WO2009120094A2 - Substituted pyrimidines and triazines and their use in cancer therapy - Google Patents

Substituted pyrimidines and triazines and their use in cancer therapy Download PDF

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Publication number
WO2009120094A2
WO2009120094A2 PCT/NZ2009/000038 NZ2009000038W WO2009120094A2 WO 2009120094 A2 WO2009120094 A2 WO 2009120094A2 NZ 2009000038 W NZ2009000038 W NZ 2009000038W WO 2009120094 A2 WO2009120094 A2 WO 2009120094A2
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WIPO (PCT)
Prior art keywords
triazin
difluoromethyl
moφholinyl
benzimidazol
methoxy
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PCT/NZ2009/000038
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French (fr)
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WO2009120094A3 (en
Inventor
Gordon William Rewcastle
Peter Robin Shepherd
Claire Chaussade
William Alexander Denny
Swarnalatha Akuratiya Gamage
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Auckland Uniservices Limited
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Application filed by Auckland Uniservices Limited filed Critical Auckland Uniservices Limited
Priority to US12/934,616 priority Critical patent/US20110053907A1/en
Priority to JP2011501736A priority patent/JP2011515462A/en
Priority to EP09724191A priority patent/EP2276750A2/en
Publication of WO2009120094A2 publication Critical patent/WO2009120094A2/en
Publication of WO2009120094A3 publication Critical patent/WO2009120094A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • substituted pyrimidine and triazine derivatives including bicyclic pyrimidine derivatives, their pharmaceutical compositions, their preparation, and their use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.
  • the substituted pyrimidine and triazine derivatives are morpholino-pyrimidine, morpholino-triazine, pyridyl-pyrimidine, and pyridyl- triazine derivatives which are selective irreversible inhibitors of the pi 10a isoform of PBK.
  • Phosphoinositide-3-kinases are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into three classes (Classes I, II, and III) and play an important role in cellular signaling (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357).
  • the Class I enzymes are further classified into Class Ia and Ib based on their mechanism of activation; the Class Ia PBKs are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi lO ⁇ , or pi 108) in complex with a regulatory p85 subunit, while the class-Ib PBK (pi lO ⁇ ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by ⁇ subunits of heterotrimeric G-proteins (Walker et al., MoI .Cell. 2000, 6, 909).
  • the human protein sequence of the pi 10a isoform is described in Volina et al., Genomics 1994, 24, All; and Stirdivant et al., Bioorg. Med. Chem. 1997, 5, 65.
  • PBKs play a variety of roles in normal tissue physiology (Foukas & Shepherd,
  • the PI3K enzymes produce phosphoinositide 3, 4,5 -triphosphate (PIP3) from the corresponding diphosphate (PBP2), thus recruiting AKT (protein kinase B) through its Pleckstrin homology (PH) domain to the plasma membrane.
  • PBP2 protein kinase B
  • PH Pleckstrin homology
  • the pi 10a isoform is selectively amplified and activated in a number of cancer types (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357; Stauffer et al., Curr. Med. Chem. - Anti-Cancer Agents 2005, 5, 449).
  • cancer types Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357; Stauffer et al., Curr. Med. Chem. - Anti-Cancer Agents 2005, 5, 449.
  • pan- PDK inhibitor LY294002 While PI3K isoenzymes play important roles in many cellular processes, published experimental studies in mice with human tumour xenografts show that the pan- PDK inhibitor LY294002 is well-tolerated, reduces signalling through the PI3K pathway, causes reduction of tumour volume, and is more active in cell lines over-expressing mutant forms of pi 1Oq than parental control cells (Semba et al., Clin. Cancer Res. 2002, 8, 1957; Hu et al., Cancer Res. 2002, 62, 1087).
  • PI3K is an interesting target for drug intervention.
  • LY 294002 non-selective
  • MoI .Cell. 2000, 6, 909 PI103 (slightly ⁇ -selective)
  • PI103 lightly ⁇ -selective
  • ZSTK474 non-selective
  • AH of the above mentioned compounds function as reversible inhibitors of the appropriate PBK isoforms.
  • irreversible activity is displayed by the fungal metabolite wortmannin and its analogues, such as PWT-458 (Zhu et al, J. Med. Chem, 2006, 49, 1373) and PX-866 (Wipf et al., Org. Biomol. Chem. 2004, 2, 1911; Zask et al., J. Med. Chem.
  • PI3K inhibitors that are more potent and more selective, exhibit better pharmacokinetic properties, and/or produce fewer side effects than the existing PI3K inhibitors.
  • each Ri is independently C 6-H aryl, heteroaryl, or heterocyclyl
  • each R 2 is independently C 6 - H aryl, heteroaryl, or heterocyclyl
  • each R 3 and R 4 is independently hydrogen, lower alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, or R 5
  • each R 5 is independently halogen or -OSO 2 R 7
  • R 6 is C 3 . 7 cycloalkyl, C 6 - H aryl, heteroaryl, or heterocyclyl
  • R 7 is lower alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C 6-H aryl, heteroaryl, or heterocyclyl;
  • Rio is (a) hydrogen, amino, or hydroxyl; or (b) lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CR 8 , with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R 8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR 9 , where R 9 is hydrogen, halogen, or lower alkyl; wherein the bonds between A, B, D, and E may be saturated or unsaturated; with the proviso that no more than one of A, B, D, and E are a direct bond; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and
  • compositions comprising a compound disclosed herein, e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
  • a compound disclosed herein e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
  • a method for treating, preventing, or ameliorating one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound disclosed herein e.g., a compound of Formula I, an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method for modulating PI3K activity comprising contacting a PI3K with a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound disclosed herein e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • FIG. 1 shows the irreversible binding of the compound of Example 4 to PI3K.
  • subject refers to an animal, including, but not limited to, a primate
  • subject e.g., human
  • cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse e.g., cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • treat means to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • terapéuticaally effective amount are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • active ingredient and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • drug refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein.
  • alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci -2 O), 1 to 15 (C MS ), 1 to 10 (Ci. io), or 1 to 6 (Ci- ⁇ ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-2O ), 3 to 15 (C 3 . 15 ), 3 to 10 (C 3-I o), or 3 to 6 (C 3 .
  • Ci -6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • alkylene refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein.
  • alkylene encompasses both linear and branched alkylene, unless otherwise specified.
  • the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C !-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-I0 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-1S ), 3 to 10 (C 3 . io), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear C 1-6 and branched C 3-6 alkylene groups are also referred as "lower alkylene.”
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
  • C 1-6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds.
  • the alkenyl may be optionally substituted as described herein.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, “Z” and “E” configurations, as appreciated by those of ordinary skill in the art.
  • alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
  • C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-I s), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
  • alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds.
  • the alkenylene may be optionally substituted as described herein.
  • alkenylene also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and “Z” configurations.
  • alkenylene encompasses both linear and branched alkenylene, unless otherwise specified.
  • C 2- 6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-I5 ), 2 to 10 (C 2 - I o), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3 - 15 ), 3 to 10 (C3- 10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4- methylbutenylene.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds.
  • the alkynyl may be optionally substituted as described herein.
  • alkynyl also encompasses both linear and branched alkynyl, unless otherwise specified.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2 _ 20 ), 2 to 15 (C 2 - 15 ), 2 to 10 (C 2 - 1 0), or 2 to 6 (C 2 - 6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3 _ 2 o), 3 to 15 (C 3- I 5 ), 3 to 10 (C 3- I 0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • C 2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • alkynylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds.
  • the alkynylene may be optionally substituted as described herein.
  • alkynylene also encompasses both linear and branched alkynylene, unless otherwise specified.
  • the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 - I5 ), 2 to 10 (C 2-I0 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3- I 5 ), 3 to 10 (C 3- I 0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-) and propargylene (-CH 2 C ⁇ C-).
  • C 2-6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted as described herein.
  • the cycloalkyl has from 3 to 20 (C 3-2O ), from 3 to 15 (C 3 - 15 ), from 3 to 10 (C 3 - I o), or from 3 to 7 (C 3-7 ) carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
  • cycloalkylene refers to a cyclic saturated bridged and/or non- bridged divalent hydrocarbon radical, which may be optionally substituted as described herein.
  • the cycloalkylene has from 3 to 20 (C 3-2O ), from 3 to 15 (C 3 . 15 ), from 3 to 10 (C 3 _io), or from 3 to 7 (C 3-7 ) carbon atoms.
  • cycloalkylene groups include, but are not limited to, cyclopropylene (e.g., 1,1-cyclopropylene and 1,2- cyclopropylene), cyclobutylene (e.g., 1 , 1 -cyclobutylene, 1 ,2-cyclobutylene, or 1,3- cyclobutylene), cyclopentylene (e.g., 1,1-cyclopentylene, 1,2-cyclopentylene, or 1,3- cyclopentylene), cyclohexylene (e.g., 1,1-cyclohexylene, 1,2-cyclohexylene, 1,3- cyclohexylene, or 1 ,4-cyclohexylene), cycloheptylene (e.g., 1,1-cycloheptylene, 1,2- cycloheptylene, 1,3-cycloheptylene, or 1 ,4-cycloheptylene), decalinylene, and adamant
  • aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6-2O ), from 6 to 15 (C 6 -I 5 ), or from 6 to 10 (C ⁇ -io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted as described herein.
  • arylene refers to a monocyclic and/or multicyclic divalent aromatic group that contain at least one aromatic hydrocarbon ring.
  • the arylene has from 6 to 20 (C 6 . 2 o), from 6 to 15 (C 6-I s), or from 6 to 10 (C ⁇ -io) ring atoms.
  • arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene.
  • Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydro-naphthylene (tetralinyl).
  • arylene may also be optionally substituted as described herein.
  • aralkyl or "aryl-alkyl” refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted as described herein.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted as described herein.
  • heteroarylene refers to a divalent aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, imidazolylene, isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene, triazinylene, and triazolylene.
  • bicyclic heteroarylene groups include, but are not limited to, benzofuranylene, benzimidazolylene, benzoisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene, benzothienylene, benzothiophenylene, benzotriazolylene, benzoxazolylene, furopyridylene, imidazopyridinylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene, isothiazolylene, naphthyridinylene, oxazolopyridinylene, phthalazinylene, pteridinylene, purinylene, pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene
  • tricyclic heteroaryl groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, perimidinylene, phenanthrolinylene, phenanthridinylene, phenarsazinylene, phenazinylene, phenothiazinylene, phenoxazinylene, and xanthenylene.
  • heteroaryl may also be optionally substituted as described herein.
  • heterocyclyl refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4- dithianyl
  • heterocyclylene refers to a divalent non-aromatic ring system and/or multicyclic ring system that contain at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclene groups include, but are not limited to, azepinylene, benzodioxanylene, benzodioxolylene, benzofuranonylene, benzopyranonylene, benzopyranylene, benzotetrahydrofuranylene, benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene, ⁇ -carbolinylene, chromanylene, chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofurylene, dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene, dioxolanylene, 1 ,4- di
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • the term "optionally substituted” is intended to mean that a group, such as an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene, may be substituted with one or more substituents independently selected from, e.g., (a) Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C3.7 cycloalkyl, C 6-H aryl, C7.
  • a group such as an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, cycloalky
  • optically active and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
  • the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • the present disclosure broadly relates to a class of compounds for use as agents or drugs for cancer therapy.
  • the disclosure relates to a class of compounds that can be used as PI3K inhibitors.
  • PI3K inhibitors are thought to be valuable for the treatment of cell proliferation disorders, in one embodiment, as anti tumor agents.
  • each Ri is independently C 6 - M aryl, heteroaryl, or heterocyclyl
  • each R 2 is independently C 6 - M aryl, heteroaryl, or heterocyclyl
  • each R 3 and R 4 is independently hydrogen, lower alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R 5
  • each R 5 is independently halogen or -OSO 2 R 7 ;
  • Re is C 3-7 cycloalkyl, C ⁇ -i 4 aryl, heteroaryl, or heterocyclyl;
  • R 7 is lower alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 3 - 7 cycloalkyl, C 6-H aryl, heteroaryl, or heterocyclyl;
  • Rio is (a) hydrogen, amino, or hydroxyl; or (b) lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CR 8 , with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R 8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR 9 , where R 9 is hydrogen, halogen, or lower alkyl; wherein the bonds between A, B, D, and E may be saturated or unsaturated; with the proviso that no more than one of A, B, D, and E are a direct bond; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and
  • each Q 1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3.7 cycloalkyl, C 6 - H aryl, C 7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R 6 , -C(O)OR 6 , -C(O)NR f R g , -C(NR e )NR f R
  • each Ri is independently substituted or unsubstituted heteroaryl, or heterocyclyl; each R 2 is independently substituted or unsubstituted C 6- I 4 aryl, heteroaryl, or heterocyclyl; each R 3 and R 4 is independently hydrogen, lower alkyl, or R 5 ; each R5 is independently halogen or -OSO 2 R?;
  • R 6 is substituted or unsubstituted C 6-H aryl or heteroaryl
  • R 7 is substituted or unsubstituted lower alkyl or C 6-I4 aryl
  • Rio is (a) hydrogen, amino, or hydroxyl; or (b) substituted or unsubstituted lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CRg, with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R 8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR 9 , where R 9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated.
  • each Ri is independently substituted or unsubstituted morpholino or pyridyl; each R 2 is independently substituted or unsubstituted aryl, heteroaryl, or heterocyclyl; each R 3 and R 4 is independently hydrogen, lower alkyl, or R 5 ; each R5 is independently halogen or -OSO 2 R 7 ;
  • R 6 is substituted or unsubstituted aryl or heteroaryl
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Rio is (a) hydrogen, amino, hydroxyl, or hydroxymethyl; or (b) substituted or unsubstituted lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CR 8 , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR 9 , where R 9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated.
  • each Ri is independently substituted or unsubstituted 4-morpholino or 4- pyridyl; each R 2 is independently substituted or unsubstituted aryl, heteroaryl, or heterocyclyl; each R 3 and R 4 is independently hydrogen, lower alkyl, or R 5 ; each R 5 is independently halogen or -OSO 2 R 7 ;
  • R 6 is substituted or unsubstituted aryl or heteroaryl
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • X, Y, and Z are each independently a nitrogen atom or CR 8 , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR 9 , where R 9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated.
  • Ri is substituted or unsubstituted morpholino or pyridyl
  • R 2 is hydroxyphenyl, hydroxymethylphenyJ, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl-hydroxy-lH-benzimidazolyl, difluromethyl-methoxy- lH-benzimidazolyl, difluromethyl-ethoxy- lH-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)-lH-benzimidazolyl;
  • R 3 and R 4 are each independently hydrogen, chloro, or methyl
  • R 5 is chloro, bromo, or -OSO 2 -methyl
  • Q is a divalent linker selected from the group consisting of azetidinyleneamino, azetidinylene(methylamino), piperidyleneoxy, piperazinylene, piperidylene, piperidyleneamino, piperidylene(methylamino), pyrrolidinyleneamino, pyrrolidinylene(methylamino), and piperidylenethio;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 2 is 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2-amino-pyrid-5-yl, 2-amino- pyrimid-5-yl, indazol-4-yl, 2-difluromethyl-lH-benzimidazolyl, 2-difluromethyl-4-hydroxy- lH-benzimidazolyl, 2-difluromethyl-4-methoxy-lH-benzimidazolyl, 2-difluromethyl-4- ethoxy- 1 H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N-dimethylamino)propoxy)- 1 H- benzimidazolyl;
  • R 3 and R 4 are each independently hydrogen, chloro, or methyl
  • R 5 is chloro, bromo, or -OSO 2 -methyl
  • Q is a divalent linker selected from the group consisting of azetidinylene-4- amino, azetidinylene-4-methylamino, piperidylene-4-oxy, 1 ,4-piperazinylene, 1 ,4- piperidylene, piperidylene-3-amino, (/?)-piperidylene-3-amino, (5')-piperidylene-3-amino, piperidylene-3-methylamino, (/?)-piperidylene-3-methylamino, (5)-piperidylene-3- methylamino, piperidylene-4-amino, piperidylene-4-methylamino, pyrrolidinylene-3-amino, (/?)-pyrrolidinylene-3-amino, (5)-pyrrolidinylene-3-amino, pyrrolidinylene-3-methylamino, ( ⁇ )-pyrrolidinylene-3-methylamino, (5)-pyrrolidiny
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.
  • Examples of the linker group defined by Q may include, but are not restricted to, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocyclylene, tetrahydropyridinylene, divalent amino (- ⁇ H— ), alkyleneamino, substituted alkyleneamino, alkenyleneamino, cycloalkyleneamino, cycloalkenyleneamino, aryleneamino, heteroaryleneamino, heterocyclyleneamino, divalent aminoarylamino, divalent aminoheteroarylamino, divalent aminoheterocyclylamino, tetrahydropyridinyleneamino, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, azetidinyleneamino, pyrrolidinyleneamino, piperidinylene,
  • R 2 may include, but are not restricted to, 3-hydroxyphenyl, 3-
  • R 6 may include, but are not restricted to, 3-hydroxyphenyl, 3-
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO2R7
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl.
  • the compound of Formula Ia has the structure of
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl;
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl.
  • the compound of Formula Ia has the structure of
  • Ri, R 3 , R 4 , R 5 , Q, T, X, Y, and Z are each as defined herein;
  • R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl; and
  • R 9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
  • V or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
  • Ri, R 3 , R 4 , R 5 , Q, T, X, Y, and Z are each as defined herein;
  • R 9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl; and
  • R 9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
  • the compound of Formula Ia has the structure of
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl.
  • the compound of Formula Ia has the structure of
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl; and
  • Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
  • the compound of Formula Ia has the structure of
  • Ri, R. 3 , R 4 , R5, Rio, T, X, Y, and Z are each as defined herein;
  • U is CH or N.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl;
  • U is CH or N
  • Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
  • the compound of Formula Ia has the structure of
  • Ri, R 3 , R 4 , R 5 , Rio, T, X, Y, and Z are each as defined herein;
  • G and J are each independently a direct bond or -CH 2 -;
  • W is a direct bond; or oxygen, sulfur, or NRn; where Rn is hydrogen, or substituted or unsubstituted lower alkyl.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CR 8 , except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl;
  • Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido;
  • G and J are each independently a direct bond or -CH 2 -;
  • W is a direct bond; or oxygen, sulfur, or NRn; where Rn is hydrogen, or substituted or unsubstituted lower alkyl.
  • Rn is hydrogen, or substituted or unsubstituted lower alkyl.
  • Ri, R 3 , R 4 , R 5 , Rio, T, X, Y, and Z are each as defined herein;
  • Rn is hydrogen, or substituted or unsubstituted lower alkyl; and
  • G and J are each independently a direct bond or -CH 2 -.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • T is -CO-, -CS-, or -SO 2 -;
  • X, Y, and Z are nitrogen atoms or CRg, except that at least two of X, Y, and Z are nitrogen atoms; where R 8 is hydrogen or lower alkyl;
  • Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido;
  • Rn is hydrogen, or substituted or unsubstituted lower alkyl
  • G and J are each independently a direct bond or -CH 2 -.
  • the compound of Formula Ic has the structure of
  • Ri, R 2 , R 3 , R4, R 5 , Q, and T are each as defined herein;
  • Rn is hydrogen, or substituted or unsubstituted lower alkyl
  • V is oxygen or sulfur.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 2 is substituted or unsubstituted aryl, heteroaryl, or heterocyclyl
  • R 3 and R 4 are each independently hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -;
  • Rn is hydrogen, or substituted or unsubstituted lower alkyl
  • V is oxygen or sulfur.
  • the compound of Formula Ic has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 5 , Q, and T are each as defined herein.
  • R 1 is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 2 is substituted or unsubstituted aryl, heteroaryl, or heterocyclyl
  • R 3 and R 4 are each independently hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -.
  • the compound of Formula Ic has the structure of
  • Ri, R 3 , R 4 , R 5 , Q, and T are each as defined herein; and R 6 is substituted or unsubstituted aryl or heteroaryl.
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are ach independently hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R 7 ;
  • R 6 is substituted or unsubstituted aryl or heteroaryl
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -.
  • the compound of Formula Ic has the structure of
  • Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl
  • R 3 and R 4 are hydrogen, lower alkyl, substituted lower alkyl, or R 5 ;
  • R 5 is halogen or -OSO 2 R7;
  • R 7 is substituted or unsubstituted lower alkyl or aryl
  • Q is a linker group as defined herein;
  • T is -CO-, -CS-, or -SO 2 -.
  • A, B, and D are each independently nitrogen or -CR9;
  • R 9 is hydrogen or lower alkyl
  • Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
  • each Ri is independently C 6 - I4 aryl, optionally substituted as described herein. In certain embodiments, each Ri is independently heteroaryl, optionally substituted as described herein. In certain embodiments, each Ri is independently pyridyl, optionally substituted as described herein. In certain embodiments, each Ri is independently 4-pyridyl, optionally substituted as described herein. In certain embodiments, each R] is independently heterocyclyl, optionally substituted as described herein. In certain embodiments, each Ri is independently morpholino, optionally substituted as described herein. In certain embodiments, each Ri is independently 4-morpholino, optionally substituted as described herein. In certain embodiments, each Ri is independently 4- morpholino or 4-pyridyl.
  • each R 2 is independently C ⁇ -u aryl, optionally substituted as described herein. In certain embodiments, each R 2 is independently C 6-I4 aryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from hydroxyl and hydroxymethyl. In certain embodiments, each R 2 is independently phenyl, optionally substituted as described herein. In certain embodiments, each R 2 is independently hydroxyphenyl (e.g., 2-hydroxyphenyl, 3- hydroxyphenyl, or 4-hydroxyphenyl) or hydroxymethylphenyl (e.g., 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, or 4-hydroxymethylphenyl).
  • hydroxyphenyl e.g., 2-hydroxyphenyl, 3- hydroxyphenyl, or 4-hydroxyphenyl
  • hydroxymethylphenyl e.g., 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, or 4-hydroxymethylphenyl.
  • each R 2 is independently heteroaryl, optionally substituted as described herein.
  • each R 2 is independently heteroaryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from the group consisting of amino, difluoromethyl, hydroxyl, methoxy, ethoxy, N,N-dimethylaminopropoxy (e.g., 3-(/V,N-dimethylamino)propoxy).
  • each R 2 is independently heterocyclyl, optionally substituted as described herein.
  • each R 2 is independently hydroxyphenyl, hydroxymethylphenyl, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl-hydroxy-lH-benzimidazolyl, difluromethyl-methoxy- 1 H-benzimidazolyl, difluromethyl-ethoxy-lH-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)-lH-benzimidazolyl.
  • each R 2 is independently 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2-amino-pyrid-5-yl, 2- amino-pyrimid-5-yl, indazol-4-yl, 2-difluromethyl- 1 H-benzimidazolyl, 2-difluromethyl-4- hydroxy-1 H-benzimidazolyl, 2-difluromethyl-4-methoxy-l H-benzimidazolyl, 2- difluromethyl-4-ethoxy-l H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N- dimethylamino)propoxy)-l H-benzimidazolyl.
  • each R 3 is independently hydrogen or lower alkyl (C ⁇ .
  • each R 3 is independently hydrogen or methyl. In certain embodiments, each R 3 is independently halogen. In certain embodiments, each R 3 is independently chloro. In certain embodiments, each R 3 is independently -OSO 2 R 7 . In certain embodiments, each R 3 is independently hydrogen, chloro, or methyl.
  • each R 4 is independently hydrogen or lower alkyl (Ci-
  • each R 4 is independently hydrogen or methyl. In certain embodiments, each R 4 is independently halogen. In certain embodiments, each R 4 is independently chloro. In certain embodiments, each R 4 is independently -OSO 2 R 7 . In certain embodiments, each R 4 is independently hydrogen, chloro, or methyl.
  • each R 5 is independently halogen. In certain embodiments, each R 5 is independently chloro or bromo. In certain embodiments, each R 5 is independently -OSO 2 R 7 . In certain embodiments, each R 5 is independently chloro, bromo, or -OSO 2 -methyl.
  • R 6 is C 3 . 7 cycloalkyl, optionally substituted as described herein.
