WO2015108490A2 - Dérivés hétéroarylalcyne et leurs utilisations - Google Patents

Dérivés hétéroarylalcyne et leurs utilisations Download PDF

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WO2015108490A2
WO2015108490A2 PCT/SG2015/050005 SG2015050005W WO2015108490A2 WO 2015108490 A2 WO2015108490 A2 WO 2015108490A2 SG 2015050005 W SG2015050005 W SG 2015050005W WO 2015108490 A2 WO2015108490 A2 WO 2015108490A2
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optionally substituted
compound
alkyl
certain embodiments
heterocyclyl
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WO2015108490A3 (fr
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Kassoum Nacro
Lohitha Rao Chennamaneni
Joseph Cherian
Anders Poulsen
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Agency For Science, Technology And Research
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the protein kinases represent a large family of proteins and play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from the inappropriate activation of the immune and nervous systems.
  • MAP Kinase-interacting kinases also known as MAP Kinase signal- integrating kinases, (MNKs)
  • MNKs MAP Kinase signal- integrating kinases
  • MNKla/b and MNK2a/b proteins differ at their C-termini, in each case the a- form possessing a longer C-terminal region than the b- form which lacks the MAP Kinase-binding region.
  • the N-termini of all forms contain a polybasic region which binds Importin a and the translation factor scaffold protein eukaryotic Initiation Factor (eIF4G).
  • eIF4G eukaryotic Initiation Factor
  • the catalytic domains of MNKla/b and MNK2a/b share three unusual features, two short inserts and a DFD tripeptide feature where other kinases have DFG.
  • Mnk isoforms differ markedly in their activity, regulation, and subcellular localization.
  • MNK substrate The best-characterized MNK substrate is eIF4E. Although the cellular role of eIF4E phosphorylation remains unclear, it may promote export of a defined set of mRNAs from the nucleus. Other Mnk substrates bind to AU-rich elements that modulate the
  • MNKl is highly expressed in hematological malignancies, and both MNKl and MNK2 are up-regulated in solid tumors such as gliomas and ovarian cancers (Worch, J.; Tickenbrock, L.; Schwable, J.; Steffen, B.; Cauvet, T.; Mlody, B.; Buerger, H.; Koeffler, H. P.; Berdel, W. E.; Serve, H.; Muller-Tidow, C.
  • MNK inhibitors can regulate the innate immune response in macrophage. It has been shown that CGP57380, a Mnk inhibitor, inhibits the release of TNF-alpha by macrophage (and not eIF4E) (Buxade, M. ; Morrice, N.; Krebs, D. L.; Proud, C. G. J. Biol. Chem. 2008, 283, 57-65). According to PCT publication, WO 2005/003785, MNK kinases are promising targets for anti-inflammatory therapy.
  • MNK 1/2 were also reported to phosphorylate a number of different proteins in addition to eIF4E. Three of these are hnRNPAl , cPLA2 and Sprouty2 (Guil, S. ; Long, J. C ; Caceres, J. F. Mol.Cell Biol. 2006, 26, 5744-5758; Hefner, Y. ; Borsch-Haubold, A. G. ;
  • hnRNPAl is overexpressed in colorectal cancer, and it could contribute to maintenance of telomere repeats in cancer cells with enhanced cell proliferation (Ushigome, M.; Ubagai, T.; Fukuda, H. ; Tsuchiya, N. ; Sugimura, T. ; Takatsuka, J. ; Nakagama, H. Int. J. Oncol. 2005, 26, 635-640). It is also reported that the expression levels of hnRNPA/B is deregulated in non-small cell lung cancer (Boukakis, G. ; Patrinou- Georgoula, M. ; Lekarakou, M. ; Valavanis, C ; Guialis, A. BMC.Cancer 2010, 10, 434).
  • MNK inhibitors are potentially useful in the treatment of cancers including breast, protate, hematological malignancies (e.g., CML, AML), head and neck, colon, 1 bladder, prostatic adenocarcinoma, lung, cervical, and lymphomas (Bianchini, A. ; Loiarro, M. ; Bielli, P. ; Busa, R. ; Paronetto, M. P. ; Loreni, F. ; Geremia, R. ; Sette, C. Carcinogenesis 2008, 29, 2279-2288; Berkel, H. J. ; Turbat-Herrera, E. A. ; Shi, R.; De Benedetti, A. Cancer Epidemiol.Biomarkers Prev.
  • Abelson (ABL)-family proteins comprise one of the best conserved branches of the tyrosine kinases.
  • Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases.
  • the Abelson non-receptor tyrosine kinase (c-Abl) is involved in signal transduction, via phosphorylation of its substrate proteins. In the cell, c-Abl shuttles between the cytoplasm and nucleus, and its activity is normally tightly regulated through a number of diverse mechanisms. Abl has been implicated in the control of growth-factor and integrin signaling, cell cycle, cell differentiation, neurogenesis, apoptosis, cell adhesion, cytoskeletal structure, and response to DNA damage and oxidative stress.
  • the present invention provides novel compounds that inhibit the activity of one or more protein kinases and are useful in the treatment of kinase-associated diseases.
  • the inventive compounds inhibit MAP kinase interacting kinases 1 and 2 (MNKl and MNK2).
  • the inventive compounds inhibit Abelson (Abl) tyrosine kinase.
  • the provided compounds are useful in the prevention and/or treatment of proliferative diseases (e.g. cancer including hematological cancers and solid tumors such as gliomas and ovarian cancers), inflammatory conditions, neurodegenerative diseases (e.g. Alzheimer's disease), and metabolic disorders (e.g. obesity, diabetes).
  • the invention provides a compound of Formula (I):
  • Ring A, Ring B, L, R , R , and t are as described herein.
  • the present invention relates to pharmaceutical compositions comprising an inventive compound and to their use for the prevention and treatment of diseases associated with a dysregulated or dysfunctional kinase pathway or aberrant kinase activity.
  • the present invention relates to methods of using the inventive compound for the prevention and treatment of diseases associated with a dysregulated or dysfunctional kinase pathway or aberrant kinase activity.
  • the disease is asscociated with increased activity of the kinase or the pathway that includes the kinase.
  • Mnkl and Mnk2 play a role in the dysregulated or dysfunctional kinase pathway (e.g.
  • Abl tyrosine kinase plays a role in the dysfunctional kinase pathway. In certain embodiments, Abl tyrosine kinase has a T315I mutation. In certain embodiments, Abl tyrosine kinase has a E255K mutation.
  • the present invention relates to pharmaceutical compositions comprising these compounds for the prevention and/or treatment of diseases such as, but not limited to, cancer, inflammatory conditions, neurodegenerative diseases, and metabolic disorders.
  • the present invention relates to methods of using the provided pharmaceutical compositions comprising these compounds for the prevention and/or treatment of diseases such as, but not limited to, cancer, inflammatory conditions, neurodegenerative diseases, and metabolic disorders.
  • the provided compounds described herein can be used as single agents or in combination with one or more additional agents.
  • the additional agent is a small molecule or biologic.
  • the additional agent is a kinase inhibitor. In some embodiments, the additional agent is a monoclonal antibody. In some embodiments, the additional agent is siRNA.
  • the invention relates to methods for modulating the activity of a protein kinase comprising contacting the protein kinase with a compound of Formula (I).
  • the protein kinase whose activity is being modulated is Mnk (e.g., Mnkl or Mnk2).
  • the protein kinase is Abl tyrosine kinase (e.g., wide type and mutants).
  • the present invention describes methods for the synthesis of compounds of Formula (I).
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the provided kits may be useful for the treatment of cancer, inflammatory conditions, neurodegenerative diseases, and metabolic disorders.
  • the kits described herein further include instructions for administering the compound of Formula (I), or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.
  • the kits may also include packaging information describing the use or prescribing information for the subject or a health care professional. Such information may be required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the kit may also optionally include a device for administration of the compound or composition, for example, a syringe for parenteral administration.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g. , enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("Q_2o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("Ci-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1 -.9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms ("Ci_8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("Ci_5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1 -4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1 -3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms (“Ci_2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • Ci_6 alkyl groups include methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C5), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n- hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i. e. , unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents.
  • the alkyl group is unsubstituted Ci_io alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted Ci_io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-2 0 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms ("C2- 10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 _ 8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms ("C 2 _6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2- alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2- alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2 ⁇ alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like.
  • Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cg), octatrienyl (Cg), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkenyl”) or substituted (a "substituted alkenyl”) with one or more substituents.
  • the alkenyl group is unsubstituted C2- 10 alkenyl. In certain embodiments, the alkenyl group is substituted C2- 10 alkenyl.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2-2 0 alkynyl”).
  • an alkynyl group has 2 to 10 carbon atoms ("C2- 10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 _g alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2 _6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • C2- alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (Cg), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents.
  • the alkynyl group is unsubstituted C2- 10 alkynyl.
  • the alkynyl group is substituted C2-10 alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3 _io carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _g carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3 _6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs_io carbocyclyl").
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C 6 ), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C 3 _s carbocyclyl groups include, without limitation, the aforementioned C 3 _6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the aforementioned C 3 _s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 1 0), cyclodecenyl (C 1 0), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic
  • carbocyclyl and can be saturated or can be partially unsaturated.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3 _io carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _io carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _s cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs_6 cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C5- 1 0 cycloalkyl").
  • C5-6 cycloalkyl groups include cyclopentyl (C 3 ⁇ 4 ) and cyclohexyl (C 3 ⁇ 4 ).
  • C 3 _6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _s cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an
  • the cycloalkyl group is unsubstituted C 3 _io cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3_io cycloalkyl.
  • Heterocyclyl refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is
  • heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and ⁇ - ⁇ ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and ⁇ - ⁇ ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [00025] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4— membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic ⁇ e.g., bicyclic or tricyclic) 4n+2 aromatic ring system ⁇ e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl").
  • an aryl group has six ring carbon atoms ("C6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted aryl”) or substituted (a
  • substituted aryl with one or more substituents.
  • the aryl group is unsubstituted C -u aryl.
  • the aryl group is substituted C 6 -i4 aryl.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl,
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • each instance of R" is, independently, selected from Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C -u aryl, and 5-14 membered heteroaryl, or two R m groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R bb is, independently, selected from hydrogen, -OH, -OR 2 *, -N(R CC )2, -CN,
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io
  • perhaloalkyl C 2 _io alkenyl, C 2 _io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from d-6 alkyl, d-6 perhaloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, C 3 _io carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, d-6 alkyl, d-6 perhaloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-
  • each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • Halo or "halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Amide nitrogen protecting groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, /?-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-
  • Carbamate nitrogen protecting groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-i- butyl-[9-( 10,10-dioxo-l 0, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ra edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • benzoylformate acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulmoyldithioacetal), pivaloate, adamantoate, crotonate, 4— methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9- fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • pharmaceutically acceptable form thereof refers to pharmaceutically acceptable salts, solvates, hydrates, prodrugs, tautomers, isomers, enantiomers, diastereomers, and/or polymorphs of a compound of the present invention.
  • the pharmaceutically acceptable form is a
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describe pharmaceutically acceptable salts in detail in /. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable form is a hydrate or solvate.
  • hydrate refers to a compound non-covalently associated with one or more molecules of water.
  • solvate refers to a compound non-covalently associated with one or more molecules of an organic solvent.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to a derivative of a parent compound that requires transformation within the body in order to release the parent compound. In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound.
  • the advantage of a prodrug can lie in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage.
  • esters as a prodrug type for compounds containing a carboxyl or hydroxyl functionality is known in the art as described, for example, in The Organic Chemistry of Drug Design and Drug Interaction by Richard Silverman, published by Academic Press (1992).
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.
  • the pharmaceutically acceptable form is an isomer.
  • the term "isomer” as used herein includes any and all geometric isomers and stereoisomers (e.g., enantiomers, diasteromers, etc.).
  • “isomer” include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched.”
