostyryl)-lH-pyrrolo[23-blpyridin-5-yl)-lH-pyrazol-l- vDpiperidine- 1 -carboxylate
[0226] To a solution of (E)-tert-buty\ 4-(4-(3-(2,5-difiuorostyryl)-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (540 mg, 1.07 mmol) in EtOH (20 mL) was added NaOH aqueous solution (10 mL, 10%). The mixture was stirred at 100 °C for 1.5 hours, and concentrated in vacuo. The residue was poured into water (20 mL), and then the mixture was extracted with CH2C12 (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (120 mg, 29%>).
MS (ESI, pos. ion) m/z: 506.0 (M+l).
Step 3) (E)-3-(2,5-difluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pw
pyridine
[0227] The title compound was prepared according to the procedure as described in
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 (CH2Cl2/MeOH/NH4OH (v/v/v) =8/1/0.02) to give the title compound as a yellow solid (85 mg, 44.2%).
MS (ESI, pos. ion) m/z: 406.0 (M+l);
¾ NMR (400 MHz, CDC13): δ 8.85 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.67 (m, 1H), 7.58 (d, J = 16.7 Hz, 1H), 7.26 (m, 1H), 7.08 (d, J = 16.5 Hz, 1H), 7.08 (m, 1H), 4.47-4.19 (m, 1H), 3.19-3,16 (m, 2H), 2.79-2.73 (m, 2H), 2.10-2.07 (m, 2H), 1.95-1.93 (m, 2H). Example 12 (E)-3-(2-chloro-6-(trifluoromethyl)styryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)- lH- rrolo[2,,3-b1pyridine
Figure imgf000074_0001
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
[0228] To a microwave vial were added tert-butyl 4-(4-(l-(phenylsulfonyl)-3-vinyl-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (1.07 g, 2.0 mmol), 2- bromo-l-chloro-3-(trifluoromethyl)benzene (780 mg, 3.0 mmol), Pd(OAc)2 (9 mg, 40 μmol), TBAB (650 mg, 2.0 mmol), K2C03 (930 mg, 6.0 mmol), DMF (10 mL) and P(t-Bu)3 (36 mg, 74 umol, 1 M in toluene). The mixture was stirred and microwaved at 150 °C for 90 minutes, then cooled to rt, washed with brine (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the PhS02-protected product (purity: 88%).
[0229] To a solution of the PhS02-protected product in EtOH (40 mL) was added NaOH aqueous solution (20 mL, 10%>). The resulted solution was heated to 90 °C and stirred further for 1.5 hours, then cooled to rt, and concentrated in vacuo. The residual aqueous solution was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a pale yellow solid (270 mg, 24%).
MS (ESI, pos. ion) m/z: 572.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 11.92 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 16.7 Hz, 1H), 6.99 (d, J = 16.7 Hz, 1H), 4.45-4.31 (m, 1H), 4.15-3.97 (m, 2H), 3.05-2.80 (br, 2H), 2.12-2.00 (m, 2H), 1.90-1.75 (m, 2H), 1.41 (s, 9H).
Step 2) (E)-3-(2-chloro-6-(trifluoromethyl)styryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine
[0230] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using (E)-tert-bvAy\ 4-(4-(3-(2-chloro-6-(trifluoromethyl)styryl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (250 mg, 0.44 mmol) and a solution of HC1 in EtOAc (3 mL, 9 mmol, 3 M). The crude product was washed with CH2CI2 (5 mL) and MeOH (5 mL) respectively, filtered and the filter cake was dried in vacuo to give the title compound as a light yellow solid (170 mg, 68%).
MS (ESI, pos. ion) m/z: 472.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 11.92 (s, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.83-7.75 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 17.8 Hz, 1H), 7.00 (d, J = 16.8 Hz, 1H), 4.27-4.14 (m, 1H), 3.12-2.97 (m, 2H), 2.70-2.50 (m, 2H), 2.08-1.95 (m, 2H), 1.90-1.75 (m, 2H).
Example 13 (E)-3-(2,6-dichloro-3-fluorostyryl)-5-(l -(piperidin-4-yl)- lH-pyrazol-4-yl)- 1H- pyrrolor2,3-b1pyridine
Figure imgf000075_0001
Step 1) l-(2,6-dichloro-3-fluorophenyl)ethanol
[0231] To a slurry of L1AIH4 (1.43 g, 37.5 mmol) in THF (40 mL) was added a solution of l-(2,6-dichloro-3-fluorophenyl)ethanone (5.2 g, 25 mmol) in THF (10 mL) at 0 °C. The resulted mixture was allowed to warm to rt and stirred further for 1 hour. The mixture was cooled to 0 °C again, then EtOAc (80 mL) was added dropwise under stirring, followed by the addition of water (80 mL). The mixture was warmed to rt and stirred further for 0.5 hour. The solid was filtered off, the organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo to give the crude product as colorless oil (4.8 g, 92%). The crude product was used in the next step directly without further purification.
Step 2) l,3-dichloro-4-fluoro-2-vinylbenzene
[0232] A slurry of l-(2,6-dichloro-3-fluorophenyl)ethanol (4.6 g, 22 mmol) and P2O5
(17.5 g, 0.12 mol) in DCM (200 mL) was stirred at rt for 16 hours. The solid was filtered off through a pad of CELITE®, and washed with DCM (200 mL) for several times. The filtrate was washed with saturated Na2C03 aqueous solution (100 mL x 2). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo. The white solid precipitated during concentration was discarded. The remained oil was dried in vacuo, and used directly in the next step without further purification (3.5 g, 83%). MS (ESI, pos. ion) m/z: 191.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 7.60-7.50 (m, 1H), 7.45-7.35 (m, 1H), 6.75-6.63 (m, 1H), 5.90-5.75 (m, 2H).
Step 3) (EVfert-butyl 4-(4-(3-(2,6-dichloro-3-fluorostyrvn-lH-pyrrolor2,3-blpyridin-5-vn-lH- pyrazol- 1 -yDpiperidine- 1 -carboxylate
[0233] To a microwave vial was added tert-butyl 4-(4-(3-iodo-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (3.80 g, 6.0 mmol), 1,3- dichloro-4-fluoro-2-vinylbenzene (3.44 g, 18 mmol), Pd(OAc)2 (0.6 mmol, 135 mg), TBAB (1.93 g, 6.0 mmol), K2C03 (2.50 g, 18 mmol), P(t-Bu)3 (1.2 mL, 1M in toluene) and DMAC (30 mL). The resulted mixture was microwaved and stirred at 120 °C for 1 hour, then cooled to rt, poured into brine (200 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the crude product as pale yellow oil (1.1 g, 33%). The crude product was used in the next step without further purification.
[0234] To a solution of the oil (1.1 g, 1.58 mmol) in EtOH (40 mL) was added NaOH aqueous solution (20 mL, 10%). The mixture was refluxed for 1.5 hours, then cooled to rt, and concentrated in vacuo. The residual aqueous layer was extracted with EtOAc (100 mL x 5). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1), followed by recrystallization from EtOAc (10 mL) to give the title compound as a light yellow solid (344 mg, 10%).
MS (ESI, pos. ion) m/z: 556.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 11.98 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.86 (d, J= 1.3 Hz, 1H), 7.59 (dd, J= 5.1, 8.8 Hz, 1H), 7.37 (t, J = 8.7 Hz, 1H), 7.32 (d, J= 16.7 Hz, 1H), 7.10 (d, J= 16.7 Hz, 1H), 4.42-4.32 (m, 1H), 4.10-4.00 (m, 2H), 3.02-2.85 (m, 2H), 2.11-2.02 (m, 2H), 1.84-1.78 (m, 2H).
Step 4) (E)-3-(2,6-dichloro-3-fluorostyryl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine
[0235] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using {E)-tert- vXy\ 4-(4-(3-(2,6-dichloro-3-fluorostyryl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (320 mg, 0.58 mmol) and a solution of
HC1 in EtOAc (3 mL, 3 M). The crude product was washed with CH2C12 (5 mL) and MeOH (5 mL) respectively, then filtered and the filter cake was dried in vacuo to give the title compound as a yellow solid (200 mg, 76%).
MS (ESI, pos. ion) m/z: 456.0 (M+l);
!H NMR (400 MHz, DMSO- e ): δ 12.00 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 1.3 Hz, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.58 (dd, J = 5.1, 8.7 Hz, 1H), 7.39-7.35 (m, 1H), 7.32 (d, J= 16.8 Hz, 1H), 7.10 (d, J = 16.8 Hz, 1H), 4.22-4.17 (m, 1H), 3.06-3.03 (m, 2H), 2.65- 2.45 (m, 2H), 2.05-1.95 (m, 2H), 1.84-1.80 (m, 2H).
Example 14 (z)-2-(2-chlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridin-3 -yPacrylonitrile
Figure imgf000077_0001
Step 1) (Z)-3-(5-bromo-lH-pyrrolo[2J-blpyridin-3-yl)-2-(2-chlorophenyl)acrylonitrile
[0236] To a solution of 2-(2-chlorophenyl)acetonitrile (728 mg, 4.8 mmol) in DMF (20 mL) was added t-BuOK (539 mg, 4.8 mmol). The resulted mixture was degassed and charged with nitrogen for three times, and stirred at 50 °C for 15 minutes. Then a solution of 5-bromo-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.461 g, 4.0 mmol) in DMF (40 mL) was added dropwise over 2 hours. The mixture was stirred at 50 °C overnight, then quenched with water (1 mL), and concentrated in vacuo. The residue was redissolved in EtOH (80 mL) and NaOH aqueous solution (40 mL, 10%). The resulted mixture was refluxed for 2 hours, then cooled to rt, and concentrated in vacuo. The residue was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (430 mg, 25%).