  • R 6 is C 6-I4 aryl, optionally substituted as described herein.
  • R 6 is C 6 - I4 aryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from hydroxyl and hydroxymethyl.
  • R 6 is phenyl, optionally substituted as described herein.
  • R 6 is hydroxyphenyl (e.g., 2-hydroxyphenyl, 3- hydroxyphenyl, or 4-hydroxyphenyl) or hydroxymethylphenyl (e.g., 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, or 4-hydroxymethylphenyl).
  • R 6 is heteroaryl, optionally substituted as described herein.
  • R 6 is heteroaryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from the group consisting of amino, difluoromethyl, hydroxyl, methoxy, ethoxy, N,N-dimethylaminopropoxy (e.g., 3-(NN- dimethylamino)propoxy).
  • R 6 is heterocyclyl, optionally substituted as described herein.
  • R 6 is hydroxyphenyl, hydroxymethylphenyl, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl- hydroxy-lH-benzimidazolyl, difluromethyl-methoxy-lH-benzimidazolyl, difluromethyl- ethoxy- 1 H-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)- 1 H- benzimidazolyl.
  • R 6 is 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2- amino-pyrid-5-yl, 2-amino-pyrimid-5-yl, indazol-4-yl, 2-difluromethyl- 1 H-benzimidazolyl, 2-difluromethyl-4-hydroxy-l H-benzimidazolyl, 2-difluromethyl-4-methoxy-lH- benzimidazolyl, 2-difluromethyl-4-ethoxy-l H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N- dimethylamino)propoxy)-lH-benzimidazolyl.
  • R 7 is lower alkyl (Ci -6 ), optionally substituted as described herein. In certain embodiments, R 7 is methyl, fluoromethyl, difluormethyl, or trifluoromethyl. In certain embodiments, R 7 is C 2-6 alkenyl, optionally substituted as described herein. In certain embodiments, R 7 is C 2-6 alkynyl, optionally substituted as described herein. In certain embodiments, R 7 is C 3 _ 7 cycloalkyl, optionally substituted as described herein. In certain embodiments, R 7 is C 6-H aryl, optionally substituted as described herein. In certain embodiments, R 7 is phenyl, optionally substituted as described herein. In certain embodiments, R 7 is heteroaryl, optionally substituted as described herein. In certain embodiments, R 7 is heterocyclyl, optionally substituted as described herein.
  • R 8 is hydrogen or lower alkyl (Ci. ⁇ ).
  • R 9 is hydrogen, halogen, cyano, amino, or hydroxyl.
  • R 9 is lower alkyl optionally substituted as described herein. In certain embodiments, R 9 is fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R 9 is lower alkylamino or lower alkoxy, each optionally substituted as described herein.
  • Rio is hydrogen, amino, or hydroxyl.
  • Rio is lower alkyl (Cj- ⁇ ), lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido, each optionally substituted as described herein.
  • Rio is hydrogen, hydroxy, methoxy, ethoxy, or 3-(N,N-dimethylamino)propoxy.
  • G is a direct bond. In certain embodiments, G is
  • J is a direct bond. In certain embodiments, J is
  • Q is absent. In certain embodiments, Q is substituted or unsubstituted heterocyclylene. In certain embodiments, Q is a divalent linker selected from the group consisting of azetidinyleneamino (e.g., azetidinylene-2-amino, (R)- azetidinylene-2-amino, (S)-azetidinylene-2-amino, azetidinylene-3-amino, (/?)-azetidinylene- 3-amino, and (S)-azetidinylene-3-amino), azetidinylene(methylamino) (e.g., azetidinylene-2- methyamino, (i?)-azetidinylene-2-methyamino, (5)-azetidinylene-2-methyamino, azetidinylene-3-
  • Q is a divalent linker selected from the group consisting of azetidinylene-4-amino, azetidinylene-4-methylamino, piperidylene-4-oxy, 1,4- piperazinylene, 1 ,4-piperidylene, piperidylene-3-amino, ( ⁇ )-piperidylene-3-amino, (S)- piperidylene-3-amino, piperidylene-3-methylamino, (7?)-piperidylene-3-methylamino, (S)- piperidylene-3-methylamino, piperidylene-4-amino, piperidylene-4-methylamino, pyrrolidinylene-3-amino, (/?)-pyrrolidinylene-3-amino, (S)-pyrrolidinylene-3-amino, pyrrolidinylene-3-methylamino, (/?)-pyrrolidinylene-3-amino, (S)-pyrrolidiny
  • T is -CO-. In certain embodiments, T is -CS-. In certain embodiments, T is -SO 2 -.
  • U is N. In certain embodiments, U is CH.
  • V is oxygen. In certain embodiments, V is sulfur.
  • W is a direct bond, oxygen, or sulfur. In certain embodiments, W is NRn; where Rn is as defined herein.
  • X is nitrogen or CR 8 . In certain embodiments, X is nitrogen or CH. In certain embodiments, Y is nitrogen or CR 8 . In certain embodiments, Y is nitrogen or CH. In certain embodiments, Z is nitrogen or CR 8 . In certain embodiments, Z is nitrogen or CH.
  • X, Y, and Z are nitrogen. In certain embodiments, X and Y are nitrogen, and Z is CH. In certain embodiments, X and Z are nitrogen, and Y is CH. In certain embodiments, Y and Z are nitrogen, and X is CH.
  • each A is independently a direct bond. In certain embodiments, each A is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each A is independently CR 9 , where R 9 is as defined herein. In certain embodiments, each A is independently CR 9 , where R 9 is hydrogen, lower alkyl, or halogen.
  • each B is independently a direct bond. In certain embodiments, each B is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each B is independently CR 9 , where R 9 is as defined herein. In certain embodiments, each B is independently CR 9 , where R 9 is hydrogen, lower alkyl, or halogen.
  • each D is independently a direct bond. In certain embodiments, each D is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each D is independently CR 9 , where R 9 is as defined herein. In certain embodiments, each D is independently CR 9 , where R 9 is hydrogen, lower alkyl, or halogen.
  • each E is independently a direct bond. In certain embodiments, each E is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each E is independently CR 9 , where R 9 is as defined herein. In certain embodiments, each E is independently CR9, where R 9 is hydrogen, lower alkyl, or halogen.
  • the compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified.
  • the compound provided herein contains an alkenyl or alkenylene group
  • the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers.
  • structural isomers are interconvertible
  • the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers.
  • a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
  • Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
  • the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. ScL 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-mo ⁇ holine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1
  • the compounds provided herein are pharmacologically acceptable salts of the compounds with one or more of hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and isoethonic acids; or with one or more of potassium carbonate , sodium or potassium hydroxide, ammonia, triethylamine, and triethanolamine.
  • the compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula I and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221- 294; Morozowich et al.
  • provided herein is a phosphate, carboxylic acid, aminoacid ester prodrug of the compound provided herein.
  • the compounds provided herein are reversible inhibitors of PI3K. In certain embodiments, the compounds provided herein are irreversible inhibitors of PI3K. In certain embodiments, the compounds provided herein are selective reversible inhibitors of PI3K isoforms. In certain embodiments, the compounds provided herein are selective irreversible inhibitors of PI3K isoforms.
  • the compounds provided herein are reversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are irreversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective reversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective irreversible inhibitors of pi 10a.
  • the compounds provided herein interact with the His-855, which is unique to pi 10a. Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein react with the His-855, which is unique to pi 10a. Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein alkylate the His-855, which is unique to pi 10a.
  • the compounds provided herein are adapted to irreversibly inhibit the pi 10a isoform of PI3K.
  • the compounds provided herein are adapted to target the His-855 group which is considered to form part of the ATP binding pocket of the p 11 Oa isoform of PI3 K, but not of the other isoforms.
  • the compounds provided herein selectively and irreversibly inhibit this PI3K isoform.
  • Irreversible inhibition of an enzyme target has a number of potential advantages: e.g., (a) kinase inhibitors that shut down the ATP site by reversible competitive blockade of ATP have to bind very tightly to the enzyme and/or maintain high plasma levels for prolonged periods, in order to compete with ATP binding, since ATP levels in cells are high; (b) the enzyme is shut down permanently, and the pathway is only reactivated upon resynthesis of the enzyme, which may take some time; (c) it allows longer times between doses, for a more achievable dosage regime; (d) it provides an additional mechanism for selectivity, in one embodiment, between different isoforms of an enzyme.
  • Formula Ia, Ib, Ic, or Id as defined herein, which comprises the step of coupling a substituted pyrimidine or triazine intermediate with a suitable species that contains an alkylhalide or alkylsulfonate.
  • a method of making a compound of Formula Ia, Ib, Ic, or Id as defined herein which comprises the step of coupling a substituted pyrimidine or triazine intermediate with a suitable species.
  • the suitable species contains an alkylhalide or alkylsulfonate that is capable of selectively alkylating the His-855 of the pi 10a subunit of PI3K.
  • the method comprises the step of reacting the pyrimidine or triazine intermediate with a suitable acylating species. In certain embodiments, the method comprises the step of reacting a halo substituted pyrimidine or triazine intermediate with a suitable acylated species.
  • the compounds provided herein can be prepared by a number of different methods, and the following examples are only representative and do not exclude other related procedures.
  • the linker group Q contains an amino substituent
  • the compounds of Formula Ia, Ib, Ic, or Id are prepared by reaction with an acylating species (e.g., acylhalide) or acid equivalent in the presence of a coupling reagent (Method A):
  • Ri, R 2 , R 3 , R 4 , R 5 , Q, X, Y, and Z are each as defined herein.
  • the compounds of Formula Ia, Ib, Ic, or Id are prepared by a halogen displacement reaction on a 2- or 4-halopyrimidine or 2-halo- 1,3,5- triazine derivative by a previously acylated species (Method B):
  • a pharmaceutical composition comprising a compound of Formula Ia, Ib, Ic, or Id as defined herein, and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection.
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, or mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such as gelatin.
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.
  • compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).
  • compositions provided herein can be provided in a unit- dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form.
  • Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. [00139] In another embodiment, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.
  • the medicament in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxye
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof.
  • the amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSlL 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide,
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly- alkylene glycol including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene
  • These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as
  • compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions provided herein can be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR).
  • electroporation iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (OAV) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsif ⁇ er, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsif ⁇ er in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL " ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellower wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • the pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as I- leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained- , pulsed-, controlled-, targeted, and programmed release.
  • modified release dosage form refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
  • modified release examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891 ; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981 ; 6,376,461 ; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
  • compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art ⁇ see, Takada et al. in "Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).
  • the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose
  • the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers
  • PEO polyethylene oxide
  • PEG poly
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21 ; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 1-21).
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918.
  • the AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
  • excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos.
  • the compounds provided herein are designed to irreversibly inhibit the pi 10a isoform of PI3K, in one embodiment, to target the His-855 group which is considered to form part of the ATP binding pocket of the pi 10a isoform of PDK, but not of the other isoforms.
  • the compounds in one embodiment, selectively and irreversibly inhibit this PI3K isoform.
  • provided herein is a method of irreversibly inhibiting
  • the compounds provided herein selectively target the His-855 moiety of the pi 10a subunit, thus selectively irreversibly inhibiting the pi lOoc isoform of PI3K.
  • a method of cancer prevention or therapy for treating cancers comprising administering a compound of Formula Ia, Ib, Ic, or Id as defined herein to a subject in need thereof.
  • a method of cancer prevention or therapy for treating cancers comprising the steps of: 1) selectively targeting a pi 10a subunit of PDK with a compound provided herein; and 2) alkylating the pi 10a subunit of PDK with the compound.
  • the compound provided herein selectively targets the pi 10a subunit of PDK.
  • a method of selectively irreversibly inhibiting the ⁇ isoform of PDK comprising the steps of: 1) selectively targeting a pi 10a subunit of PDK with a compound provided herein; and 2) alkylating the pi 10a subunit of PDK with the compound.
  • the compound provided herein selectively targets the pi 10a subunit of PDK.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition associated with PDK activity in a subject which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition responsive to the modulation of PDK activity in a subject which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PDK enzyme in a subject which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of cancer in a subject which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer.
  • the compound selectively targets the pi 10a subunit of PBK.
  • the compound selectively inhibits the PI3K via its interaction with its pi 10a subunit.
  • the compound selectively alkylates the pi 10a subunit of PBK.
  • the subject is a mammal. In another embodiment, the subject is a human. In yet another embodiment, the subject is a primate other than a human, a farm animal such as cattle, a sport animal, or a pet such as a horse, dog, or cat.
  • the disorders, diseases, or conditions treatable with a compound provided herein include, but are not limited to, ( 1 ) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasital cutaneous pathologies, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including
  • the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocyte, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, chronic lymphocytic leuk
  • the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period.
  • an appropriate dosage level generally is ranging from about 0.001 to 100 mg per kg subject body weight per day (mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses.
  • the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg per day.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1 ,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • Also provided herein are methods of modulating PI3K activity comprising contacting a PIK3 enzyme with a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PIK3 enzyme is inside a cell.
  • the compounds provided herein e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, can also be combined or used in combination with other agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions for which the compounds provided herein are useful, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, infectious diseases, and those pathologies noted herein.
  • agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases,
  • Suitable other therapeutic agents can also include, but are not limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.
  • NEP neutral endopeptidase
  • hormonal agents such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate
  • immunosuppressants such as mineralocorticoid receptor antagonists, such as spironolactone and eplerenone
  • microtubule-disruptor agents such as ecteinascidins
  • microtubule-stabilizing agents such as pacitaxel, docetaxel, and epothilones A-F
  • MTP Inhibitors such as MTP Inhibitors; (37) niacin; (38) phosphodie
  • the other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biologic response modifiers ⁇ e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects ⁇ e.g., antiemetics).
  • biologic response modifiers e.g., interferons, interleukins, and tumor necrosis factor (TNF)
  • hyperthermia and cryotherapy e.g., hyperthermia and cryotherapy
  • agents to attenuate any adverse effects ⁇ e.g., antiemetics.
  • the other therapeutic agents that may be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine), and methotrexate), purine antagonists and pyrimidine antagonists (6- mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (as)
  • alkylating drugs me
  • the method provided herein comprises administration of a compound of Formula Ia, Ib, Ic, or Id together with administering one or more chemotherapeutic agents and/or therapies selected from: alkylation agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumour antibiotics (e.g., adriamymycin and bleomycin); antitumour vegetable alkaloids (e.g., taxol and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumour immunological agents (e.g., interferon ⁇ , ⁇ , and ⁇ ); radiation therapy; and surgery.
  • the one . or more chemotherapeutic agents and/or therapies are administered to the subject before, during, or after the administration of the compound of Formula Ia, Ib, Ic, or Id as defined here
  • Such other agents, or drugs can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, e.g., a compound of Formula I, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required.
  • the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.
  • the weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a NSAID, the weight ratio of the compound to the NSABD can range from about 1,000:1 to about 1 : 1,000, or about 200: 1 to about 1:200. Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
  • Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles including, but not limited to,
  • 6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole (Example 5)
  • 0.48 g (2.3 mmol) of tert-butyl methyl(4-piperidinyl)carbamate, and 0.6 g DDPEA in 20 mL T ⁇ F was stirred at room temperature for 1 hr. After dilution with water containing 1 mL acetic acid, the product was extracted in to EtOAc, washed successively with water and aq. NaHCO 3 , and dried.

Abstract

Provided herein are substituted pyrimidine and triazine derivatives, including bicyclic pyrimidine derivatives, their pharmaceutical compositions, their preparation, and their use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs. In one embodiment, the pyrimidine and triazine derivatives are morpholino-pyrimidine, morpholino-triazine, pyridyl-pyrimidine, and pyridyl-triazine derivatives which are selective irreversible inhibitors of the p110α isoform of PI3K.

Description

SUBSTITUTED PYRIMIDINES AND TRIAZINES AND THEIR USE IN CANCER
THERAPY
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of the priority of U.S. Provisional
Application No. 61/040,064, filed March 27, 2008, the disclosure of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein are substituted pyrimidine and triazine derivatives, including bicyclic pyrimidine derivatives, their pharmaceutical compositions, their preparation, and their use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs. In one embodiment, the substituted pyrimidine and triazine derivatives are morpholino-pyrimidine, morpholino-triazine, pyridyl-pyrimidine, and pyridyl- triazine derivatives which are selective irreversible inhibitors of the pi 10a isoform of PBK.
BACKGROUND
[0003] Phosphoinositide-3-kinases (PBKs) are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into three classes (Classes I, II, and III) and play an important role in cellular signaling (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357). The Class I enzymes are further classified into Class Ia and Ib based on their mechanism of activation; the Class Ia PBKs are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi lOβ, or pi 108) in complex with a regulatory p85 subunit, while the class-Ib PBK (pi lOγ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by βγ subunits of heterotrimeric G-proteins (Walker et al., MoI .Cell. 2000, 6, 909). The human protein sequence of the pi 10a isoform is described in Volina et al., Genomics 1994, 24, All; and Stirdivant et al., Bioorg. Med. Chem. 1997, 5, 65.
[0004] PBKs play a variety of roles in normal tissue physiology (Foukas & Shepherd,
Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with pi 10a having a specific role in cancer growth, pi lOβ in thrombus formation mediated by integrin απβ3 (Jackson et al., Nat. Med. 2005, 11, 507), and pi lOγ in inflammation, rheumatoid arthritis (Camps et al., Nat. Med. 2005, 11, 936) and other chronic inflammation states (Barber et al., Na/. Med. 2005, //, 933). The PI3K enzymes produce phosphoinositide 3, 4,5 -triphosphate (PIP3) from the corresponding diphosphate (PBP2), thus recruiting AKT (protein kinase B) through its Pleckstrin homology (PH) domain to the plasma membrane. Once bound, AKT is phosphorylated and activated by other membrane bound kinases and is central to a cascade of events that lead to inhibition of apoptosis (Berrie, Exp.Opin. Invest. Drugs 2001, 10, 1085).
[0005] The pi 10a isoform is selectively amplified and activated in a number of cancer types (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357; Stauffer et al., Curr. Med. Chem. - Anti-Cancer Agents 2005, 5, 449). In addition, there is a high frequency of non- random mutations in specific sites, primarily in the C2 domain and or the activation loop, of the kinase in several human cancer cell lines, including colon, brain, breast, and stomach (Samuels et al., Science 2004, 304, 554). This results in a constitutively active enzyme (Ikenoue et al., Cancer Res. 2005, 65, 4562; Kang et al., Proc. Natl. Acad. ScL USA 2005, 102, 802), making pi 10a one of the most highly mutated oncogenes found in human tumors. Structural studies have shown that many of the mutations occur at residues lying at the interfaces between pi 10a and p85α or between the kinase domain of pi 10a and other domains within the catalytic subunit (Miled et al., Science 2007, 317, 239; Huang et al., Science 2007, 318, 1744).
[0006] While PI3K isoenzymes play important roles in many cellular processes, published experimental studies in mice with human tumour xenografts show that the pan- PDK inhibitor LY294002 is well-tolerated, reduces signalling through the PI3K pathway, causes reduction of tumour volume, and is more active in cell lines over-expressing mutant forms of pi 1Oq than parental control cells (Semba et al., Clin. Cancer Res. 2002, 8, 1957; Hu et al., Cancer Res. 2002, 62, 1087).
[0007] Thus, PI3K, especially the pi 10a isoform, is an interesting target for drug intervention. Several classes of compounds have been identified as reversible inhibitors; for example, LY 294002 (non-selective) (Walker et al., MoI .Cell. 2000, 6, 909), PI103 (slightly α-selective) (Knight et al., Cell 2006, 125, 733; Hayakawa et al., Bioorg. Med. Chem. Lett. 2007, 17, 2438; Raynaud et al., Cancer Res. 2007, 67, 5840), ZSTK474 (non-selective) (Yaguchi et al., J. Natl. Cancer Inst. 2006, 98, 545; Kong et al,Cancer ScL 2007, 98, 1639), TGX221 (β-selective) (Jackson et al., Nat. Med. 2005, 11, 507), oxazines (γ-selective) (Lanni et al., Bioorg. Med. Chem. Lett. 2007, 17, 756), IC87114 (^-selective) (Sadhu et al. WO 2001/81346; Billottet et al., Oncogene 2006, 25, 6648), AS605240 (γ-selective) (Camps et al., Nat. Med. 2005, 11, 936), the imidazo[l,2-α]pyridines (α-selective) (Hayakawa et al., Bioorg. Med. Chem. 2007, 75, 403; Hayakawa et al., Bioorg. Med. Chem. 2007, 15, 5837), and the imidazo[4,5-c]quinoline NVP-BEZ235 (Garcia-Echeverria, et al., WO 2006/122806).
Figure imgf000004_0001
LY294002 PI103 ZSTK474
Figure imgf000004_0003
Figure imgf000004_0002
Oxazines
Figure imgf000004_0004
[0008] AH of the above mentioned compounds function as reversible inhibitors of the appropriate PBK isoforms. Although irreversible activity is displayed by the fungal metabolite wortmannin and its analogues, such as PWT-458 (Zhu et al, J. Med. Chem, 2006, 49, 1373) and PX-866 (Wipf et al., Org. Biomol. Chem. 2004, 2, 1911; Zask et al., J. Med. Chem. 2008, 57, 1319), these compounds are not selective for individual PI3K isoforms, undergoing reaction with a conserved lysine amino group (e.g., Lys-802 in pi 10a, Lys-805 in pi lOβ, Lys-833 in pi lOγ, and Lys-799 in pi 105).
[0009] Despite the advances in developing PI3K inhibitors, there is an unmet need for
PI3K inhibitors that are more potent and more selective, exhibit better pharmacokinetic properties, and/or produce fewer side effects than the existing PI3K inhibitors.
SUMMARY OF THE DISCLOSURE
[0010] Provided herein is a compound of Formula Ia, Ib, Ic, or Id:
Figure imgf000005_0001
Ib
Ia
Figure imgf000005_0002
Id or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each Ri is independently C6-H aryl, heteroaryl, or heterocyclyl; each R2 is independently C6-H aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, C2.6 alkenyl, C2-6 alkynyl, or R5; each R5 is independently halogen or -OSO2R7; R6 is C3.7 cycloalkyl, C6-H aryl, heteroaryl, or heterocyclyl;
R7 is lower alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, heteroaryl, or heterocyclyl;
Rio is (a) hydrogen, amino, or hydroxyl; or (b) lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CR8, with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, halogen, or lower alkyl; wherein the bonds between A, B, D, and E may be saturated or unsaturated; with the proviso that no more than one of A, B, D, and E are a direct bond; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) Q-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7_ι5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(O)Ra, -C(O)OR3, -C(O)NRbRc, -C(NRa)NRbRc, -ORa, -OC(O)R3, -OC(O)OR3, -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)R3, -OS(O)2R3, -OS(O)NRbRc, -OS(O)2NRbRc, -NRV, -NRaC(O)Rd, -NRaC(O)ORd, -NR3C(O)NRV, -NR3C(=NRd)NRbRc, -NRaS(O)Rd, -NR3S(O)2Rd, -NR3S(O)NRV, -NR3S(O)2NRV, -SR3, -S(O)R3, -S(O)2R3, -S(O)NRV, and -S(O)2NRV, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7.^ aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)OR6, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(=NRe)NRfRg, -OS(O)R6, -OS(O)2R6, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRε, -NReC(O)Rh, -NReC(O)ORh, -NReC(O)NRfRg, -NReC(=NRh)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2R6, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) d.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7.15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0011] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers.
[0012] Additionally provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0013] Further provided herein is a method for modulating PI3K activity, comprising contacting a PI3K with a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows the irreversible binding of the compound of Example 4 to PI3K.
DETAILED DESCRIPTION
[0015] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0016] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0017] The term "subject" refers to an animal, including, but not limited to, a primate
(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
[0018] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0019] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
[0020] The term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0021] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical P reformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.
[0022] The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0023] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.