  • “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer.
  • the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid
  • the pharmaceutically acceptable form is a polymorph.
  • polymorph refers to a crystalline compound existing in more than one crystalline form/structure. When polymorphism exists as a result of difference in crystal packing it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans ⁇ i.e. , a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys.
  • the subject is an animal.
  • the animal may be of either sex and may be of any stage of development.
  • the animal is a mammal.
  • the subject is a human.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal such as a dog or cat.
  • the subject is a livestock animal such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal.
  • Treating encompasses an action that occurs while a subject is suffering from a condition (e.g., a "MNKl - or MNK2-related” disease, disorder, or condition, e.g., a disease, disorder, or condition in which MNKl and/or MNK2 is known to play role) which reduces the severity of the condition or retards or slows the progression of the condition (“therapeutic treatment”).
  • a condition e.g., a "MNKl - or MNK2-related disease, disorder, or condition, e.g., a disease, disorder, or condition in which MNKl and/or MNK2 is known to play role
  • inhibitor refers to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process relative to vehicle.
  • the biological process is in vitro (e.g., a biochemical or cellular assay). In certain embodiments, the biological process is in vivo.
  • an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., treat the condition.
  • the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • the effective amount of a compounds refers to an amount sufficient to inhibit the activity of a kinase.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount effective to inhibit cell growth or induce cell death.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • kinase represent a class of enzymes that are able to transfer a phosphate group from a donor molecule to an acceptor molecule, e.g., an amino acid residue of a protein or a lipid molecule.
  • kinases include Abl, ACK, Aktl/ ⁇ , ⁇ 3 ⁇ 42/ ⁇ , Akt3/PKBy, ALK1, ALK2, Alk4, AMPKal/ ⁇ / ⁇ , ⁇ 1/ ⁇ 1/ ⁇ 2, ⁇ 1/ ⁇ 1/ ⁇ 3, ⁇ 1/ ⁇ 2/ ⁇ 1, ⁇ 2/ ⁇ 1/ ⁇ 1, ⁇ 2/ ⁇ 2/ ⁇ 2, Abl2, ARKS, Askl, Aurora A, Aurora B, Aurora C, Axl, BARK1, Blk, Bmx, B-Raf, Brk, BrSKl , BrSK2, Btk, CaMKla, CaMK ⁇ , CaMKly, CaMK15, CAMK2a, CaMK2 ⁇ , CAMK25, CAMK2y, CAMK4, CAMKK1, CAMKK2, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKl/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK3/cyclin
  • CDK9/cyclin Tl CHK1, CHK2, CKl(y), CK15, CK2al, CK2a2, cKit, c-RAF, CLK1, CLK2, CLK3, COT, Csk, DAPK1, DAPK2, DAPK3, DCAMLK2, DDR2, DMPK, DRAK1, DYRK1A, DYRK2, DYRK3, eEF2K, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EphBl, EphB2, EphB3, EphB4, ErbB4, Erkl, Erk2, FAK, Fer, Fes, FGFR1, Flt2, Flt4, FLT3 D835Y, FGFR2, FGFR3, FGFR4, Fgr, Fltl, Flt3, Fms, FRK, FynA, GCK, GPRK5, GRK2, GRK4, GRK6, GRK7, G
  • mutant Abl tyrosine kinase refers to an Abl tyrosine kinase with a single or multiple amino acid changes as compared to the wild-type protein. Mutations in Abl tyrosine kinase act by disrupting critical contact points between protein and inhibitor (for example, Gleevec, and the like), more often, by inducing a transition from the inactive to the active state.
  • inhibitor for example, Gleevec, and the like
  • Exemplary Abl tyrosine kinase point mutations include: M224V, L248V, G250E, G250R, Q252R, Q252H, Y253H, Y253F, E255K, E255V, D276G, T277A, V289A, F311L, T3151, T315N, F317L, M343T, M315T, E355G, F359V, F359A, V379I, F382L, L387M, L387F, H396P, H396R, A397P, S417Y, E459K, and F486S. Unless otherwise stated for this invention, Abl refers to wild-type and mutant forms of the enzyme.
  • small molecule refers to a non-peptidic, non- oligomeric organic compound either synthesized in the laboratory or found in nature.
  • Small molecules can refer to compounds that are "natural product-like", however, the term “small molecule” is not limited to "natural product-like” compounds. Rather, a small molecule is typically characterized in that it contains several carbon-carbon bonds, and has a molecular weight of less than 2000 g/mol, preferably less than 1500 g/mol, although this characterization is not intended to be limiting for the purposes of the present invention. Small molecules are typically characterized by multiple carbon-carbon bonds and may have one or more stereocenters. In certain embodiments, the small molecule is not polymeric or oligomeric. In certain embnodiments, the small molecule is not a nucleic acid, protein, or peptide.
  • biologicals refer to products created by a biological process.
  • exemplary biologies include, but are not limited to, natural or synthetic growth hormone, natural or synthetic human insulin and its analogues, monoclonal antibodies, receptor constructs, vaccines, antibodies, blood, cells, organs, grafts, or tissues.
  • Monoclonal antibodies are highly specific, being directed against a single antigenic site and generally to a single epitope on an antigen.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and does not require that the antibody be produced by any particular method or be the only antibody in the composition.
  • Antibody as used herein encompasses polyclonal and monoclonal antibodies, and further encompasses antibodies of any class (e.g. , IgM, IgG, and subclasses thereof).
  • Antibody also encompasses hybrid antibodies, bispecific antibodies, heteroantibodies, chimeric antibodies, humanized antibodies, and functional fragments thereof which retain antigen binding.
  • the term "antibody” encompasses compositions comprising an antigen- binding protein, individually or as a preparation comprising a plurality thereof, having one or more polypeptides that can be genetically encodable by immunoglobulin genes, or fragments of immunoglobulin genes, or that comprise CDRs ob tainted or derived from
  • immunoglobulins and which bind an antigen of interest.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains can be classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • Antibody also encompasses single-chain antibodies that contain a heavy chain and a light chain linked together as a single polypeptide, each of such linked heavy or light chains nonetheless being referred to herein as a heavy chain or a light chain.
  • Antibody also encompasses intact immunoglobulins as well antigen-binding fragments of antibodies.
  • the term "antibody”, as used herein also includes an antigen-binding portion of an antibody, which can be produced by the modification of whole antibodies or synthesized de novo using recombinant DNA methodologies.
  • siRNA refers to an isolated RNA molecule, preferably greater than 10 nucleotides in length, more preferably greater than 15 nucleotides in length, and most preferably 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length, that functions as a key intermediate in triggering sequence- specific RNA degradation. A range of 19-25 nucleotides is the most preferred size for siRNAs.
  • siRNAs can also include short hairpin RNAs (shRNA) in which both strands of an siRNA duplex are included within a single RNA molecule. Double-stranded siRNAs generally include a sense and anti-sense strand.
  • siRNAs generally consist of only the antisense strand that is complementary to the target gene or mRNA.
  • siRNA includes any form of RNA, preferably dsRNA (proteolytically cleaved products of larger dsRNA, partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA) as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution, and/or alteration of one or more nucleotides (Yair Dorsett; Thomas Tuschl, Nature Reviews Drug Discovery, 2004, 3, 318-329). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
  • the invention provides heteroaryl alkyne derivatives as kinase inhibitors.
  • the provided compounds act as inhibitors of the MAP kinase interacting kinases 1 and 2 (MNK1 and MNK2) and/or Abl-tyrosine kinase.
  • MNK1 and MNK2 MAP kinase interacting kinases 1 and 2
  • the provided compounds and pharmaceutical compositions thereof are useful in treating diseases associated with aberrant MNK or Abl-tyrosine kinase activity or dysregulation of the corresponding pathway.
  • the provided compounds and pharmaceutical compositions can be used to prevent and/or treat cancer (such as solid tumor and hematological tumor), an inflammatory disease, a neurodegenerative disease (such as Alzheimer's disease), or a metabolic disorder (such as diabetes, hyperlipidemia and obesity).
  • the provided compounds are heteroaryl alkyne derivatives.
  • the present invention provides a compound of Formula (I):
  • Ring A is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, optionally substituted 5,6- or 6,6-bicyclic heteroaryl, or optionally substituted 5,6- or 6,6-bicyclic heterocycle;
  • Ring B is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, or optionally substituted 5,6-bicyclic heteroaryl;
  • R L1 is hydrogen or optionally substituted Ci_6 alkyl
  • each of R N1 and R N2 is independently hydrogen, optionally substituted Ci_6 alkyl, or optionally substituted C3-6 carbocyclyl, or R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted heterocyclic moiety;
  • t is 1, 2, or 3;
  • s is 1, 2, or 3.
  • Ring A is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, optionally substituted 5,6- or 6,6-bicyclic heteroaryl, or optionally substituted 5,6- or 6,6- bicyclic heterocycle. In certain embodiments, Ring A is optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, optionally substituted 5,6- or 6,6- bicyclic heteroaryl, or optionally substituted 5,6- or 6,6-bicyclic heterocycle. In certain embodiments, Ring A is optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, or optionally substituted 5,6- or 6,6-bicyclic heteroaryl.
  • Rin A is optionally substituted phenyl of the formula
  • each instance of is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, optionally substituted C3-6 carbocyclyl, optionally substituted phenyl, optionally substituted four-, five-, or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, optionally substituted acyl, -CN, -OR AO , or -N(R AN ) 2 ; each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; and
  • each instance of R 1 ⁇ and R ⁇ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R RAN are taken with the intervening nitrogen to form an optionally substituted heterocyclyl, or two R ⁇ are taken with the intervening nitrogen to form an optionally substituted heterocyclyl; and
  • np 0, 1 , 2, 3, 4, or 5.
  • np is 0. In certain embodiments, np is 1. In certain embodiments, np is 2. In certain embodiments, np is 3. In certain embodiments, np is 4. In certain embodiments, np is 5.
  • Ring A is of the formula .
  • Ring A is optionally substituted five-membered heteroaryl. In certain embodiments, Ring A is optionally substituted five-membered heteroaryl with one heteroatom selected from the group consisting of O, S, and N. In certain embodiments, Ring A is optionally substituted five-membered heteroaryl with two heteroatoms selected from the group consisting of O, S, and N. In certain embodiments, Ring A is one of the following formulae:
  • each instance of is independently hydrogen, halogen, optionally substituted Ci alkyl, optionally substituted Cj- carbocyclyl, optionally substituted phenyl, optionally substituted four-, five-, or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, optionally substituted acyl, -CN, -OR AO , or -N(R AN ) 2 ;
  • each instance of R AO is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R 1 ⁇ and is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R RAN are taken with the intervening nitrogen to form an optionally substituted heterocyclyl, or two R ⁇ are taken with the intervening nitrogen to form an optionally substituted heterocyclyl; and
  • nl 0, 1 or 2.
  • nl is 0. In certain embodiments, nl is 1. In certain embodiments, nl is 2.
  • each instance of R RA is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted four-, five-, or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, optionally substituted acyl, -CN, - OR AO , or -N(R AN )2.
  • R RA is hydrogen.
  • R 1 ⁇ is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted four-, five-, or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, optionally substituted acyl, -CN, - OR AO , or -N(R AN )2.
  • R RA is hydrogen.
  • R 1 ⁇ is
  • R is -F, -CI, -Br, or -I.
  • R is - CN.
  • R RA is optionally substituted Ci_6 alkyl. In certain embodiments, is unsubstituted Ci_6 alkyl. In certain embodiments, R RA is methyl, ethyl, n-propyl, iso-
  • R is substituted Ci_6 alkyl.
  • R RA is -CF 3 , -CHF2, or -CH2F.
  • R RA is acetyl.
  • is -C( 0)NH 2 .
  • R RA is -OR AO , wherein each instance of R AO is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group.
  • R RA is -OH.