MS (ESI, pos. ion) m/z: 358.0 (M+l).
!H NMR (400 MHz, DMSO-de): δ 12.82 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 3.0 Hz, 1H), 8.42 (d, J= 2.1 Hz, 1H), 7.95 (s, 1H), 7.67-7.58 (m, 2H), 7.51-7.46 (m, 2H).
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
[0237] The title compound was prepared according to the procedure as described in
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 Na2C03 (318 mg, 3.0 mmol) in water (2.5 mL) and Pd(PPh3)2Cl2 (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%).
MS (ESI, pos. ion) m/z: 529.0 (M+l);
lU NMR (400 MHz, DMSO- e): δ 12.58 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.67-7.60 (m, 2H), 7.51- 7.46 (m, 2H), 4.42-4.33 (m, 1H), 4.12-3.98 (m, 2H), 3.17-2.85 (br, 2H), 2.10-2.02 (m, 2H), 1.87- 1.72 (m, 2H), 1.42 (s, 9H).
Step 3) (Z)-2-(2-chlorophenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b1pyridin-3-yl)acrylonitrile
[0238] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 429.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 8.65 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.68-7.64 (m, 1H), 7.64-7.60 (m, 1H), 7.54-7.46 (m, 2H), 4.25-4.15 (m, 1H), 3.10-3.00 (m, 2H), 2.66-2.55 (m, 2H), 2.05-1.95 (m, 2H), 1.86-1.70 (m, 2H).
Example 15 (Z)-2-(2-chloro-6-fluorophenyl)-3-(5-(l -(piperidin-4-yl)- lH-pyrazol-4-yl)- 1H- rrolo[2,3-blpyridin-3-yl)acrylonitrile
Figure imgf000078_0001
Step 1) (z^-3-(5-bromo-lH-pwolor2J-b1pyridin-3-yl)-2-(2-chloro-6-fluorophenyl)acrylonitrile
[0239] The title compound was prepared according to the procedure as described in
Example 14 Step 1 by using 2-(2-chloro-6-fluorophenyl)acetonitrile (2.04 g, 12.0 mmol) and t- BuOK (1.35 g, 12.0 mmol), a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridine-3-carbaldehyde (3.65 g, 10.0 mmol) in DMF (80 mL), EtOH (60 mL) and NaOH aqueous solution (30 mL, 10%). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as a yellow solid (250 mg, 5%).
MS (ESI, pos. ion) m/z: 376.0 (M+l);
¾ NMR (400 MHz, DMSO- e): δ 12.90 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 8.42 (d, J= 2.2 Hz, 1H), 7.97 (s, 1H), 7.57-7.48 (m, 2H), 7.44-7.38 (m, 1H).
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
[0240] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2-chloro-6- fluorophenyl) acrylonitrile (234 mg, 0.62 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l -carboxylate (351 mg, 0.93 mmol), a solution of Na2C03 (197 mg, 1.86 mmol) in water (1.6 mL) and Pd(PPh3)2Cl2 (40 mg, 0.06 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 (125 mg, 37%).
MS (ESI, pos. ion) m/z: 547.0 (M+l);
lU NMR (400 MHz, DMSO-de): δ 12.69 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.60-7.51 (m, 2H), 7.49- 7.42 (m, 1H), 4.48-4.33 (m, 1H), 4.15-3.95 (m, 2H), 3.10-2.80 (br, 2H), 2.12-2.02 (m, 2H), 1.88- 1.73 (m, 2H), 1.42 (s, 9H).
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
[0241] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-(2-chloro-6-fluorophenyl)-2-cyanovinyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (100 mg, 0.18 mmol) and a solution of HCl in EtOAc (2 mL, 6 mmol, 3M). 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 (Z/E = 97%/3%, 65 mg, 81%).
MS (ESI, pos. ion) m/z: 447.0 (M+l); !H NMR (400 MHz, DMSO- e): δ 8.65 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.58-7.51 (m, 2H), 7.48-7.41 (m, 1H), 4.23-4.15 (m, 1H), 3.10-3.00 (m, 2H), 2.62-2.55 (m, 2H), 2.04-1.95 (m, 2H), 1.83-1.73 (m, 2H).
Example 16 ( ^-2-phenyl-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pwolor2J-b1pyridin-3- acrylonitrile
Step 1) (Z)-3-(5-bromo-lH-pyrrolo[2J-blpyridin-3-yl)-2-phenylacrylonitrile
[0242] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 324.0 (M +1);
!H NMR (400 MHz, DMSO-de): δ 12.75 (s, 1H), 8.88 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.55-7.46 (m, 2H), 7.43- 7.35 (m, 1H).
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
[0243] The title compound was prepared according to the procedure as described in
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 Na2C03 (350 mg, 3.3 mmol) in water (3 mL) and Pd(PPh3)2Cl2 (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%).
MS (ESI, pos. ion) m/z: 495.0 (M+l);
lU NMR (400 MHz, DMSO-de): δ 12.53 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.83-7.77 (m, 2H), 7.55-7.48 (m, 2H), 7.44-7.37 (m, 1H), 4.48-4.37 (m, 1H), 4.15-4.00 (m, 2H), 3.05-2.85 (br, 2H), 2.12-2.02 (m, 2H), 1.89-1.77 (m, 2H), 1.43 (s, 9H).
Step 3) (2r)-2-phenyl-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-lH-pyn-olor2,3-b1pyridin-3- yPacrylonitrile
[0244] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using (Z)-tert-butyl 4-(4-(3-(2-cyano-2-phenylvinyl)-lH-pyrrolo[2,3- b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (350 mg, 0.71 mmol) and a solution of HCl in EtOAc (3.5 mL, 14 mmol, 4 M). The crude product was washed with DCM/MeOH (10/1, 2 mL), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (Z/E = 99%/l%, 260 mg, 93%).
MS (ESI, pos. ion) m/z: 395.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 8.72 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.83-7.77 (m, 2H), 7.57-7.48 (m, 2H), 7.44-7.36 (m, 1H), 4.28-4.18 (m, 1H), 3.10-3.02 (m, 2H), 2.67-2.57 (m, 2H), 2.08-1.96 (m, 2H), 1.89-1.77 (m, 2H).
Example 17 (Z)-2-(5-chloro-2-(trifluoromethyl)phenyl)-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4- -lH-pyrrolo[2,3-blpyridin-3-yl)acrylonitrile
Figure imgf000081_0001
Step 1) 3-(5-bromo-lH-pyrrolo[2J-blpyridin-3-yl)-2-(5-chloro-2-(trifluoromethyl)phenyl) acrylonitrile
[0245] The title compound was prepared according to the procedure as described in
Example 14 Step 1 by using 2-(5-chloro-2-(trifluoromethyl)phenyl)acetonitrile (1.6 g, 7.2 mmol), t-BuOK (0.81 g, 7.2 mmol), a solution of 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3- b]pyridine-3-carbaldehyde (2.2 g, 6.0 mmol) in DMF (60 mL), EtOH (40 mL) and NaOH aqueous solution (20 mL, 10%). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (510 mg, 20%).
MS (ESI, pos. ion) m/z: 426.0 (M+l). Step 2) (Z)-tert-bvA.y\ 4-(4-(3-(2-(5-chloro-2-(trifluoromethyl)phenyl)-2-cyanovinyl)-lH- pwolor2J-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate
[0246] The title compound was prepared according to the procedure as described in
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 Na2C03 (382 mg, 3.6 mmol) in water (3.0 mL) and Pd(PPh3)2Cl2 (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%).
MS (ESI, pos. ion) m/z: 597.0 (M+l);
¾ NMR (400 MHz, CDC13): δ 11.79 (s, 1H), 8.65 (s, 1H), 8.63 (d, J= 1.8 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.73 (d, J= 8.5 Hz, 1H), 7.60-7.56 (m, 1H), 7.56-7.51 (m, 1H), 7.47 (s, 1H), 4.40-4.18 (m, 3H), 3.00-2.83 (m, 2H), 2.25-2.15 (m, 2H), 2.06-1.92 (m, 2H), 1.48 (s, 9H).
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
[0247] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 497.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 8.66 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.94-7.85 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H), 4.28-4.16 (m, 1H), 3.12-3.03 (m, 2H), 2.70- 2.57 (m, 2H), 2.08-1.95 (m, 2H), 1.90-1.76 (m, 2H).
Example 18 (Z)-2-(2,6-dichlorophenyl)-3-(5-(2-(piperazin-l-yl)pyridin-4-yl)-lH-pyrrolo[2,3-bl pyridin-3 -yDacrylonitrile
Figure imgf000082_0001
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%).
¾ NMR (400 MHz, DMSO- e): δ 12.92 (s, 1H), 8.71 (d, 1H), 8.51 (d, 1H), 8.44 (d, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.55-7.51 (m, 1H).
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
[0249] The title compound was prepared according to the procedure as described in
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). The crude product was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) = 10/1/0.05), followed by the recrystallization from EtOAc (5 mL) to give the title compound as a yellow solid (80 mg, 42%).
MS (ESI, pos. ion) m/z: 475.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 8.84 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.56-7.51 (m, 1H), 7.19 (s, 1H), 7.11 (d, J= 5.2 Hz, 1H), 3.63 (s, 2H), 2.95 (s, 2H).