[0024] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
[0025] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkyl" also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci-2O), 1 to 15 (CMS), 1 to 10 (Ci. io), or 1 to 6 (Ci-ό) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-2O), 3 to 15 (C3.15), 3 to 10 (C3-Io), or 3 to 6 (C3.6) carbon atoms. As used herein, linear Ci-6 and branched C3-6 alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
[0026] The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkylene" encompasses both linear and branched alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C!-20), 1 to 15 (C1-15), 1 to 10 (C1-I0), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-1S), 3 to 10 (C3. io), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkylene groups are also referred as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, C1-6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
[0027] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted as described herein. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-Is), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
[0028] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenylene may be optionally substituted as described herein. Similarly, the term "alkenylene" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. As used herein, the term "alkenylene" encompasses both linear and branched alkenylene, unless otherwise specified. For example, C2-6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-I5), 2 to 10 (C2-Io), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-2o), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4- methylbutenylene.
[0029] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynyl may be optionally substituted as described herein. The term "alkynyl" also encompasses both linear and branched alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3_2o), 3 to 15 (C3-I5), 3 to 10 (C3-I0), or 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
[0030] The term "alkynylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynylene may be optionally substituted as described herein. The term "alkynylene" also encompasses both linear and branched alkynylene, unless otherwise specified. In certain embodiments, the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-I5), 2 to 10 (C2-I0), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-I5), 3 to 10 (C3-I0), or 3 to 6 (C3-6) carbon atoms. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-) and propargylene (-CH2C≡C-). For example, C2-6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
[0031] The term "cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-2O), from 3 to 15 (C3-15), from 3 to 10 (C3-Io), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
[0032] The term "cycloalkylene" refers to a cyclic saturated bridged and/or non- bridged divalent hydrocarbon radical, which may be optionally substituted as described herein. In certain embodiments, the cycloalkylene has from 3 to 20 (C3-2O), from 3 to 15 (C3. 15), from 3 to 10 (C3_io), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene (e.g., 1,1-cyclopropylene and 1,2- cyclopropylene), cyclobutylene (e.g., 1 , 1 -cyclobutylene, 1 ,2-cyclobutylene, or 1,3- cyclobutylene), cyclopentylene (e.g., 1,1-cyclopentylene, 1,2-cyclopentylene, or 1,3- cyclopentylene), cyclohexylene (e.g., 1,1-cyclohexylene, 1,2-cyclohexylene, 1,3- cyclohexylene, or 1 ,4-cyclohexylene), cycloheptylene (e.g., 1,1-cycloheptylene, 1,2- cycloheptylene, 1,3-cycloheptylene, or 1 ,4-cycloheptylene), decalinylene, and adamantylene.
[0033] The term "aryl" refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-2O), from 6 to 15 (C6-I5), or from 6 to 10 (Cδ-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted as described herein.
[0034] The term "arylene" refers to a monocyclic and/or multicyclic divalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6.2o), from 6 to 15 (C6-Is), or from 6 to 10 (Cβ-io) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene. Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydro-naphthylene (tetralinyl). In certain embodiments, arylene may also be optionally substituted as described herein. [0035] The term "aralkyl" or "aryl-alkyl" refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted as described herein.
[0036] The term "heteroaryl" refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein.
[0037] The term "heteroarylene" refers to a divalent aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, imidazolylene, isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene, triazinylene, and triazolylene. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofuranylene, benzimidazolylene, benzoisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene, benzothienylene, benzothiophenylene, benzotriazolylene, benzoxazolylene, furopyridylene, imidazopyridinylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene, isothiazolylene, naphthyridinylene, oxazolopyridinylene, phthalazinylene, pteridinylene, purinylene, pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, perimidinylene, phenanthrolinylene, phenanthridinylene, phenarsazinylene, phenazinylene, phenothiazinylene, phenoxazinylene, and xanthenylene. In certain embodiments, heteroaryl may also be optionally substituted as described herein.
[0038] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4- dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, moφholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamoφholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted as described herein.
[0039] The term "heterocyclylene" refers to a divalent non-aromatic ring system and/or multicyclic ring system that contain at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclene groups include, but are not limited to, azepinylene, benzodioxanylene, benzodioxolylene, benzofuranonylene, benzopyranonylene, benzopyranylene, benzotetrahydrofuranylene, benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene, β-carbolinylene, chromanylene, chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofurylene, dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene, dioxolanylene, 1 ,4- dithianylene, furanonylene, imidazolidinylene, imidazolinylene, indolinylene, isobenzotetrahydrofuranylene, isobenzotetrahydrothienylene, isochromanylene, isocoumarinylene, isoindolinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene, octahydroindolylene, octahydroisoindolylene, oxazolidinonylene, oxazolidinylene, oxiranylene, piperazinylene, piperidinylene, 4-piperidonylene, pyrazolidinylene, pyrazolinylene, pyrrolidinylene, pyrrolinylene, quinuclidinylene, tetrahydrofurylene, tetrahydroisoquinolinylene, tetrahydropyranylene, tetrahydrothienylene, thiamorpholinylene, thiazolidinylene, tetrahydroquinolinylene, and 1,3,5-trithianylene. In certain embodiments, heterocyclic may also be optionally substituted as described herein.
[0040] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.
[0041] The term "optionally substituted" is intended to mean that a group, such as an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene, may be substituted with one or more substituents independently selected from, e.g., (a) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C6-H aryl, C7.15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (b) halo, cyano (-CN), nitro (-NO2), -C(O)R3, -C(O)ORa, -C(O)NRbRc, -C(NRa)NRbRc, -OR\ -OC(O)R3, -OC(O)OR", -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)R3, -OS(O)2R3, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(O)Rd, -NR3S(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)R3, -S(O)2R3, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C6-H aryl, C7 15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.
[0042] In one embodiment, each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Q-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6_i4 aryl, C7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)OR6, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(O)R6, -OC(O)OR6, -OC(O)NRfR8, -OC(=NR6)NRfRg, -OS(O)R6, -OS(O)2R6, -OS(O)NRfRε, -OS(O)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(O)ORh, -NReC(0)NRfRε, -NR6C(=NRh)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(0)2NRfRg, -SRe, -S(O)R6, -S(O)2R6, -S(0)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-I4 aryl, C7-I5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0043] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
[0044] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.
[0045] The term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
Compounds
[0046] Compounds that have been shown to have activity against PI3K have been disclosed in WO 2004/048365 (Chiron), WO 2007/066099 and 2007/066103 (AstraZeneca), WO 2007/084786 (Novartis), WO 2006/095906 (Zenyaku Kogyo Kabushiki Kaisha), WO 2007/127183 (Genentech / Piramed), WO 2008/018426 (Chugai Seiyaku Kabushiki Kaisha), and WO2008/0322028, WO2008/0322033, WO2008/0322036, WO2008/0322041, WO2008/0322060, WO2008/0322064, WO2008/0322072, WO2008/0322089, WO2008/0322091 (AstraZeneca), WO2008/115974, and WO2008/116129 (Wyeth).
[0047] The present disclosure broadly relates to a class of compounds for use as agents or drugs for cancer therapy. In certain embodiments, the disclosure relates to a class of compounds that can be used as PI3K inhibitors. PI3K inhibitors are thought to be valuable for the treatment of cell proliferation disorders, in one embodiment, as anti tumor agents.
[0048] In one embodiment, provided herein is a compound of Formula Ia, Ib, Ic, or Id:
Figure imgf000018_0001
Ia Ib
Figure imgf000018_0002
Id or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each Ri is independently C6-M aryl, heteroaryl, or heterocyclyl; each R2 is independently C6-M aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, C2-6 alkenyl, C2-6 alkynyl, or R5; each R5 is independently halogen or -OSO2R7;
Re is C3-7 cycloalkyl, Cό-i4 aryl, heteroaryl, or heterocyclyl;
R7 is lower alkyl, C2.6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, heteroaryl, or heterocyclyl;
Rio is (a) hydrogen, amino, or hydroxyl; or (b) lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CR8, with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, halogen, or lower alkyl; wherein the bonds between A, B, D, and E may be saturated or unsaturated; with the proviso that no more than one of A, B, D, and E are a direct bond; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-I4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(NRa)NRbRc, -OR\ -OC(O)R3, -OC(O)OR3, -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)R3, -OS(O)2R3, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NR3C(O)Rd, -NRaC(O)ORd, -NR3C(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(O)Rd, -NR3S(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SR3, -S(O)R3, -S(O)2R3, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-i4 aryl, C7. i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C6-H aryl, C7-I5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R6, -C(O)OR6, -C(O)NRfRg, -C(NRe)NRfRg, -OR6, -OC(O)R6, -OC(O)OR6, -OC(O)NRfR8, -OC(=NRe)NRfRg, -OS(O)R6, -OS(O)2R6, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORh, -NReC(O)NRfRε, -NReC(=NRh)NRfRg, -NR6S(O)R11, -NR6S(O)2R*1, -NReS(O)NRfRg, -NR6S(O)2NRfRg, -SRe, -S(O)R6, -S(O)2R6, -S(O)NRfRg, and -S(O)2NRfRg; wherein each R6, Rf, Rε, and Rh is independently (i) hydrogen; (ii) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-i4 aryl, C-7.15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0049] In one embodiment, in Formula Ia, Ib, Ic, or Id: each Ri is independently substituted or unsubstituted heteroaryl, or heterocyclyl; each R2 is independently substituted or unsubstituted C6-I4 aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, or R5; each R5 is independently halogen or -OSO2R?;
R6 is substituted or unsubstituted C6-H aryl or heteroaryl;
R7 is substituted or unsubstituted lower alkyl or C6-I4 aryl;
Rio is (a) hydrogen, amino, or hydroxyl; or (b) substituted or unsubstituted lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CRg, with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated.
[0050] In another embodiment, in Formula Ia, Ib, Ic, or Id: each Ri is independently substituted or unsubstituted morpholino or pyridyl; each R2 is independently substituted or unsubstituted aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, or R5; each R5 is independently halogen or -OSO2R7;
R6 is substituted or unsubstituted aryl or heteroaryl;
R7 is substituted or unsubstituted lower alkyl or aryl;
Rio is (a) hydrogen, amino, hydroxyl, or hydroxymethyl; or (b) substituted or unsubstituted lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CR8, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated. [0051] In still another embodiment, in Formula Ia, Ib, Ic, or Id: each Ri is independently substituted or unsubstituted 4-morpholino or 4- pyridyl; each R2 is independently substituted or unsubstituted aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, or R5; each R5 is independently halogen or -OSO2R7;
R6 is substituted or unsubstituted aryl or heteroaryl;
R7 is substituted or unsubstituted lower alkyl or aryl;
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CR8, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, lower alkyl, or halogen; wherein the bonds between A, B, D, and E may be saturated or unsaturated.
[0052] In one embodiment, in Formula Ia:
Ri is substituted or unsubstituted morpholino or pyridyl;
R2 is hydroxyphenyl, hydroxymethylphenyJ, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl-hydroxy-lH-benzimidazolyl, difluromethyl-methoxy- lH-benzimidazolyl, difluromethyl-ethoxy- lH-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)-lH-benzimidazolyl;
R3 and R4 are each independently hydrogen, chloro, or methyl;
R5 is chloro, bromo, or -OSO2-methyl;
Q is a divalent linker selected from the group consisting of azetidinyleneamino, azetidinylene(methylamino), piperidyleneoxy, piperazinylene, piperidylene, piperidyleneamino, piperidylene(methylamino), pyrrolidinyleneamino, pyrrolidinylene(methylamino), and piperidylenethio;
T is -CO-, -CS-, or -SO2-; and
X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.
[0053] In another embodiment, in Formula Ia:
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R2 is 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2-amino-pyrid-5-yl, 2-amino- pyrimid-5-yl, indazol-4-yl, 2-difluromethyl-lH-benzimidazolyl, 2-difluromethyl-4-hydroxy- lH-benzimidazolyl, 2-difluromethyl-4-methoxy-lH-benzimidazolyl, 2-difluromethyl-4- ethoxy- 1 H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N-dimethylamino)propoxy)- 1 H- benzimidazolyl;
R3 and R4 are each independently hydrogen, chloro, or methyl;
R5 is chloro, bromo, or -OSO2-methyl;
Q is a divalent linker selected from the group consisting of azetidinylene-4- amino, azetidinylene-4-methylamino, piperidylene-4-oxy, 1 ,4-piperazinylene, 1 ,4- piperidylene, piperidylene-3-amino, (/?)-piperidylene-3-amino, (5')-piperidylene-3-amino, piperidylene-3-methylamino, (/?)-piperidylene-3-methylamino, (5)-piperidylene-3- methylamino, piperidylene-4-amino, piperidylene-4-methylamino, pyrrolidinylene-3-amino, (/?)-pyrrolidinylene-3-amino, (5)-pyrrolidinylene-3-amino, pyrrolidinylene-3-methylamino, (Λ)-pyrrolidinylene-3-methylamino, (5)-pyrrolidinylene-3-methylamino, and piperidylene-4- thio;
T is -CO-, -CS-, or -SO2-; and
X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.
[0054] Examples of the linker group defined by Q may include, but are not restricted to, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocyclylene, tetrahydropyridinylene, divalent amino (-ΝH— ), alkyleneamino, substituted alkyleneamino, alkenyleneamino, cycloalkyleneamino, cycloalkenyleneamino, aryleneamino, heteroaryleneamino, heterocyclyleneamino, divalent aminoarylamino, divalent aminoheteroarylamino, divalent aminoheterocyclylamino, tetrahydropyridinyleneamino, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, azetidinyleneamino, pyrrolidinyleneamino, piperidinyleneamino, piperazinyleneamino, azetidinylenecarbonylamino, pyrrolidinylenecarbonylamino, piperidinylenecarbonylamino, piperazinylenecarbonylamino, alkyleneoxy, alkenyleneoxy, alkynyleneoxy, cycloalkyleneoxy, cycloalkenyleneoxy, aryleneoxy, heteroaryleneoxy, heterocyclyleneoxy, divalent aminoalkoxy, divalent aminoalkenyloxy, divalent aminoalkynyloxy, divalent aminocycloalkyloxy, divalent aminocycloalkenyloxy, divalent aminoaryloxy, divalent aminoheteroaryloxy, azetidinyleneoxy, pyrrolidinyleneoxy, piperidinyleneoxy, piperazinyleneoxy, alkylenethio, alkenylenethio, alkynylenethio, cycloalkylenethio, cycloalkenylenethio, arylenethio, heteroarylenethio, heterocyclylenethio, divalent aminoalkylthio, divalent aminoalkenylthio, divalent aminoalkynylthio, divalent aminocycloalkylthio, divalent aminocycloalkenylthio, divalent aminoarylthio, divalent aminoheteroarylthio.and divalent aminoheterocyclylthio.
[0055] Examples of R2 may include, but are not restricted to, 3-hydroxyphenyl, 3-
(hydroxymethyl)phenyl, 3-pyridinyl, 4-pyridinyl, 3-pyridinylamino, 4-pyridinylamino, 4- indazolyl, 4-indazolylamino, 5-indazolylamino, 6-indazolylamino 7-indazolylamino, 1- benzimidazolyl, 2-methyl-l-benzimidazolyl, 2-fluoromethyl-l-benzimidazolyl, 2- difluoromethyl- 1 -benzimidazolyl, 2-trifluoromethyl- 1 -benzimidazolyl, 2-difluoromethyl-4- hydroxy- 1 -benzimidazolyl, 4-alkoxy-2-difluoromethyl- 1 -benzimidazolyl, 4-amino-2- difluoromethyl- 1 -benzimidazolyl, 4-alkylamino-2-difluoromethyl-l -benzimidazolyl, 2- amino-5-pyridinyl, 2-amino-4-chloro-5-pyridinyl, 2-amino-4-methyl-5-pyridinyl, 2-amino-4- trifluoromethyl-5-pyridinyl, 2-amino-4-cyano-5-pyridinyl, 2-amino-4-methoxy-5-pyridinyl, 2-amino-5-pyrimidinyl, 2,4-diamino-5-pyrimidinyl, 2-amino-4-methyl-5-pyrimidinyl, 2- amino-4-trifluoromethyl-5-pyrimidinyl, 2-amino-4-chloro-5-pyrimidinyl, 2-amino-4-cyano- 5-pyrimidinyl, 2-amino-4-methoxy-5-pyrimidinyl, and 2-amino-4-oxo-5-pyrimidinyl.
[0056] Examples of R6 may include, but are not restricted to, 3-hydroxyphenyl, 3-
(hydroxymethyl)phenyl, 3-pyridinyl, 4-pyridinyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7- indazolyl, 2-amino-5-pyridinyl, 2-amino-4-chloro-5-pyridinyl, 2-amino-4-methyl-5-pyridinyl, 2-amino-4-trifluoromethyl-5-pyridinyl, 2-amino-4-cyano-5-pyridinyl, 2-amino-4-methoxy-5- pyridinyl, 2-amino-5-pyrimidinyl, 2,4-diamino-5-pyrimidinyl, 2-amino-4-methyl-5- pyrimidinyl, 2-amino-4-trifluoromethyl-5-pyrimidinyl, 2-amino-4-chloro-5-pyrimidinyl, 2- amino-4-cyano-5-pyrimidinyl, 2-amino-4-methoxy-5-pyrimidinyl, 2-amino-4-oxo-5- pyrimidinyl. [0057] In one embodiment, the compound of Formula Ia has the structure of Formula
II:
Figure imgf000024_0001
π or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Ri, R3, R4, R5, Q, T, X, Y, and Z are each as defined herein.
[0058] In one embodiment, in Formula II,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-; and
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl.
[0059] In another embodiment, the compound of Formula Ia has the structure of
Formula III:
Figure imgf000024_0002
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Ri, R3, R4, R5, Q, T, X, Y, and Z are each as defined herein.
[0060] In one embodiment, in Formula III,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5; R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl; Q is a linker group as defined herein; T is -CO-, -CS-, or -SO2-; and
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl.
[0061] In yet another embodiment, the compound of Formula Ia has the structure of
Formula FV:
Figure imgf000025_0001
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R3, R4, R5, Q, T, X, Y, and Z are each as defined herein; and
R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
[0062] In one embodiment, in Formula IV,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl; and
R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen. [0063] In yet another embodiment, the compound of Formula Ia has the structure of
Formula V:
Figure imgf000026_0001
V or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R3, R4, R5, Q, T, X, Y, and Z are each as defined herein; and
R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
[0064] In one embodiment, in Formula V,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl; and
R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
[0065] In yet another embodiment, the compound of Formula Ia has the structure of
Formula VI:
Figure imgf000026_0002
VI or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R5, Q, T, X, Y, and Z are each as defined herein.
[0066] In one embodiment, in Formula VI,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-; and
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl.
[0067] In yet another embodiment, the compound of Formula Ia has the structure of
Formula VII:
Figure imgf000027_0001
VII or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R5, Rio, Q, T, X, Y, and Z are each as defined herein.
[0068] In one embodiment, in Formula VII,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl; and
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
[0069] In yet another embodiment, the compound of Formula Ia has the structure of
Formula VIII:
Figure imgf000028_0001
VIII or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R.3, R4, R5, Rio, T, X, Y, and Z are each as defined herein; and
U is CH or N.
[0070] In one embodiment, in Formula VIII,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl;
U is CH or N; and
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
[0071] In yet another embodiment, the compound of Formula Ia has the structure of
Formula EX:
Figure imgf000029_0001
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R3, R4, R5, Rio, T, X, Y, and Z are each as defined herein;
G and J are each independently a direct bond or -CH2-; and
W is a direct bond; or oxygen, sulfur, or NRn; where Rn is hydrogen, or substituted or unsubstituted lower alkyl.
[0072] In one embodiment, in Formula IX,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CR8, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl;
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido;
G and J are each independently a direct bond or -CH2-; and
W is a direct bond; or oxygen, sulfur, or NRn; where Rn is hydrogen, or substituted or unsubstituted lower alkyl. [0073] In yet another embodiment, the compound of Formula Ia has the structure of
Formula X:
Figure imgf000030_0001
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R3, R4, R5, Rio, T, X, Y, and Z are each as defined herein; Rn is hydrogen, or substituted or unsubstituted lower alkyl; and G and J are each independently a direct bond or -CH2-.
[0074] In one embodiment, in Formula X,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
T is -CO-, -CS-, or -SO2-;
X, Y, and Z are nitrogen atoms or CRg, except that at least two of X, Y, and Z are nitrogen atoms; where R8 is hydrogen or lower alkyl;
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido;
Rn is hydrogen, or substituted or unsubstituted lower alkyl; and
G and J are each independently a direct bond or -CH2-. [0075] In yet another embodiment, the compound of Formula Ic has the structure of
Formula XI:
Figure imgf000031_0001
XI or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R2, R3, R4, R5, Q, and T are each as defined herein;
Rn is hydrogen, or substituted or unsubstituted lower alkyl; and
V is oxygen or sulfur.
[0076] In one embodiment, in Formula XI,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R2 is substituted or unsubstituted aryl, heteroaryl, or heterocyclyl;
R3 and R4 are each independently hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-;
Rn is hydrogen, or substituted or unsubstituted lower alkyl; and
V is oxygen or sulfur.
[0077] In yet another embodiment, the compound of Formula Ic has the structure of
Formula XII:
Figure imgf000031_0002
xii or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, Q, and T are each as defined herein.
[0078] In one embodiment, in Formula XII,
R1 is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R2 is substituted or unsubstituted aryl, heteroaryl, or heterocyclyl;
R3 and R4 are each independently hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein; and
T is -CO-, -CS-, or -SO2-.
[0079] In yet another embodiment, the compound of Formula Ic has the structure of
Formula XIII:
Figure imgf000032_0001
XIII or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
Ri, R3, R4, R5, Q, and T are each as defined herein; and R6 is substituted or unsubstituted aryl or heteroaryl.
[0080] In one embodiment, in Formula XIII,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are ach independently hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R6 is substituted or unsubstituted aryl or heteroaryl;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein; and
T is -CO-, -CS-, or -SO2-. [0081] In still another embodiment, the compound of Formula Ic has the structure of
Formula XIV:
Figure imgf000033_0001
xrv or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Ri, R3, R4, R5, Rio, Q, T, A, B, and D are each as defined herein.
[0082] In one embodiment, in Formula XIV,
Ri is substituted or unsubstituted 4-morpholino or 4-pyridyl;
R3 and R4 are hydrogen, lower alkyl, substituted lower alkyl, or R5;
R5 is halogen or -OSO2R7;
R7 is substituted or unsubstituted lower alkyl or aryl;
Q is a linker group as defined herein;
T is -CO-, -CS-, or -SO2-.
A, B, and D are each independently nitrogen or -CR9;
R9 is hydrogen or lower alkyl; and
Rio is hydrogen, amino, lower alkylamino, substituted lower alkylamino, hydroxy, lower alkoxy, substituted lower alkoxy, hydroxymethyl, carboxamido, or substituted carboxamido.
[0083] The groups, R1, R2, R3, R4, R5, R6, R7, R8, R9, Rio, Rn, A, B, D, E, G, J, Q, T,
U, V, W, X, Y, and Z in Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV are further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of this disclosure.
[0084] In certain embodiments, each Ri is independently C6-I4 aryl, optionally substituted as described herein. In certain embodiments, each Ri is independently heteroaryl, optionally substituted as described herein. In certain embodiments, each Ri is independently pyridyl, optionally substituted as described herein. In certain embodiments, each Ri is independently 4-pyridyl, optionally substituted as described herein. In certain embodiments, each R] is independently heterocyclyl, optionally substituted as described herein. In certain embodiments, each Ri is independently morpholino, optionally substituted as described herein. In certain embodiments, each Ri is independently 4-morpholino, optionally substituted as described herein. In certain embodiments, each Ri is independently 4- morpholino or 4-pyridyl.