  • R RA is -OR AO , wherein R AO is independently optionally substituted Ci_6 alkyl, optionally substituted C 3 -6 carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group.
  • R RA is -OR AO , wherein R AO is optionally substituted Ci_6 alkyl. In certain embodiments, R RA is -OR AO , wherein R AO is unsubstituted Ci_6 alkyl. In certain embodiments,
  • R RA is -O-methyl, -O-ethyl, -O-propyl, or -O-isopropyl.
  • R RA is -OR AO , wherein R AO is optionally substituted heterocyclyl.
  • R RA is -OR AO , wherein R AO is optionally substituted aryl.
  • R RA is -O-phenyl.
  • R RA is -OR AO , wherein R AO is optionally substituted heteroaryl.
  • R 1 ⁇ is -OR AO , wherein R AO is an oxygen protecting group.
  • R RA is -OR AO , wherein R AO is Ac, Boc, TBS, TIPS, Bn, or Bz.
  • R RA is -N(R each instance of R ⁇ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, a nitrogen protecting group, or two R RAN are taken with the intervening nitrogen to form an optionally substituted heterocyclyl.
  • R RAN is -N(R wherein each instance of R ⁇ is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group.
  • R RA is In some embodiments, is -N(R In certain embodiments, is -NHR ⁇ , wherein R ⁇ is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R RA is -NHR ⁇ , wherein R ⁇ is optionally substituted Ci alkyl. In certain embodiments, R RA is -NHR ⁇ , wherein R ⁇ is unsubstituted Ci alkyl. In certain
  • R RA is -NH-methyl, -NH-ethyl, -NH- «-propyl, or -NH-wo-propyl.
  • R RA is -NHR ⁇ , wherein R ⁇ is a nitrogen protecting group.
  • R RA is In certain embodiments, R RA is In certain embodiments, two R RAN are taken with the intervening nitrogen to form an optionally substituted heterocyclyl. In certain embodiments, two RAN are taken with the intervening nitrogen to form an optionally substituted four-, five-,
  • R is ⁇ ⁇ " , , or ⁇ .
  • R RA is of the formula is independently optionally substituted Ci alkyl, optionally substituted C3-6 carbocyclyl, optionally substituted phenyl, optionally substituted five- or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, -OR A , or -N(R
  • R 1 ⁇ 1 is independently optionally substituted Ci alkyl.
  • R is unsubstituted Ci alkyl.
  • R is methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, or tert-butyl.
  • R RA1 is substituted Ci alkyl.
  • R RA1 is -CH 2 C1, -CHC1 2 , -CHF 2, -CH 2 F , or -CF 3 .
  • R is optionally substituted C3_6 carbocyclyl.
  • R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R ⁇ 1 is optionally substituted phenyl. In certain embodiments, R ⁇ 1 is phenyl. In certain embodiments, R RAl is substituted phenyl. In certain embodiments, R RAl is optionally substituted five- or six-membered heterocyclyl. In certain embodiments, R ⁇ 1 is optionally substituted five-membered heterocyclyl. In certain embodiments, R ⁇ 1 is optionally substituted six-membered heterocyclyl. In certain embodiments, R RA1 is optionally substituted five- or six-membered heteroaryl. In certain embodiments, R RA1 is optionally substituted five-membered heteroaryl. In certain embodiments, R RA1 is optionally substituted six-membered heteroaryl. In certain embodiments, R ⁇ 1 is optionally substituted pyridine. In certain embodiments, R ⁇ 1 is pyridine.
  • R RA is optionally substituted four-, five-, or six- membered heterocyclyl.
  • R ⁇ is optionally substituted four- membered heterocyclyl.
  • R ⁇ is optionally substituted four-
  • R is optionally substituted five-membered heterocyclyl.
  • R ⁇ is optionally substituted five-membered heterocyclyl with one or two heteroatoms each independently
  • R is optionally substituted six-membered heterocyclyl.
  • R RA is optionally substituted six-membered heterocyclyl with one or two heteroatoms each independently selected from the group consisting of N, S, and O.
  • R RA is optionally substituted five- or six-membered heteroaryl. In certain embodiments, R RA is optionally substituted five-membered heteroaryl.
  • R is optionally substituted five-membered heteroaryl with one N, O, or S.
  • R ⁇ is optionally substituted five-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, S, or O.
  • R is optionally substituted six-membered heteroaryl.
  • R RA is optionally substituted six-membered heteroaryl with one N, O, or S.
  • R ⁇ is optionally substituted six-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, S, or O.
  • R RA is substituted pyridine.
  • R RA is pyridine.
  • Ring A is one of the following formulae:
  • Ring A is optionally substituted six-membered heteroaryl. In certain embodiments, Ring A is is optionally substituted six-membered heteroaryl with one or two N. In certain embodiments, Ring A is one of the following formulae:
  • R RA is as defined herein, and each instance of n2 is independently 0, or an integer of 1 to 4, inclusive.
  • each instance of n2 is independently 0 or an integer of 1 to 4, inclusive. In certain embodiments, n2 is 0. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4.
  • each instance of R RN1 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R RN1 is hydrogen.
  • R 1 ⁇ 1 is optionally substituted alkyl.
  • R RN1 is optionally substituted Ci_6 alkyl.
  • R 1 ⁇ 1 is unsubstituted Ci_6 alkyl.
  • R RN1 is methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, or tert-butyl. In certain embodiments, R RN1 is substituted Ci-6 alkyl. In certain embodiments, R RN1 is -CH 2 C1, -CHC1 2 , -CHF 2, -CH 2 F or -CF 3 . In certain embodiments, R RN1 is optionally substituted carbocyclyl. In certain embodiments, R 1 ⁇ 1 is optionally substituted C 3 _6 carbocyclyl.
  • R RN1 is cycloproyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R RN1 is optionally substituted aryl. In certain embodiments, R RN1 is optionally substituted phenyl. In certain embodiments, R 1 ⁇ 1 is phenyl. In certain embodiments, R 1 ⁇ 1 is substituted phenyl. In certain embodiments, R 1 ⁇ 1 is optionally substituted heterocyclyl. In certain embodiments, R 1 ⁇ 1 is optionally substituted five- or six-membered heterocyclyl. In certain embodiments, R 1 ⁇ 1 is optionally substituted heteroaryl. In certain embodiments, R 1 ⁇ 1 is optionally substituted five- or six- membered heteroaryl.
  • each instance of R 1 ⁇ 1 and R ⁇ 1 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • each instance of R RA1 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R RAl is hydrogen.
  • R RAl is optionally substituted alkyl.
  • R RA1 is optionally substituted Ci_6 alkyl.
  • R 1 ⁇ 1 is unsubstituted Ci_6 alkyl.
  • R RA1 is methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, or tert-butyl. In certain embodiments, R RA1 is substituted Ci-6 alkyl. In certain embodiments, R RA1 is -CH 2 C1, -CHC1 2 , -CHF 2, -CH 2 F or -CF 3 . In certain embodiments, R RAl is optionally substituted carbocyclyl. In certain embodiments, R RAl is optionally substituted C3_6 carbocyclyl.
  • R RA1 is cycloproyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R RA1 is optionally substituted aryl. In certain embodiments, R RA1 is optionally substituted phenyl. In certain embodiments,
  • R RAl is phenyl. In certain embodiments, R RAl is substituted phenyl. In certain embodiments,
  • R RAl is optionally substituted heterocyclyl. In certain embodiments, R RAl is optionally substituted five- or six-membered heterocyclyl. In certain embodiments, R 1 ⁇ 1 is optionally substituted heteroaryl. In certain embodiments, R 1 ⁇ 1 is optionally substituted five- or six- membered heteroaryl.
  • Ring A is optionally substituted 5,6- or 6,6-bicyclic heteroaryl. In certain embodiments, Ring A is optionally substituted 5,6- or 6,6-bicyclic heteroaryl with one, two, or three N. In certain embodiments, Ring A is one of the following formulae:
  • R RA is as defined herein; each instance of n3 is independently 0 or an integer of 1 to
  • each instance of n3 is independently 0 or an integer of 1 to 6, inclusive, as valency permits.
  • n3 is 0.
  • n3 is 1.
  • n3 is 2.
  • n3 is 3.
  • n3 is 4.
  • n3 is 5.
  • n3 is 6.
  • n3 is an integer of 1 to 6, inclusive, as valency permits.
  • n3 is 1 or 2 as valency permits.
  • R ⁇ , R AO and R ⁇ 1 are as define herein.
  • R RA is hydrogen. In certain embodiments, R RA is halogen. In certain embodiments, R RA is F. In certain embodiments, R RA is CI. In certain embodiments, R RA is Br. In certain
  • R RA is I. In certain embodiments, R RA is optionally substituted Ci_6 alkyl. In certain embodiments, R ⁇ is substituted Ci_6 alkyl. In certain embodiments, R RA is unsubstituted Ci_6 alkyl. In certain embodiments, R ⁇ is methyl, ethyl, n-propyl, or iso-propyl.
  • Ring A is optionally substituted 5,6- or 6,6-bicyclic heteroaryl
  • Ring A is optionally substituted 5,6- or 6,6-bicyclic is optionally substituted phenyl of the formula:
  • each instance of R is independently hydrogen, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted acyl; and
  • p is an integer of 1 to 5, inclusive.
  • p is an integer of 1 to 5, inclusive, as valency permits. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5.
  • each instance of is independently hydrogen, halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted acyl.
  • R ⁇ is CN.
  • R ⁇ is halogen (e.g. F, CI, Br, or I).
  • R is optionally substituted five-membered heterocyclyl having two heteroatoms ech independently selected from the group consisting of N, O, and S. ⁇ In certain embodiments, R ⁇ is optionally substituted six-
  • R is optionally substituted six-membered heterocyclyl having two heteroatoms ech independently selected from the group consisting of N, O, and S.
  • Ring A when Ring A is optionally substituted 5,6- or 6,6-bicyclic heteroaryl, each instance of is independently -CN, -F, -CI, -CH 3 , -C2H5, - ! Pr, -Ph, -0 ! Pr, -OCH 3 , -OC 2 H 5 , -NH 2 , -NHCH 2 ! Pr, -N(CH 3 ) 2 , -NHCH 3 , -N(C 2 H 5 ) 2 , -NH-(CH 2 ) 3 -OH, - N(CH 3 )-(CH 2 )2-OCH 3 ,
  • Ring A is optionally substituted 5,6- or 6,6-bicyclic heterocycle. In certain embodiments, Ring A is optionally substituted 5,6- or 6,6-bicyclic heterocycle with one, two, or three N. In certain embodiments, Ring A is one of the following formulae: is as defined herein; and each instance of n4 is independently 0 or an integer of 1 to 6, inclusive, as valency permits. In certain embodiments, n4 is 0. In certain embodiments, n4 is 1. In certain embodiments, n4 is 2. In certain embodiments, n4 is 3. In certain embodiments, n4 is 4. In certain embodiments, n4 is 5. In certain embodiments, n4 is 6.
  • Ring A is of the formula or
  • Ring B is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, or optionally substituted 5,6-bicyclic heteroaryl.
  • Rin B is optionall substituted phenyl of the formula:
  • each instance of R RB is independently hydrogen, halogen, or optionally substituted Ci_6 alkyl; a indicates the point of attachment to alkynyl;
  • ml is 1 , 2, 3, or 4. [000101] As generally used herein, ml is 1, 2, 3, or 4. In certain embodiments, ml is 1. In certain embodiments, ml is 2. In certain embodiments, ml is 3. In certain embodiments, ml is 4.
  • each instance of R RB is independently hydrogen, halogen, or optionally substituted Ci_6 alkyl.
  • R RB is hydrogen.
  • R RB is CN.
  • R RB is halogen (e.g. , F, CI, Br, or I).
  • R RB is optionally substituted alkyl.
  • R RB is substituted Ci_6 alkyl.
  • R RB is unsubstituted Ci_6 alkyl.