Example 19 (Z)-3-(5-(6-aminopyridin-3-yl)-lH-pyrrolo[2J-b]pyridin-3-yl)-2-(2,6-dichloro- phenvDacrylonitrile
Figure imgf000083_0001
[0250] The title compound was prepared according to the procedure as described in
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). 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 (55 mg, 45%). MS (ESI, pos. ion) m/z: 406.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 12.68 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J= 2.3 Hz, 1H), 7.95 (s, 1H), 7.79 (dd, J= 2.5, 8.6 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.56-7.50 (m, 1H), 6.54 (d, J= 8.6 Hz, 1H), 6.06 (s, 2H).
Example 20 (Z)-2-(2,6-dichlorophenyl)-3-(5-(4-(3-hydroxypyrrolidine-l -carbonyl)phenyl)-lH- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile
Figure imgf000084_0001
Step 1) (4-bromophenyl)(3-hvdroxypyrrolidin-l-yl)methanone
[0251] A suspension of 4-bromobenzoic acid (5.0 g, 25 mmol) in SOCb (20 mL) was stirred at 90 °C for 2 hours, then cooled to rt, and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and was added dropwise to the solution of pyrrolidin-3-ol hydrochloride (3.1 g, 25 mmol) and Et3N (10.5 mmol) in DCM (90 mL). The mixture was stirred at rt for 30 hours, then washed with water (50 mL x 2), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) =40/1) to give the title compound as a white solid (3.5 g, 52%).
MS (ESI, pos. ion) m/z: 270.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 7.67-7.61(m, 2H), 7.50-7.44 (m, 2H), 5.05-4.95 (m, 1H), 4.38-4.20 (m, 1H), 3.62-3.30 (m, 4H), 2.00-1.73 (m, 2H).
Step 2) (3-hydroxypyrrolidin-l-yl)(4-(4^,5,5-tetramethyl-13,2-dioxaborolan-2-yl)phenyl) methanone
[0252] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by using (4-bromophenyl)(3-hydroxypyrrolidin-l-yl)methanone (1.35 g, 5.0 mmol), 4,4,4*,4*,5,5,5*,5*-octamethyl-2,2,-bi(l,3,2-dioxaborolane) (1.78 g, 7.0 mmol), CH3COOK (1.47 g, 15.0 mmol), and Pd(dppf)Cl2-CH2Cl2 (0.20 g, 0.25 mmol). The crude product was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 3/1) to give the title compound as brown oil (1.59 g, 100 %).
MS (ESI, pos. ion) m/z: 318.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 7.74-7.70 (m, 2H), 7.53-7.47 (m, 2H), 5.05-4.93 (m, 1H), 4.38-4.20 (m, 1H), 3.62-3.30 (m, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 1.30 (s, 12H). Step 3) (Z)-2-(2,6-dichlorophenyl)-3-(5-(4-(3-hydroxypyrrolidine-l -carbonyl)phenyl)-lH- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile
[0253] The title compound was prepared according to the procedure as described in
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 Cs2C03 (391 mg, 1.2 mmol) in water (2 mL), and Pd(dppf)Cl2-CH2Cl2 (33 mg, 0.04 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) =20/1), followed by recrystallization from EtOAc (10 mL) to give the title compound as a light yellow solid (80 mg, 40%).
MS (ESI, pos. ion) m/z: 503.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 12.80 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.50 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.65-7.59 (m, 2H), 7.56-7.50 (m, 2H), 5.17-4.90 (m, 1H), 4.29 (d, J = 38.4 Hz, 1H), 3.70-3.58 (m, 2H), 3.58- 3.40 (m, 2H), 2.02-1.75 (m, 2H).
Example 21 (z^-2-(2,6-dichlorophenyl)-3-(5-(6-methoxypyridin-3-yl)-lH-pwolor2J-b1pyridin- 3 -yDacrylonitrile
Figure imgf000085_0001
[0254] The title compound was prepared according to the procedure as described in
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 Cs2CC"3 (782 mg, 2.4 mmol) in water (4.0 mL), and Pd(dppf)Cl2-CH2Cl2 (65 mg, 0.08 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1), followed by recrystallization from PE/EtOAc (8/1, 5 mL) to give the title compound as a white solid (120 mg, 36%).
MS (ESI, pos. ion) m/z: 421.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 12.77 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.57 (d, J= 2.4 Hz, 1H), 8.49 (s, 1H), 8.10 (dd, J= 2.6, 8.6 Hz, 1H), 7.94 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.56-7.50 (m, 1H), 6.94 (d, J= 8.7 Hz, 1H), 3.90 (s, 3H).
Example 22 (Z)-2-(2,6-dichlorophenyl)-3-(5-(6-(piperazin-l-yl)pyridin-3-yl)-lH-pyrrolo[2,3-b] p yridin-3 -yDacrylonitrile
Figure imgf000086_0001
[0255] The title compound was prepared according to the procedure as described in
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). The crude product was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) = 100/8/1), followed by a preparative HPLC (DCM/MeOH/Et3N (v/v/v) = 100/10/1), then washed with EtOAc (10 mL), and filtered to give the title compound as a light yellowish solid (70 mg, 38%).
HPLC: 97%;
MS (ESI, pos. ion) m/z: 475.0 (M+l);
1HNMR (400 MHz, DMSO-Λ): δ 8.68 (d, J = 1.6 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J= 1.9 Hz, 1H), 8.46 (s, 1H), 8.47 (s, 1H), 7.94-7.92 (m, 2H), 7.93 (s, 1H), 7.69-7.67 (d, J = 8.1 Hz, 2H), 7.55- 7.51 (t, J= 7.9 Hz, 1H), 6.92-6.90 (d, J= 8.8 Hz, 1H), 3.47 (s, 4H), 2.81 (s, 4H).
Example 23 (Z)-2-(2,6-dichlorophenyl)-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)- -pyrrolo[2,3-blpyridin-3-yl)acrylonitrile
Figure imgf000086_0002
Step 1) 4-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole
[0256] To a stirred solution of tetrahydro-2H-pyran-4-ol (1.0 g, 10.0 mmol) in DCM (25 mL) was added Et3N (1.5 mL, 11.0 mmol) slowly at 0 °C, followed by the addition of MsCl (0.9 mL, 11.0 mmol) and DMAP (60 mg, 0.5 mmol). The mixture was stirred at rt overnight, then diluted with DCM (25 mL), and washed with water (30 mL x 2). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the crude product as light yellow oil (1.6 g, 88%>). The crude product was used in the next step without further purification.
[0257] To a solution of 4-iodo-lH-pyrazole (388 mg, 2.0 mmol) in dry DMF (20 mL) was added NaH (90 mg, 3.0 mmol, 80% NaH/mineral oil) slowly at 0 °C. The mixture was stirred at 0 °C for 1 hour, then a solution of the crude product above (396 mg, 2.2 mmol) in DMF (5 mL) was added dropwise at 0 °C. The mixture was heated to 100 °C and stirred further for 24 hours, then cooled to rt, quenched with water (0.5 mL), and concentrated in vacuo. The residue was suspended in DCM (100 mL) and washed with water (50 mL). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as a white solid (410 mg, 74%).
MS (ESI, pos. ion) m/z: 279.0 (M +1);
¾ NMR (400 MHz, CDC ): δ 7.52 (s, 1H), 7.48 (s, 1H), 4.42-4.30 (m, 1H), 4.15-4.05 (m, 2H), 3.58-3.47 (m, 2H), 2.12-1.98 (m, 4H).
Step 2) 1 -(tetrahydro-2H-pyran-4-yl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1H- pyrazole
[0258] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by 4-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole (278 mg, 1.0 mmol), Bis(pinacolato)diboron (355 mg, 1.4 mmol), CH3COOK (392 mg, 4.0 mmol), and Pd(dppf)Cl2-CH2Ci2 (82 mg, 0.1 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a brown solid (225 mg, 81%).
MS (ESI, pos. ion) m/z: 279.0 (M+l);
¾ NMR (400 MHz, CDCb): δ 7.81 (s, 1H), 7.76 (s, 1H), 4.43-4.32 (m, 1H), 4.13-4.07 (m, 2H), 3.58-3.48 (m, 2H), 2.17-1.98 (m, 4H), 1.32 (s, 12H).
Step 3) (Z)-2-(2,6-dichlorophenvn-3-(5-(l-(tetrahvdro-2H-pyran-4-vn-lH-pyrazol-4-vn-lH- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile
[0259] The title compound was prepared according to the procedure as described in
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-CH2Ci2 (41 mg, 0.05 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 30/1), followed by recrystallization from EtOAc (5 mL) to give the title compound as a white solid (Z/E = 98%/2%, 35 mg, 15%).
MS (ESI, pos. ion) m/z: 464.0 (M+l); ¾ NMR (400 MHz, CDCb): δ 11.35 (s, 1H), 8.70 (s, 1H), 8.62 (d, J= 1.8 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.49-7.42 (m, 3H), 7.34-7.28 (m, 1H), 4.48-4.38 (m, 1H), 4.20- 4.10 (m, 2H), 3.62-3.53 (m, 2H), 2.25-2.08 (m, 4H).
Example 24 (z^-2-(2,6-dichlorophenyl)-3-(5-(l-(tetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-blpyridin-3-yl)acrylonitrile
Figure imgf000088_0001
Step 1) 4-iodo-l-(tetrahvdrofuran-3-yl)-lH-pyrazole
[0260] To a stirred solution of tetrahydrofuran-3-ol (1.8 g, 20.0 mmol) in DCM (50 mL) was added Et3N (3.0 mL, 22.0 mmol) slowly at 0 °C, followed by the addition of MsCl (1.7 mL, 22.0 mmol) and DMAP (catalytic ammount). The mixture was stirred at rt overnight, then diluted with DCM (50 mL) and washed with water (30 mL x 2). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the crude product as light yellow oil (3.0 g, 90%).