[0085] In certain embodiments, each R2 is independently Cβ-u aryl, optionally substituted as described herein. In certain embodiments, each R2 is independently C6-I4 aryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from hydroxyl and hydroxymethyl. In certain embodiments, each R2 is independently phenyl, optionally substituted as described herein. In certain embodiments, each R2 is independently hydroxyphenyl (e.g., 2-hydroxyphenyl, 3- hydroxyphenyl, or 4-hydroxyphenyl) or hydroxymethylphenyl (e.g., 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, or 4-hydroxymethylphenyl). In certain embodiments, each R2 is independently heteroaryl, optionally substituted as described herein. In certain embodiments, each R2 is independently heteroaryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from the group consisting of amino, difluoromethyl, hydroxyl, methoxy, ethoxy, N,N-dimethylaminopropoxy (e.g., 3-(/V,N-dimethylamino)propoxy). In certain embodiments, each R2 is independently heterocyclyl, optionally substituted as described herein. In certain embodiments, each R2 is independently hydroxyphenyl, hydroxymethylphenyl, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl-hydroxy-lH-benzimidazolyl, difluromethyl-methoxy- 1 H-benzimidazolyl, difluromethyl-ethoxy-lH-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)-lH-benzimidazolyl. In certain embodiments, each R2 is independently 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2-amino-pyrid-5-yl, 2- amino-pyrimid-5-yl, indazol-4-yl, 2-difluromethyl- 1 H-benzimidazolyl, 2-difluromethyl-4- hydroxy-1 H-benzimidazolyl, 2-difluromethyl-4-methoxy-l H-benzimidazolyl, 2- difluromethyl-4-ethoxy-l H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N- dimethylamino)propoxy)-l H-benzimidazolyl.
[0086] In certain embodiments, each R3 is independently hydrogen or lower alkyl (C \.
(,). In certain embodiments, each R3 is independently hydrogen or methyl. In certain embodiments, each R3 is independently halogen. In certain embodiments, each R3 is independently chloro. In certain embodiments, each R3 is independently -OSO2R7. In certain embodiments, each R3 is independently hydrogen, chloro, or methyl.
[0087] In certain embodiments, each R4 is independently hydrogen or lower alkyl (Ci-
6). In certain embodiments, each R4 is independently hydrogen or methyl. In certain embodiments, each R4 is independently halogen. In certain embodiments, each R4 is independently chloro. In certain embodiments, each R4 is independently -OSO2R7. In certain embodiments, each R4 is independently hydrogen, chloro, or methyl.
[0088] In certain embodiments, each R5 is independently halogen. In certain embodiments, each R5 is independently chloro or bromo. In certain embodiments, each R5 is independently -OSO2R7. In certain embodiments, each R5 is independently chloro, bromo, or -OSO2-methyl.
[0089] In certain embodiments, R6 is C3.7 cycloalkyl, optionally substituted as described herein. In certain embodiments, R6 is C6-I4 aryl, optionally substituted as described herein. In certain embodiments, R6 is C6-I4 aryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from hydroxyl and hydroxymethyl. In certain embodiments, R6 is phenyl, optionally substituted as described herein. In certain embodiments, R6 is hydroxyphenyl (e.g., 2-hydroxyphenyl, 3- hydroxyphenyl, or 4-hydroxyphenyl) or hydroxymethylphenyl (e.g., 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, or 4-hydroxymethylphenyl). In certain embodiments, R6 is heteroaryl, optionally substituted as described herein. In certain embodiments, R6 is heteroaryl, optionally substituted with one or more substituents, in one embodiment, one or two, substituents, each independently selected from the group consisting of amino, difluoromethyl, hydroxyl, methoxy, ethoxy, N,N-dimethylaminopropoxy (e.g., 3-(NN- dimethylamino)propoxy). In certain embodiments, R6 is heterocyclyl, optionally substituted as described herein. In certain embodiments, R6 is hydroxyphenyl, hydroxymethylphenyl, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH-benzimidazolyl, difluromethyl- hydroxy-lH-benzimidazolyl, difluromethyl-methoxy-lH-benzimidazolyl, difluromethyl- ethoxy- 1 H-benzimidazolyl, or difluromethyl-((N,N-dimethylamino)propoxy)- 1 H- benzimidazolyl. In certain embodiments, R6 is 3-hydroxyphenyl, 3-hydroxymethylphenyl, 2- amino-pyrid-5-yl, 2-amino-pyrimid-5-yl, indazol-4-yl, 2-difluromethyl- 1 H-benzimidazolyl, 2-difluromethyl-4-hydroxy-l H-benzimidazolyl, 2-difluromethyl-4-methoxy-lH- benzimidazolyl, 2-difluromethyl-4-ethoxy-l H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N- dimethylamino)propoxy)-lH-benzimidazolyl. [0090] In certain embodiments, R7 is lower alkyl (Ci-6), optionally substituted as described herein. In certain embodiments, R7 is methyl, fluoromethyl, difluormethyl, or trifluoromethyl. In certain embodiments, R7 is C2-6 alkenyl, optionally substituted as described herein. In certain embodiments, R7 is C2-6 alkynyl, optionally substituted as described herein. In certain embodiments, R7 is C3_7 cycloalkyl, optionally substituted as described herein. In certain embodiments, R7 is C6-H aryl, optionally substituted as described herein. In certain embodiments, R7 is phenyl, optionally substituted as described herein. In certain embodiments, R7 is heteroaryl, optionally substituted as described herein. In certain embodiments, R7 is heterocyclyl, optionally substituted as described herein.
[0091] In certain embodiments, R8 is hydrogen or lower alkyl (Ci.ό).
[0092] In certain embodiments, R9 is hydrogen, halogen, cyano, amino, or hydroxyl.
In certain embodiments, R9 is lower alkyl
Figure imgf000036_0001
optionally substituted as described herein. In certain embodiments, R9 is fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R9 is lower alkylamino or lower alkoxy, each optionally substituted as described herein.
[0093] In certain embodiments, Rio is hydrogen, amino, or hydroxyl. In certain embodiments, Rio is lower alkyl (Cj-β), lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido, each optionally substituted as described herein. In certain embodiments, Rio is hydrogen, hydroxy, methoxy, ethoxy, or 3-(N,N-dimethylamino)propoxy.
[0094] In certain embodiments, G is a direct bond. In certain embodiments, G is
-CH2-.
[0095] In certain embodiments, J is a direct bond. In certain embodiments, J is
-CH2-.
[0096] In certain embodiments, Q is absent. In certain embodiments, Q is substituted or unsubstituted heterocyclylene. In certain embodiments, Q is a divalent linker selected from the group consisting of azetidinyleneamino (e.g., azetidinylene-2-amino, (R)- azetidinylene-2-amino, (S)-azetidinylene-2-amino, azetidinylene-3-amino, (/?)-azetidinylene- 3-amino, and (S)-azetidinylene-3-amino), azetidinylene(methylamino) (e.g., azetidinylene-2- methyamino, (i?)-azetidinylene-2-methyamino, (5)-azetidinylene-2-methyamino, azetidinylene-3-methyamino, (/?)-azetidinylene-3-methyamino, and (S)-azetidinylene-3- methyamino), piperidyleneoxy (e.g., 2-piperidyleneoxy, 2(/?)-piperidyleneoxy, 2(S)- piperidyleneoxy, 3-piperidyleneoxy, 3(/?)-piperidyleneoxy, 3(S)-piperidyleneoxy, and 4- piperidyleneoxy), piperazinylene (e.g., 1 ,2-piperazinylene, 1,3-piperazinylene, and 1,4- piperazinylene), piperidylene (1,2-piperidylene, 1,3-piperidylene, and 1,4-piperidylene), piperidyleneamino (e.g., piperidylene-2-amino, (/?)-piperidylene-2-amino, (S)-piperidylene- 2-amino, piperidylene-3 -amino, (/?)-piperidylene-3-amino, (S)-piperidylene-3 -amino, and piperidylene-4-amino), piperidylene(methylamino) (e.g., piperidylene-2-methylamino, (R)- piperidylene-2-methylamino, (5)-piperidylene-2-methylamino, piperidylene-3-methylamino, (/?)-piperidylene-3-methylamino, (S)-piperidylene-3-methylamino, and piperidylene-4- methylamino), pyrrolidinyleneamino (e.g., pyrrolidinylene-2-amino, (/?)-pyrrolidinylene-2- amino, (S)-pyrrolidinylene-2-amino, pyrrolidinylene-3-amino, (i?)-pyrrolidinylene-3-amino, and (S)-pyrrolidinylene-3-amino), pyrrolidinylene(methylamino) (e.g., pyrrolidinylene-2- methylamino, (R)-pyrrolidinylene-2-methylamino, (S)-pyrrolidinylene-2-methylamino, pyrrolidinylene-3-methylamino, (/?)-pyrrolidinylene-3-methylamino, and (S)-pyrrolidinylene- 3-methylamino), and piperidylthio (e.g., 2-piperidylenethio, 2(/?)-piperidylenethio, 2(S)- piperidylenethio, 3-piperidylenethio, 3(/?)-piperidylenethio, 3(S)-piperidylenethio, and 4- piperidylenethio). In certain embodiments, Q is a divalent linker selected from the group consisting of azetidinylene-4-amino, azetidinylene-4-methylamino, piperidylene-4-oxy, 1,4- piperazinylene, 1 ,4-piperidylene, piperidylene-3-amino, (Λ)-piperidylene-3-amino, (S)- piperidylene-3-amino, piperidylene-3-methylamino, (7?)-piperidylene-3-methylamino, (S)- piperidylene-3-methylamino, piperidylene-4-amino, piperidylene-4-methylamino, pyrrolidinylene-3-amino, (/?)-pyrrolidinylene-3-amino, (S)-pyrrolidinylene-3-amino, pyrrolidinylene-3-methylamino, (/?)-pyrrolidinylene-3-methylamino, (S)-pyrrolidinylene-3- methylamino, and piperidylene-4-thio.
[0097] In certain embodiments, T is -CO-. In certain embodiments, T is -CS-. In certain embodiments, T is -SO2-.
[0098] In certain embodiments, U is N. In certain embodiments, U is CH.
[0099] In certain embodiments, V is oxygen. In certain embodiments, V is sulfur.
[00100] In certain embodiments, W is a direct bond, oxygen, or sulfur. In certain embodiments, W is NRn; where Rn is as defined herein. [00101] In certain embodiments, X is nitrogen or CR8. In certain embodiments, X is nitrogen or CH. In certain embodiments, Y is nitrogen or CR8. In certain embodiments, Y is nitrogen or CH. In certain embodiments, Z is nitrogen or CR8. In certain embodiments, Z is nitrogen or CH.
[00102] In certain embodiments, X, Y, and Z are nitrogen. In certain embodiments, X and Y are nitrogen, and Z is CH. In certain embodiments, X and Z are nitrogen, and Y is CH. In certain embodiments, Y and Z are nitrogen, and X is CH.
[00103] In certain embodiments, each A is independently a direct bond. In certain embodiments, each A is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each A is independently CR9, where R9 is as defined herein. In certain embodiments, each A is independently CR9, where R9 is hydrogen, lower alkyl, or halogen.
[00104] In certain embodiments, each B is independently a direct bond. In certain embodiments, each B is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each B is independently CR9, where R9 is as defined herein. In certain embodiments, each B is independently CR9, where R9 is hydrogen, lower alkyl, or halogen.
[00105] In certain embodiments, each D is independently a direct bond. In certain embodiments, each D is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each D is independently CR9, where R9 is as defined herein. In certain embodiments, each D is independently CR9, where R9 is hydrogen, lower alkyl, or halogen.
[00106] In certain embodiments, each E is independently a direct bond. In certain embodiments, each E is independently a nitrogen, oxygen, or sulfur atom. In certain embodiments, each E is independently CR9, where R9 is as defined herein. In certain embodiments, each E is independently CR9, where R9 is hydrogen, lower alkyl, or halogen.
[00107] In one embodiment, provided herein is a compound selected from:
3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl]phenol; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-ethoxy- 1 H-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-mθφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol; l-[4- [4-(chloroacetyl)- 1 -piperazinyl] -6-(4-pyridiny 1 )- 1 , 3 ,5 -triazin-2-yl] -2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole; l-[4-[4-(dichloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]- 2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
2-(difluoromethyl)- 1 - { 4-(4-moφholinyl)-6-[4-(trichloroacetyl)- 1 -piperazinyl] - l,3,5-triazin-2-yl}-lH-benzimidazol-4-yl methyl ether;
2-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)- 1 ,3,5-triazin-2-yl]- 1 -piperazinyl } -2-oxoethyl methanesulfonate; l-[4-[4-(2-chloropropanoyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl] -2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
1 -[4- {4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole; l-[4-{4-[(bromomethyl)sulfonyl]-l -piperazinyl }-6-(4-moφholinyl)-l, 3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
N-(3- { [ 1 -[4- { 4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)- l,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-yl]oxy}propyl)-N,N- dimethylamine;
1 -[4- { 4- [(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)-2- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[6- {4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -2-(4-moφholinyl)-4- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[2-{4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)-4- pyrimidinyl] -2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyI)-4-methoxy-lH- benzimidazol- 1 -yl]-N-methyl-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine; N-[l-(chloroacetyl)-4-piperidinyl]-4-{2-(difluoromethyl)-4-[3-
(dimethylamino)propoxy]- 1 H-benzimidazol- 1 -yl } -N-methyl-6-(4-morpholinyl)- 1 ,3,5-triazin- 2-amine;
N-{ l-[(chloromethyl)sulfonyl]-4-piperidinyl}-4-[2-(difluoromethyl)-4- methoxy- 1 H-benzimidazol- 1 -yl]-N-methyl-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
2-chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4- morpholinyl)- 1 ,3,5-triazin-2-yl] -4-piperidinyl } acetamide;
2-chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl}-N-methylacetamide;
2-chloro-N-{ l-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-lH- benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl] -4-piρeridinyl } -N-methylacetamide;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl} acetamide;
2-chloro-N- { (35)- 1 - [4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] - 6-(4-morpholinyl)-l ,3,5-triazin-2-yl]pyrrolidinyl } acetamide;
2-chloro-N- [(3R)- l-[4-[2-(difluoromethyl)-4-methoxy-l H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl}-N-methylacetamide;
2-chloro-N- { (35)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]- 6-(4-morpholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl} -N-methylacetamide;
N-[(3Λ)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(35)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl] -6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
N-[QR)- 1 -(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(35)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2-yl]piperidinyl } acetamide;
2-chloro-N- { (35)- 1 - [4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] - 6-(4-moφholinyl)- 1 ,3,5-triazin-2-yl]piperidinyl } acetamide;
2-chloro-N- { (3R)- 1 - [4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl} -N-methylacetamide;
2-chloro-N-{(35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl}-N-methylacetamide;
N-[(3/?)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl] -N-methyl-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
N-[QS)- 1 -(chloroacetyOpiperidinyl^-^-Cdifluorornethyl^-methoxy- 1 H- benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine;
N-[(3/?)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-N-methyl-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine;
N-[(3S)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-3-azetidinyl}acetamide;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)- 1 ,3,5-triazin-2-yl] -3-azetidinyl } -N-methylacetamide;
N-[l-(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[l-(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy-l//- benzimidazol-l-yl]-yV-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl] -2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
3- { [ 1 -[4- { [ 1 -(chloroacetyO^-piperidinylJoxy } -6-(4-moφholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-yl]oxy}-N^V-dimethyl-l-propanamine;
3-{[l-[4-({ l-[(chloromethyl)sulfonyl]-4-piperidinyl}oxy)-6-(4-moφholinyl)- 1 ,3,5-triazin-2-yl]-2-(difluoromethyl)- 1 H-benzimidazol-4-yl]oxy } -N,N-dimethyl- 1 - propanamine; and l-{ l-[(chloromethyl)sulfonyl]-4-piperidinyl}-6-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-4-(4-moφholinyl)-lH-pyrazolo[3,4-rf]pyrimidine; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[00108] In another embodiment, provided herein is a compound selected from: l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)- 1 Η-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-ethoxy- 1 H-benzimidazole; 1 -[4-[4-(chloroacetyl)- 1 -piperazinyl]-6-(4-pyridinyl)- 1 ,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol;
3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]phenol;
[3-[4-[4-(chloroacetyl)- 1 -piperazinyl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]phenyl] methanol ;
[3-[4-[4-(chloroacetyl)-l -piperazinyl]-6-(4-pyridinyl)- 1 ,3,5-triazin-2- yl]phenyl]methanol;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- pyridinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- pyridinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- pyrimidinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- pyrimidinamine;
4-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]- lH-indazole;
4-[4-[4-(chloroacetyl)- 1 -piperazinyl]-6-(4-pyridinyl)- 1 ,3,5-triazin-2-yl]- 1 H- indazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)- 1 H-benzimidazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l ,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-ethoxy- 1 H-benzimidazole;
N-[ 1 -(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]amino } -6-(4-moφholinyl)- 1 ,3,5-triazin- 2-y 1] -2-(difluoromethyl )- 1 H-benzimidazol-4-ol ;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-ethoxy-lH- benzimidazol- 1 -yl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-lH-benzimidazole;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-lH-benzimidazol-4-ol;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]sulfanyl } -6-(4-moφholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)- 1 H-benzimidazole;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl] sulfanyl } -6-(4-morpholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-ol;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl] sulfanyl } -6-(4-moφholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]sulfanyl } -6-(4-morpholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-lH-benzimidazol-l-yl]-6-(4- moφholinyl)- 1 ,3,5-triazin-2-yl]-4-piperidinyl } acetamide;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-hydroxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)-l ,3,5-triazin-2-yl]-4-piperidinyl } acetamide; and
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-ethoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl}acetarnide; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[00109] The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cisltrans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[00110] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
[0011 1] When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. ScL 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
[00112] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene- 1 ,5-disulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino- salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.
[00113] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-moφholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1 -(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l,3-propanediol, and tromethamine.
[00114] In certain embodiments, the compounds provided herein are pharmacologically acceptable salts of the compounds with one or more of hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and isoethonic acids; or with one or more of potassium carbonate , sodium or potassium hydroxide, ammonia, triethylamine, and triethanolamine.
[00115] The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula I and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221- 294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asghamejad in "Transport Processes in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185- 218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Λdv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, S, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381 ; Farquhar et al., J. Pharm. ScL 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. ScL 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63- 80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.
[00116] In certain embodiments, provided herein is a phosphate, carboxylic acid, aminoacid ester prodrug of the compound provided herein.
[00117] In certain embodiments, the compounds provided herein are reversible inhibitors of PI3K. In certain embodiments, the compounds provided herein are irreversible inhibitors of PI3K. In certain embodiments, the compounds provided herein are selective reversible inhibitors of PI3K isoforms. In certain embodiments, the compounds provided herein are selective irreversible inhibitors of PI3K isoforms.
[00118] In certain embodiments, the compounds provided herein are reversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are irreversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective reversible inhibitors of pi 10a. In certain embodiments, the compounds provided herein are selective irreversible inhibitors of pi 10a.
[00119] Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein interact with the His-855, which is unique to pi 10a. Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein react with the His-855, which is unique to pi 10a. Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein alkylate the His-855, which is unique to pi 10a.
[00120] Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein are adapted to irreversibly inhibit the pi 10a isoform of PI3K. Without being bound by any theory, it is believed that, in certain embodiments, the compounds provided herein are adapted to target the His-855 group which is considered to form part of the ATP binding pocket of the p 11 Oa isoform of PI3 K, but not of the other isoforms. Without being bound by any theory, it is believed that, in certain embodiments, by targeting the His-855 of pi 10a, the compounds provided herein selectively and irreversibly inhibit this PI3K isoform.
[00121] Irreversible inhibition of an enzyme target has a number of potential advantages: e.g., (a) kinase inhibitors that shut down the ATP site by reversible competitive blockade of ATP have to bind very tightly to the enzyme and/or maintain high plasma levels for prolonged periods, in order to compete with ATP binding, since ATP levels in cells are high; (b) the enzyme is shut down permanently, and the pathway is only reactivated upon resynthesis of the enzyme, which may take some time; (c) it allows longer times between doses, for a more achievable dosage regime; (d) it provides an additional mechanism for selectivity, in one embodiment, between different isoforms of an enzyme.
Methods of Synthesis
[00122] In one embodiment, provided herein is a method of making a compound of
Formula Ia, Ib, Ic, or Id as defined herein, which comprises the step of coupling a substituted pyrimidine or triazine intermediate with a suitable species that contains an alkylhalide or alkylsulfonate.
[00123] In certain embodiments, provided herein is a method of making a compound of Formula Ia, Ib, Ic, or Id as defined herein, which comprises the step of coupling a substituted pyrimidine or triazine intermediate with a suitable species. In one embodiment, the suitable species contains an alkylhalide or alkylsulfonate that is capable of selectively alkylating the His-855 of the pi 10a subunit of PI3K.
[00124] In certain embodiments, when the linker group Q of a compound of Formula I contains an NH group, the method comprises the step of reacting the pyrimidine or triazine intermediate with a suitable acylating species. In certain embodiments, the method comprises the step of reacting a halo substituted pyrimidine or triazine intermediate with a suitable acylated species.
[00125] The compounds provided herein can be prepared by a number of different methods, and the following examples are only representative and do not exclude other related procedures. [00126] In one embodiment, when the linker group Q contains an amino substituent, the compounds of Formula Ia, Ib, Ic, or Id are prepared by reaction with an acylating species (e.g., acylhalide) or acid equivalent in the presence of a coupling reagent (Method A):
Figure imgf000048_0001
wherein Ri, R2, R3, R4, R5, Q, X, Y, and Z are each as defined herein.
[00127] The example shown in Scheme 1 is provided as an illustration of Method A.
Figure imgf000048_0002
Scheme 1. Synthesis of 3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]phenol
[00128] In another embodiment, the compounds of Formula Ia, Ib, Ic, or Id are prepared by a halogen displacement reaction on a 2- or 4-halopyrimidine or 2-halo- 1,3,5- triazine derivative by a previously acylated species (Method B):
Figure imgf000049_0001
[00129] The example shown in Scheme 2 is provided as an illustration of Method B.
Figure imgf000049_0002
Figure imgf000049_0003
K2CO3 / DMF / RT
Figure imgf000049_0004
Scheme 2. Synthesis of l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-morpholinyl)- l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole
[00130] Table 1 gives details of representative compounds provided herein, and preparable by the methods outlined in Schemes 1 and 2.
Table 1. Examples of representative compounds provided herein3
Figure imgf000049_0005
VII XIV
Figure imgf000049_0006
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0002
Figure imgf000053_0001
combustion analyses for C, H, and N.
Pharmaceutical Compositions
[00131] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula Ia, Ib, Ic, or Id as defined herein, and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
[00132] In one embodiment, the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection.
[00133] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, or mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin.
[00134] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers. Where pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles, such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection. Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.
[00135] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
[00136] The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art {see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).
[00137] The pharmaceutical compositions provided herein can be provided in a unit- dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00138] The pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. [00139] In another embodiment, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.
[00140] In yet another embodiment, provided herein is the use of a compound of
Formula Ia, Ib, Ic, or Id in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the medicament is in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein.
A. Oral Administration
[00141] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
[00142] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH- 101, AVICEL-PH- 103, AVICEL RC-581, AVICEL-PH- 105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
[00143] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
[00144] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00145] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSlL 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
[00146] Suitable glidants include, but are not limited to, colloidal silicon dioxide,
CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
[00147] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00148] The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
[00149] The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
[00150] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. [00151] The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
[00152] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
[00153] The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[00154] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
[00155] Coloring and flavoring agents can be used in all of the above dosage forms.
[00156] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
B. Parenteral Administration
[00157] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
[00158] The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
[00159] The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. [00160] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
[00161] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).
[00162] When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art. [00163] In one embodiment, the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
[00164] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00165] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
[00166] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
[00167] Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
C. Topical Administration
[00168] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[00169] The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
[00170] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
[00171] The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).
[00172] The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (OAV) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.
[00173] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifϊer, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifϊer in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
[00174] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL " ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
[00175] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
[00176] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellower wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
[00177] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
[00178] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
[00179] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00180] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. [00181] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as I- leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
[00182] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained- , pulsed-, controlled-, targeted, and programmed release.
D. Modified Release
[00183] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
[00184] Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891 ; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981 ; 6,376,461 ; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
1. Matrix Controlled Release Devices
[00185] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art {see, Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).
[00186] In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
[00187] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid- glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
[00188] In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
[00189] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
[00190] The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
2. Osmotic Controlled Release Devices
[00191] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s). [00192] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
[00193] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.