  • R RB is methyl, ethyl, n-propyl, or iso-propyl.
  • Ring B is of the formula:
  • Ring B is optionally substituted five-membered heteroaryl. In certain embodiments, Ring B is optionally substituted five-membered heteroaryl with one N, O, or S. In certain embodiments, Ring B is optionally substituted five- membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S. In certain embodiments, Ring B is of one of the following formulae:
  • Ring B is optionally substituted six-membered heteroaryl. In certain embodiments, Ring B is optionally substituted six-membered heteroaryl with one N, O, or S. In certain embodiments, Ring B is optionally substituted six-membered heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S. In certain embodiments, Ring B is of one of the following formulae:
  • a indicates the point of attachment to alkynyl
  • n2 is 1, 2, or 3 and R RB is as defined herein.
  • m2 is 1, 2, or 3. In certain embodiments, m2 is 1. In certain embodiments, m2 is 2. In certain embodiments, m2 is 3.
  • Ring B is optionally substituted 5,6-bicyclic heteroaryl. In certain embodiments, Ring B is optionally substituted 5,6-bicyclic heteroaryl with one N, O, or S. In certain embodiments, Ring B is optionally substituted 5,6-bicyclic heteroaryl with two heteroatoms each independently selected from the group consisting of N, O, and S.
  • Ring B is one of the following formulae:
  • R is independently hydrogen, optionally substituted Ci_6 alkyl, or optionally substituted C3_6 carbocyclyl.
  • R N1 is hydrogen.
  • R N1 is optionally substituted Ci_6 alkyl.
  • R N1 is unsubstituted Ci-6 alkyl.
  • R N1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
  • R N1 is substituted Ci_6 alkyl.
  • R N1 is optionally substituted carbocyclyl.
  • R N1 is optionally substituted C3_6 carbocyclyl.
  • R N1 is cycloproyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R N2 is independently hydrogen, optionally substituted Ci-6 alkyl, or optionally substituted C3-6 carbocyclyl. In certain embodiments, R N2 is hydrogen. In certain embodiments, R is optionally substituted Ci_6 alkyl. In certain embodiments, R is unsubstituted Q_6 alkyl. In certain embodiments, R N2 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In certain embodiments, R N2 is substituted Ci-6 alkyl. In certain embodiments, R N2 is optionally substituted carbocyclyl. In certain embodiments, R N2 is optionally substituted carbocyclyl. In certain embodiments, R N2 is cycloproyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R N1 and R N2 each are independently optionally substituted Ci_6 alkyl. In certain embodiments, R N1 and R N2 each are independently unsubstituted Ci-6 alkyl. In certain embodiments, R N1 and R N2 each are independently methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R N1 and R N2 are the same. In certain embodiments, R N1 and R N2 are different. In certain embodiments, R N1 and R N2 are both methyl, ethyl, n-propyl, or iso-propyl.
  • R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted heterocyclic moiety. In certain embodiments, R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted three-, four-, five-, or six-membered heterocyclic moiety. In certain embodiments, R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted six-membered heterocyclic moiety of
  • R is independently hydrogen, optionally substituted Q_6 alkyl, or a nitrogen protecting group.
  • R N3 is hydrogen. In certain embodiments, R N3 is optionally substituted Ci-6 alkyl. In certain embodiments, R N3 is unsubstituted Ci-6 alkyl. In certain embodiments, R N3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R N3 is substituted Ci-6 alkyl. In certain embodiments, R N3 is a nitrogen protecting group. In certain embodiments, R N3 is Bn, Bz, or Boc.
  • R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted four-membered heterocyclic moiety. In certain embodiments, R N1 and R N2 are taken with the intervening nitrogen to form an optionally substituted azetidinyl moiety. In certain embodiments, R N1 and R N2 are taken with the intervening nitrogen to form one of the following formulae: . In certain embodiments, R and R are taken with the intervening
  • R and R are taken with the intervening nitrogen to form an optionally substituted six-membered heterocyclic moiety of the formula:
  • t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.
  • the compound of Formula (I) is of one of the following formulae:
  • Ring A, L, R , R , ml, m2, and m3 are as defined herein.
  • the compound of Formula (I) is of one of the following:
  • R RA , nl, n2, and n3 are as defined herein.
  • R RA and R ⁇ 1 are as defined herein.
  • Ring A is of the formula: , wherein R RA is as defined herein.
  • Ring A is of the formula: , wherein R K/Y is as defined herein.
  • Ring A is of the formula: , wherein R RA is as defined herein.
  • a provided compound is of one of the formulae in Table 1.
  • Table 1 Exemplified Compounds.
  • Enzymatic assays have shown that compounds of Formula (I) are inhibitors of Abl-wild type and Abl-T315I with IC5 0 values in the range of approximately 12 ⁇ to lower than approximately 1 nM.
  • the provided compounds inhibit Mnkl and/or Mnk2 with IC5 0 values in the range of approximately 10 ⁇ to lower than approximately 30 nM.
  • the provided compounds inhibit Mnkl and/or Mnk2 with the IC5 0 values in the range of approximately 8 ⁇ to lower than approximately 50 nM.
  • the provided compounds inhibit Mnkl and/or Mnk2 with the IC5 0 values in the range of approximately 5 ⁇ to lower than approximately 100 nM. In certain embodiments, the provided compounds inhibit Mnkl and/or Mnk2 with the IC5 0 values in the range of approximately 1 ⁇ to lower than approximately 500 nM.
  • the provided compounds have the IC5 0 S values varying from as low as approximately 7 nM to approximately 16 ⁇ in the phosphorylation inhibition assay in Hela cell line. In certain embodimetns, the provided compounds have IC5 0 S varying from as low as approximately 50 nM to approximately 10 ⁇ in the phosphorylation inhibition assay in Hela cell line. In certain embodimetns, the provided compounds have the IC5 0 S values varying from as low as approximately 100 nM to approximately 5 ⁇ in the phosphorylation inhibition assay in Hela cell line. In certain embodimetns, the provided compounds have IC5 0 S varying from as low as approximately 500 nM to approximately 1 ⁇ in the phosphorylation inhibition assay in Hela cell line.
  • compositions comprising an effective amount of a compound described herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salt or prodrug) thereof, and, optionally, a
  • compositions agents include any and all solvents, diluents or other liquid vehicles, 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.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. bentonite (aluminum silicate) and Veegum (mag
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, poly aery lie acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene sorbitan monolaurate Tween 20
  • polyoxyethylene sorbitan Tween 60
  • polyoxyethylene sorbitan monooleate Tween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
  • sucrose fatty acid esters e.g.
  • CREMOPHOR polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer PI 88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • polyoxyethylene ethers e.g. polyoxyethylene lauryl ether (Brij 30)
  • poly(vinyl-pyrrolidone) diethylene glycol monolaurate
  • triethanolamine oleate sodium oleate
  • potassium oleate ethyl oleate
  • oleic acid ethyl la
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • starch e.g. cornstarch and starch paste
  • gelatin e.g. cornstarch and starch paste
  • sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. acacia
  • exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g. , citric
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • the liquid dosage forms may comprise 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 (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • 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
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CREMOPHOR, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can 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 can 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.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates 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 ingredient.
  • 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 ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient 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, 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 g
  • Solid compositions of a similar type can 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 comprise opacifying agents and can 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 which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can 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 polethylene glycols and the like.
  • the active ingredients can 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 ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may 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 comprise buffering agents. They may optionally comprise opacifying agents and can 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.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquids to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Patents 5,480,381 ; 5,599,302; 5,334,144;
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1 % to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal
  • formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. Kits
  • kits e.g. , pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • compositions or compound provided in the container and the second container are combined to form one unit dosage form.
  • a single container may comprise one or more compartments for containing an inventive pharmaceutical composition or compound, and/or a pharmaceutically acceptable excipient for suspension or dilution.
  • a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments.
  • a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated.
  • a kit may thus comprise such multi-compartment containers providing an inventive pharmaceutical composition or compound and one or more pharmaceutically acceptable excipients.
  • instructions for use are additionally provided in such kits of the invention.
  • Such instructions may provide, generally, for example, instructions for dosage and administration.
  • instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration.
  • instructions may provide specialized instructions for use in conjunction and/or in combination with an additional therapeutic agent.
  • compositions of the present invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g. , compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g. , compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • peptides e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulation
  • an additional therapeutically active agent is a kinase inhibitor.
  • an additional kinase inhibitor is Axitinib, Crizotinib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Nilotinib, Pazopanib, Ruxolitinib, Sorafenib, Sunitinib, Vandetanib.
  • Exemplary additional therapeutically active agents include, but are not limited to, biologies such as naturla of synthetic growth hormone, natural or synthetic human insulin and its analogues, monoclonal antibodies, receptor constructs, vaccines, antibodies, blood, organs or tissues.
  • kinases [000178] Compounds and compositions described herein are generally useful for the inhibition of one or more kinases.
  • a partial, non-limiting, list of these kinases include:
  • PDGF-R platelet-derived growth factor receptor kinase
  • trkB nerve growth factor receptor
  • Met the nerve growth factor receptor
  • FGFR3 the fibroblast growth factor receptor
  • non-receptor tyrosine kinases such Abl and the fusion kinase BCR-Abl, Lck, Csk, Fes, Bmx and c-src
  • serine/threonine kinases such as b-RAF, c-RAF, sgk, MAP kinases (e.g., MNK1 , MNK2, MKK4, MKK6, etc.) and SAPK2a, SAPK2 and SAPK3.
  • compounds and compositions described herein are generally useful for the inhibition of MNK1 and/or MNK2. In certain embodiments, compounds and compositions described herein are generally useful for the inhibition of Abelson (Abl) tyrosine kinase. In certain embodiments, the Abelson (Abl) tyrosine kinase is wild type Abl tyrosine kinase. In certain embodiments, the Abelson (Abl) tyrosine kinase is a mutant Abl tyrosine kinase.
  • the Abelson (Abl) tyrosine kinase is a mutant Abl tyrosine kinase having a mutation selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315I, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K and F486S.
  • the Abelson (Abl) tyrosine kinase is a mutant Abl tyrosine kinase having the mutation T315I. In certain embodiments, the Abelson (Abl) tyrosine kinase is a mutant Abl tyrosine kinase having the mutation E255K.
  • methods of treating kinase -related disorder in a subject comprise administering an effective amount of a compound described herein (e.g. , a compound of Formula (I)), or a pharmaceutically acceptable form thereof), to a subject in need of treatment.
  • a compound described herein e.g. , a compound of Formula (I)
  • a pharmaceutically acceptable form thereof e.g., a compound of Formula (I)
  • methods of treating MNK1- and/or MNK2-related disorder in a subject comprise administering an effective amount of a compound described herein (e.g. , a compound of Formula (I)), or a pharmaceutically acceptable form thereof), to a subject in need of treatment.
  • methods of treating Abl- related disorder in a subject which comprise administering an effective amount of a compound described herein (e.g. , a compound of Formula (I)), or a pharmaceutically acceptable form thereof), to a subject in need of treatment.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject is suffering from a MNK1 -related disorder. In certain embodiments, the subject is susceptible to a MNK1 -mediated disorder. In certain embodiments, the subject is suffering from a MNK2-related disorder. In certain embodiments, the subject is susceptible to a MNK2- mediated disorder.
  • Exemplary MNK-related disorders include, but are not limited to, metabolic diseases such as obesity, as well as related disorders such as eating disorder, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, and sleep apnea, neurodegenerative disorders such as autism, Alzheimer's disease, and cancer such as breast, protate, hematological malignancies (e.g., CML, AML), head and neck, colon, bladder, prostatic adenocarcinoma, lung, cervical, and lymphomas.
  • the subject is suffering from an Abl-related disorder.
  • the subject is susceptible to a Abl-mediated disorder.
  • the subject is suffering from a Abl-related disorder.
  • the subject is susceptible to a Abl-mediated disorder.