[0261] NaH (240 mg, 8.0 mmol, 80% NaH/mineral oil) was added slowly to the solution of 4-iodo-lH-pyrazole (776 mg, 4.0 mmol) in dry DMF (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then a solution of the crude product above (731 mg, 4.4 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was heated to 100 °C and stirred further for 24 hours, then cooled to rt, quenched with water (0.5 mL), and concentrated in vacuo. The residue was suspended in DCM (50 mL) and washed with water (30 mL). The separated organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the title product as a white solid (1.0 g, 90%>).
MS (ESI, pos. ion) m/z: 265.0 (M+l).
Step 2) l-(tetrahvdrofuran-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
[0262] The title compound was prepared according to the procedure as described in
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-CH2Cl2 (164 mg, 0.2 mmol). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a brown solid (500 mg, 95%). MS (ESI, pos. ion) m/z: 265.0 (M+l);
¾ NMR (400 MHz, CDC ): δ 7.79 (s, 2H), 5.05-4.95 (m, 1H), 4.20-4.00 (m, 3H), 3.98-3.89 (m, 1H), 2.52-2.40 (m, 1H), 2.38-2.28 (m, 1H), 1.32 (s, 12H).
Step 3) (z^-2-(2,6-dichlorophenyl)-3-(5-(l-(tetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)-lH- pyrrolo[2,3-blpyridin-3-yl)acrylonitrile
[0263] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (275 mg, 0.70 mmol), l-(tetrahydrofuran-3-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (240 mg, 0.91 mmol), a solution of CS2CO3 (685 mg, 2.1 mmol) in water (7 mL), and Pd^ppfjCk'CE Ck (57 mg, 0.07 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1), followed by washing with EtOAc (5 mL) to give the title compound as a yellow solid (125 mg, 40%).
MS (ESI, pos. ion) m/z: 450.0 (M+l);
'H NMR (400 MHz, CDCI3+CD3OD): δ 8.57 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.88-7.80 (m, 2H), 7.52-7.41 (m, 3H), 7.34-7.29 (m, 1H), 5.10-5.00 (m, 1H), 4.23-4.12 (m, 2H), 4.12-4.03 (m, 1H), 4.02-3.93 (m, 1H), 2.60-2.48 (m, 1H), 2.42-2.33 (m, 1H).
Example 25 ( )-2-(2,6-dichlorophenyl)-3-(5-(7-methoxyquinolin-3-yl)-lH-pyrrolor2,3-b1 pyridin-3 -yPacrylonitrile
Figure imgf000089_0001
Step 1 ) 7-methoxy-3 -(4,4 ,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)quinoline
[0264] To a mixture of 3-bromo-7-methoxyquinoline (1.00 g, 4.2 mmol), CH3COOK
(1.24 g, 12.60 mmol)) and Bis(pinacolato)diboron (1.28 g, 5.04 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl2-CH2Cb (342 mg, 0.42 mmol) under N2 atmosphere, the mixture was heated to reflux and stirred further for 14 hours, then cooled to rt, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a brown solid (740 mg, 61%).
!H NMR (400 MHz, DMSO-Λ): δ 8.93 (d, J = 1.6 Hz, 1H), 8.58 (s, 1H), 7.98-7.96 (d, J = 9.0 Hz, 1H), 7.39-7.38 (d, J = 2.2 Hz, 1H), 7.27-7.25 (dd, J = 2.4, 8.9 Hz, 1H), 3.92 (s, 3H), 1.33 (s, 12H). Step 2) (Z)-2-(2,6-dichlorophenyl)-3-(5-(7-m
vDacrylonitrile
[0265] The title compound was prepared according to the procedure as described in
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 Η2Ο (0.5 mL), and Pd(dppf)Cl2-CH2Cb (41.4 mg, 0.05 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 20/1), followed by washing with MeOH (2 mL) to afford the title compound as a light yellowish solid (68 mg, 28%).
HPLC: 98%;
MS (ESI, pos. ion) m/z: 471.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 9.26 (s, 1H), 8.93 (s, 1H), 8.86 (s, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.00 (s, 1H), 7.94-7.92 (d, J = 9.2 Hz, 1H), 7.68-7.66 (d, J = 8.4 Hz, 2H), 7.55-7.51 (t, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.31-7.29 (d, J= 8.8 Hz, 1H), 3.93 (s, 3H).
Example 26 ( ^-3-(5-(4-(3-aminopwolidine-l-carbonyl)phenyl)-lH-pyrrolor2,3-b1pyridin-3- -2-(2,6-dichlorophenyl)acrylonitrile
Figure imgf000090_0001
Step 1) tert-butyl (l-(4-bromobenzoyl)pyrrolidin-3-yl)carbamate
[0266] To a suspension of 4-bromobenzoic acid (1.13 g, 5.64 mmol) in DCM (150 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (1.00 g, 5.37 mmol), followed by the addition of ΗΟΑΤ (0.49 g, 0.56 mmol) and EDCI (0.32 g,1.68 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 minutes, then warm to rt and stirred overnight. The mixture was washed with brine (200 mL), and the separated organic phase was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white needle solid (1.63 g, 82%>). lU NMR (400 MHz, CDCI3): δ 7.55-7.53 (m, 2H), 7.41-7.38 (m, 2H), 4.71-4.64 (m, 1H), 4.30- 4.11 (m, 1H), 3.90-3.70 (m, 2H), 3.54-3.27 (m, 2H), 2.31-2.14 (m, 1H), 1.90-1.85 (m, 1H), 1.40 (s, 9H).
Step 2) tert-butyl (l-(4-(4^,5,5-tetramethyl-13,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3- vDcarbamate [0267] To a suspension of tert-butyl (l-(4-bromobenzoyl)pyrrolidin-3-yl)carbamate (1.50 g, 4.06 mmol), Bis(pinacolato)diboron (1.24 g, 4.87 mmol) and CH3COOK (1.20 g, 12.19 mmol) in 1,4-dioxane (30 mL) was added Pd(dppf)Ci2-CH2Ci2 (0.662 g (0.812 mmol) under N2 atmosphere. The mixture was heated to reflux and stirred further overnight, then cooled to rt, and fitered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to afford the title compound as a pink solid (1.32 g, 78%).
!H NMR (400 MHz, CDCI3): δ 7.84-7.82 (m, 2H), 7.50-7.45 (m, 2H), 4.71-4.61 (m, 1H), 4.30- 4.11 (m, 1H), 3.91-3.86 (m, 1H), 3.78-3.65 (m, 1H), 3.52-3.45 (m, 1H), 3.28-3.24 (m, 1H), 2.23- 2.14 (m, 1H), 1.87-1.86 (m, 1H), 1.40 (s, 9H), 1.35 (s, 12H).
Step 3) (Z)-tert- vXy\ (l-(4-(3-(2-cvano-2-(2,6-dichlorophenyl)vinyl)-lH-pyrrolor2,3-b1pyridin- 5-yl)benzoyl)pyrrolidin-3-yl)carbamate
[0268] The title compound was prepared according to the procedure as described in
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 H20 (0.5 mL) and Pd(PPh3)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%).
!H NMR (400 MHz, CDCI3): δ 10.93 (s, 1H), 8.68 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 7.66-7.62 (m, 1H), 7.46-7.43 (m, 5H), 7.32-7.29 (m, 2H), 4.67 (m, 1H), 4.32-4.20 (m, 1H), 3.94-3.92 (m, 1H), 3.79-3.75 (m, 1H), 3.63-3.56 (m, 1H), 3.39-3.36 (m, 1H), 2.27-2.20 (m, 1H), 1.93-1.89 (m, 1H), 1.47-1.40 (d, 9H).
Step 4) (Z)-3-(5-(4-(3-aminopwolidine-l-carbony
(2,6-dichlorophenyl)acrylonitrile
[0269] The title compound was prepared according to the procedure as described in
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%).
HPLC: 97%; MS (ESI, pos. ion) m/z: 502.0 (M+l);
HNMR (400 MHz, DMSO-t ί): δ 8.80 (s, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.84-7.82 (d, J= 7.2 Hz, 2H), 7.67-7.61 (m, 4H), 7.54-7.52 (m, 1H), 3,86-3,28 (m, 5H), 2.21-2.19 (m, 1H), 1.97-1.95 (m, 1H).
Example 27 (Z)-2-(2,6-dichlorophenyl)-3-(5-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)-lH- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile
Figure imgf000092_0001
Step 1) fert-butyl 3-hvdroxypyrrolidine-l-carboxylate
[0270] To a solution of pyrrolidin-3-ol hydrochloride (5.00 g, 40.46 mmol) and DMAP
(0.50 g, 4.046 mmol) in MeOH (300 mL) was added Et3N (17 mL, 121.4 mmol), followed by adding (Boc)20 (10.4 mL, 48.55 mol) dropwise at 0 °C. The mixture was stirred at rt overnight, and concentrated in vacuo. The residue was diluted with EtOAc (200 mL), and the resulted mixture was washed with water (100 mL), NaHC03 aqueous solution (100 mL) and brine (100 mL). The separated organic layer was dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (6.75 g, 89.1%).
MS (ESI, pos. ion) m/z: 132.0 (M-56+1);
¾ NMR (400 MHz, CDC13): δ 4.41 (s, 1H), 3.88 (br, 1H), 3.47-3.30 (m, 4H), 1.94-1.93 (m, 2H), 1.45 (s, 9H).