[00194] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
[00195] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
[00196] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00197] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00198] The delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
[00199] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
[00200] The pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
[00201] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art {see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21 ; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 1-21).
[00202] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
[00203] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[00204] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
[00205] Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.
4. Targeted Delivery
[00206] The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751 ; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.
Methods of Use
[00207] In one embodiment, the compounds provided herein are designed to irreversibly inhibit the pi 10a isoform of PI3K, in one embodiment, to target the His-855 group which is considered to form part of the ATP binding pocket of the pi 10a isoform of PDK, but not of the other isoforms. In targeting the His-855 group of pi 10a, the compounds, in one embodiment, selectively and irreversibly inhibit this PI3K isoform.
[00208] In one embodiment, provided herein is a method of irreversibly inhibiting
PI3K. In certain embodiments, the compounds provided herein selectively target the His-855 moiety of the pi 10a subunit, thus selectively irreversibly inhibiting the pi lOoc isoform of PI3K. [00209] In one embodiment, provided herein is a method of cancer prevention or therapy for treating cancers, comprising administering a compound of Formula Ia, Ib, Ic, or Id as defined herein to a subject in need thereof.
[00210] In another embodiment, there is provided a method of cancer prevention or therapy for treating cancers, wherein the method comprises the steps of: 1) selectively targeting a pi 10a subunit of PDK with a compound provided herein; and 2) alkylating the pi 10a subunit of PDK with the compound. In certain embodiments, the compound provided herein selectively targets the pi 10a subunit of PDK.
[00211] In yet another embodiment, there is provided a method of selectively irreversibly inhibiting the α isoform of PDK, wherein the method comprises the steps of: 1) selectively targeting a pi 10a subunit of PDK with a compound provided herein; and 2) alkylating the pi 10a subunit of PDK with the compound. In certain embodiments, the compound provided herein selectively targets the pi 10a subunit of PDK.
[00212] In one embodiment, provided is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition associated with PDK activity in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00213] In another embodiments, provided is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition responsive to the modulation of PDK activity in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00214] In yet another embodiment, provided is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PDK enzyme in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00215] In yet another embodiment, provided is a method of treating, preventing, or ameliorating one or more symptoms of cancer in a subject, which comprises administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00216] In yet another embodiment, there is provided the use of a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the compound selectively targets the pi 10a subunit of PBK. In certain embodiments, the compound selectively inhibits the PI3K via its interaction with its pi 10a subunit. In certain embodiments, the compound selectively alkylates the pi 10a subunit of PBK.
[00217] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In yet another embodiment, the subject is a primate other than a human, a farm animal such as cattle, a sport animal, or a pet such as a horse, dog, or cat.
[00218] The disorders, diseases, or conditions treatable with a compound provided herein, include, but are not limited to, ( 1 ) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasital cutaneous pathologies, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, exercise induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung diseases, and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) graft rejection (including allograft rejection and graft-v-host disease), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue disease, and sarcoidosis, (13) genital and reproductive conditions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurologic disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (17) pain; (18) renal disorders; (19) ocular disorders, including glaucoma,; and (20) infectious diseases, including HIV.
[00219] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocyte, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget' s disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget' s disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer , including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et ai, 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).
[00220] Depending on the disorder, disease, or condition to be treated, and the subject's condition, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period. [00221] In the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to 100 mg per kg subject body weight per day (mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg per day.
[00222] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1 ,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
[00223] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[00224] Also provided herein are methods of modulating PI3K activity, comprising contacting a PIK3 enzyme with a compound provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PIK3 enzyme is inside a cell.
[00225] The compounds provided herein, e.g., a compound of Formula Ia, Ib, Ic, or Id, including an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, can also be combined or used in combination with other agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions for which the compounds provided herein are useful, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, infectious diseases, and those pathologies noted herein.
[00226] Suitable other therapeutic agents can also include, but are not limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8) antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole; (9) antiinflammatories, e.g., non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; (11) anti-platelet agents, such as GPϋb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferatives, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) beta-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) calcium channel blockers, such as amlodipine besylate; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprine and cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; (24) enzymes, such as L-asparaginase; (25) Factor Vila Inhibitors and Factor Xa Inhibitors; (26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK- 104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP) inhibitors; (31) hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; (34) microtubule-disruptor agents, such as ecteinascidins; (35) microtubule-stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafϊl, and vardenafil); (39) plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (41) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids, such as aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (Cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents, such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; and (54) other miscellaneous agents, such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds.
[00227] In certain embodiments, the other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biologic response modifiers {e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects {e.g., antiemetics).
[00228] In certain embodiments, the other therapeutic agents that may be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine), and methotrexate), purine antagonists and pyrimidine antagonists (6- mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies; See, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.
[00229] In another embodiment, the method provided herein comprises administration of a compound of Formula Ia, Ib, Ic, or Id together with administering one or more chemotherapeutic agents and/or therapies selected from: alkylation agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumour antibiotics (e.g., adriamymycin and bleomycin); antitumour vegetable alkaloids (e.g., taxol and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumour immunological agents (e.g., interferon α, β, and γ); radiation therapy; and surgery. In certain embodiments, the one . or more chemotherapeutic agents and/or therapies are administered to the subject before, during, or after the administration of the compound of Formula Ia, Ib, Ic, or Id as defined herein.
[00230] Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, e.g., a compound of Formula I, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. When a compound provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.
[00231] The weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a NSAID, the weight ratio of the compound to the NSABD can range from about 1,000:1 to about 1 : 1,000, or about 200: 1 to about 1:200. Combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
[00232] The compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
[00233] Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [00234] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
[00235] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
[00236] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00237] The disclosure will be further understood by the following non-limiting examples.
EXAMPLES
[00238] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); M (molar); mM (millimolar); μM (micromolar); eq. (equivalent); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); cone, (concentrated); mp (melting point); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); DMF (dimethyformamide); DMSO (dimethylsulfoxide); DMSO-d^ (deuterated dimethylsulfoxide); EtOH (ethanol); EtOAc (ethyl acetate); /-PrOH (isopropanol); MeOH (methanol); THF (tetrahydrofuran); DEPEA (N,N-diisopropylethylamine); TFA (triethylacetic acid); TBDMSCl (tert-butylchlorodimethylsilane); TBAF, (tetra-n-butylammonium fluoride); PdCl2(dppf), ((1,1 '-bis(diphenylphosphino)ferrocene) dichloropalladium(II)); EDTA, (ethylenediaminetetraacetic acid); Me (methyl); Et (ethyl); /Bu (tert-butyl); and Boc {tert- butoxylcarbony).
[00239] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in 0C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
General Experimental Information.
[00240] The following examples are representative of the disclosure, and provide detailed methods for preparing the compounds of the disclosure, including the preparation of intermediate compounds. In these examples, elemental analyses (combustion analysis) were carried out in the Microchemical Laboratory, University of Otago, Dunedin, NZ. Melting points were determined on an Electrothermal 9100 Melting Point Apparatus. NMR spectra were obtained on a Bruker Avance-400 spectrometer at 400 MHz for 1H and 100 MHz for 13C spectra, referenced to TMS (Si(CH3)4). Mass spectra were determined on a VG-70SE mass spectrometer using an ionizing potential of 70 eV at a nominal resolution of 1000. High-resolution spectra were obtained at nominal resolutions of 3000, 5000, or 10000 as appropriate. All spectra were obtained as electron impact (EI) using Perfluorokerosene (PFK) as the reference unless otherwise stated. Column chromatography was carried out on silica gel (Merck 230-400 mesh), unless otherwise stated. Example 1
Synthesis of 3-r4-[4-(chioroacetyl)-l-piperazinyll-6-(4-moφholinyl)-l,3,5-triazin-2- yli phenol
Figure imgf000085_0001
[00241] The compound was prepared according to Scheme 1 using Method A.
[00242] A mixture of 2.35 g (10 mmol) of 2,4-dichloro-6-(4-morpholinyl)- 1,3,5- triazine, 1.93 g (10.5 mmol) of tert-butyl 1 -piperazinecarboxylate (1-Boc-piperazine), and 1.38 g (10 mmol) powdered K2CO3 in 20 mL acetone was stirred at room temperature for 30 min before being diluted with water to give 3.70 g (96% yield) of tert-butyl 4-[4-chloro-6-(4- morpholinyl)-l,3,5-triazin-2-yl]-l -piperazinecarboxylate as a white solid: mp (CH2Cl2/MeOH) 178-1800C; 1H NMR (CDCl3) δ 3.78 (m, 8H), 3.71 (m, 4H), 3.46 (m, 4H), 1.48 (s, 9H); MS (APCI+) 385.8 (MH+); Anal. Calcd. for C16H25ClN6O3: C, 49.9; H, 6.55; N, 21.8; Found: C, 50.15; H, 6.5; N, 22.1%.
[00243] A mixture of 0.385 g (1 mmol) of tert-butyl 4-[4-chloroa-6-(4-morpholinyl)- l,3,5-triazin-2-yl]-l -piperazinecarboxylate, 0.33 g (1.5 mmol) of 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol, 8 mL of 2 M Na2CO3, and 56 mg (0.08 mmol) of PdCl2(dppf) in 40 mL dioxane was refluxed under an atmosphere of nitrogen for 3 hrs. After cooling, the dioxane was removed under vacuum and the residue was extracted with CH2Cl2. After drying, the solvent was removed and the product was purified by chromatography on silica gel, eluting with CH2Cl2/EtOAc (4:1), to give 0.39 g (88 % yield) of tert-butyl 4-[4-(3- hydroxyphenyl)-6-(4-morpholinyl)-l,3,5-triazin-2-yl]piperazine-l-carboxylate: mp (MeOH) 180-182 0C; 1H NMR (CDCl3) δ 7.95 (d, J = 7.9 Hz, IH), 7.29 (m, IH), 7.30 (t, J = 7.9 Hz, IH), 6.96 (dd, J = 8.0, 2.7 Hz, IH), 5.36 (m, exchangeable with D2O, IH), 3.90 (m, 8 H), 3.76 (m, 4H), 3.59 (m, 4H), 1.50 (s, 9H); MS (APCf) 444.1 (MH+); Anal. Calcd. for C22H30N6O4: C, 59.71; H, 6.83; N, 18.99; Found: C, 59.6; H, 7.0; N, 19.0%. [00244] A mixture of 0.32 g (0.723 mmol) of ter/-butyl 4-[4-(3-hydroxyphenyl)-6-(4- moφholinyl)-l,3,5-triazin-2-yl]piperazine-l-carboxylate and 0.41 g (3.6 mmol) of trifluoroacetic acid in 5 mL of CH2Cl2 was stirred at room temperature for 1 hr, before the solution was diluted with further CH2Cl2 and washed with 2 M aqueous ammonia. The organic layer was then dried and removed under vacuum to give 0.246 g (99% yield) of 3-[4- (4-moφholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]phenol: mp (MeOH/Z-PrOH) 273-277 0C; 1H NMR (DMSO-^5) δ 9 Al (s, exchangeable with D2O, IH), 7.76 (m, 2H), 7.25 (t, J = 8.1 Hz, IH), 6.90 (m, IH), 3.79 (m, 8H), 3.65 (m, 4H), 2.73 (m, 4H); MS (APCI+) 343.7 (MH+); Anal. Calcd. For CnH22N6O2: C, 59.6; H, 6.5; N, 24.5; Found: C, 59.6; H, 6.4; N, 24.65%.
[00245] A stirred mixture of 103 mg (0.3 mmol) of 3-[4-(4-morpholinyl)-6-( 1 - piperazinyl)-l ,3,5-triazin-2-yl]phenol and 120 mg (0.9 mmol) of N-ethyl-N,N- diisopropylamine in 100 mL of CH2Cl2 was cooled to 0 0C and treated dropwise with 85 mg (0.7 mmol) of 2-chloroacetyl chloride. The mixture was allowed to warm to room temperature, and was then washed successively with dilute aqueous acetic acid and aqueous NaHCO3 solution. The organic solvent was removed under vacuum, and the residue was dissolved in a mixture of acetone and aqueous NaHCO3 solution. After TLC indicated complete hydrolysis of the initially formed 0-(2-chloroacetate), the acetone was removed under vacuum and the residue was extracted with CH2Cl2. After drying, the solvent was removed to give 100 mg (80 % yield) of 3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]phenol: mp (MeOH) 242-245 0C; 1H NMR (DMSO-J6) δ 9.51 (s, exchangeable with D2O, IH), 7.78 (m, 2 H), 7.26 (t, J = 7.8 Hz, IH), 6.92 (m, 1H),4.44 (s, 2H), 3.82 (m, 8H), 3.38 (m, 4H), 3.57 (m, 4H); MS (APCI+) 419.9 (MH+); Anal. Calcd. for C19H23ClN6O3: C, 54.5; H, 5.5; N, 20.1 ; Found: C, 54.4; H, 5.6; N, 19.8%.
Example 2
Synthesis of l-r4-[4-(chloroacetyl)-l-piperazinyll-6-(4-moφholinyl)-l,3,5-triazin-2-yll-2- (difluoromethyl)-4-ethoxy-lH-benzimidazole
Figure imgf000087_0001
[00246] The compound was prepared according to Scheme 2 using Method B.
[00247] Treatment of tert-butyl 4-(chloroacetyl)piperazine- 1 -carboxylate (An et al. ,
Tetrahedron, 1998, 54, 3999) with excess trifluoroacetic acid in CΗ2CI2 at room temperature, followed by removal of the solvent under vacuum gave crude 4-(chloroacetyl)-l- piperazinium trifluoroacetate: 1H NMR (DMSO-dg) δ 8.94 (br s, exchangeable with D2O, 2H), 4.44 (s, 2H), 3.66 (m, 4H), 3.13 (m, 4H), MS (APCI+) 163.5 (MH+).
[00248] A solution of 1.64 g (9 mmol) of 2-ethoxy-6-nitroaniline in methanol was hydrogenated over palladium on carbon. After filtration through celite, the solution was acidified with cone. HCl and evaporated to dryness. The residue was combined with 1.73 g (18 mmol) of difluoroacetic acid in 10 mL 4 M HCl and the solution was heated under reflux for 4 hrs. After dilution with water, decolorization with charcoal, and filtration through celite, the cooled solution was made basic with cone, aqueous ammonia to give 1.29 g (68 % yield) of 2-(difluoromethyl)-4-ethoxy-lH-benzimidazole: mp (MeOΗ/Η2O) 185-187 0C; 1H NMR (DMSO-^5) (tautomeric mixture) δ 13.30 (m, exchangeable with D2O, IH), 7.20 (t, 7HF = 53.3 Hz, IH), 7.19 (m, 2 H), 6.78 (br d, J = 7.5 Hz, IH), 4.24 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H); MS (APCI+) 213.3 (MH+); Anal. Calcd. for C0H10F2N2O: C, 56.6; H, 4.75; N, 13.2; Found: C, 56.9; H, 4.8; N, 13.4%.
[00249] A mixture of 0.85 g (4 mmol) of 2-(difluoromethyl)-4-ethoxy-lH- benzimidazole, 0.94 g (4 mmol) of 2,4-dichloro-6-(4-morpholinyl)-l,3,5-triazine, and 4.4 g (32 mmol) of powdered K2CO3 in 25 mL DMF was stirred at room temperature overnight. The mixture was diluted with water and the precipitate was collected and washed successively with water and cold ethanol to give 1.48 g (90% yield) of l-[4-chloro-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole: mp (EtOH) 272-275 0C; 1H NMR (CDCl3) δ 7.98 (d, J = 8.4 Hz, IH), 7.47 (t, 7HF = 53.4 Hz, IH), 7.38 (t, J = 8.3 Hz, IH), 6.86 (d, J = 8.1 Hz, IH), 4.33 (q, J = 7.0 Hz, 2H), 3.96 (m, 4H), 3.81 (m, 4H), 1.56 (s, 3H); MS (APCI+) 411.7/413.7 (MH+); Anal. Calcd. for CnH17ClF2N6O2: C, 49.7; H, 4.2; N, 20.5; Found: C, 49.8; H, 4.4; N, 20.6%.
[00250] A suspension of 103 mg (0.25 mmol) of l-[4-chloro-6-(4-moφholinyl)-l,3,5- triazin-2-yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole and 200 mg (0.75 mmol) of 4- (chloroacetyl)-l-piperazinium trifluoroacetate in 20 mL of TΗF was treated with 0.16 g (1.25 mmol) of N-ethyl-N,N-diisopropylamine and the mixture was stirred at room temperature for 3 hrs. The resulting clear solution was diluted with water to give 127 mg (94% yield) of 1- [4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)- 4-ethoxy-7H-benzimidazole: mp (CΗ2Cl2/Et0Η ) 217-219 0C; 1H ΝMR (CDCl3) δ 7.86 (d, J = 8.4 Hz, IH), 7.44 (t, 7HF = 53.5 Hz, IH), 7.33 (t, J = 8.3 Hz, IH), 6.82 (d, J = 7.9 Hz, IH), 4.33 (q, J = 7.0 Hz, 2H), 4.13 (s, 2H), 3.99 (m, 2H), 3.89 (m, 6H), 3.79 (m, 4H), 3.74 (m, 2H), 3.64 (m, 2H), 1.56 (t, J = 7.0 Hz, 3H); MS (APCI+) 538.3/540.3 (MH+); Anal. Calcd. for C23H27ClF2N8O3: C, 51.45; H, 5.1 ; N, 20.9; Found: C, 51.75; H, 5.3; N, 21.0%.
Example 3
Synthesis of l-[4-f4-(Chloroacetyl)-l-piperazinyll-6-(4-moφholinyl)-l,3,5-triazin-2-yll-2-
(difluoromethyl)-lH-benzimidazole
Figure imgf000088_0001
[00251] The compound was prepared according to Scheme 2 using Method B.
[00252] Reaction of 2-(difluoromethyl)- 1 H-benzimidazole with of 2,4-dichloro-6-(4- moφholinyl)-l,3,5-triazine as in Example 2 gave l-[4-chloro-6-(4-moφholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole (U.S. Pat. Appl. No. 2007/244110): mp (CΗCls/EtOΗ) 249-252 0C; 1H NMR (CDCl3) δ 8.42 (d, J = 7.4 Hz, IH), 7.90 (d, J = 7.4 Hz, IH), 7.57 (t, /HF = 53.5 Hz, IH), 7.50 (m, 2H), 3.98 (m, 4H), 3.83 (m, 4H); MS (APCr+) 367.2/369.2 (MH+); Anal. Calcd. for C15H13ClF2N6O: C, 49.1 ; H, 3.6; N, 22.9; Found: C, 49.3; H, 3.5; N, 22.S
[00253] Reaction of 1 -[4-chloro-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-lH-benzimidazole with 4-(chloroacetyl)- 1 -piperazinium trifluoroacetate as in Example 2 gave l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-morpholinyl)-l,3,5-triazin-2- yl]-2-(difluoromethyl)-lH-benzimidazole: mp (/-PrOH) 189-191 0C; 1H NMR(DMSOd6) δ 8.35 (d, J = 8.1 Hz, IH), 7.85 (d, J = 7.9 Hz, IH), 7.75 (t, /HF = 52.7 Hz, IH), 7.51 (U J = U Hz, IH), 7.44 (t, J = 7.6 Hz, IH), 4.46 (s, 2H), 3.89 (m, 2H), 3.83 (m, 6H), 3.70 (m, 4H), 3.61 (m, 4H); MS (APCf) 493.8/495.8 (MH+); Anal. Calcd. for C2]H24Cl2F2N8O2: C, 51.2; H, 4.7; N, 22.7; Cl, 7.2; Found: C, 51.1 ; H, 4.65; N, 22.4; Cl, 7.5%.
Example 4
Synthesis of l-r4-14-(Chloroacetyl)-l-piperazinyll-6-(4-moφholinyl)-l,3,5-triazin-2-vn-2- (difIuoromethyl)-4-methox v- 1 H-benzimi dazole
Figure imgf000089_0001
[00254] The compound was prepared according to Scheme 2 using Method B.
[00255] Reaction of 2-(difluoromethyl)-4-methoxy- lH-benzimidazole with of 2,4- dichloro-6-(4-morpholinyl)-l,3,5-triazine as in Example 2 gave l-[4-chloro-6-(4- morpholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (CHCl3 /EtOH) 263-266 0C; 1H NMR (CDCl3) δ 7.99 (d, / = 8.4 Hz, IH), 7.48 (t, /HF = 53.4 Hz, IH), 7.40 (t, J = 8.3 Hz, IH), 6.86 (d, J = SA Hz, IH), 4.05 (s, 3H), 3.96 (m, 4H), 3.82 (m, 4H); MS (APCI+) 397.8/399.8 (MH+); Anal. Calcd. for C16Hi5ClF2N6O2: C, 48.4; H, 3.8; N, 21.2; Found: C, 48.3; H, 3.8; N, 21.1%.
[00256] Reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy- 1 H-benzimidazole with 4-(chloroacetyl)- 1 -piperazinium trifluoroacetate as in Example 2 gave l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 241-243 0C; 1H NMR (CDCl3) δ 7.87 (d, J = 8.4 Hz, IH), 7.45 (t, /HF = 53.5 Hz, IH), 7.36 (t, J = 8.2 Hz, IH), 6.82 (d, J = 7.8 Hz, IH), 4.13 (s, 2H), 4.05 (s, 3H), 3.99 (m, 2H), 3.89 (m, 6H), 3.79 (m, 4H), 3.74 (m, 2H), 3.65 (m, 2H); MS (APCI+) 524.0/526.0 (MH+); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N, 21.4; Cl, 6.8; Found: C, 50.7; H, 4.8; N, 21.4; Cl, 6.9%.
Example 5
Synthesis of l-r4-r4-(Chloroacetyl)-l-piperazinyll-6-(4-moφholinyl)-l,3,5-triazin-2-yll-2-
(difluorometh vD- 1 H-benzimidazol-4-ol
Figure imgf000090_0001
[00257] The compound was prepared according to Scheme 1 using Method A.
[00258] Reaction of 4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)- IH- benzimidazole with 2,4-dichloro-6-(4-morpholinyl)-l,3,5-triazine as in Example 2, but using acetone as solvent, followed by chromatography on silica gel (eluting with CΗ2Cl2/hexanes (3: 1)) gave 4-(fer?-butyldimethylsilyloxy)-l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]- 2-(difluoromethyl)-lH-benzimidazole: mp (hexanes) 143-145 0C; 1H NMR (CDCl3) δ 7.99 (d, J = 8.4 Hz, IH), 7.46 (t, 7HF = 53.5 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.88 (d, J = 8.0 Hz, IH), 3.96 (m, 3.5H), 3.88 (m, 0.5H), 3.81 (m, 3.5H), 3.75 (m, 0.5H), 1.05 (s, 9H), 0.29 (s, 6H); MS (APCf) 497.9/499.9 (MH+); Anal. Calcd. for C2IH27ClF2N6O2Si: C, 50.75; H, 5.5; N, 16.9; Found: C, 50.7; H, 5.6; N, 17.0%.
[00259] Reaction of 4-(terf-butyldimethylsilyloxy)- 1 -[4-chloro-6-(4-morpholinyl)- l,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole with 2.2 equivalents of tert-butyl 1- piperazinecarboxylate in TΗF at room temperature gave a quantitative yield of tert-butyl 4- [4-[4-(ferr-butyldimethylsilyloxy)-2-(difluoromethyl)-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l ,3,5-triazin-2-yl]piperazine-l-carboxylate as an oil: 1H NMR (CDCl3) 57.91 (d, J = 8.2 Hz, IH), 7.45 (t, /HF = 53.6 Hz, IH), 7.26 (t, 7 = 8.1 Hz, IH), 6.83 (d, J = 7.9 Hz, IH), 3.85 (m, 8H), 3.77 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H); MS (APCI+) 648.7 (MH+).