  • Exemplary Abl-mediated disorders include, but are not limited to, hematopoietic tumor, mammary cancer, uterine body cancer, uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brain neoplasm.
  • methods of treating kinase -related disorder in a subject comprise administering an effective amount of a compound described herein (e.g. , a compound of Formula (I)) in combination with another agent, to a subject in need of treatment.
  • the agent is a small molecule or biologic.
  • the agent is a kinase inhibitor.
  • the agent is a chemotherapeutic agent.
  • the agent is a monoclonal antibody.
  • the agent is an siRNA.
  • kinase-related disorder means any disease, disorder, or other pathological condition in which a kinase (e.g., MNK1 and/or MNK2 and/or Abl) is known to play a role.
  • a kinase e.g., MNK1 and/or MNK2 and/or Abl
  • the present disclosure relates to treating or lessening the severity of one or more diseases in which MNK1 and/or MNK2 is known to play a role.
  • the present disclosure relates to treating or lessening the severity of one or more diseases in which Abl tyrosine kinase is known to play a role.
  • the kinase-related condition is selected from the group consisting of proliferative diseases, neurodegenerative diseases, autoimmune diseases, and inflammatory diseases.
  • a provided compound is useful for treating a proliferative disease, e.g. , cancer. In certain embodiments, a provided compound is useful for treating a solid tumor. In certain embodiments, a provided compound is useful for treating a hematological malignancy.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • endotheliosarcoma e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma
  • endometrial cancer e.g., uterine cancer, uterine sarcoma
  • esophageal cancer e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma
  • Ewing sarcoma eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocy
  • B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphom
  • MM multiple myeloma
  • heavy chain disease e.g. , alpha chain disease, gamma chain disease, mu chain disease
  • hemangioblastoma e.g., alpha chain disease, gamma chain disease, mu chain disease
  • hypopharynx cancer e.g., hemangioblastoma
  • hypopharynx cancer e.g., hemangioblastoma
  • hypopharynx cancer e.g., inflammatory myofibroblastic tumors
  • immunocytic amyloidosis e.g., nephroblastoma a.k. a.
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • leiomyosarcoma LMS
  • mastocytosis e.g., systemic mastocytosis
  • muscle cancer myelodysplastic syndrome (MDS); mesothelioma;
  • myeloproliferative disorder e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocar
  • IPMN intraductal papillary mucinous neoplasm
  • IPMN Islet cell tumors
  • penile cancer e.g., Paget's disease of the penis and scrotum
  • pinealoma primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms
  • prostate cancer e.g., prostate adenocarcinoma
  • rectal cancer rhabdomyosarcoma
  • salivary gland cancer skin cancer [e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)] ; small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST
  • a provided compound is useful for treating hematopoietic tumor, breast cancer, colon cancer, lung cancer, lymphomas, mammary cancer, uterine body cancer, cervix cancer, prostatic cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer, rectal cancer, pancreatic cancer, lung cancer, gliomas, ovarian cancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brain neoplasm.
  • a provided compound is useful for treating a
  • neurodegenerative disease exemplary neurodegenerative diseases include, but are not limited to, Alzheimer' s disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, Pick's disease, Parkinson's disease, Lewy body disease, and amyotropic lateral sclerosis (ALS).
  • Alzheimer' s disease Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, Pick's disease, Parkinson's disease, Lewy body disease, and amyotropic lateral sclerosis (ALS).
  • ALS amyotropic lateral sclerosis
  • a provided compound is useful for treating a
  • neurodevelopmental disorder refers to impairments of the growth and development of the brain or central nervous system.
  • a neurodevelopmental disorder also refers to a disorder of brain function that affects emotion, learning ability, self-control and memory and that unfolds as the individual grows.
  • Disorders considered neurodevelopmental in origin, or that have neurodevelopmental consequences when they occur in infancy and childhood include, but are not limited to autism and autism spectrum disorders (e.g. Asperger syndrome or Mendelsohnn's Syndrome), fetal alcohol spectrum disorder, motor disorders (e.g. developmental coordination disorder, stereotypic movement disorder and the tic disorders including Tourette syndrome), traumatic brain injury (e.g. congenital injuries), genetic disorders (e.g.
  • the neurodevelopmental disorder is autism.
  • a provided compound is useful for treating an autoimmune disease.
  • autoimmune diseases include, but are not limited to, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g.
  • eosinophilic disease e.g. , selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. , eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD) (e.g.
  • GSD gastroesophageal reflux disease
  • NUD non-ulcerative dyspepsia
  • NCCP non-cardiac chest pain
  • a provided compound is useful for treating an inflammatory disease.
  • inflammatory disease refers to those conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and/or loss of function (functio laesa, which can be partial or complete, temporary or permanent.
  • Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation.
  • Exemplary inflammatory diseases include, but are not limited to, inflammation associated with acne, asthma, arteritis (e.g.
  • polyarteritis e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g. , crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, dry eye syndrome, diverticulitis, diabetes (e.g.
  • type I diabetes mellitus type 2 diabetes mellitus
  • a skin condition e.g. , psoriasis, eczema, burns, dermatitis, pruritus (itch)
  • endometriosis Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasaki disease,
  • glomerulonephritis glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g. , migraine headaches, tension headaches), ileus (e.g. , postoperative ileus and ileus during sepsis), idiopathic
  • thrombocytopenic purpura interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g. , selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. , eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea,
  • gastrointestinal disorder e.g. , selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. , eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea,
  • GSD gastroesophageal reflux disease
  • IBD inflammatory bowel disease
  • IBS inflammatory bowel syndrome
  • morphea myeasthenia gravis
  • myocardial ischemia nephrotic syndrome
  • pemphigus vulgaris pernicious aneaemia
  • peptic ulcers polymyositis
  • neuroinflammation associated with brain disorders e.g.
  • prostatitis chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g. , frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener's granulomatosis.
  • trauma or injury e.g. , frostbite, chemical irritants, toxins, scarring, burns, physical injury
  • vasculitis vitiligo and Wegener's granulomatosis.
  • the inflammatory disorder is selected from arthritis (e.g. , rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis, prostatistis, appendicitis, Blau syndrome, blepharitis, bronchiolitis, cervicitis, cholangitis, cholecystitis, chronic recurrent multifocal osteomyelitis (CRMO), cryopyrin associated periodic syndrome (CAPS), dacryoadenitis, dermatomyositis, dry eye syndrome, encephalitis, endocarditis, endometritis, enterocolitis, epicondylitis, epididymitis, familial cold-induced autoinflammatory syndrome, familial Mediterranean fever (FMF), fasciitis, fibrositis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, men
  • arthritis
  • the inflammatory condition is a chronic inflammatory condition (e.g. , conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • the compounds may also be useful in treating inflammation associated with cancer.
  • a provided compound is useful for treating or lessening the severity of hyperproliferative diseases including, but not limited to, psoriasis or smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis, and restenosis.
  • a provided compound is useful for treating or lessening the severity of endometriosis, uterine fibroids, endometrial hyperplasia, and benign prostate hyperplasia.
  • a provided compound is useful for treating or lessening the severity of one or more diseases and conditions, wherein the disease or condition is selected from immune-related conditions or diseases, which include, but are not limited to transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • immune-related conditions or diseases include, but are not limited to transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • a provided compound is useful for treating a metabolic disorder (e.g., diabetes, hyperlipidemia and obesity).
  • a metabolic disorder e.g., diabetes, hyperlipidemia and obesity.
  • the present disclosure provides methods of inhibiting a kinase comprising contacting the kinase with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable form thereof.
  • the present disclosure provides a method of inhibiting MNKl comprising contacting MNKl with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable form thereof.
  • the present disclosure provides a method of inhibiting MNK2 comprising contacting MNK2 with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable form thereof.
  • the present disclosure provides a method of inhibiting Abl tyrosine kinase comprising contacting Abl-tyrosine kinase with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable form thereof.
  • a compound described herein e.g., a compound of Formula (I)
  • the MNKl , MNK2, Abl tyrosine kinase may be purified, partially purified, isolated, or crude, and may be present in a cell, tissue, or subject.
  • the method is an in vitro method, e.g., such as an assay method.
  • MNKl , MNK2, or Abl- tyrosine kinase does not necessarily require that all of the MNKl, MNK2, or Abl-tyrosine kinase be inhibited.
  • Exemplary levels of inhibition of MNKl , MNK2, or Abl-tyrosine kinase include at least 10% inhibition, about 10% to about 25% inhibition, about 25% to about 50% inhibition, about 50% to about 75% inhibition, at least 50% inhibition, at least 75% inhibition, about 80% inhibition, about 90% inhibition, and greater than 90% inhibition.
  • Exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl- tyrosine kinase are from about 1 nM to about 20 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl-tyrosine kinase are from about 1 nM to about 15 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl , MNK2, or Abl-tyrosine kinase are from about 1 nM to about 10 ⁇ .
  • the exemplary concentrations of the provided compounds to inhibit MNKl , MNK2, or Abl-tyrosine kinase are from about 1 nM to about 8 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl , MNK2, or Abl-tyrosine kinase are from about 1 nM to about 6 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl-tyrosine kinase are from about 1 nM to about 4 ⁇ .
  • the exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl- tyrosine kinase are from about 1 nM to about 2 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl-tyrosine kinase are from about 1 nM to about 1 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl, MNK2, or Abl-tyrosine kinase are from about 1 nM to about 0.5 ⁇ . In certain embodiments, the exemplary concentrations of the provided compounds to inhibit MNKl , MNK2, or Abl-tyrosine kinase are from about 1 nM to about 0.1 ⁇ .
  • a method of inhibiting kinase activity in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein (e.g. , a compound of Formula (I)), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof.
  • a method of inhibiting MNKl and/or MNK2 and/or Abl-tyrosine kinase activity in a subject in need thereof e.g.
  • a subject diagnosed as having a MNKl - and/or MNK2- and/or Abl-tyrosine kinase-related disorder comprising administering to the subject an effective amount of a compound described herein (e.g. , a compound of Formula (I)), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof.
  • a compound described herein e.g. , a compound of Formula (I)
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate Methanaminium
  • HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoiO-phosphate
  • Pd(PPh 3 )4 Teti'akis(triphenylphosphine)palladium(0)
  • Step 1 Preparation of 6-chloro-3-((trimethylsilyl)ethynyl)imidazo[l,2-b]pyridazine
  • the title compound was prepared following general procedure B and starting from 6-chloro-3-iodoimidazo[l,2-b]pyridazine and ethynyltrimethylsilane.
  • the reaction crude product was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate 50:50) to afford 6-chloro-3-((trimethylsilyl)ethynyl)imidazo[l,2-b]pyridazine (3 g) as a yellow solid.
  • MS (ESI) m/z 250.13 [CnH 12 ClN 3 Si+H] + .
  • Step 1 Preparation of 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyridine
  • Step 2 Preparation of 6-bromo-3-ethynylimidazo[l,2-a]pyridine
  • a solution of crude 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyridine and TBAF (5.38 g, 19.34 mmol) in a mixture of THF (60 mL) and H 2 0 (2 mL) was stirred at room temperature for lh then was concentrated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel to afford 6-bromo-3-ethynylimidazo[l,2- a]pyridine as a brown solid (2.2 g, 64% over two steps).
  • Step 1 Preparation 5-chloro-3-((trimethylsilyl)ethynyl)pyrazolo[l,5-a]pyrimidine
  • Step 1 Preparation of 6-chloro-3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyrazine
  • Step 1 Preparation of N-methylimidazo[l,2-b]pyridazin-6-amine
  • Step 2 Preparation of 3-iodo-N-methylimidazo[l,2-b]pyridazin-6-amine [000209] A mixture of solution of N-methylimidazo[l,2-b]pyridazin-6-amine (3.5 g, 23.64 mmol) and S (6.38 g, 28.37 mmol) in DMF (25 mL) was stirred at room temperature for 4 h and was poured into ice-cold water. The solid that has precipitated was isolated by filtration and dried to afford 3-iodo-N-methylimidazo[l,2-b]pyridazin-6-amine (4 g, 51.2%) as a pale brown solid.