Step 2) tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate
[0271] To a solution of tert- vXy\ 3-hydroxypyrrolidine-l-carboxylate (4.00 g, 21.36 mmol) in DCM (50 mL) was added Et3N (4.7 mL, 32.04 mmol) slowly at 0 °C, followed by the addition of MsCl (2.0 mL, 25.64 mmol) and a solution of DMAP (26.1 mg, 0.214 mmol) in DCM (4 mL). The mixture was stirred at rt for 4 hours, then quenched with water (50 mL), and extracted with DCM (50 mL x 3). The combined organic layers was dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as yellow oil (6.63 g, 117.0%).
MS (ESI, pos. ion) m/z: 210.0 (M-56+1);
'H NMR (400 MHz, CDC13): δ 5.10 (s, 1H), 3.55-3.29 (m, 4H), 2.92 (s, 3H), 2.11-2.01 (m, 2H), 1.32 (s, 9H).
Step 3) fert-butyl 3-(4-iodo-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate [0272] To a stirred solution of 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. The mixture was heated to 100 °C and stirred further for 17 hours, then cooled to rt, quenched with H20 (5 mL), and concentrated in vacuo. The residue was washed with H20 (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers was dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (6.28 g, 98.7%).
MS (ESI, pos. ion) m/z: 308.0 (M-56+1);
¾ NMR (400 MHz, CDCb): δ 7.53 (s, 1H), 7.46 (s, 1H), 4.89-4.86 (m, 1H), 3.85-3.52 (m, 4H),
2.38- 2.33 (m, 2H), 1.47 (s, 9H).
Step 4) tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl) pyrrolidine- 1 -carboxylate
[0273] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by using tert-butyl 3-(4-iodo-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate (5.00 g, 13.77 mmol), Bis(pinacolato)diboron (5.25 g, 20.65 mmol), CH3COOK (5.41 g, 55.07 mmol), and Pd(PPh3)2Cl2 (483.2 mg, 0.688 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 (4.00 g, 80.8%).
MS (ESI, pos. ion) m/z: 308.0 (M-56+1);
¾ NMR (400 MHz, CDCb): δ 7.80 (s, 1H), 7.73 (s, 1H), 4.93-4.87 (m, 1H), 3.87-3.53 (m, 4H),
2.39- 2.34 (m, 2H), 1.47 (s, 9H), 1.32 (s, 12H).
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
[0274] A mixture of (Z)-3-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl)acrylonitrile (623.3 mg, 1.586 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate (480.0 mg, 1.321 mmol),
Pd(PPh3)4 (106.9 mg, 0.092 mmol) and K2C03 (547.8 mg, 3.964 mmol) in previously degassed
DME/H20 (4/1,15 mL) was placed in a microwave vial, degassed and charged with N2 for 3 times. The mixture was microwaved and stirred at 100 °C for 90 minutes, then cooled to rt, filtered through a pad of CELITE®, and the filter cake was washed with EtOAc (50 mL). The filtrate was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (pure PE) to give the title compound as a yellow solid (275.0 mg, 37.9%).
MS (ESI, pos. ion) m/z: 549.0 (M+l);
¾ NMR (400 MHz, DMSO-t ί): δ 12.67 (s, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.63 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 8.4 Hz, 1H), 4.98-4.96 (m, 1H), 3.75-3.41 (m, 4H), 2.45-2.20 (m, 2H), 1.39 (s, 9H).
Step 6) ( ^-2-(2,6-dichlorophenyl)-3-(5-(l-(pwolidin-3-yl)-lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1 pyridin-3 -yDacrylonitrile
[0275] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using {Z)-tert- vXy\ 3-(4-(3-(2-cyano-2-(2,6-dichlorophenyl)vinyl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate (275.0 mg, 0.501 mmol) and a solution of HCl in EtOAc (2.5 mL, 10.00 mmol, 4M). The crude product was washed with EtOAc (10 mL) several times, then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (223.3 mg, 99.2%).
MS (ESI, pos. ion) m/z: 449.0 (M+l);
!H NMR (400 MHz, DMSO-t ί): δ 8.66 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.53 (t, 1H), 4.84-4.78 (m, 1H), 3.18-2.83 (m, 4H), 2.24-2.01 (m, 2H).
Example 28 (z)-2-(5-chloro-2-(trifluoromethyl)phenyl)-3-(5-(l -methyl- lH-pyrazol-4-yl)-lH- pyrrolo[2,3-blpyridin-3-yl)acrylonitrile (3a)
(E)-2-(5 -chloro-2-(trifluoromethyl)phenyl)-3 -(5 -( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile (3b)
Figure imgf000094_0001
Step 1) 4-iodo-l -methyl- lH-pyrazole
[0276] To a suspension of NaH (0.463 g, 15.47 mmol, 80% NaH/mineral oil) in DMF
(100 mL) was added 4-iodo-pyrazole (1.0 g, 5.16 mmol) at 0 °C under N2 atmosphere, the mixture was stirred at 0 °C for 30 minutes, then iodomethane (0.64 mL, 10.31 mmol, d = 2.28) was added. The resulted mixture was warmed to rt and stirred overnight, then quenched with brine (100 mL), and concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and washed with water (100 mL). The separated organic phase was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a light yellowish solid (490 mg, 45%).
¾ NMR (400 MHz, CDCb): δ 7.48 (s, 1H), 7.40 (s, 1H), 3.91 (s, 3H).
Step 2) l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
[0277] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by using 4-iodo-l -methyl- lH-pyrazole (1.0 g, 4.81 mmol), Bis(pinacolato)diboron (1.83 g, 7.21 mmol), CH3COOK (1.42 g, 14.42 mmol), and Pd(dppf)Cl2-CH2Cb (392 mg, 0.481 mmol, 10 mmol%). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as brown oil (720 mg, 72%).
¾ NMR (400 MHz, CDCb): δ 7.75 (s, 1H), 7.46 (s, 1H), 3.89 (s, 3H), 1.30 (s, 12H).
Step 3) (Z)-2-(5 -chloro-2-(trifluoromethyl)phenyl)-3 -(5 -( 1 -methyl- lH-pyrazol-4-yl)- 1 H- pyrrolor2,3-b1pyridin-3-yl)acrylonitrile (3a)
(E)-2-(5 -chloro-2-(trifluoromethyl)phenyl)-3 -(5 -( 1 -methyl- 1 H-p yrazol-4-yl)- 1 H- pyrrolo[2,3-blpyridin-3-yl)acrylonitrile (3b)
Figure imgf000095_0001
3a 3b
[0278] The title compound was prepared according to the procedure as described in
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 Η2Ο (4 mL), and Pd(dppf)Cb'CH2Cb (57 mg, 10 mmol%>). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1), followed by a preparative HPLC (DCM/MeOH (v/v) = 25/1) to give the title compound (3a) (Z)-2-(5-chloro-2- (trifluoromethyl)phenyl)-3-(5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl) acrylonitrile as a yellowish solid (87 mg, 28.7%>) and (3b) (E)-2-(5-chloro-2- (trifluoromethyl)phenyl)-3-(5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl) acrylonitrile as a white solid (28 mg, 9.3%>). The title compound (3a) (2)-2-(5-chloro-2-(trifluoromethyl)phenyl)-3 -(5 -(1 -methyl- lH-pyrazol-
4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)acrylonitrile:
HPLC: 95%;
MS (ESI, pos. ion) m/z: 428.0 (M+l);
¾ NMR (400 MHz, CDC ): δ 12.63 (s, 1H), 8.62-8.61 (d, J = 1.9 Hz, 1H), 8.58 (d, J= 1.9 Hz, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 7.93-7.91 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.80-7.78 (d, J= 8.4 Hz, 1H).
The title compound (3b) (E)-2-(5-chloro-2-(trifluoromethyl)phenyl)-3- (5 -(1 -methyl- lH-pyrazol-
4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl)acrylonitrile:
HPLC: 98%;
MS (ESI, pos. ion) m/z: 428.0 (M+l);
!H NMR (400 MHz, CDCb): δ 12.25 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.27-8.26 (d, J= 1.8 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 8.07-8.05 (d, J= 8.5 Hz, 1H), 7.91-7.89 (d, J= 8.6 Hz, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 6.43 (s, 1H).
Example 29 ( )-3-(5-(lH-pyrazol-4-yl)-lH-pyrrolor2,3-b1pyridin-3-yl)-2-(5-chloro-2-
(trifluoromethyl)phenyl)acrylonitrile (2a)
(E)-3-(5-(lH-pyrazol-4-yl)-lH-pyrrolo[2J-blpyridin-3-yl)-2-(5-chloro-2- (trifluoromethyl)phenyl)acrylonitrile (2b)
Figure imgf000096_0001
2a 2b
Step 1 ) 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole
[0279] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by using 4-iodo-lH-pyrazole (1.0 g, 5.16 mmol), Bis(pinacolato)diboron (1.96 g, 7.73 mmol), CH3COOK (1.52 g, 15.47 mmol), and Pd(dppf)Cl2-CH2Cl2 (421 mg, 0.516 mmol, 10 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 (550 mg, 55%>).
¾ NMR (400 MHz, CDCb): δ 7.90 (s, 2H), 1.33 (s, 12H).