[00260] Reaction of crude tert-butyl 4-[4-[4-(teAY-butyldimethylsilyloxy)-2-
(difluoromethyl)- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]piperazine- 1 - carboxylate with tetrabutylammonium fluoride in TΗF at 0 0C gave a quantitative yield of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)- l,3,5-triazin-2-yl]piperazine-l-carboxylate: mp (MeOH) 228-230 0C; 1H NMR (CDCl3) δ 7.81 (d, J = 8.4 Hz, IH), 7.55 (t, /HF = 53.6 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.90 (d, J = 8.0 Hz, IH), 3.88 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); MS (APCI+) 534.1 (MH+); Anal. Calcd. for C24H30F2N8O4: C, 54.1 ; H, 5.7; N, 21.0; Found: C, 54.15; H, 5.8; N, 21.3%.
[00261] Reaction of terf-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-lH-benzimidazol- l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]piperazine-l-carboxylate with 5 equivalents of trifluoroacetic acid in CH2Cl2 at room temperature gave an 86% yield of 2-(difluoromethyl)- l-[4-(4-moφholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]-lH-benzoimidazol-4-ol: mp (MeOH) 269-271 0C; 1H NMR (DMSO-J6) δ 7.73 (d, J = 8.2 Hz, IH), 7.69 (t, 7HF = 52.9 Hz, IH), 7.25 (t, J = 8.1 Hz, IH), 6.76 (d, J = 7.8 Hz, IH), 3.74 (m, 12H), 2.76 (m, 4H); MS (APCI+) 433.9 (MH+); Anal. Calcd. for C19H22F2N8O2: C, 52.8; H, 5.1; N, 25.9; Found: C, 52.7; H, 5.2; N, 25.85%.
[00262] A suspension of 0.22 g (0.5 mmol) of 2-(difluoromethyl)- 1 -[4-(4- moφholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]-lH-benzoimidazol-4-ol in 200 mL CH2Cl2 containing 0.25 g (2.5 mmol) triethyamine was cooled to 0 0C where 0.23 g (2 mmol) of chloroacetyl choride was added dropwise. The mixture was allowed to warm to room temperature for 2 hrs before being quenched with water. After being washed successively with dilute aqueous acetic acid and NaHCO3 solutions, the CH2Cl2 was removed under vacuum and the residue was dissolved in a mixture of acetone and 2 M aqueous NaHCO3. After 4 hrs the acetone was removed under vacuum and the residue was extracted into CH2Cl2. Chromatography on silica gel, eluting with CH2Cl2/Et0Ac (3:2), gave 145 mg (53 % yield) of l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol: mp (CΗ2Cl2/Me0Η) 267-270 0C; 1H NMR (DMSO- d6) δ 10.21 (br s, exchangeable with D2O, IH), 7.75 (d, J = 8.2 Hz, IH), 7.71 (t, JHF = 52.9 Hz, IH), 7.27 (t, J = 8.1 Hz, IH), 6.77 (d, J = 7.9 Hz, IH), 4.45 (s, 2H), 3.86 (m, 2H), 3.82 (m, 6H), 3.69 (m, 4H), 3.61 (m, 4H); MS (APCI+) 510.1 (MH+); Anal. Calcd. for C2IH23ClF2N8O3: C, 49.6; H, 4.6; N, 22.0; Found: C, 49.35; H, 4.75; N, 22.0%.
Example 6
Synthesis of l-r4-r4-(chloroacetyl)-l-piperazinyll-6-(4-pyridinyl)-l,3,5-triazin-2-yll-2- (difluoromethyl)-4-methox v- 1 H-benzimidazole
Figure imgf000092_0001
[00263] The compound was prepared according to Scheme 1 using Method A.
[00264] A mixture of 0.99 g (50 mmol) of 2-(difluoromethyl)-4-methoxy-lH- benzimidazole, 2.0 g tert-b\xty\ 4-(4,6-dichloro-l,3,5-triazin-2-yl)piperazine-l -carboxylate (Lowik et al., Eur. J. Org. Chem., 2001, 2825), and 3.5 g (250 mmol) powdered K2CO3 in 40 mL DMF was stirred at room temperature for 1 hr. Water was added and the product was collected by filtration and washed with water and cold ethanol to give 2.14g (86% yield) of tert-buty\ 4-(4-chloro-6-(2-(difluorornethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl)- 1 ,3,5-triazin- 2-yl)piperazine-l-carboxylate: mp (CΗ2Cl2/EtOΗ) > 300 0C; 1H NMR (CDCl3) δ 7.99 (d, / = 8.3 Hz, IH), 7.48 (t, 7HF = 53.4 Hz, IH), 7.41 (t, J = 8.3 Hz, IH), 6.87 (d, J = 8.0 Hz, IH), 4.06 (s, 3H), 3.95 (m, 4H), 3.58 (m, 4H), 1.50 (s, 9H); MS (APCI+) 497.1/499.1 (MH+); Anal. Calcd. for C21H24ClF2N7O3: C, 50.9; H, 4.9; N, 19.8; Found: C, 51.1; H, 4.9; N, 19.95%.
[00265] A mixture of 0.496 g ( 1 mmol) of terr-butyl 4-(4-chloro-6-(2-
(difluoromethyl)-4-methoxy- 1 H-benzoimidazol- 1 -yl)- 1 ,3,5-triazin-2-yl)piperazine- 1 - carboxylate, 0.18 g (1.5 mmol) 4-pyridyl boronic acid, 8 mL of 4 M Na2CO3 solution and 56 mg PdCl2(dppf) in 40 mL dioxane was heated under reflux under an atmosphere of nitrogen for 1 hr. The dioxane was removed under vacuum and the product was collected and washed with water. Chromatography on alumina, eluting with CΗ2Cl2/EtOAc (95:5), gave 0.152 g (28% yield) of tert-butyl 4-(4-(2-(difluoromethyl)-4-methoxy-l H-benzimidazol- 1 -yl)-6-(4- pyridinyl)-l,3,5-triazin-2-yl)piperazine-l -carboxylate: mp (CΗ2Cl2/Me0Η) 242-245 0C; 1H NMR (CDCl3) δ 8.86 (dd, J = 4.5, 1.5 Hz, 2H), 8.27 (dd, J = 4.5, 1.6 Hz, 2H), 8.07 (d, J = 8.3 Hz, IH), 7.52 (t, 7HF = 53.4 Hz, IH), 7.45 (t, J = 8.2 Hz, IH), 6.88 (d, J = 8.0 Hz, IH), 4.13 (m, 2H), 4.08 (s, 3 H) 4.00 (m, 2H), 3.63 (m, 4H), 1.52 (s, 9H); MS (APCI+) 540.4 (MH+); Anal. Calcd. for C26H28F2N8O3: C, 58.0; H, 5.2; N, 20.8; Found: C, 57.9; H, 5.2; N, 21.0%.
[00266] A solution of 0.12 g (0.22 mmol) tert-butyl 4-(4-(2-(difluoromethyl)-4- methoxy- lH-benzimidazol- 1 -yl)-6-(4-pyridinyl)- 1 ,3,5-triazin-2-yl)piperazine- 1 -carboxylate was treated with an excess of trifluoroacetic acid in CH2Cl2 to give crude 2-(difluoromethyl)- 4-methoxy- 1 -[4-(piperazin- 1 -yl)-6-(4-pyridinyl)- 1 ,3,5-triazin-2-yl]- 1 H-benzimidazole: 1H NMR (DMSO-d6) δ 8.87 (dd, J = 4.4, 1.6 Hz, 2H), 8.30 (dd, J = 4.5, 1.6 Hz, 2H), 8.06 (d, J = 7.9 Hz, IH), 7.81 (t, Jm = 52.7 Hz, IH), 7.49 (t, J = 8.2 Hz, IH), 7.01 (d, J = 7.9 Hz, IH), 6.20 (br m, exchangeable with D2O, IH), 4.10 (m, 2H), 4.00 (s, 3H), 3.95 (m, 2H), 3.01 (m, 4H); MS (APCI+) 440.0 (MH+). [00267] A solution of crude 2-(difluoromethyl)-4-methoxy- 1 -[4-(piperazin- 1 -yl)-6-(4- pyridinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole and diisopropylethylamine in CH2Ch was treated with chloroacetyl chloride at 00C. After 30 min the solution was washed successively with dilute aqueous acetic acid and NaHCO3 solution, and dried. The solution was eluted through a short column of alumina and HCl in methanol was added. The solvent was removed and the residue was recrystallized from methanol to give l-[4-[4-(chloroacetyl)-l- piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH- benzimidazole hydrochloride: mp > 300 0C; 1H NMR (DMSO-^6) δ 8.91 (d, J = 6.0 Hz, 2H), 8.37 (d, J = 6.1 Hz, 2H), 8.09 (d, J = 8.3 Hz, IH), 7.84 (t, JHF = 52.6 Hz, IH), 7.51 (t, J = 8.2 Hz, IH), 7.03 (d, J = 8.1 Hz, IH), 4.50 (s, 2H), 4.16 (m, 2H), 4.00 (s, 3H), 3.98 (m, 2H), 3.71 (m, 4H); MS (APCI+) 516.2/518.2 (MH+); Anal. Calcd. for C23H22Cl2F2N8O2: C, 50.1 ; H, 4.0; N, 20.3; Found: C, 49.9; H, 4.1 ; N, 20.2%.
Example 7
Synthesis of l-[4-f4-(dichloroacetyl)-l-piperazinyll-6-(4-morpholinyl)-l,3,5-triazin-2-yll-2- (difluoromethyl)-4-methox v- 1 H-benzimidazole
Figure imgf000093_0001
[00268] A mixture of 1.98 g (5 mmol) of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-
2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole, 1.16 g (6.25 mmol) of tert-butyl 1- piperazinecarboxylate, and 1.29 g (10 mmol) of DIPEA in 100 mL of TΗF was stirred at room temperature for 1 hr, and the solution was concentrated under vacuum. The residue was diluted with water containing 1 mL of acetic acid and the resulting precipitate was collected, washed with water, and dried, to give 2.71 g, (99% yield) of rm-butyl 4-[4-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-l- piperazinecarboxylate: mp (MeOH) 221-223 0C; 1H NMR (CDCl3) δ 7.88 (dd, J = 8.4, 0.6 Hz, IH), 7.47 (t, JHF = 53.5 Hz, IH), 7.35 (t, J = 8.2 Hz, IH), 6.81 (d, J = 7.7 Hz, IH), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5; Found: C, 54.9; H, 5.9; N, 20.5%.
[00269] Reaction of the above carbamate with an excess of TFA (10 mL) in CH2Cl2 at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 2-(difluoromethyl)-4- methoxy-l-[4-(4-moφholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole in 100% yield: mp (EtOH) 228-231 0C: 1H NMR (CDCl3) «57.90 (d, J = 7.9 Hz, IH), 7.50 (t, JHF = 53.5 Hz, 1 H), 7.34 (t, J = 8.3 Hz, IH), 6.81 (d, J = 7.8 Hz, IH), 4.05 (s, 3 H), 3.87 (m, 8 H), 3.78 (m, 4H), 2.95 (m, 4H); Anal. Calcd. for C20H24F2N8O2: C, 53.8; H, 5.4; N, 25.1 ; Found: C, 53.8; H, 5.6; N, 25.3%.
[00270] Reaction of the above amine with dichloroacetyl chloride in CH2Cl2 gave 1 -
[4-[4-(dichloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy-lH-benzimidazole in 97% yield: mp (CΗ2Cl2/MeOΗ) 275-278 0C; 1H NMR (DMSO-^6) δ 7.90 (d, J = 8.0 Hz, IH), 7.70 (t, yHF = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 7.29 (s, IH), 6.96 (d, J = 7.8 Hz, IH), 3.98 (s, 3H), 3.89-3.88 (m, 8H), 3.70 (m, 8H); Anal. Calcd. for C22H24Cl2F2N8O30.15CH2Cl2: C, 46.7; H, 4.3; N, 19.7; Found: C, 46.8, H, 4.3; N, 19.6%. Example 8
Synthesis of 2-(difluoromethyl)- 1 - f 4-(4-moφholinyl)-6-f 4-(trichloroacetyl)- 1 -piperazinyli- l,3,5-triazin-2-yl}-lH-benzimidazoI-4-yl methyl ether
Figure imgf000095_0001
[00271] Reaction of 2-(difluoromethyl)-4-methoxy-l-[4-(4-morpholinyl)-6-(l- piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole with trichloroacetyl chloride in CH2Cl2 gave 2-(difluoromethyl)- 1 - { 4-(4-morpholinyl)-6-[4-(trichloroacetyl)- 1 -piperazinyl]- 1 ,3,5- triazin-2-yl}-lH-benzimidazol-4-yl methyl ether in 87% yield: mp (CΗ2Cl2/MeOΗ) 252 0C (dec); 1H NMR (DMSO-d6) δ 7.90 (d, J = 8.0 Hz, IH), 7.71 (t, 7HF = 52.8 Hz, IH), 7.42 (t, J = 8.2 Hz, IH), 6.96 (d, J = 7.8 Hz, IH), 3.98 (s, 3H), 3.96-3.70 (m, 16H); Anal. Calcd. for C22H23Cl3F2N8: C, 44.7; H, 3.9; N; 18.9; Found: C, 44.9; H, 3.9; N, 19.0%.
Example 9
Synthesis of 2- f 4-r4-r2-(difluorometh yl)-4-methox v- 1 H-benzimidazol- 1 - yll -6-(4- morpholinyl)- 1 ,3,5-triazin-2-yll- 1 -piperazinyl ) -2-oxoethyl methanesulfonate
Figure imgf000095_0002
[00272] A mixture of 2-(difluoromethyl)-4-methoxy-l-[4-(4-morpholinyl)-6-(l- piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole (403 mg, 0.9 mmol) and DIPEA (1 mL) in CH2Cl2 (25 mL) was treated with acetoxyacetyl chloride (1 mL) at 0 0C. The reaction mixture was allowed to warm to room temperature, and after being stirred for 4 hrs it was diluted with water (30 mL). The organic layer was separated, dried (Na2SO4), and evaporated to give a crude product which was chromatographed on silica, eluting with CH2Cl2/EtOAc (4: 1) to give 2-{4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]-l-piperazinyl }-2-oxoethyl acetate in 85% yield: 1H NMR (DMSO-J6) δ 7.90 (d, J = 7.9 Hz, IH), 7.70 (t, JHF = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz), 6.96 (d, J = 7.8 Hz, IH), 4.84 (s, 2H), 3.97 (s, 3H), 3.87-3.89 (m, 8H), 3.87-3.81 (m, 8H), 3.71-3.70 (m, 4H), 3.56 (m, 4H), 2.03 (s, 3H).
[00273] The above acetate (387 mg, 0.71 mmol) was dissolved in a mixture of THF
(10 mL) and H2O (4 mL), and Cs2CO3 (829 mg, 7.1 mmol) was added. The reaction mixture was refluxed for 48 hrs, cooled to 20 0C and diluted with water. The resulting precipitate was filtered, washed with water, and chromatographed on silica eluting first with CH2Cl2ZEtOAc (7:3) then with CH2Cl2/MeOH (49: 1) to give 2-{4-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-l-piperazinyl}-2-oxoethanol in 85% yield: 1H NMR (DMSO-J6) δ 7.90 (d, J = 8.36 Hz, IH) 7.70 (t, Jw = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.96 (d, J = 7.8 Hz, IH), 4.63 (t, J = 5.2 Hz, exchangeable with D2O, IH), 4.15 (d, J = 5.2 Hz, 2H), 3.97 (s, 3H), 3.84-3.81 (m, 8H), 3.71-3.70 (m, 4H), 3.60-3.49 (m, 4H).
[00274] The above alcohol (158 mg, 0.31 mmol) and Et3N (0.16 mL) were dissolved in dry CH2Cl2 (10 mL), and cooled in an ice bath. Methanesulphonyl chloride (0.05 mL) was added, and the mixture was allowed to warm to room temperature with stirring over 2 hrs. The reaction mixture was diluted with water (10 mL) and the organic layer was separated, dried (Na2SO4), and evaporated to give a 92% yield of 2-{4-[4-[2-(difluoromethyl)-4- methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 -piperazinyl } -2- oxoethyl methanesulfonate as a white solid: mp (CΗ2Cl2/hexanes) 176-180 °C; 1H NMR (DMSO-J6) δ 7.90 (d, J = 8.4 Hz, IH), 7.70 (t, /HF = 52.8 Hz, IH), 7.41 (t, 7 = 8.1 Hz, IH), 6.96 (d, J = 7.8 Hz, IH), 5.09 (s, 2H), 3.97 (s, 3H), 3.88-3.82 (m, 8H), 3.70 (m, 4H), 3.59- 3.40 (m, 2H), 3.28 (s, 3H); Anal. Calcd. for C23H28F2N8O6S H2O: C, 46.0; H, 5.0; N; 18.7; Found: C, 46.2; H, 5.1; N, 17.9%. Example 10
Synthesis of 1 -f4-[4-(2-chloropropanoyl)- 1 -piperazinyll-6-(4-morpholinyl)-l,3,5-triazin-2- vH-2-(difluoromethyl)-4-methoxy-lH-benzimidazole
Figure imgf000097_0001
[00275] Reaction of 2-(difluoromethyl)-4-methoxy- 1 -[4-(4-morpholinyl)-6-( 1 - piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole with 2-chloropropionyl chloride in CH2Cl2 as above gave l-[4-[4-(2-chloropropanoyl)-l-piperazinyl]-6-(4-morpholinyl)-l,3,5-triazin-2- yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole in 89% yield: 1H NMR (DMSO-J6) (57.90 (d, J = 8.1 Hz, IH), 7.70 (t, JH¥ = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.96 (d, J = 7.8 Hz, IH), 5.12 (d, J = 5.9 Hz, IH), 3.98 (s, 3H), 3.88-3.82 (m, 8H), 3.71-3.63 (m, 8H), 1.55 (d, J = 6.4 Hz, 3H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.45; H, 5.1; N; 20.9; Found: C, 51.6; H, 5.2; N, 21.0%.
Example 11
Synthesis of 1 -14- {4-l(chloromethyl)sulfonyll-l-piperazinvπ-6-(4-morpholinyl)- 1,3,5- triazin-2-yll-2-(difluoromethyl)-4-methoxy-lH-benzimidazole
Figure imgf000097_0002
[00276] The compound was prepared according to Scheme 1 using Method A.
[00277] A solution of 224 mg (0.5 mmol) of 2-(difluoromethyl)-4-methoxy- 1 -[4-(4- moφholinyl)-6-(l-piperazinyl)-l,3,5-triazin-2-yl]-lH-benzimidazole in 10 mL of pyridine was cooled to 0° C and 0.112 g (0.75 mmol) of chloromethanesulfonyl chloride was added over 5 min. The mixture was allowed to warm to room temperature. After 1 hr, it was diluted with water to give a precipitate which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 100 mg (36% yield) of l-[4-{4- [(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 261-263 0C; 1H NMR (CDCl3) δ 7.85 (d, J = 8.3 Hz, IH), 7.43 (t, 7HF = 53.5 Hz, IH), 7.35 (t, J = 8.2 Hz, IH), 6.82 (d, / = 8.0 Hz, IH), 4.55 (s, 2H), 4.05 (s, 3H), 4.00 (m, 4H), 3.88 (m, 4H), 3.79 (m, 4H), 3.57 (m, 4H); Anal. Calcd. for C21H25ClF2N8O4S: C, 45.1 ; H, 4.5; N, 20.05; Found: C, 45.3; H, 4.5; N, 20.2%.
Example 12
Synthesis of 1 -F4- f 4-f (bromometh vDsulfon yl] - 1 -piperazinyl ) -6-(4-morpholinyl)- 1,3,5- triazin-2-yll-2-(difluoromethyl)-4-methoxy-lH-benzimidazole
Figure imgf000098_0001
[00278] The compound was prepared according to Scheme 1 using Method A.
[00279] A solution of 0.5 g ( 1.1 mmol) of 2-(difluoromethyl)-4-methoxy- 1 -[4-(4- morpholinyl)-6-(l -piperazinyl)- l,3,5-triazin-2-yl]-lH-benzimidazole and a suspension of 0.8 g powdered K2CO3 in CH2Cl2 (50 mL) was cooled to 0 0C and 0.8 g (3.3 mmol) of bromomethylsulfonyl bromide (Block and Aslam, Org. Synth. Coll. Vol. 1987, S, 212) was added. The stirred mixture was allowed to warm to room temperature overnight, and was diluted with water and aq. NH3. After drying (Na2SO4) and removal of the solvent, the white solid was chromatographed on silica, eluting with CH2Cl2/EtOAc (9:1) to give 335 mg (50% yield) of 1 -[4- { 4-[(bromomethyl)sulfonyl]- 1 -piperazinyl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 259-262 0C; 1H NMR (CDCl3) δ 7.86 (dd, J = 8.4, 0.6 Hz, IH), 7.44 (t, 7HF = 53.5 Hz, IH), 7.36 (t, J = 8.2 Hz, IH), 6.83 (d, J = 7.8 Hz, IH), 4.46 (s, 2H), 4.05 (s, 3H), 4.01 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.58 (m, 4H); Anal. Calcd. for C2 ,H25BrF2N8O4S: C, 41.8; H, 4.2; N, 18.6; Found: C, 41.8; H, 4.4; N, 18.6%. Example 13
Synthesis of N-(3- { 11 -f 4- ( 4-r(chloromethyl)sulfonvn- 1 -piperazinyl } -6-(4-morpholinyl)- l,3,5-triazin-2-vπ-2-(difluoromethyl)-lH-benzimidazol-4-yl1oxylpropyl)-N,N- dimethylamine
Figure imgf000099_0001
[00280] The compound was prepared according to Scheme 1 using Method A.
[00281] A mixture of 0.60 g (1.1 mmol) of
Figure imgf000099_0002
4-[4-[2-(difluoromethyl)-4- hydroxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperazine-l- carboxylate (Example 5), 0.47 g (3.3 mmol) of 3-bromo-l-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water gave 0.66 g (99% yield) of fm-butyl 4-[4-[2-(difluoromethyl)-4-(3- hydroxypropoxy)-lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- 1 - piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J = 8.4. 0.7 Hz, IH), 7.49 (t, JHF - 53.4 Hz, IH), 7.34 (t, J = 8.1 Hz, IH), 6.92 (dd, J = 8.0, 0.6 Hz, IH), 4.47 (t, J = 5.9 Hz, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, IH), 2.14 (pentet, J = 5.8 Hz, 2H), 1.50 (s, 9H).
[00282] A mixture of the above alcohol and 0.34 g (3.3 mmol) of Et3N in 20 mL of
THF was cooled to 0 0C and 0.32 g (2.8 mmol) of methanesulfonyl chloride was added dropwise. After 1 hr, 6 g of 40% aqueous Me2NH was added, and the resulting mixture was stirred at room temperature for 36 hr. The THF was removed under vacuum and the residue was diluted with water and extracted into CH2Cl2. Drying and removal of the solvent gave tert-bvAy\ 4-[4- { 2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]- lH-benzimidazol- 1 -yl } -6- (4-morpholinyl)-l,3,5-triazin-2-yl]-l -piperazinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.87 (dd, J = 8.4. 0.6 Hz, IH), 7.48 (t, /HF = 53.5 Hz, IH), 7.33 (t, J = 8.2 Hz, IH), 6.85 (d, J = 7.8 Hz, IH), 4.31 (t, J = 6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51 (t, J = 7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J = 7.0 Hz, 2H), 1.50 (s, 9H). [00283] Treatment of the above crude carbamate with TFA in CH2Cl2 gave N-[3-( { 2-
(difluoromethyl)- 1 -[4-(4-morpholinyl)-6-( 1 -piperazinyl)- 1 ,3,5-triazin-2-yl]- IH- benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine as a solid: 1H ΝMR (CDCl3) δ 7.89 (dd, J = 8.4. 0.7 Hz, IH), 7.50 (t, 7HF = 53.5 Hz, IH), 7.31 (t, J = 8.2 Hz, IH), 6.84 (d, J = 8.0 Hz, IH), 4.32 (t, J = 6.8 Hz, 2H), 3.86 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H), 2.53 (t, J = 7.2 Hz, 2H), 2.27 (s, 6H), 2.13 (pentet, J = 6.9 Hz, 2H).