  • Step 3 preparation of N-methyl-3-((trimethylsilyl)ethynyl)imidazo[l,2-b]pyridazin-6-amine
  • TEA 4-aminoethynyltrimethylsilane
  • Cul 415.8 mg, 2.18 mmol
  • ethynyltrimethylsilane 64.1 mL, 43.77 mmol
  • Pd(PPh 3 ) 4 842 mg, 0.729 mmol.
  • reaction mixture was heated at 80 °C for 3 h then, was diluted with EtOAc and filtered through a short pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, eluent:
  • Step 4 preparation of 3-ethynyl-N-methylimidazo[l,2-b]pyridazin-6-amine
  • Step 1 Preparation of 3-iodo-N,N-dimethylimidazo[l,2-b]pyridazin-6-amine [000211] To a solution of N,N-dimethylimidazo[l,2-b]pyridazin-6-amine (15 g, 92.59 mmol) in acetonitrile (100 mL) was added S (24.88 g, 111.11 mmol) at 0 °C.
  • Step 2 Preparation of N,N-dimethyl-3-((trimethylsilyl)ethynyl)imidazo[l,2-b]pyridazin-6- amine
  • Step 3 Preparation of 3-ethynyl-N,N-dimethylimidazo[l,2-b]pyridazin-6-amine
  • Step 1 Preparation of 3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyridine
  • Step 1 Preparation of 3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyrazine
  • Step 2 Preparation of 3-ethynylimidazo[l,2-a]pyrazine [000217] To a solution of 3-((trimethylsilyl)ethynyl)imidazo[l,2-a]pyrazine (161 mg, 0.75 mmol) in methanol (4 mL) was added potassium carbonate (103 mg, 0.75 mmol) and was stirred at room temperature for 3 h before concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Hexane/Ethyl acetate 4:1) to afford 3- ethynylimidazo[l,2-fl]pyrazine (58 mg, 54%) as yellow solid.
  • Step 1 Preparation of 3-((trimethylsilyl)ethynyl)pyrazolo[l,5-a]pyrimidine
  • Step 1 Preparation of 4-fluoro-5-((trimethylsilyl)ethynyl)-lH-pyrrolo[2,3-b]pyridine
  • Step 1 Preparation of teri-butyl 5-((6-(dimemylamino)imidazo[l,2-b]pyridazin-3- yl)ethynyl)thiazol-2-ylcarbamate
  • teri-butyl 5-bromothiazol-2-ylcarbamate 600mg, 2.159 mmol
  • THF tetrahydrofuran
  • PdCl 2 dppf DCM
  • dppf 60 mg, 0.107 mmol
  • Cul 61.5mg, 0.323 mmol
  • TEA 700 mg, 6.47 mmol
  • 3-ethynyl-NN- dimethylimidazo[l,2-b]pyridazin-6-amine 400 mg, 2.15 mmol
  • Step 2 Preparation of 5-((6-(dimethylamino)imidazo[l,2-b]pyridazin-3-yl)ethynyl)thiazol-2- amine
  • Step 1 preparation of N-(4-bromopyridin-2-yl)-4-methyl-3-(trifluoromethyl)benzamide
  • Step 2 preparation of 4-(bromomethyl)-N-(4-bromopyridin-2-yl)-3-(trifluoromethyl)
  • Step 3 Preparation of teri-butyl 4-(4-(4-bromopyridin-2-ylcarbamoyl)-2- (trifluoromethyl)benzyl)piperazine- 1 -carboxylate.
  • Step 1 Preparation of teri-butyl 4-(2-(trifluoromethyl)-4-(4-((trimethylsilyl)ethynyl)pyridin- 2-ylcarbamoyl)benzyl)piperazine- 1 -carboxylate
  • Step 2 Preparation teri-butyl 4-(4-(4-ethynylpyridin-2-ylcarbamoyl)-2- (trifluoromethyl)benzyl)piperazine- 1 -carboxylate
  • Step 1 Preparation of N-(4-bromopyridin-2-yl)-4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamide
  • Step 2 Preparation of 4-((4-methylpiperazin-l-yl) methyl)-3-(trifluoromethyl)-N-(4- ((trimethylsilyl) ethynyl) pyridin-2-yl) benzamide
  • Step 3 Preparation N-(4-ethynylpyridin-2-yl)-4-((4-methylpiperazin-l-yl) methyl)-3- (trifluoromethyl)benzamide
  • Step 1 Preparation of N-(4-bromopyridin-2-yl)-4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamide
  • reaction crude was purified by flash column chromatography (silica gel, eluent DCM/MeOH/NFLOH) to afford N-(4-bromopyridin-2-yl)- 4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamide (6 g, 12%, AUC HPLC 95.8%) as an off white solid.
  • Step 2 Preparation of 4-((4-ethylpiperazin-l-yl) methyl)-3-(trifluoromethyl)-N-(4- ((trimethylsilyl) ethynyl) pyridin-2-yl) benzamide
  • Step 3 Preparation of 4-((4-ethylpiperazin-l-yl)methyl)-N-(4-ethynylpyridin-2-yl)-3- (trifluoromethyl)benzamide
  • Step 2 Preparation of teri-butyl 4-(4-(3-(4-bromopyridin-2-yl)ureido)-2- (trifluoromethyl)benzyl)piperazine- 1 -carboxylate.
  • Step 1 teri-butyl 4-(2-(trifluoromethyl)-4-(3-(4-((trimethylsilyl)ethynyl)pyridin-2- yl)ureido)benzyl)piperazine- 1 -carboxylate.
  • Step 1 Preparation of l-(4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)phenyl)-3-(4-((trimethylsilyl)ethynyl)pyridin-2-yl)urea.
  • the title compound was prepared in a similar fashion as described in step 1 of intermediate 13 synthesis starting from l-(4-bromopyridin-2-yl)-3-(4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)phenyl)urea (1 g, 2.12 mmol).
  • Step 2 l-(4-ethynylpyridin-2-yl)-3-(4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)phenyl)urea.
  • the title compound was prepared in a similar fashion as described in step 2 of intermediate 13 synthesis starting from l-(4-((4-methylpiperazin-l- yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-((trimethylsilyl)ethynyl)pyridin-2-yl)urea (800 mg, 1.63 mmol).
  • the crude product was further purified by column chromatography (neutral alumina, eluent: hexanes/EtOAc 8:2:1% NH 4 OH) to afford l-(4-ethynylpyridin-2-yl)-3-(4- ((4-methylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea (500 mg, 73%, AUC HPLC 94.2 %) as a pale yellow solid.
  • Step 1 Preparation of l-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4- ((trimethylsilyl)ethynyl)pyridin-2-yl)urea
  • Step 2 Preparation of l-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4- ethynylpyridin-2-yl)urea
  • Step 1 Preparation of 4-((dimethylamino)methyl)-3-(trifluoromethyl)benzoyl azide
  • Step 2 Preparation of l-(4-bromopyridin-2-yl)-3-(4-((dimethylamino)methyl)-3- (trifluoromethyl)phenyl)urea
  • Step 1 preparation of 4-((4-methylpiperazin-l-yl)methyl)-3-(trifluoromethyl)-N-(5- ((trimethylsilyl)ethynyl)thiazol-2-yl)benzamide
  • Step 2 preparation of N-(5-ethynylthiazol-2-yl)-4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamide
  • Step 1 Preparation of 4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)-N-(5- ((trimethylsilyl)ethynyl)thiazol-2-yl)benzamide
  • Step 2 Preparation of 4-((4-ethylpiperazin-l-yl)methyl)-N-(5-ethynylthiazol-2-yl)-3- (trifluoromethyl)benzamide
  • Step 1 Preparation of 4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzoyl azide
  • Step 1 Preparation of phenyl 5-bromothiazol-2-ylcarbamate
  • Step 2 Preparation of l-(5-bromothiazol-2-yl)-3-(4-((4-methylpiperazin-l-yl)methyl)-3- (trifluoromethyl)phenyl)urea
  • Step 1 Preparation of 6-(prop-l-en-2-yl)imidazo[l ,2-b]pyridazine.
  • 6-chloroimidazo[l,2-b]pyridazine (4 g, 26.43mmol)
  • K 3 PO4 11.08 g, 52.28 mmol
  • 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane 5.7 g, 33.98 mmol
  • 1 ,4- dioxan 25 mL
  • water 4 mL
  • Pd(PPh 3 ) 4 1.5 g, 1.30 mmol
  • Step 2 Preparation of 6-isopropylimidazo[l,2-b]pyridazine.
  • 6-(prop-l-en-2- yl)imidazo[l,2-b]pyridazine(3.8 g) in ethanol(30 mL) was added Pd/C(380 mg, 10% w/w) and stirred under hydrogen (60 psi) for 16 h.
  • the reaction mixture was filtered through celite pad, and the filtrate was concentrated to afford 6-isopropylimidazo[l,2-b]pyridazine (4.0 g, LC-MS 78%) as an orange oil.
  • MS (ESI) m/z: 162.2 [C 9 H 9 N 3 +H] + .
  • Step 3 Preparation of 3-iodo-6-isopropylimidazo[l,2-b]pyridazine.
  • 6- isopropylimidazo[l,2-b]pyridazine 3.5 g 18.63 mmol
  • DMF(10 mL) DMF(10 mL)
  • N- iodosuccinimide N- iodosuccinimide
  • the reaction mixture was diluted with water, the solid that has precipitated was isolated by filtration and washed several times with water to afford 3-iodo-6-isopropylimidazo[l,2-b]pyridazine(3.5 g, LC-MS 74%) as a yellow solid.
  • MS (ESI) m/z: 288.02 [C 9 H 8 N 3 I+H] +
  • Step 4 Preparation of teri-butyl 5-((6-isopropylimidazo[l,2-b]pyridazin-3- yl)ethynyl)thiazol-2-ylcarbamate.
  • Step 5 Preparation of 5-((6-isopropylimidazo[l,2-b]pyridazin-3- yl)ethynyl)thiazol-2-amine.
  • teri-butyl 5-((6-isopropylimidazo[l,2- b]pyridazin-3-yl)ethynyl)thiazol-2-ylcarbamate (2 g, 5.22 mmol) in dichloromethane (10 mL) and TFA (8 mL) was stirred at room temperature for 3 h.
  • the reaction mixture was diluted with water and basified with NaHC0 3, extracted with CHC1 3 .
  • Step 1 Preparation of 6-cyclopropyl-3-iodoimidazo[l,2-b]pyridazine.
  • a mixture of 6-cyclopropylimidazo[l,2-b]pyridazine (700 mg, 4.4 mmol) and N-iodosuccinimide (1 g, 4.84 mmol) in DMF (5 mL) was stirred at room temperature for 2 h.
  • the reaction mixture was diluted with water, the precipitate was washed several times with water to afford 6- cyclopropyl-3-iodoimidazo[l,2-b]pyridazine (800 mg, LC-MS 70%) as a yellow solid.
  • Step 2 Preparation of teri-butyl 5-((6-cyclopropylimidazo[l,2-b]pyridazin-3- yl)ethynyl)thiazol-2-ylcarbamate.
  • Step3 Preparation of 5-((6-cyclopropylimidazo[l,2-b]pyridazin-3- yl)ethynyl)thiazol-2-amine.
  • the reaction mixture was diluted with water and basified with 30% NaOAc solution and extracted with CHC1 3 .
  • Step 1 Preparation of teri-butyl 5-(imidazo[l,2-b]pyridazin-3-ylethynyl)thiazol-2- ylcarbamate.