Step 2) (Z)-3-(5-(lH-pyrazol-4-vn-lH-pyrrolor2,3-blpyridin-3-vn-2-(5-chloro-2-
(trifluoromethyl)phenyl)acrylonitrile (2a) (E -3-(5-(lH-pyrazol-4-yl)-lH-pyrrolo[2J-blpyridin-3-yl)-2-(5-chloro-2-
(trifluoromethyl)phenyl)acrylonitrile (2b)
Figure imgf000097_0001
2a 2b
[0280] The title compound was prepared according to the procedure as described in
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 Η2Ο (2 mL), and Pd(dppf)Ci2-CH2Ci2 (1 14 mg, 20 mmol%). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 40/1), followed by washing with (DCM/PE (v/v) = 1/1) to give the title compound (a mixture of 2a and 2b) as a yellowish solid (Z/E = 35%/65%, 44 mg, 15%).
HPLC: 98%;
MS (ESI, pos. ion) m/z: 414.0 (M+l).
Example 30 (E)-5-(3 -(5 -chloro-2-(trifluoromethyl)styryl)- 1 H-pyrrolo[2,3 -blpyridin-5 -yl) pyridin-2-amine
Figure imgf000097_0002
[0281] The title compound was prepared according to the procedure as described in
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). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 20/1), followed by recrystallization from EtOAc (5 mL) to give the title compound as a light brown solid (62 mg, 38%).
MS (ESI, pos. ion) m/z: 415.0 (M+l);
¾ NMR (400 MHz, DMSO- e): δ 12.09 (s, 1H), 8.55-8.47 (m, 1H), 8.40-8.35 (m, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.1 1 (s, 1H), 7.90 (s, 1H), 7.82-7.68 (m, 3H), 7.46 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 16.4 Hz, 1H), 6.59 (d, J= 8.6 Hz, 1H), 6.07 (s, 2H).
Figure imgf000098_0001
Step 1) (E)-tert-butyl 6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pytTolor2,3-b1pyridin-5-yl)- 3,4-dihydroisoquinoline-2(lH)-carboxylate
[0282] The title compound was prepared according to the procedure as described in
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%).
MS (ESI, pos. ion) m/z: 554.0 (M+l);
'H NMR (400 MHz, CDCb): δ 9.69 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 7.83-7.79 (m, 1H), 7.63-7.56 (m, 2H), 7.54-7.44 (m, 4H), 7.34-7.26 (m, 3H), 4.66 (s, 2H), 3.80-
3.67 (m, 2H), 3.00-2.90 (m, 2H), 1.52 (s, 9H).
Step 2) (E)-6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolor2,3-b1pyridin-5-yl)-l, 2,3,4- tetrahvdroisoquinoline
[0283] The title compound was prepared according to the procedure as described in
Example 1 Step 8 by using {E)-tert-bvXy\ 6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH- pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (160 mg, 0.29 mmol) and a solution of HCl in EtOAc (10 mL, 3M). The crude product was washed with EtOAc (5 mL) to give the title compound as a grey solid (70 mg, 52%).
MS (ESI, pos. ion) m/z: 454.0 (M+l).
!H NMR (400 MHz, DMSO-de): δ 8.57 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.82-
7.68 (m, 2H), 7.53-7.37 (m, 3H), 7.31-7.23 (m, 1H), 7.15 (d, J = 7.7 Hz, 1H), 3.88 (s, 2H), 3.02- 2.91 (m, 2H), 2.84-2.74 (m, 2H).
Example 32 (E)-6-(3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2,3-b1pyridin-5-yl)- 1 ,2,3 ,4-tetrahydro- 1 ,8-naphthyridine
Figure imgf000099_0001
Step 1) (2-aminopyridin-3-yl)methanol
[0284] To a suspension of 2-aminonicotinic acid (25.0 g, 0.18 mol) in THF (500 mL) was added L1AIH4 (13.7 g, 0.36 mol) portion-wise at 0 °C. The mixture was heated to reflux and stirred further for 18 hours, then cooled to rt, and quenched by the sequential drop wise addition of water (16 mL), NaOH aqueous solution (16 mL, 15%), and water (50 mL). The resulted mixture was stirred at rt for 20 minutes, then filtered through a CELITE®. The filter cake was washed thoroughly with THF (100 mL) and MeOH/CHCb (1/20 (v/v), 200 mL). The combined filtrates were concentrated in vacuo to give the title compound as yellow oil (21.6 g, 96%).
MS (ESI, pos. ion) m/z: 125.0 (M +1).
!H NMR (400 MHz, CDCb): δ 3.93 (s, 2H), 4.54 (s, 2H), 5.15 (s, 1H), 6.55-6.70 (s, 1H), 7.30- 7.40 (m, 1H), 7.83-7.90 (m, 1H).
Step 2) (2-amino-5-bromopyridin-3-yl)methanol hydrobromide
[0285] To a stirred solution of (2-aminopyridin-3-yl)methanol (22.1 g, 178 mmol) in
AcOH (350 mL) was added bromine (9.0 mL, 178 mol) drop wise at rt over 1 hour. The reaction mixture was stirred at rt overnight, then filtered. The filter cake was washed with MTBE (50 mL) and dried in vacuo at 60 °C for 2 hours to give the title compound as a yellow solid (37.9 g, 75%).
MS (ESI, pos. ion) m/z: 203.0 (M-80 +1).
Step 3) 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide
[0286] A suspension of (2-amino-5-bromopyridin-3-yl)methanol hydrobromide (28.9 g,
1.02 mol) in aqueous HBr (2.9 L, 40%>) was stirred at 140 °C for 15 hours, then cooled to rt. Filtered, and the filter cake was washed with ethyl acetate (50 mL) and acetone (20 mL), then dried in vauo to give the title compound as a yellow solid (13.1 g, 47%). The crude product was used directly in the next step without further purification.
Step 4) methyl 6-bromo-2-oxo-l,2,3,4-tetrahydro-l,8-naphthyridine-3-carboxylate
[0287] To a solution of dimethyl malonate (11.3 mL, 98.4 mmol) in DMF (100 mL) and
THF (100 mL) was added NaH (2.95 g, 98.4 mmol, 80% NaH/mineral oil) portion-wise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 15 minutes, then 5-bromo-3- (bromomethyl)pyridin-2-amine hydrobromide (11.36 g, 32.8 mmol) was added portion-wise over 15 minutes. The resulted mixture was warmed to rt and stirred overnight, then heated to 80 °C and stirred for 2 hours. After cooling to rt, filtered, and the filter cake was washed with ethyl acetate (15 mL) and stirred vigorously with water (150 mL) for 15 minutes. Filtered, and the filter cake was washed with MeOH (10 mL) to give the title compound as a yellow solid (5.90 g, 63%).
MS (ESI, pos. ion) m/z: 285.0 (M+l).
!H NMR (400 MHz, DMSO- e): δ 3.16 (d, J = 7.8 Hz , 2H), 3.65 (s, 3H), 3.77 (t, J = 8.0 Hz, 1H), 7.85-7.92 (m, 1H), 8.18-8.27 (m, 1H), 11.00 (s, 1H).
Step 5) 6-bromo-3,4-dihydro-l,8-naphthyridin-2(lH)-one
[0288] To a solution of methyl 6-bromo-2-oxo-l,2,3,4-tetrahydro-l,8-naphthyridine-3- carboxylate (6.8 g, 23.9 mmol) in MeOH (250 mL) was added NaOH aqueous solution (105 mL, 1 M). The reaction was heated to reflux and stirred further for 4 hours, then cooled to rt, and neutralized with HCl aqueous solution (100 mL, 1 M). The resulted mixture was re fluxed overnight, and concentrated in vacuo. The residue was suspended in CHCI3/CH3OH (95/5, 25 mL), then filtered, and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (2.5 g, 46%).
MS (ESI, pos. ion) m/z: 227.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 2.46-2.55 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 7.85 (d, J = 1.5 Hz, 1H), 8.20 (d, J= 2.3 Hz, 1H), 10.62 (s, 1H).
Step 6) 6-bromo-l,2,3,4-tetrahydro-l,8-naphthyridine
[0289] To a mixture of NaBH4 (950 mg, 25.0 mmol) and a solution of 6-bromo-3,4- dihydro-l,8-naphthyridin-2(lH)-one (1.135 g, 5.0 mmol) in anhydrous THF (100 mL) was added a solution of BF3-Et20 (9.5 mL, 35.0 mmol, 47%) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at rt for 2 hours, quenched with saturated NH4C1 aqueous solution (25 mL), and the resulted mixture was extracted with DCM/MeOH (10/1, 50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as a white solid (2.8 g. >100%). The crude product was used directly in the next step without further purification.
MS (ESI, pos. ion) m/z: 213.0 (M+l);
!H NMR (400 MHz, DMSO-de): δ 1.70-1.87 (m, 2H), 2.76 (t, J = 6.1 Hz , 2H), 3.38 (t, J = 5.6 Hz, 2H), 7.84 (d, J= 0.9 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 8.18 (br, 1H). Step 7) (5,6J,8-tetrahydro-l ,8-naphthyridin-3-yl)boronic acid
[0290] The title compound was prepared according to the procedure as described in
Example 1 Step 3 by using 6-bromo-l ,2,3,4-tetrahydro-l ,8-naphthyridine (1.1 g, 5.0 mmol), Bis(pinacolato)diboron (1.9 g, 7.5 mmol), CH3COOK (1.5 g, 15.0 mmol), and Pd(PPh3)2Cl2 (0.35 g, 0.5 mmol). The crude product was purified by a silica gel column chromatography (MeOH/AcOH (v/v) = 10/1) to give the title compound as a white solid (2.3 g, Y>100%, mixed with silica gel).
MS (ESI, pos. ion) m/z: 179.0 (M+l).