[00284] A mixture of 0.42 g (0.81 mmol) of the above amine and 1 g powdered K2CO3 in CH2Cl2 was cooled to 0 0C and 0.36 g (2.4 mmol) of chloromethanesulfonyl chloride was added dropwise. The mixture was allowed to warm to room temperature, and after 1 hr water was added. The solvent was dried, and the solution was absorbed on to a column of alumina. Νon-polar impurities were removed by elution with CH2Cl2/Et0Ac 9: 1 and fractions containing the product were obtained by subsequent elution with CH2Cl2/EtOAc 1:1. The solution was acidified with HCl in MeOH (1.25 M), and the solvents were removed under vacuum. The resulting solid was recrystallised from EtOH/EtOAc to give N-(3-{ [l-[4-{4- [(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-yl]oxy}propyl)-N,N-dimethylamine hydrochloride: mp (EtOΗ/EtOAc) 243-247 0C; 1H ΝMR (DMSO-^5) δ 10.26 (m, exchangeable with D2O, IH), 7.92 (d, J = 8.3 Hz, IH), 7.70 (t, JHf = 52.8 Hz, IH), 7.42 (t, J = 8.2 Hz, IH), 6.99 (d, J = 7.9 Hz, IH), 4.33 (t, J = 6.1 Hz, 2H), 3.94 (m, 4H), 3.82 (m, 4H), 3.70 (m, 4H), 3.29 (m, 2H), 3.22 (m, 4H), 2.91 (s, 3H), 2.81 (s, 6H), 2.25 (m, 2H); Anal. Calcd. for C25H35Cl2F2N9O4S H2O: C, 43.9; H, 5.45; Cl, 10.4, N, 18.4; Found: C, 43.5; H, 5.5; Cl, 10.0; N, 18.3%.
Example 14
Synthesis of 1 -\4- { 4-[(chloromethyl)sulfonyll- 1 -piperazinyl ) -6-(4-morpholinyl)-2- pyrimidinyll -2-(difluoromethyl)-4-methox v- 1 H-benzimidazole
Figure imgf000100_0001
[00285] The compound was prepared according to Scheme 1 using Method A.
[00286] A solution of 0.223 g (0.5 mmol) of o 2-(difluoromethyl)-4-methoxy- 1 -[4-(4- moφholinyl)-6-(l-piperazinyl)-2-pyrimidinyl]-lH-benzimidazole (WO 2008/032064) and 0.10 g ( 1 mmol) of Et3N in 20 mL CH2Cl2 was cooled to 00C, and 0.112 g (0.75 mmol) of chloromethanesulfonyl chloride was added dropwise. The reaction mixture was allowed to warm to room temperature and, after 1 hr, water was added. The organic layer was separated, washed successively with aqueous acetic acid and aq. ammonia, and dried. Polar impurities were removed by elution through a column of alumina with CH2Cl2, and the solvent was then removed to give 0.197 g (71% yield) of l-[4-{4-[(chloromethyl)sulfonyl]-l-piperazinyl}-6- (4-moφholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 229-232 0C; 1H NMR (CDCl3) δ 1.1 A (d, J = 7.9 Hz, IH), 7.37 (t, 7HF = 53.5 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.79 (t, J = 7.9 Hz, IH), 5.53 (s, IH), 4.55 (s, 2H), 4.05 (s, 3H), 3.82 (m, 4H), 3.78 (m, 4H), 3.64 (m, 4H), 3.59 (m, 4H); Anal. Calcd. for C22H26ClF2N7O4S: C, 47.35; H, 4.7; N, 17.6; Found: C, 47.5; H, 4.8; N, 17.5%.
Example 15
Synthesis of 1 -f 6- { 4-l(chloromethvπsulfonyll- 1 -piperazinyl ) -2-(4-morpholinyl)-4- pyrimidinyll-2-(difluorornethyl)-4-methoxy-lH-benzimidazole
Figure imgf000101_0001
[00287] The compound was prepared according to Scheme 1 using Method A.
[00288] A mixture of 7.72 g (0.04 mol) 4,6-dichloro-2-(methylsulfanyl)pyrimidine,
7.93 g (0.04 mol) 2-(difluoromethyl)-4-methoxy-lH-benzimidazole, and 22 g (0.26 mol) of powdered K2CO3 in 100 mL DMSO was stirred at room temperature for 3 days and diluted with water. The solid was collected, washed with water, and dried. Chromatography on silica, eluting with CΗ2Cl2/Et0Ac (95:5) gave 5.91 g (41% yield) of l-[6-chloro-2- (methylsulfanyl)-4-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (/- Pr2O/hexanes) 120-121 0C; 1H NMR (CDCl3) δ 7.40 (t, J = 8.2 Hz, IH), 7.32 (s, IH), 7.26 (dd, J = 8.4, 0.7 Hz, IH), 7.18 (t, JHF = 53.3 Hz, IH), 6.85 (d, J = 7.9 Hz, IH), 4.07 (s, 3H), 2.62 (s, 3H); MS (APCI+) m/z 357.6 (MH+); Anal. Calcd. for Ci4H11ClF2N4OS: C, 47.1; H, 3.1; N, 15.7; Found C, 47.3; H, 3.4; N, 15.7%. Further elution with CH2Cl2/EtOAc (9:1) gave 4.16 g (20% yield) of the bis-addition byproduct, 2-(difluoromethyl)- 1 -[6-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-2-(methylsulfanyl)-4-pyrimidinyl]-4- methoxy-lH-benzimidazole: XH NMR (CDCl3) δ 7.64 (s, 1Η), 7.45-7.38 (m, 4Η), 7.26 (t, 7HF - 53.3 Hz, 2H), 6.87 (dd, / = 6.9, 2.0 Hz, 2H), 4.07 (s, 6H), 2.62 (s, 3H).
[00289] A mixture of 2 g (5.6 mmol) of 1 -[6-chloro-2-(methylsulfanyl)-4- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole and 2.6 g (14 mmol) of tert- butyl 1-piperazinecarboxylate in 50 mL of TΗF was stirred at room temperature for 2 hrs before being diluted with water containing 1 mL of acetic acid. The precipitate was collected, dried (Na2SO4), and chromatographed on silica, eluting with CΗ2Cl2/EtOAc (95:5) to give 2.72 g (96% yield) of tert-buiy\ 4-[6-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-2-(methylsulfanyl)-4-pyrimidinyl]- 1-piperazinecarboxylate: mp (MeOH) 160-161 0C; 1H NMR (CDCl3) 5 7.32 (t, J = 8.1 Hz, IH), 7.22 (dd, J = 8.4, 0.7 Hz, IH), 7.18 (t, /HF = 53.4 Hz, IH), 6.79 (dd, J = 7.9, 0.5 Hz, I H), 6.43 (s, IH), 4.06 (s, 3H), 3.72 (m, 4H), 3.57 (m, 4H), 2.54 (s, 3H), 1.49 (s, 9H); Anal. Calcd. for C23H28F2N6O3S: C, 54.5; H, 5.6; N, 16.6; Found: C, 54.6; H, 5.5; N, 16.6%.
[00290] A solution of 2.53 g (50 mmol) of the above compound in a mixture of 500 mL of acetone and 50 mL of acetic acid was treated with a solution of 5 g KMnO4 in water (100 mL) in portions over 5 min. The resulting mixture was stirred at room temperature for 3 hrs, decolourized with aqueous Na2SO3, and diluted with water, to give a white solid which was extracted with CH2Cl2, washed with water, and dried, to give 1.80 g (67 % yield) of tert- butyl 4-[6-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-2-(methylsulfonyl)-4- pyrimidinyl]-l-piperazinecarboxylate: mp (MeOH) 199 0C (dec); 1H NMR (CDCl3) δ 7.38 (t, J = 8.2 Hz, IH), 7.26 (d, J = 8.3 Hz, IH), 7.13 (t, JHF = 53.2 Hz, IH), 6.87 (s, IH), 6.84 (d, J = 7.6 Hz, IH), 4.07 (s, 3H), 3.80 (m, 4H), 3.62 (m, 4H), 3.31 (s, 3H), 1.50 (s, 9H); Anal. Calcd. for C23H28F2N6O5S: C, 51.3; H, 5.2; N, 15.6; Found: C, 51.4; H, 5.3; N, 15.5%.
[00291] A solution of 1.077 g (2 mmol) of the above sulfone and 0.87 g (10 mmol) of morpholine in 50 mL of THF was heated under reflux overnight, and, after cooling, water was added, to give 1.09 g (100% yield) of tert-butyl 4-[6-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-2-(4-morpholinyl)-4-pyrimidinyl]-l-piperazinecarboxylate: mp (MeOH) 177-179 0C; 1H NMR (CDCl3) δ 7.31 (t, J = 8.1 Hz, IH), 7.22 (dd, J = 8.3, 0.7 Hz, IH), 7.15 (t, 7HF = 53.4 Hz, IH), 6.78 (d, J = 7.4 Hz, IH), 6.09 (s, IH), 4.05 (s, 3H), 3.81-3.74 (m, 8H), 3.67 (m, 4H), 3.56 (m, 4H), 1.49 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1; N, 18.0; Found: 57.3; H, 6.2; N, 18.0%.
[00292] Treatment of the above carbamate with TFA in CH2Cl2 gave 2-
(difluoromethyl)-4-methoxy-l-[2-(4-moφholinyl)-6-(l-piperazinyl)-4-pyrimidinyl]-lH- benzimidazole which was treated with chloromethanesulfonyl chloride as above. Chromatography on silica, eluting with CΗ2Cl2/EtOAc (9:1) gave l-[6-{4- [(chloromethyl)sulfonyl]- 1 -piperazinyl } -2-(4-moφholinyl)-4-pyrimidinyl]-2- (difluoromethyl)-4-methoxy-lH-benzimidazole in 72% yield: mp (MeOH) 220-222 0C; 1H NMR (CDCl3) δ 7.31 (t, J = 8.1 Hz, IH), 7.21 (d, J = 8.3 Hz, IH), 7.14 (t, yHF = 53.3 Hz, IH), 6.79 (d, J = 7.9 Hz, IH), 6.12 (s, IH), 4.55 (s, 2H), 4.06 (s, 3H), 3.81-3.74 (m, 12H), 3.58 (m, 4H); Anal. Calcd. for C22H26ClF2N7O4S: C, 47.35; H, 4.7; N, 17.6; Found: C, 47.5; H, 4.7; N, 17.8%.
Example 16
Synthesis of l-f2-f4-f(chloromethyl)sulfonyll-l-piperazinyl)-6-(4-moφholinyl)-4- pyrimidinyll-2-(difluoromethyl)-4-methoxy-lH-benzimidazole
Figure imgf000103_0001
[00293] The compound was prepared according to Scheme 1 using Method A.
[00294] A mixture of 3.57 g (10 mmol) of l-[6-chloro-2-(methylsulfanyl)-4- pyrimidinyl]-2-(difluorornethyl)-4-methoxy-lH-benzimidazole (see previous example) and 2.18 g (25 mmol) of morpholine in 50 mL TΗF was stirred at room temperature for 30 min, and diluted with water, to give 3.85 g (94% yield) of 2-(difluoromethyl)-4-methoxy-l-[2- (methylsulfanyl)-6-(4-moφholinyl)-4-pyrimidinyl]-lH-benzimidazole: mp (MeOH) 169-171 0C; 1H NMR (CDCl3) δ 7.32 (t, J = 8.2 Hz, IH), 7.22 (dd, J = 8.4, 0.7 Hz, IH), 7.18 (t, Jm = 53.4 Hz, IH), 6.79 (d, J = 7.5 Hz, I H), 6.42 (s, IH), 4.06 (s, 3H), 3.82 (m, 4H), 3.71 (m, 4H), 2.54 (s, 3H); Anal. Calcd. for C18Hi9F2N5O2S: C, 53.1; H, 4.7; N, 17.2; Found: C, 53.1 ; H,
4.7; N, 17.3%.
[00295] A solution of 2.04 g (5 mmol) of the above sulfide in a mixture of 500 mL acetone and 50 mL acetic acid was combined with a solution of 5 g KMnO4 in 100 mL water and the resulting mixture was stirred at room temperature for 1 hr. Dilution with water and decolourization with NaHSO3 gave 1.80 g (82% yield) of 2-(difluoromethyl)-4-methoxy-l- [2-(methylsulfonyl)-6-(4-moφholinyl)-4-pyrimidinyl]-lH-benzimidazole as a white solid: mp (MeOH) 190-191 0C; 1H NMR (CDCl3) δ 7.38 (t, J = 8.2 Hz, IH), 7.26 (dd, J = 8.4, 0.7 Hz, IH), 7.13 (t, 7HF = 53.2 Hz, IH), 6.86 (s, IH), 6.83 (d, J = 7.8 Hz, IH), 4.07 (s, 6H), 3.85 (m, 4H), 3.31 (s, 3H); Anal. Calcd. for Ci8H19F2N5O4S: C, 49.2; H, 4.4; N, 15.9; Found: C, 49.4; H, 4.25; N, 15.9%.
[00296] A mixture of 1.099 g (2.5 mmol) of the above sulfone and 1.16 g (6.25 mmol) of tørf-butyl 1 -piperazinecarboxylate in 50 mL of THF was heated at reflux overnight before being diluted with water containing 1 mL of acetic acid. The product was extracted into CH2Cl2, washed with aq. NH3, and dried. Chromatography on silica, eluting with CH2Cl2/Et0Ac (9: 1 ) gave 1.23 g (90% yield) of te/?-butyl 4-[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-2-pyrimidinyl]-l -piperazinecarboxylate: mp (hexanes) 149-152 0C; 1H NMR (CDCl3) δ 7.30 (t, J = 8.1 Hz, IH), 7.22 (dd, J = 8.3, 0.6 Hz, IH), 7.14 (t, JHF = 53.4 Hz, IH), 6.78 (d, J = 7.6 Hz, IH), 6.08 (s, IH), 4.06 (s, 3H), 3.80 (m, 8H), 3.64 (m, 4H), 3.50 (m, 4H), 1.48 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1 ; N, 18.0; Found: 57.4; H, 6.1 ; N, 17.9%.
[00297] Treatment of the above carbamate with TFA in CH2Cl2 gave 2-
(difluoromethyl)-4-methoxy- 1 -[6-(4-morpholinyl)-2-( 1 -piperazinyl)-4-pyrimidinyl]- IH- benzimidazole which was treated with chloromethanesulfonyl chloride as above. Chromatography on silica, eluting with CΗ2Cl2/EtOAc (9:1) gave (in 88% yield) l-[2-{4- [(chloromethyl)sulfonyl]-l-piperazinyl}-6-(4-moφholinyl)-4-pyrimidinyl]-2- (difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 215-218 0C; 1H NMR (CDCl3) δ 7.31 (t, J = 8.1 Hz, IH), 7.20 (d, J = 8.3 Hz, IH), 7.10 (t, /HF = 53.3 Hz, IH), 6.79 (d, J = 7.9 Hz, IH), 6.11 (s, IH), 4.55 (s, 2H), 4.06 (s, 3H), 3.93 (m, 4H), 3.81 (m, 4H), 3.65 (m, 4H), 3.53 (m, 4H); Anal. Calcd. for C22H26ClF2N7O4S: C, 47.35; H, 4.7; N, 17.6; Found: C, 47.6; H, 4.7; N, 17.9%. Example 17
Synthesis of 1 -\4-\ 1 -(chloroacetyl)-4-piperidinyll-6-(4-moφholinyl)- 1 ,3,5-triazin-2-yll-2- (difluoromethyl)-4-methoxv- 1 H-benzimidazole
Figure imgf000105_0001
[00298] The compound was prepared according to Scheme 1 using Method A.
[00299] A mixture of 0.397 g (1 mmol) of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-
2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole, 0.464 g (1.5 mmol) of tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-l(2H)-pyridinecarboxylate, 56 mg PdCl2(dppf)2, and 8 mL of 2 M aq. Na2CO3 in 40 mL of dioxane was heated under reflux under nitrogen for 2 hrs. The dioxane was removed under vacuum and the residue was extracted in to CH2Cl2. Chromatography on silica, eluting with CH2Cl2ZEtOAc (95:5) gave 0.51 g (94% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-3,6-dihydro- 1 (2H)-pyridinecarboxylate: mp (MeOH) 223-225 0C; 1H NMR (CDCl3) δ 8.00 (dd, J = 8.4, 0.6 Hz, IH), 7.56 (t, JHF = 53.5 Hz, IH), 7.39 (t, J = 8.2 Hz, IH), 7.38 (m, IH), 6.85 (d, J = 7.7 Hz, IH), 4.23 (br d, J = 3.0 Hz, 2H), 4.06 (s, 3H), 4.01 (m, 2H), 3.95 (m, 2H), 3.82 (m, 4H), 3.65 (t, J = 5.7 Hz, 2H), 2.69 (m, 2H), 1.54-1.45 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C26H3]F2N7O4: C, 57.45; H, 5.75; N, 18.0; Found: C, 57.4; H, 5.9; N, 18.15%.
[00300] A solution of the above compound in a 1 : 1 mixture of MeOH and THF (100 mL) was hydrogenated over 100 mg of 5% Pd on carbon. After removal of the hydrogen, the mixture was heated under reflux in air for 2 hrs. The Pd on C was removed by filtration through celite, and the solvents were removed under vacuum. Recrystallization of the residue from methanol gave terf-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6- (4-moφholinyl)-l,3,5-triazin-2-yl]-l-piperidinecarboxylate: mp (MeOH) 177-179 0C; 1H NMR (CDCl3) δ 8.01 (dd, J = 8.4, 0.7 Hz, IH), 7.58 (t, /HF = 53.6 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 6.84 (d, J = 7.8 Hz, IH), 4.22 (m, 2H), 4.05 (s, 3H), 3.99 (m, 2H), 3.94 (m, 2H), 3.81 (m, 4H), 2.94 - 2.78 (m, 3H), 2.05 (dd, / = 13.0, 1.9 Hz, 2H), 1.81 (qd, 7 = 12.7, 4.4 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1 ; N, 18.0; Found: C, 57.4; H, 6.15; N, 18.1%.
[00301] Reaction of 0.13 g (0.24 mmol) of the above carbamate with TFA (5 mL) in
CH2Cl2 (10 mL) gave 2-(difluoromethyl)-4-methoxy-l-[4-(4-morpholinyl)-6-(4-piperidinyl)- l,3,5-triazin-2-yl]-lH-benzimidazole which was treated with chloroacetyl chloride as before, to give a reaction product which was purified by chromatography on alumina, eluting with CΗ2Cl2/Et0Ac (4:1), to give 73 mg (48% yield) of l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole: mp (MeOH) 241-243 0C; 1H NMR (CDCl3) δ 7.99 (dd, J = 8.4, 0.4 Hz, IH), 7.55 (t, 7HF = 53.6 Hz, IH), 7.39 (t, J = 8.3 Hz, IH), 6.85 (d, J = 8.0 Hz, IH), 4.64 (br d, J = 13.6 Hz, 2H), 4.12 (d, J = 4.2 Hz, 2H), 4.06 (s, 3H), 4.01-3.92 (m, 5H), 3.82 (m, 4H), 3.31 (br t, J = 11.8 Hz, IH), 2.99 - 2.84 (m, 3H), 2.17 (br t, J = 13.3 Hz, 2H), 2.01 - 1.82 (m, 2H); Anal. Calcd. for C23H26ClF2N7O3: C, 52.9; H, 5.0; Cl, 6.8; N, 18.8; Found: C, 52.85; H, 5.0; Cl, 6.8; N, 18.7%.
Example 18
Synthesis of N-f l-(chloroacetyl)-4-piperidinyll-4-r2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -vπ-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine
Figure imgf000106_0001
[00302] The compound was prepared according to Scheme 2 using Method B.
[00303] A stirred mixture of 1 g (5 mmol) of ter/-butyl 4-piperidinylcarbamate and 1.3 g (10 mmol) of DIPEA in 25 mL of CH2Cl2 was cooled to 0 0C and 0.85 g (7.5 mmol) of chloroacetyl chloride was added. The solution was allowed to warm to room temperature overnight before being quenched with water, washed successively with aqueous acetic acid and NaHCO3, and dried. Elution through a short column of alumina with CH2Cl2 gave 0.89 g (64% yield) of '
Figure imgf000106_0002
l-(chloroacetyl)-4-piperidinylcarbamate: mp (CH2Cl2/hexanes) 102- 103 0C; 1H NMR (CDCl3) δ 4.44 (br d, J = 12.2 Hz, IH), 4.06 (q, 7 = 12.1 Hz, 2H), 3.82 (br d, J = 12.4 Hz, IH), 3.69 (m, IH), 3.20 (br t, J = 13.1 Hz, IH), 2.82 (br t, J =11.4 Hz, IH), 2.09-1.94 (m, 2H), 1.45 (s, 9H), 1.44-1.28 (m, 2H); Anal. Calcd. for Ci2H2iClN2O3: C, 52.1; H, 7.65; N, 10.1; Found: C, 52.0; H, 7.85; N, 10.2%.
[00304] A mixture of 0.55 g (2 mmol) of tert-butyl 1 -(chloroacetyl)-4- piperidinylcarbamate and 5 g TFA in 20 mL CH2Cl2 was stirred at room temperature overnight and the resulting solution was evaporated to dryness, to give l-(chloroacetyl)-4- piperidinamine trifluoroacetate as an oil: 1H NMR (DMSO-ck) δ 7.50 (m, exchangeable with D2O, 3H), 4.41-4.28 (m, 3H), 3.86 (br d, J = 13.7 Hz, IH), 3.28 (m, IH), 3.12 (t, J = 12.3 Hz, 1 H), 2.71 (t, J = 12.1 Hz, 1 H), 1.92 (br d, J = 12.1 Hz, 2H), 1.52-1.44 (m, 1 H), 1.39- 1.27 (m, IH).
[00305] A mixture of the above crude trifluoroacetate, 0.397 g (1 mmol) of l-[4- chloro-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH- benzimidazole, and 0.52 g (4 mmol) of DEPEA in 50 mL of TΗF was stirred at room temperature for 5 days when water was added. The precipitate was collected, dried, and chromatographed on silica, eluting with CΗ2Cl2/EtOAc (1 : 1), to give 0.28 g (52% yield) of N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-morpholinyl)-l,3,5-triazin-2-amine: mp (EtOH) 270-273 0C; 1H NMR (CDCl3) (rotamers; ratio ca. 3:2) δ 7.94 (dd, J = 8.4, 0.6 Hz, IH), 7.53 and 7.50 (2t, /HF = 53.6 Hz, IH), 7.35 (t, J = 7.9 Hz, IH), 6.82 (t, J = 6.8 Hz, IH), 5.22 and 5.17 (2d, J = 7.5 Hz, exchangeable with D2O, IH), 4.56 (m, IH), 4.23-4.07 (m, 3H), 4.05 (s, 3H), 3.91-3.70 (m, 9H), 3.31 (t, 7 =11.5 Hz, IH), 2.95 (m, IH), 2.35-2.00 (m, 2H), 1.34 - 1.25 (m, 2H); Anal. Calcd. for C23H27ClF2N8O30.2 H2O: C, 51.1; H, 5.1 ; N, 20.7; Found: C, 51.3; H, 5.1; N, 20.4%.
Example 19
Synthesis ofN-f l-(chloroacetylV4-piperidinyll-4-r2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-vIl-N-methyl-6-(4-morpholinyl)-l,3,5-triazin-2-amine
Figure imgf000108_0001
[00306] The compound was prepared according to Scheme 1 using Method A.
[00307] A mixture of 0.397 g (1 mmol) of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-
2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole, 0.24 g (1.2 mmol) of tert-buty\ 4- amino-1-piperidinecarboxylate and 0.194 g (1.5 mmol) of DIPEA in 25 mL of TΗF was stirred at room temperature overnight. Dilution with water and extraction with CΗ2CI2, followed by chromatography on silica, eluting with CH2CbZEtOAc (4: 1), gave 0.51 g (91% yield) of 4-{ [4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- mθφholinyl)-l,3,5-triazin-2-yl]amino}-l-piperidinecarboxylate: mp (hexanes/CΗaCh ) 142- 145 0C; 1H ΝMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.96 and 7.95 (2d, J = 8.3 and 7.9 Hz, IH), 7.54 and 7.52 (2t, yHF = 53.6 Hz, IH), 7.34 (br t, J = 8.1 Hz, I H), 6.81 (t, J = 6.9 Hz, IH), 5.22 and 5.17 (2d, J = 7.4 and 7.6 Hz, exchangeable with D2O, IH), 4.10 (m, 3H), 4.05 (s, 3H), 3.87 (m, 4H), 3.78 (m, 4H), 2.93 (t, J = 12.1 Hz, 2H) 2.06 (m, 2H), 1.48 (s, 9H), 1.43 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0; Found: C, 55.6; H, 6.2; N, 20.0%.