  • teri-butyl 5-ethynylthiazol-2-ylcarbamate 918 mg, 4.09 mmol
  • 3-iodoimidazo[l,2-b]pyridazine (1 g, 4.09 mmol)
  • Cul (12 mg, 0.614 mmol)
  • DIPEA (1.15 mL, 0.614 mmol) in acetonitrile (15 mL) under argon were added Pd(PPh 3 ) 4 (236 mg, 0.204 mmol) and PPh 3 (53 mg, 0.204 mmol).
  • Step 2 Preparation of 5-(imidazo[l,2-b]pyridazin-3-ylethynyl)thiazol-2-amine.
  • the reaction mixture was diluted with water and basified with a 30% aqueous solution of NaOAc and extracted with ethyl acetate.
  • Step 1 Preparation of phenyl 3-ethynylphenylcarbamate.
  • 3-ethynylaniline 5 g, 42.73 mmol
  • pyridine 2 mL
  • dichloromethane 20 mL
  • phenylchloroformate 3 mL dissolved in 5 mL DCM
  • Step 2 Preparation of l-(3-ethynylphenyl)-3-(4-((4-methylpiperzin-l-yl) methyl)- (Trifluoromethyl) phenyl) urea.
  • Step 1 Preparation of teri-butyl 4-(4-(4-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-2- ylcarbamoyl)-2-(trifluoromethyl)benzyl)piperazine- 1 -carboxylate
  • Step 2 Preparation of N-(4-((l -methyl- lH-pyrazol-4-yl) ethynyl) pyridin-2-yl)-4-(piperazin- 1 -ylmethyl)-3-(trifluoromethyl) benzamide
  • Example 2 4-(( 4-ethylpiperazin-l-yl jmethyl )-N-(4-( (6-( methylamino )pyridin-3- yl)ethynyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide
  • Step 1 Preparation of teri-butyl 5-bromopyridin-2-yl(methyl)carbamate
  • Step 2 Preparation of teri-butyl methyl (5-((trimethylsilyl)ethynyl)pyridin-2- yl)carbamate; The title compound was synthesized from teri-butyl 5-bromopyridin-2- yl(methyl) carbamate and ethynyltrimethylsilane following a method similar to general procedure A.
  • reaction crude product was purified by chromatography (silica gel, eluent hexanes/ethyl acetate 98:2) to afford teri-butyl methyl(5-((trimethylsilyl)ethynyl)pyridin-2- yl)carbamate (1.3 g, 68.4%) as a brown liquid.
  • Step 3 Preparation of teri-butyl 5-ethynylpyridin-2-yl(methyl)carbamate; A solution of tert- butyl methyl (5-((trimethylsilyl)ethynyl)pyridin-2-yl)carbamate (1.3 g, 4.26 mmol) and K2CO 3 (1.15 g, 8.52 mmol) in methanol (20 mL) was stirred at room temperature for 3 h and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed in turn with water and brine.
  • Step 4 Preparation of teri-butyl 5-((2-(4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzanndo)pyridin-4-yl)ethynyl)pyridin-2-yl(methyl)carbamate ;
  • the title compound was synthesized from teri-butyl 5-ethynylpyridin-2-yl(methyl)carbamate and N- (4-bromopyridin-2-yl)-4-((4-emylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamide following a method similar to general procedure A.
  • Step 5 preparation of 4-((4-ethylpiperazin-l-yl)methyl)-N-(4-((6- (memylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide;
  • the title compound was synthesized from teri-butyl 5-((2-(4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamido)pyridin-4-yl)ethynyl)pyridin-2-yl(methyl)carbamate following a method similar to general procedure D.
  • Step 1 Preparation of N-(3-methyl-5-((trimethylsilyl)ethynyl)pyridin-2- yl)acetamide;
  • the title compound was synthesized from N-(5-bromo-3-methylpyridin-2- yl)acetamide and ethynyltrimethylsilane following a method similar to general procedure A.
  • the residue mixture was purified by column chromatography (silica gel, eluents
  • Step 2 Preparation of N-(5-ethynyl-3-methylpyridin-2-yl)acetamide; To a solution of N-(3-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)acetamide (153 mg, 0.62 mmol) in MeOH (10 mL) was added potassium carbonate (300 mg, 3.49 mmol) and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, then diluted with water (100 mL) and extracted with DCM (3x15 mL).
  • Step 3 Preparation of N-(4-((6-acetamido-5-methylpyridin-3-yl)ethynyl)pyridin- 2-yl)-4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benz amide
  • the title compound was prepared following a method similar to general procedure A and starting from N-(4-bromopyridin-2-yl)-4-((4-ethylpiperazin- l-yl)methyl)-3- (trifluoromethyl)benzamideamine and N-(5-ethynyl-3-methylpyridin-2-yl)acetamide.
  • Example 7 4-(( 4-ethylpiperazin-l-yl )methyl )-N-(4-( (6-( methylsulfonamido )pyridin-3- yl)ethynyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide
  • Step 1 Preparation of 5-((trimethylsilyl) ethynyl) pyridine-2, 3-diamine;
  • the title compound was synthesized from 5-bromopyridine-2,3-diamine and ethynyltrimethylsilane following a method similar to general procedure A.
  • Crude product was purified by column chromatography (silica gel, methnol/dichloromethane 1 : 100) to afford 5- ((trimethylsilyl)ethynyl)pyridine-2,3-diamine (600 mg, 60 %) as pale brown color solid.
  • MS (ESI) m/z 206.3 [C 10 Hl5N 3 Si] +
  • Step 2 Preparation of 5-ethynylpyridine-2, 3-diamine;
  • a solution of 5- ((trimethylsilyl) ethynyl) pyridine-2,3-diamine (600 mg, 2.92 mmol) and LiOH (184 mg,4.39 mmol) in mixture of THF (10 mL) and water (5 mL) was stirred at room temperature for 3 h.
  • the reaction mixture was concentrated under reduce pressure, the residue was diluted with EtOAc and washed in turn with water and brine.
  • Organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford 5-ethynylpyridine-2, 3-diamine (300 mg, 79 %) as pale brown color solid.
  • MS (ESI) m/z 134 [C 7 H 7 N 3 +H] +
  • Step 3 Preparation of N-(4-((5, 6-diaminopyridin-3-yl) ethynyl) pyridin-2-yl)-4- ((4-ethylpiperazin-l-yl) methyl)-3-(trifluoromethyl) benzamide;
  • the title compound was synthesized from5-ethynylpyridine-2, 3-diamine and N-(4-bromopyridin-2-yl)-4-((4- ethylpiperazin-l-yl) methyl)-3-(trifluoromethyl) benzamide following a method similar to general procedure A.
  • Example 11 4-((4-ethylpiperazin-l-yl)methyl)-N-(4-((6-pivalamidopyridin-3- yl)ethynyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide H
  • Example 17 N-(4-(2-(5-(cyclopropanecarboxamido)pyridin-3-yl)ethynyl)pyridin-2-yl)-4-((4- ethyl)-3-(trifluoromethyl)benzamide
  • Example 18 N-(4-(2-(6-aminopyridazin-3-yl)ethynyl)pyridin-2-yl)-4-((4-ethylpiperazin-l- yl )methyl )-3-( trifluoromethyl )benzamide
  • Example 20 4-(piperazin-l-ylmethyl)-N-(4-(pyrimidin-5-ylethynyl) pyridin-2-yl)-3-
  • Step 1 Preparation of teri-butyl 4-(4-(4-(pyrimidin-5-ylethynyl) pyridin-2- ylcarbamoyl)-2-(trifluoromethyl) benzyl) piperazine-l-carboxylate;
  • the title compound was synthesized from teri-butyl4-(4-(4-bromopyridin-2-y5-ethynylpyrimidine carbanoyl)-2- (trifluoromethyl)benzyl)piperazine-l-carboxylate and 5-ethynylpyrimidine in a similar method to that described in general procedure A.
  • Step 2 Preparation of 4-(piperazin-l-ylmethyl)-N-(4-(pyrimidin-5-ylethynyl) pyridin-2-yl)-3-(trifluoromethyl) benzamide; The title compound was synthesized from tert- butyl 4-(4-(4-(pyrimidin-5-ylethynyl)pyridin-2-ylcarbamoyl)-2-
  • Step 1 Preparation of teri-butyl 5-((trimethylsilyl)ethynyl)thiazol-2-ylcarbamate;
  • the title compound was synthesized from teri-butyl 5-bromothiazol-2-yl carbamate and Ethynyltrimethylsilane following a method similar to general procedure A.
  • the crude product was purified by column chromatography (silica gel, hexane/ethyl acetate 95:5) to afford tert- butyl 5-((trimethylsilyl)ethynyl)thiazol-2-ylcarbamate (1.4 g).
  • Step 2 Preparation of teri-butyl 5-ethynylthiazol-2-ylcarbamate; A solution of LiOH in water was added to a solution of teri-butyl 5-((trimethylsilyl)ethynyl)thiazol-2- ylcarbamate (1.4 g, 5.04 mmol) in THF (15 mL). Reaction was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, extracted into EtOAc. The extracts were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • Step 3 Preparation of teri-butyl 5-((2-(4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamido)pyridin-4-yl)ethynyl)thiazol-2-ylcarbamate;
  • the title compound was synthesized from N-(4-bromopyridin-2-yl)-4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamide and teri-butyl 5-ethynylthiazol-2-ylcarbamate following a method similar to general procedure A.
  • Step 4 Preparation of N-(4-((2-aminothiazol-5-yl)ethynyl)pyridin-2-yl)-4-((4- ethylpiperazin-l-yl)memyl)-3-(trifluoromethyl)benzamide;
  • the title compound was synthesized from teri-butyl 5-((2-(4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamido)pyridin-4-yl)ethynyl)thiazol-2-ylcarbamate in a similar method as described in general procedure D.
  • Step 1 Preparation of N-(5-bromothiazol-2-yl)acetamide
  • Acetyl chloride (0.14 mL, 1.924 mmol) was added drop wise to a cooled mixture of 5- bromothiazol-2-amine hydrobromide (500 mg, 1.92 mmol) and triethyl amine (0.53 mL, 3.85 mmol) in CH2CI2 (5 mL) at room temperature.
  • the reaction mixture was stirred at room temperature for 14 h and was diluted with CH 2 CI 2 , washed with a saturated aqueous solution of NaHC(3 ⁇ 4, followed by brine.
  • the organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column
  • Step 2 Preparation of N-(4-((2-acetamidothiazol-5-yl) ethynyl) pyridin-2-yl)-4- ((4-ethylpiperazin-l-yl) methyl)-3-(trifluoromethyl) benzamide;
  • the title compound was synthesized from N-(5-bromothiazol-2-yl) acetamide and 4-((4-ethylpiperazin-l-yl)methyl)- N-(4-ethynylpyridin-2-yl)-3-(trifluoromethyl)benzamide following a method similar to general procedure A.
  • reaction crude product was purified by preparative HPLC to afford N-(4-((2-acetamidothiazol-5-yl) ethynyl) pyridin-2-yl)-4-((4-ethylpiperazin-l-yl) methyl)-3- (trifluoromethyl) benzamide (110 mg, AUC HPLC 98.5 %) as an off-white solid.
  • reaction crude product was purified by preparative HPLC to afford N-(4-((2- (cyclopropanecarboxamido)thiazol-5-yl)ethynyl)pyridin-2-yl)-4-((4-ethylpiperazin-l- yl)methyl)-3-(trifluoromethyl)benzamide (12 mg, 12.6%, AUC HPLC 95.1%) as a yellow solid.
  • Step 1 Preparation of teri-butyl 4-(4-(4-((l-methyl-lH-pyrazol-5-yl) ethynyl) pyridin-2-ylcarbamoyl)-2-(trifluoromethyl) benzyl) piperazine-l-carboxylate;
  • the title compound was synthesized from teri-butyl 4-(4-(4-ethynylpyridin-2-ylcarbamoyl)-2- (trifluoromethyl)benzyl)piperazine- 1 -carboxylate and 5-iodo- 1 -methyl- lH-pyrazole following a method similar to general procedure A.