Step 8) (iT)-6-(3-(5-chloro-2-(trifluorometh^
tetrahydro-1 ,8-naphthyridine
[0291] The title compound was prepared according to the procedure as described in
Example 1 Step 7 by using (5,6,7,8-tetrahydro-l ,8-naphthyridin-3-yl)boronic acid (134 mg, 0.75 mmol), 5-bromo-3-(5-chloro-2-(trifluoromethyl)styryl)-lH-pyrrolo[2,3-b]pyridine (201 mg, 0.5 mmol), a solution of Cs2C03 (489 mg, 1.5 mmol) in water (2.5 mL), and Pd(dppf)Cl2-CH2Cl2 (41 mg, 0.05 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 20/1), followed by washing with EtOAc (5 mL) to give the title compound as a yellow solid (143 mg, 63%).
MS (ESI, pos. ion) m/z: 455.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 1.70-1.87 (m, 2H), 2.76 (t, J = 6.1 Hz, 2H), 3.34 (m, 2H), 6.60 (s, 1H), 7.26 (dd, J = 2.1 , 16.1 Hz, 1H), 7.43-7.49 (m, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.70- 7.78 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H), 8.10-8.16 (m, 2H), 8.36 (d, J = 1.92 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 12.07 (d, J = 2.1 Hz, 1H).
Example 33 (Z)-3-(2,6-dichioro-3-fluorostyryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrazolo[3,4-b]pyridine (3a)
(E)-3-(2,6-dichloro-3-fluorostyryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrazolo[3,4-b]pyridine (3b)
Figure imgf000101_0001
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
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 (7.5 g, 20.0 mmol), 5-bromo-lH-pyrazolo[3,4-b]pyridine (2.6 g, 13.3 mmol), a solution of CS2CO3 (13.0 g, 39.9 mmol) in water (27 mL), and Pd(dppf)Cl2-CH2Ci2 (1.1 g, 1.3 mmol). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 40/1), followed by washing with EtOAc (5 mL) to give the title compound as a light yellow solid (4.2 g, 80%).
MS (ESI, pos. ion) m/z: 369.0 (M+l);
!H NMR (400 MHz, DMSO- e): δ 13.60 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.39-8.35 (m, 2H), 8.1 1 (d, J = 1.1 Hz, 1H), 8.00 (s, 1H), 4.45-4.33 (m, 1H), 4.13-3.98 (m, 2H), 3.05-2.85 (br, 2H), 2.10-2.01 (m, 2H), 1.88-1.75 (m, 2H), 1.42 (s, 9H).
Step 2) tert-butyl 4-(4-(3-iodo-lH-pyrazolor3,4-b1pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate
[0293] A mixture of tert-butyl 4-(4-(lH-pyrazolo[3,4-b]pyridin-5-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (4.0 g, 10.9 mmol) and NIS (3.7 g, 16.3 mmol) in dichloroethane (350 mL) was refluxed for 16 hours, then cooled to rt, and filtered. The filter cake was washed with DCM (100 mL) and dried in vacuo to give the title compound as a white solid (4.8 g, 89%).
MS (ESI, pos. ion) m/z: 495.0 (M+l);
lU NMR (400 MHz, DMSO-de): δ 8.88 (d, J = 2.0 Hz, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 4.45-4.33 (m, 1H), 4.13-3.98 (m, 2H), 3.05-2.85 (br, 2H), 2.10-2.01 (m, 2H), 1.88-1.75 (m, 2H), 1.43 (s, 9H).
Step 3) ( ^-3-(2,6-dichloro-3-fluorostyryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrazolo[3,4-b]pyridine (3a)
(E)-3-(2,6-dichloro-3-fluorostyryl)-5-(l -(piperidin-4-yl)-lH-pyrazol-4-yl)-lH- pyrazolo[3,4-b]pyridine (3b)
Figure imgf000102_0001
3a 3b
[0294] A mixture of tert-butyl 4-(4-(3-iodo-lH-pyrazolo[3,4-b]pyridin-5-yl)-lH-pyrazol- l-yl)piperidine-l-carboxylate (989 mg, 2.0 mmol), l ,3-dichloro-4-fluoro-2-vinylbenzene (1.2 g, 6.0 mmol), Pd(OAc)2 (23 mg, 0.1 mmol), P(0-Tol)3 (79 mg, 0.26 mmol), Proton Sponge (471 mg, 2.2 mmol), LiBr (1076 mg, 12.4 mmol), and NMP (10 mL) was degassed and charged with nitrogen three times, then heated to 110 °C and stirred further for 36 hours. The mixture was poured into brine (50 mL) and extracted with DCM (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the crude product.
[0295] To a solution of the crude product in THF/DCM (1/4, 100 mL) was added a solutin of HCl in EtOAc (6 mL, 3 M) at 0 °C. The mixture was warmed to rt and stirred further for 24 hours, and concentrated in vacuo. The residue was redissolved in water (30 mL), and the mixture was extracted with DCM/MeOH (8/1, 100 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH/EtOAc (v/v/v) = 140/20/3) to give the title compound (a mixture of 3a and 3b) as a white solid (E/Z = 8/1, 50 mg, 5%).
MS (ESI, pos. ion) m/z: 457.0 (M+l);
Compound (3b): ¾ NMR (400 MHz, DMSO-de): δ 8.90 (d, J= 1.7 Hz, 1H), 8.04 (d, J= 1.7 Hz, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.65 (dd, J= 5.0, 9.0 Hz, 1H), 7.58-7.43 (m, 2H), 7.39 (d, J = 17.0 Hz, 1H), 4.30-4.15 (m, 1H), 3.20-3.00 (m, 2H), 2.72-2.50 (m, 2H), 2.10-1.95 (m, 2H), 1.90- 1.75 (m, 2H).
BIOLOGICAL TESTING
[0296] 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.
Table A
Figure imgf000103_0001
[0297] An Agilent XDB-C18, 2.1 x 30 mm, 3.5 μΜ column was used for the analysis. 5 of the samples were injected. Analysis condition: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 mL/min. And the gradient of Mobile phase was in the Table B Table B
Figure imgf000104_0001
[0298] Alternatively, an Agilent 6330 series LC/MS/MS spectrometer equipped with
G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis. An ESI source was used on the LC/MS/MS spectrometer. The analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution. A Capcell MP-C18 100 x 4.6 mm I.D., 5 μΜ column (Phenomenex, Torrance, California, USA) was used during the analysis. 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.
Example A: Compound Stability In Human And Rat Liver Microsomes
[0299] 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 μΜ) and NADPH (1.0 mM) in a total volume of 200 μΐ^ potassium phosphate buffer (PBS, 100 mM, pH7.4). 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.
[0300] The concentrations of compounds in the incubation mixtures of human liver microsomes were determined by a LC/MS/MS method. The ranges of the linearity in the concentration range were determined for each tested compounds.
[0301] A parallel incubation was performed using denatured microsomes as the negative control, and reactions were terminated at various time points (0, 15, 60 min) after incubation at 37°C. [0302] Dextromethorphan (70 μΜ) was selected as the positive control, and reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) after incubation at 37 °C. Both positive and negative control samples were included in each assay to ensure the integrity of the microsomal incubation system.
Data Analysis
[0303] The concentrations of compounds in human liver microsome incubations were plotted as a percentage of the relevant zero time point control for each reaction. The in vivo CLint were extrapolated (ref : Naritomi, Y.; Terashita, S.; Kimura, S.; Suzuki, A.; Kagayama, A.; and Sugiyama, Y.; Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab. Dispos., 2001, 29: 1316-1324).
Table 2 Human and rat liver microsomes stability
Figure imgf000105_0001
[0304] The compounds disclosed herein exhibited desirable half-life (T1/2) when the compounds were incubated in human and rat liver microsomes. Example B: Evaluation of Pharmacokinetics after Intravenous and Oral Administration of The Compounds Disclosed Herein In Mice, Rats, Dogs And Monkeys
[0305] Compounds disclosed herein are assessed in pharmacokinetic studies in mice, rats, dogs or monkeys. The compounds are administered as a water solution, 2% HPMC + 1% TWEEN®80 in water solution, 5% DMSO + 5% solutol in saline, 4% MC suspension or capsule. For the intravenous administration, the animals are generally given at 1 or 2 mg/kg dose. For the oral (p.o.) dosing, mice and rats are generally given 5 or 10 mg/kg dose, and dogs and monkeys are generally given 10 mg/kg dose. The blood samples (0.3 mL) are drawn at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h time points or 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h time points and centrifuged at 3,000 or 4000 rpm for 2 to 10 min. The plasma solutions are collected, and stored at -20 °C or -70 °C until analyzed by LC/MS/MS as described above.
Table 3 Pharmacokinetic profiles in rats
Figure imgf000106_0001
[0306] The compounds disclosed herein exhibited optimized pharmacokinetic properties with desirable clearance (CI), half-life (T1/2) and excellent oral bioavailability when the compounds were administered intravenously.
Example C: Kinase Assays
[0307] Kinase assays can be performed by measurement of incorporation of γ-33Ρ ATP into immobilized myelin basic protein (MBP). High binding white 384 well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubation of 60 μΕ/well of 20 μg/mL MBP in Tris- buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4°C. Plates are washed 3 x with 100 TBS. Kinase reactions are carried out in a total volume of 34 μΐ^ in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #1- 5506), 10 mM MgCl2, 1 mM DTT, 0.02% TritonX-100). Compound dilutions are performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point is measured in duplicate, and at least two duplicate assays are performed for each individual compound determination. Enzyme is added to final concentrations of 10 nM or 20 nM, for example. A mixture of unlabeled ATP and γ-33Ρ ATP is added to start the reaction (2 x 106 cpm of γ-33Ρ ATP per well (3000 Ci/mmole) and 10 μΜ unlabeled ATP, typically. The reactions are carried out for 1 h at rt with shaking. Plates are washed 7x with TBS, followed by the addition of 50 μΕΛνεΙΙ scintillation fluid (Wallac). Plates are read using a Wallac Trilux counter. This is only one format of such assays; various other formats are possible, as known to one skilled in the art.
[0308] The above assay procedure can be used to determine the IC50 for inhibition and/or the inhibition constant, K. The IC50 is defined as the concentration of compound required to reduce the enzyme activity by 50%> under the condition of the assay. The IC50 value is estimated by preparing a 10 point curve using a ½ log dilution series (for example, a typical curve may be prepared using the following compound concentrations: 10 μΜ, 3 μΜ, 1 μΜ, 0.3 μΜ, 0.1 μΜ, 0.03 μΜ, 0.01 μΜ, 0.003 μΜ, 0.001 μΜ and 0 μΜ).
[0309] The kinase assays described herein were performed at Millipore UK Ltd, Dundee
Technology Park, Dundee DD2 1 SW, UK.
ALK (h) Kinase Assay
[0310] ALK (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ
KKKSPGEYVNIEFG, 10 mM MgAcetate and [γ-33Ρ-ΑΤΡ] (specific activity aprrox. 500 pcm/pmol, concentration as required (10 μΜ)). The reaction is initiated by the addition of the MgATO mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μΐ^ of the reaction is then spotted onto a P30 filter mat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. c-Met (h) Kinase Assay
[031 1] Met (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ KK SPGEYVNIEFG, 10 mM MgAcetate and [γ-33Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol, concentration as required (10 μΜ)). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
Table 4 Kinase inhibition data
Figure imgf000108_0001
NT: Not tested
[0312] The compounds disclosed herein exhibited potent activities in the ALK and c-Met
(h) assays.
[0313] Alternatively, the kinase activities of the compounds can be measured using
KJNOMEscan™, which is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed ligand. The assay was performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand was measured via quantitative PCR of the DNA tag.
[0314] For most assays, kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SEABLOCK™ (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SEABLOCK™, 0.17x PBS, 0.05% TWEEN®20, 6 mM DTT). All reactions were performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% TWEEN®20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% TWEEN®20, 0.5 μΜ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
[0315] The kinase assays described herein were performed using KTNOMEscan™
Profiling Service at DiscoveRx Corporation, 42501 Albrae St. Fremont, CA 94538, USA.
[0316] Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive and the invention is not be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims. All publications and patents cited herein are incorporated by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound having Formula (I):
Figure imgf000110_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
each of Wi, W2 and W3 is independently N or CRC;
each of Ai, A2 and A3 is independently H, D, CN, N3, -C(=0)ORa, -C(=0)NRaRb, (Ci-C6)alkyl, -(Ci-C4)alkylene-CN, -(Ci-C4)alkylene-ORa, -(Ci-C4)alkylene-NRaRb, (C3- C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, (C3-Cs)heterocyclyl, -(Ci- C4)alkylene-(C3-C8)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, -C(=0)ORa, -C(=0)NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, optionally substituted (C6-Cio)aryl, and optionally substituted 5-10 membered heteroaryl comprising 1 , 2, 3 or 4 heteroatom(s) independently selected from O, S and ;
Figure imgf000110_0002
wherein each of Zi, Z2 and Z3 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH; each R1 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, - C(=0)NRaRb, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci- C4)alkylene-CN, -(Ci-C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-Cio)cycloalkyl, - (Ci-C4)alkylene-(C3-Cio)cycloalkyl, (C3-Cio)heterocyclyl, -(Ci-C4)alkylene-(C3- Cio)heterocyclyl, (C6-Cio)aryl, 5-10 membered heteroaryl comprising 1 , 2, 3 or 4 heteroatom(s) independently selected from O, S and N, -(Ci-C4)alkylene-(C6-Cio)aryl, - (Ci-C4)alkylene-(5-10 membered heteroaryl), or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and , (C3-Ce)cycloalkyl, or (C3-Ce)heterocyclyl ring, wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups.
each R2 is independently D, F, CI, Br, I, CN, N02, N3, ORa, SRa, NRaRb, (Ci- C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C4)alkylene-CN, -(Ci- C4)alkylene-NRaRb, -(Ci-C4)alkylene-ORa, (C3-C8)cycloalkyl, -(Ci-C4)alkylene-(C3- C8)cycloalkyl, (C3-Cs)heterocyclyl, or -(Ci-C4)alkylene-(C3-C8)heterocyclyl;
each Ra and Rb is independently H, (Ci-Ce)aliphatic, (C3-Ce)cycloalkyl, -(Ci- C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, -(Ci-C4)alkylene-(C3-
C6)heterocyclyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic ring, wherein each of the above substituents is optionally substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci-Ce)alkoxy, and (Ci-C6)alkylamino; and each Rc is independently H, D, F, CI, Br, I, N3, CN, NH2, -NHS(=0)2(Ci-C6)alkyl, -N(Ra)C(=0)(Ci-C6)alkyl,
Figure imgf000111_0001
(Ci- C6)alkyl, (Ci-Ce)alkoxy, (Ci-C6)alkylamino, (C3-Ce)cycloalkyl, (C3-Ce)heterocyclyl, (C6- Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci-C6)alkyl, (C3-C6)cycloalkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, and (Ci- C6)alkylamino.
2. The compound according to claim 1 , wherein each of Wi and W2 is independently CRC; and W3 is N or CRC.
3. The compound according to claim 1, wherein each of Ai, A2 and A3 is independently H, D, CN, N3, -C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, (C6-Cio)aryl, or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from O, S and N, and wherein each of Ai, A2 and A3 is optionally independently substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from D, F, CI, CN, ORa, NRaRb, -C(=0)ORa, -C(=0)NRaRb, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl.
4. The compound according to claim 1 , wherein Z is
Figure imgf000112_0001
wherein each of Zi and Z2 is independently N or CH, and Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
5. The compound according to claim 1, wherein each R1 is independently D, F, CI, ORa, NRaRb, -C(=0)NRaRb, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C2-C4)alkenyl, -(Ci- C2)alkylene-NRaRb, -(Ci-C2)alkylene-ORa, (C3-C6)cycloalkyl, -(Ci-C2)alkylene-(C3- C6)cycloalkyl, (C3-Ce)heterocyclyl, -(Ci-C2)alkylene-(C3-C6)heterocyclyl, or optionally two adjacent R1 groups, together with the atoms they are attached to, form a (C6-Ci2)aryl, (C3-Ce)cycloalkyl, or (C3-Ce)heterocyclyl ring, and wherein each of the above substituents is optionally independently substituted with 1, 2, 3, or 4 R2 groups.
6. The compound according to claim 1, wherein each R2 is independently D, F, CI, ORa, NRaRb, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-C6)cycloalkyl, or (C3-C6)heterocyclyl.
7. The compound according to claim 1, wherein each Ra and Rb is independently H, (Ci-C3)alkyl, (C3-Ce)cycloalkyl, (C3-Ce)heterocyclyl, or Ra and Rb 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, NH2, (Ci- C3)alkoxy, and (Ci-C3)alkylamino.
8. The compound according to claim 1 , wherein each Rc is independently H, D, F, CI, CN, NH2, -NHS(=0)2(Ci-C3)alkyl,
Figure imgf000113_0001
-
Figure imgf000113_0002
(Ci-C3)alkyl, (Ci-C3)alkoxy, (Ci-C3)alkylamino, (C3- C6)cycloalkyl, or (C3-C6)heterocyclyl, and wherein each Rc is optionally independently substituted with 1, 2, 3 or 4 substituent(s) independently selected at each occurrence from D, F, CI, CN, N3, OH, NH2, (Ci-C3)alkyl, (C3-C6)cycloalkyl, (Ci-C3)haloalkyl, (Ci- C3)alkoxy, and (Ci-C3)alkylamino.
9. The compound according to claim 1 , wherein Z is
Figure imgf000113_0003
wherein Z is optionally independently substituted with 1, 2, or 3 R1 groups; provided that when Z is phenyl, each R1 is not OH.
10. The compound of claim 1 having one of the following structures:
Figure imgf000113_0004
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
Figure imgf000115_0004
Figure imgf000115_0005
Figure imgf000116_0001
11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
12. The pharmaceutical composition according to claim 1 1 further comprising a therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.
13. The pharmaceutical composition according to claim 12, wherein 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, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof.
14. The compound according to any one of claims 1 to 10 or the pharmaceutical composition according to any one of claims 1 1 to 13 for use in preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.
15. The compound or pharmaceutical composition of claim 14, wherein the proliferative disorder is metastatic cancer, 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, a myeloproliferative disorder, atherosclerosis or lung fibrosis.
16. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to any one of claims 1 1 to 13 in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.
17. The use of claim 16, wherein the proliferative disorder is metastatic cancer, 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, a myeloproliferative disorder, atherosclerosis or lung fibrosis.
18. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to any one of claims 11 to 13.
19. The method of claim 18, wherein the proliferative disorder is metastatic cancer, 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, a
myeloproliferative disorder, atherosclerosis or lung fibrosis.
20. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to any one of claims 11 to 13.
21. The method of claim 20, wherein the protein kinase is receptor tyrosine kinase.
22. The method of claim 21, wherein the receptor tyrosine kinase is ALK, c-Met, or a combination thereof.
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