  • Step 2 Preparation of N-(4-((l-methyl-lH-pyrazol-5-yl) ethynyl) pyridin-2-yl)-4- (piperazin-l-ylmethyl)-3-(trifluoromethyl) benzamide;
  • the title compound was synthesized from teri-butyl 4-(4-(4-((l-methyl-lH-pyrazol-5-yl)ethynyl)pyridin-2-ylcarbamoyl)-2- (trifluoromethyl)benzyl)piperazine-l -carboxylate in a similar method as described in general procedure D.
  • Example 25 4-((4-ethylpiperazin-l-yl)methyl)-N-(4-((3-methyl-lH-pyrazol-4- yl)ethynyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide
  • Step 1 Preparation of teri-butyl 4-(4-(4-((l,2-dimethyl-lH-imidazol-5-yl)ethynyl)pyridin-2- ylcarbamoyl)-2-(trifluoromethyl)benzyl)piperazine- 1 -carboxylate
  • Step 2 preparation of N-(4-((l,2-dimethyl-lH-imidazol-5-yl)ethynyl)pyridin-2-yl)-4- (piperazin- 1 -ylmethyl)-3-(trifluoromethyl)benzamide
  • Step 1 Preparation of teri-butyl 4-(4-(4-(pyridin-3-ylethynyl) pyridin-2-ylcarbamoyl)-2- (trifluoromethyl) benzyl) piperazine-l-carboxylate
  • Step 2 Preparation of 4-(piperazin-l-ylmethyl)-N-(4-(pyridin-3-ylethynyl)pyridin-2-yl)-3- (trifluoromethyl)benzamide
  • Step 1 Preparation of 5-((trimethylsilyl)ethynyl)pyridin-2-amine.
  • Step 3 Preparation of N-(4-((6-aminopyridin-3-yl)ethynyl)pyridin-2-yl)-4-((4-ethylpiperazin- l-yl)methyl)-3-(trifluoromethyl)benzamide
  • the title compound was synthesized following a method similar to general procedure A and starting from N-(4-bromopyridin-2-yl)-4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)benzamide and 5-ethynylpyridin-2-amine.
  • the reaction crude product was purified by preparative HPLC to afford N-(4-((6-aminopyridin-3-yl)ethynyl)pyridin-2-yl)-4- ((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamide (90 mg, 21%, AUC HPLC 99.4%) as an off white solid.
  • Step 1 Preparation of l-(5-bromopyridin-2-yl)ethanone
  • Step 2 Preparation of N-(4-((6-acetylpyridin-3-yl)ethynyl)pyridin-2-yl)-4-((4-ethylpiperazin- l-yl)methyl)-3-(trifluoromethyl)benzamide
  • Step 1 Preparation of N-(4-((6-(cyclopropanecarboxamido) pyridin-3-yl) ethynyl) pyridin-2- yl)-4-((4-ethylpiperazin- 1 -yl) methyl)-3-(trifluoromethyl) benzamide
  • Step 1 Preparation of N-(5-((trimethylsilyl) ethynyl) pyridin-2-yl) acetamide.
  • Step 2 Preparation of N-(5-ethynylpyridin-2-yl) acetamide.
  • Step 3 preparation of N-(4-((6-acetamidopyridin-3-yl) ethynyl) pyridin-2-yl)-4-((4- ethylpiperazin-l-yl) methyl)-3-(trifluoromethyl) benzamide
  • Step 1 Preparation of 5-((trimethylsilyl)ethynyl)pyrimidin-2-amine
  • Step 3 Preparation of N-(4-((2-aminopyrimidin-5-yl) ethynyl) pyridin-2-yl)-4-((4- ethylpiperazin- 1 -yl) methyl)-3-(trifluoromethyl)benzamide
  • Example 35 4-((4-ethylpiperazin-l-yl)methyl)-N-(4-(thiazol-5-ylethynyl)pyridin-2-yl)-3- ide

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Abstract

La présente invention porte sur certains composés hétéroarylalcyne de formule (I) qui sont utiles en tant qu'inhibiteurs de kinase. La présente invention porte en outre sur des compositions pharmaceutiques comprenant ces composés, sur l'utilisation de ces composés pour la prévention et le traitement de maladies (par exemple, des maladies prolifératives (par exemple, le cancer), de maladies inflammatoires, de maladies auto-immunes, de maladies métaboliques, de maladies neurodégénératives (par exemple, la maladie d'Alzheimer) ou de troubles neurologiques du développement (par exemple, l'autisme); ainsi que sur des méthodes de traitement de ces maladies.
PCT/SG2015/050005 2014-01-17 2015-01-19 Dérivés hétéroarylalcyne et leurs utilisations WO2015108490A2 (fr)

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GB1400787.6A GB2522226A (en) 2014-01-17 2014-01-17 Heteroaryl alkyne derivatives and uses thereof
GB1400787.6 2014-01-17

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WO2018161033A1 (fr) * 2017-03-02 2018-09-07 Wright, Adrian Inhibiteurs ire1-alpha à petites molécules
WO2019013703A1 (fr) * 2017-07-14 2019-01-17 Agency For Science, Technology And Research (A*Star) Dérivés alcyne bicycliques et leurs utilisations
JP2019527725A (ja) * 2016-08-15 2019-10-03 パデュー リサーチ ファウンデイション ４位置換アミノイソキノリン誘導体
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JP2020503299A (ja) * 2016-12-15 2020-01-30 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ−ｋｉｔ阻害剤としてのベンズイミダゾール化合物
WO2020206583A1 (fr) * 2019-04-08 2020-10-15 Qilu Regor Therapeutics Inc. Inhibiteurs de kinase et leurs utilisations
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JP2018530598A (ja) * 2016-04-18 2018-10-18 リミテッド・ライアビリティ・カンパニー・《フュージョン・ファーマ》Ｌｉｍｉｔｅｄ Ｌｉａｂｉｌｉｔｙ Ｃｏｍｐａｎｙ （Ｆｕｓｉｏｎ Ｐｈａｒｍａ） 医学的適用用の３−（１，２，４−トリアゾロ［４，３−ａ］ピリジン−３−イルエチニル）−４−メチル−Ｎ−（４−（（４−メチルピペラジン−１−イル）メチル）−３−トリフルオロメチルフェニル）ベンズアミドの新規な結晶性塩形態
WO2017184032A1 (fr) 2016-04-18 2017-10-26 Limited Liability Company «Fusion Pharma» Nouvelles formes de sel cristallin du 3-(1,2,4-triazolo[4,3-a]pyridin-3-yléthynyl)-4-méthyl-n-(4-((4-méthylpipérazin-1-yl)méthyl)-3-trifluorométhylphényl)benzamide pour une application médicale
EA032865B1 (ru) * 2016-04-18 2019-07-31 Общество С Ограниченной Ответственностью "Фьюжн Фарма" НОВАЯ КРИСТАЛЛИЧЕСКАЯ СОЛЕВАЯ ФОРМА 3-(1,2,4-ТРИАЗОЛО[4,3-a]ПИРИДИН-3-ИЛЭТИНИЛ)-4-МЕТИЛ-N-(4-((4-МЕТИЛПИПЕРАЗИН-1-ИЛ)МЕТИЛ)-3-ТРИФТОРМЕТИЛФЕНИЛ)БЕНЗАМИДА ДЛЯ МЕДИЦИНСКОГО ПРИМЕНЕНИЯ
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WO2018068739A1 (fr) * 2016-10-13 2018-04-19 深圳市塔吉瑞生物医药有限公司 Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase
JP7158382B2 (ja) 2016-12-15 2022-10-21 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ－ｋｉｔ阻害剤としてのアミノチアゾール化合物
AU2022201082B2 (en) * 2016-12-15 2023-11-02 Ariad Pharmaceuticals, Inc. Benzimidazole compounds as c-Kit inhibitors
JP2020503297A (ja) * 2016-12-15 2020-01-30 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ−ｋｉｔ阻害剤としてのアミノチアゾール化合物
JP2020503299A (ja) * 2016-12-15 2020-01-30 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ−ｋｉｔ阻害剤としてのベンズイミダゾール化合物
JP2022185110A (ja) * 2016-12-15 2022-12-13 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ－ｋｉｔ阻害剤としてのベンズイミダゾール化合物
US11753404B2 (en) 2016-12-15 2023-09-12 Ariad Pharmaceuticals, Inc. Aminothiazole compounds as c-Kit inhibitors
JP2022185107A (ja) * 2016-12-15 2022-12-13 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ－ｋｉｔ阻害剤としてのアミノチアゾール化合物
JP7158383B2 (ja) 2016-12-15 2022-10-21 アリアド ファーマシューティカルズ， インコーポレイテッド Ｃ－ｋｉｔ阻害剤としてのベンズイミダゾール化合物
CN110582483A (zh) * 2017-02-20 2019-12-17 中国科学院上海药物研究所 含邻氨基杂芳环炔基的化合物及其制备方法和用途
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RU2797694C2 (ru) * 2017-02-20 2023-06-07 Шангхаи Институте Оф Материа Медика, Чайнесе Академи Оф Сайнсес О-аминогетероарилалкинилсодержащее соединение, способ его получения и его применение
JP2020510642A (ja) * 2017-02-20 2020-04-09 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｍａｔｅｒｉａ Ｍｅｄｉｃａ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ ｏ−アミノヘテロアリールアルキニル基含有化合物およびその製造方法と用途
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CN108456163A (zh) * 2017-02-20 2018-08-28 中国科学院上海药物研究所 含邻氨基杂芳环炔基的化合物及其制备方法和用途
WO2018149382A1 (fr) 2017-02-20 2018-08-23 中国科学院上海药物研究所 Composé contenant un alcynyle o-aminohétéroaryle, son procédé de préparation et son utilisation
WO2018161033A1 (fr) * 2017-03-02 2018-09-07 Wright, Adrian Inhibiteurs ire1-alpha à petites molécules
WO2019013703A1 (fr) * 2017-07-14 2019-01-17 Agency For Science, Technology And Research (A*Star) Dérivés alcyne bicycliques et leurs utilisations
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US20220041590A1 (en) * 2018-09-28 2022-02-10 Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of dyrk/clk and uses thereof
WO2020206583A1 (fr) * 2019-04-08 2020-10-15 Qilu Regor Therapeutics Inc. Inhibiteurs de kinase et leurs utilisations
CN114340734A (zh) * 2019-06-24 2022-04-12 博善人工智能生物科技有限公司 新化合物和方法
WO2021164045A1 (fr) * 2020-02-21 2021-08-26 Ascentage Pharma (Suzhou) Co., Ltd. Procédé de préparation d'un composé contenant un alcynyle et d'un intermédiaire de celui-ci
CN113292556A (zh) * 2020-02-21 2021-08-24 苏州亚盛药业有限公司 一种含炔基的化合物的制备方法及其中间体
WO2022053014A1 (fr) * 2020-09-10 2022-03-17 Ascentage Pharma (Suzhou) Co., Ltd. Procédé de préparation de composé contenant un alcynyle et de son intermédiaire
CN114163434A (zh) * 2020-09-10 2022-03-11 苏州亚盛药业有限公司 一种含炔基化合物及其中间体的制备方法
WO2022149855A1 (fr) * 2021-01-05 2022-07-14 주식회사 비투에스바이오 Composé dérivé hétéroaryl-éthynyle et son utilisation
WO2022217821A1 (fr) * 2021-04-13 2022-10-20 深圳市新樾生物科技有限公司 Composé d'alkynylphénylbenzamide et son utilisation
US11834454B2 (en) 2021-04-13 2023-12-05 Shenzhen Newdel Biotech Co., Ltd. Alkynylphenylbenzamide compounds and applications thereof
WO2024062360A1 (fr) 2022-09-21 2024-03-28 Pfizer Inc. Inhibiteurs hétérocycliques de sik

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