[00308] A solution of 0.30 g (5.4 mmol) of the above compound in 10 mL of DMF was treated sequentially with excess NaH and iodomethane at room temperature for 2 hrs. Dilution with water and workup in CH2Cl2, followed by chromatography on silica, eluting with CH2Cl2/Et0Ac (4: 1) gave 0.286 g (93 % yield) of te/t-butyl 4-[[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l- piperidinecarboxylate: mp (MeOΗ/CΗ2Cl2) 200-202 0C; 1H NMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.98 and 7.91 (2d, J = 8.4 Hz, IH), 7.57 and 7.47 (2t, 7HF = 53.5 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.81 (d, J = 7.9 Hz, IH), 4.82 and 4.70 (2m, IH), 4.29 (m, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.79 (m, 4H), 3.10 and 3.05 (2s, 3H), 2.84 (m, 2H), 1.73 (m, 4H), 1.49 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5; Found: C, 56.6; H, 6.4; N, 19.6%.
[00309] Treatment of 0.173 g (0.3 mmol) of the above carbamate with TFA (5 mL) in
CH2Cl2 (10 mL) at room temperature gave 0.143 g (100% yield) of crude 4-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-(4- piperidinyl)-l,3,5-triazin-2-amine: 1H ΝMR (CDCl3) (rotamers; ratio ca. 3:2) δ 7.99 and 7.94 (2d, J = 8.4 Hz, IH), 7.59 and 7.52 (2t, Jm = 53.6 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.81 (d, J = 8.0 Hz, IH), 4.80-4.63 (m, IH), 4.06 (s, 3H), 3.88 (m, 4H), 3.79 (m, 4H), 3.25 (m, 2H), 3.13 and 3.09 (2s, 3H), 2.88-2.73 (m, 2H), 1.98-1.72 (m, 4H), 1.49 (s, 9H).
[00310] A stirred mixture of 0.143 g (0.3 mmol) of the above amine and 0.12 g (0.9 mmol) of DEPEA in 20 mL CH2Cl2 was cooled to 0 0C and treated with 51 mg (0.45 mmol) of chloroacetyl chloride. The mixture was allowed to warm to room temperature and was quenched with water after 2 hrs. After being washed successively with aqueous acetic acid and NaHCO3 solutions, the solvent was dried and removed. Chromatography on silica, eluting with CH2Cl2/EtOAc (7:3), gave 0.146 g (88% yield) of N-[l-(chloroacetyl)-4- piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-/V-methyl-6-(4- morpholinyl)-l,3,5-triazin-2-amine: mp (MeOH) 211-213 0C; 1H ΝMR (CDCl3) (rotamers; ratio ca. 3:2) δ 7.97 and 7.89 (2d, J = 8.4 Hz, IH), 7.56 and 7.44 (2t, 7HF = 53.5 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.82 (d, J = 8.0 Hz, IH), 4.95 and 4.78 (2m, 2H), 4.17 - 3.99 (m, 3H), 4.05 (s, 3H), 3.89 (m, 4H), 3.79 (m, 4H), 3.28 (m, IH), 3.12 and 3.05 (2s, 3H), 2.75 (m, IH), 1.82 (m, 4H); Anal. Calcd. for C24H29ClF2N8O3: C, 52.3; H, 5.3; N, 20.3; Found: C, 52.3; H, 5.2; N, 20.5%.
Example 20
Synthesis of N-f l-(chloroacetyl)-4-piperidinyl]-4-f 2-(difluoromethyl)-4-[3- (dimethylamino)propoxyi- lH-benzimidazol- 1 -yl ) -N-methyl-6-(4-morpholinyl)- 1 ,3,5-triazin-
2-amine
Figure imgf000109_0001
[00311] The compound was prepared according to Scheme 1 using Method A.
[00312] A mixture of 4-{ [terr-Butyl(dimethyl)silyl]oxy}-l-[4-chloro-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole (see Example 5) (783 mg, 1.58 mmol), terf-butyl 4-(methylamino)-l-piperidinecarboxylate (337 mg, 1.58 mmol) and DIPEA (excess) in TΗF (12 mL) was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water, extracted into CH2Cl2, dried (Na2SO4), and the solvent was removed. The resulting residue was chromatographed on silica, eluting with CH2Cl2/Et0Ac (9:1), to give rm-butyl 4-[[4-[4-{ [tert-butyl(dimethyl)silyl]oxy}-2- (difluoromethyl)-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl](methyl)amino]-l-piperidinecarboxylate (892 mg, 84%) as a white solid: 1H NMR (DMSO-J6) (rotamers) δ 7.99 and 7.93 (2d, J = 8.4 Hz, IH), 7.74 and 7.70 (2t, /HF = 53.0 Hz, IH), 7.38-7.32 (m, IH), 6.86 (d, J = 6.9 Hz, IH), 4.74-4.63 (m, IH), 4.16-4.07 (m, 2H), 3.80 (m, 4H), 3.69 (m, 4H), 3.06 and 3.03 (2s, 3H), 2.84 (m, 2H), 1.67 (m, 4H), 1.42 (s, 9H), 1.02 (s, 9H), 0.26 (s, 6H).
[00313] To a solution of the above compound (850 mg, 1.26 mmol) in THF ( 15 mL) was added TBAF (5 mL, 1 M solution in THF), and the reaction mixture was stirred at 20 0C for 30 min. The reaction solution was concentrated under vacuum at 20 0C and the residue was diluted with water. The resulting precipitate was filtered, washed with water, and dried to give tert-butyl 4-[[4-[2-(difluoromethyl)-4-hydroxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l-piperidinecarboxylate (620 mg, 88%) as a white solid: 1H NMR (DMSO-J6) (rotamers) δ 10.24 (br s, exchangeable with D2O, IH), 7.81 and 7.75 (2d, J = 8.3, 8.2 Hz, IH), 7.75 and 7.71 (2t, JHF = 53.0 Hz, IH), 7.29-7.23 (m, IH), 6.76 (dd, J = 7.9, 0.6 Hz, IH), 4.76-4.60 (m, IH), 4.15-4.08 (m, 2H), 3.80 (m, 4H), 3.70 (m, 4H), 3.06 and 3.03 (2s, 3H), 2.82 (m, 2H), 1.67 (m, 4H), 1.42 (s, 9H).
[00314] To a mixture of the above phenol (531 mg, 0.95 mmol), and K2CO3 (2 g) in
DMF (6 mL) was added 3-bromo- 1 -propanol (0.4 mL, 4.75 mmol). The reaction mixture was stirred at 200C for 20 hrs. The reaction mixture was diluted with water, and the resulting precipitate was filtered, washed with water, and dried. Recrystallization from CH2Cl2/hexanes gave tert-butyl 4-[[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l- piperidinecarboxylate (537 mg, 91%) as a white solid: 1H NMR (DMSO-J6) (rotamers) δ 7.96 and 7.89 (2d, J = 8.4 Hz, IH), 7.74 and 7.70 (2t, 7HF = 53.3, 52.9 Hz, IH), 7.42-7.36 (m, IH), 6.95 (d, J = 8.1 Hz, IH), 4.73-4.63 (m, IH), 4.56 (t, J = 5.1 Hz, exchangeable with D2O, IH), 4.29 (t, J = 6.4 Hz, 2H), 4.14-4.07 (m, 2H), 3.81 (m, 4H), 3.69 (m, 4H) 3.65-3.61 (m, 2H), 3.06 and 3.03 (2s, 3H), 2.82 (m, 2H), 2.01-1.94 (m, 2H), 1.67 (m, 4H), 1.42 (s, 9H).
[00315] To a cooled (ice/salt) mixture of the above alcohol (503 mg; 0.81 mmol) and
Et3N (0.5 mL, excess) in THF (10 mL) was added methanesulfonyl chloride (0.5 mL) and the resulting mixture was stirred at this temperature for 30 min. A solution of 40% aq. dimethylamine (5 mL) was added, and the reaction mixture was allowed to warm to room temperature. After 20 hrs, the mixture was diluted with water, and the resulting precipitate was collected and dried. Chromatography on neutral alumina, eluting with CH2Cl2/MeOH (49:1), gave 523 mg (100% yield) of terr-butyl 4-[[4-{2-(difluoromethyl)-4-[3- (dimethylamino)propoxy]- lH-benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl](methyl)amino]-l-piperidinecarboxylate as a sticky solid: 1H NMR (DMSO-d6) (rotamers) δ 7.95 and 7.89 (2d, / = 8.4 Hz, IH), 7.70 and 7.67 (2t, 7HF = 52.9 Hz, IH), 7.42-7,35 (m, IH), 6.93 (d, 7 = 8.1 Hz, IH), 4.73-4.63 (m, IH), 4.25 (t, J = 6.5 Hz, 2H), 4.15-4.07 (m, 2H), 3,80 (m, 4H), 3.70 (m, 4H), 3.06 and 3.03 (2 s, 3H), 2.83 (s, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.16 (s, 6H), 1.20-1.92 (m, 2H), 1.62 (m, 4H), 1.42 (s, 9H).
[00316] To a solution of the above carbamate (530 mg, 0.82 mmol) in CH2Cl2 (10 mL) was added TFA (10 mL) and the reaction mixture was stirred at 20 0C for 1 hr. The solvents were removed under vacuum at 20 0C and the residue was diluted with water ( 100 mL), and basified with aq. NH3. The resulting precipitate was filtered, washed with water, and dried, to give 390 mg (87% yield) of 4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-lH- benzimidazol- 1 -yl } -N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)- 1 ,3,5-triazin-2-amine as a white solid: 1H ΝMR (DMSO-^6) (rotamers) δ 7.96 and 7.88 (2d, J = 8.3 Hz, IH), 7.72 and 7.59 (2t, 7HF = 53. 0, 52.8 Hz, IH), 7.41-7.36 (m, IH), 6,95 (d, J = 8.0 Hz, IH), 4.81-4.70 (m, IH), 4.26 (t, J = 6.4 Hz, 2H), 3.82 (m, 4H), 3.70 (m, 4H), 3.08 and 4.04 (2s, 3H), 3.28 (m, 2H), 3.06-2.87 (m, 2H), 2.55-2.51 (m, 2H), 2.26 (s, 6H), 2.03-1.79 (m, 6H).
[00317] To a suspension of the above amine (254 mg, 0.46 mmol) and powdered
K2CO3 (3 g) in CH2Cl2 (5 mL) at 00C was added chloroacetyl chloride (1 mL) and the reaction mixture was allowed to warm to room temperature. After 1 hr, the mixture was diluted with H2O (50 mL) and the organic layer was separated and dried (Na2SO4). The solution was absorbed on to column of neutral alumina, and the.column was then eluted with CH2Cl2ZMeOH (49: 1). The combined fractions containing the product were acidified with 1.25 M HCl in MeOH (2 mL), and the solution was evaporated to dryness. Recrystallization of the residue from CH2Cl2/EtOAc/hexanes gave 85 mg (28% yield) of N-[l-(chloroacetyl)- 4-piperidinyl]-4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-2,3-dihydro-lH- benzimidazol-l-yl}-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine hydrochloride as a white solid: mp 128 0C (dec); 1H ΝMR (DMSO-^5) (rotamers) δ 10.08 (br s, exchangeable with D2O, IH), 8.00 and 7.94 (d, J = 8.4 Hz, IH), 7.75 and 7.73 (2t, Λ,F = 52.9 Hz, IH), 7.45-7.39 (m, IH), 6.99 (d, J = 8.1 Hz, IH), 4.81-4.72 (m, IH), 4,56-4.48 (m, IH), 4.42 (br s, 2H), 4.34 (t, J = 6.0 Hz, 2H), 4.01-3.95 (m, IH), 3.81 (m, 4H), 3.70 (m, 4H), 3.28 (m, 2 H), 3.22-3.11 (m, I H), 3.06 and 3.03 (2s, 3H), 2.82 (s, 6H), 2.82-2.66 (m, IH), 2.28-2.21 (m, 2H), 1.89-1.66 (m, 4H); Anal. Calcd. for C28H39Cl2F2N9O3. 1.2 H2O: C, 49.4; H, 6.1; Cl, 10.4; N, 18.5; Found: C, 49.8; H, 6.1; Cl, 10.2; N, 18.0%.
Example 21
Synthesis of N- ( l-[(chloromethyl)sulfonyll-4-piperidinvU-4-r2-(difluoromethyl)-4-methoxy- lH-benzimidazol-l-yll-N-methyl-6-(4-moφholinyl)-1.3,5-triazin-2-amine
Figure imgf000112_0001
[00318] Reaction of 4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-N- methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-l,3,5-triazin-2-amine (Example 19) with chloromethanesulphonyl chloride and powdered K2CO3 in CH2Cl2 gave N-( I- [(chloromethyl)sulfonyl]-4-piperidinyl}-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol- l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine in 19% yield: mp (CΗ2Cl2/MeOΗ) 212-215 0C; 1H ΝMR (DMSO-^6) (rotamers) δ 7.97 and 7.90 (2d, J = 8.4 Hz, IH), 7.74 and 7.70 (2t, 7HF = 52.9, 52.8 Hz, IH), 7.44-7.39 (m, IH), 7.44-7.39 (m, IH), 6.96 (d, J = 8.1 Hz IH), 5.15 and 5.1 1 (2s, 2H), 4.73-4.66 (m, 2H), 3.98 (s, 3H), 3.91-3.81 (m, 6H), 3.70 (m, 4H) 3.18-3.05 (m, 2H), 3.09 and 3.05 (2s, 3H), 1.90-1.78 (m, 4H), Anal. Calcd. for C23H29ClF2N8O4S: C, 47.1, H, 5.0, N, 19.1; Found: C, 47.2; H, 5.3; N,19.2%.
- I l l - Example 22
Synthesis of 2-chloro-N- { 1 -r4-r2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yll-6-(4- morpholinyl)-l ,3,5-triazin-2-vn-4-piperidinyl}acetamide
Figure imgf000113_0001
[00319] The compound was prepared according to Scheme 1 using Method A.
[00320] A mixture of 0.992 g (2.5 mmol) of l-[4-chloro-6-(4-morpholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole, 1.00 g (5 mmol) ter/-butyl 4- piperidinylcarbamate, and 0.65 g (5 mmol) DIPEA in 100 mL of TΗF was stirred at room temperature for 30 min, before the solution was concentrated, and diluted with water containing 1 mL of acetic acid. The resulting solid was collected, washed with water, and dried to give 1.38 g (98%) of tert-butyl l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinylcarbamate: mp (MeOH) 208-209 0C; 1H ΝMR (CDCl3) δ 7.88 (d, J = 8.1 Hz, IH), 7.48 (t, 7HF = 53.6 Hz, IH), 7.34 (t, 7 = 8.2 Hz, IH), 6.81 (d, J = 7.9 Hz, IH), 4.66 (br d, J = 13.4 Hz, 2H), 4.46 (m, exchangeable with D2O, IH), 4.04 (s, 3H), 3.87 (m, 4H), 3.78 (m, 5H), 3.12 (m, 2H), 2.07 (br d, J = 14.0 Hz, 2H), 1.46 (s, 9H), 1.45-1.33 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0; Found: C, 55.85; H, 6.1; N, 20.1%.
[00321] Treatment of 0.28 g (0.5 mmol) of the above carbamate with TFA (5 mL) in
CH2Cl2 (10 mL) gave a quantitative yield of crude l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinamine: 1H NMR (CDCl3) δ 7.90 (d, J = 8.4 Hz, IH), 7.51 (t, Jw = 53.6 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.81 (d, J = 8.0 Hz, IH), 4.66 (br d, J = 13.1 Hz, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.15 - 2.96 (m, 3H), 1.94 (m, 2H), 1.39-1.25 (m, 2H).
[00322] Treatment of the preceding amine with chloroacetyl chloride as before gave a crude product which was recrystallized from methanol to give 0.165 g (61% yield) of (2- chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- l,3,5-triazin-2-yl]-4-piperidinyI}acetamide: mp 252-254 0C; 1H NMR (CDCl3) δ 7.88 (d, J = 8.1 Hz, IH), 7.48 (t, 7HF = 53.6 Hz, IH), 7.35 (t, J = 8.2 Hz, IH), 6.81 (d, J = 7.9 Hz, IH), 6.47 (d, J = 7.9 Hz, exchangeable with D2O, IH), 4.72 (br d, J = 13.6 Hz, 2H), 4.13 (m, IH), 4.06 (s, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.15 (m, 2H), 2.09 (br dd, J = 12.6, 2.7 Hz, 2H), 1.56-1.44 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.45; H, 5.1; N, 20.9; Found: C, 51.45; H, 5.0; N, 20.9%.
Example 23
Synthesis of 2-chloro-ΛH l-r4-f2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-vn-6-(4- moφholinyl)-l,3.5-triazin-2-yll-4-piperidinyl|-N-methylacetamide
Figure imgf000114_0001
[00323] The compound was prepared according to Scheme 1 using Method A.
[00324] Methylation of 0.31 g (5.5 mmol) of tert-butyl l-[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4- piperidinylcarbamate (Example 22) with 3 equivalents of 60% NaH dispersion in oil (27.5 mg, 16.5 mmol) and iodomethane in DMF (35 mL) gave 0.31 g (98% yield) of terf-butyl 1- [4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl]-4-piperidinyl(methyl)carbamate: mp (MeOH) 182-183 0C; 1H NMR (CDCl3) δ 7.89 (d, J = 8.0 Hz, IH), 7.50 (t, JHF = 52.8 Hz, IH), 7.34 (t, J = 7.5 Hz, IH), 6.81 (d, J = 7.9 Hz, IH), 4.90 (br d, J = 12.2 Hz, 2H), 4.27 (m, IH), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 2.96 (m, 2H), 2.72 (s, 3H), 1.78 (m, 2H), 1.71-1.59 (m, 2H), 1.48 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5; Found: C, 56.4; H, 6.2; N, 19.6%.
[00325] Treatment of 0.173 g (0.3 mmol) of the above carbamate with TFA (5 mL) in
CH2Cl2 (10 mL) gave a quantitative yield of l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-N-methyl-4-piperidinamine: 1H ΝMR (CDCl3) δ 7.90 (dd, J = 8.4, 0.7 Hz, IH), 7.51 (t, JHV = 53.6 Hz, IH), 7.34 (t, J = 8.2 Hz, IH), 6.80 (d, J = 7.6 Hz, IH), 4.63 (br d, J = 13.2 Hz, 2H), 4.04 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.12 (m, 2H), 2.70 (m, IH), 2.48 (s, 3H), 2.03 (m, 2H), 1.41-1.30 (m, 2H).
[00326] Treatment of the above amine with chloroacetyl chloride as before, followed by chromatography on silica, eluting with CH2Cl2/Et0Ac (7:3) gave 0.20 g (81% yield) of 2- chloro-N-{ 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morphoIinyl)- l,3,5-triazin-2-yl]-4-piperidinyl}-N-methylacetamide: mp (MeOH) 206-208 0C; 1H ΝMR (CDCl3) δ 7.89 (d, J = 8.4 Hz, IH), 7.49 (t, 7HF = 53.6 Hz, IH), 7.35 (t, J = 8.2 Hz, IH), 6.81 (d, J = 8.0 Hz, IH), 4.94 (m, 2H), 4.74 (m, IH), 4.09 (s, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.07-2.83 (m, 2H), 2.93 (s, 3H), 1.93-1.57 (m, 4 H); Anal. Calcd. for C24H29ClF2N8O3: C, 52.3; H, 5.3; N, 20.3; Found: C, 52.4; H, 5.3; N, 20.3%.
Example 24
Synthesis of 2-chloro-N-f l-[4-f 2-(difluoromethyl)-4-r3-(dimethylamino)propoxy1-lH- benzimidazol- 1 -yl I -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yll-4-piperidinyl } -N-methylacetamide
Figure imgf000115_0001
[00327] The compound was prepared according to Scheme 1 using Method A.
[00328] A mixture of 1.11 g (2.2 mmol) of 4-(terf-butyldimethylsilyloxy)-l-[4-chloro-
6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole (Example 5), 0.48 g (2.3 mmol) of tert-butyl methyl(4-piperidinyl)carbamate, and 0.6 g DDPEA in 20 mL TΗF was stirred at room temperature for 1 hr. After dilution with water containing 1 mL acetic acid, the product was extracted in to EtOAc, washed successively with water and aq. NaHCO3, and dried. Chromatography on silica, eluting with CH2Cl2/hexane (19:1) gave 1.20 g (81% yield) of
Figure imgf000115_0002
l-[4-[4-[ [terNbutyl(dimethyl)silyl]oxy}-2-(difluoromethyl)-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate as an oil: 1H NMR (CDCl3) δ 7.90 (d, J = 8.0 Hz, IH), 7.47 (t, Jw = 53.6 Hz, IH), 7.26 (t, J = 8.1 Hz, IH), 6.83 (d, J = 7.5 Hz, IH), 4.89 (m, 2H), 4.27 (m, IH), 3.87 (m, 4H), 3.78 (m, 4H), 2.95 (m, 2H), 2.72 (s, 3H), 1.70-1.59 (m, 4H), 1.48 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H). [00329] Reaction of the above silyl ether in 20 mL of THF with 1 M TBAF in THF
(3.65 mL, 2 equiv), followed by quenching with water and recrystallization from aq. MeOH gave 0.79 g (79% yield) of tert-butyl l-[4-[2-(difluoromethyl)-4-hydroxy-lH-benzimidazol- l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate: mp 220-222 0C; 1H NMR (DMSCW6) δ 10.20 (s, exchangeable with D2O, IH), 7.74 (dd, J = 8.3, 0.6 Hz, IH), 7.70 (t, /HF = 53.0 Hz, IH), 7.26 (t, J = 8.1 Hz, IH), 6.76 (dd, J = 7.9, 0.7 Hz, IH), 4.78 (m, 2H), 4.10 (m, IH), 3.80 (m, 4H), 3.69 (m, 4H), 2.99 (m, 2H), 2.66 (s, 3H), 1.67 (m, 4H), 1.41 (s, 9H); Anal. Calcd. for C26H34IF2N8O4: C, 55.7; H, 6.1; N, 20.0; Found: C, 55.9; H, 6.0; N, 20.0%.
[00330] A mixture of 0.448 g (0.8 mmol) of the above phenol, 0.34 g (2.4 mmol) of 3- bromo-1-propanol and 138 mg (1.0 mmol) of K2CO3 in DMF (20 mL) was stirred at room temperature overnight. Dilution with water gave an oily solid which was extracted with CH2Cl2 and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (1 :1), gave 0.484 g (98% yield) of tert-butyl l-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-lH-benzimidazol- l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate: 1H NMR (OMSO-d6) δ 7.88 (d, J = 8.0 Hz, IH), 7.69 (t, 7HF = 52.9 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 6.94 (d, J = 7.8 Hz, IH), 4.82-4.73 (m, 2H), 4.56 (t, 7 = 5.1 Hz, IH), 4.28 (t, J = 6.4 Hz, 2H), 4.09 (m, I H), 3.80 (m, 4H), 3.69 (m, 4H), 3.63 (dd, J = 1 1.5, 6.1 Hz, 2H), 3.00 (m, 2H), 2.66 (s, 3H), 1.97 (pentet, J = 6.3 Hz, 2H), 1.67 (m, 4H), 1.41 (s, 9H).
[00331] The above alcohol was combined with 0.23 g (2 mmol) of methanesulphonyl chloride and 0.2 g (2 mmol) of Et3N in THF at 0 0C, and after 1 hr the mixture was diluted with 5 mL of 40% aq. Me2NH. The resulting mixture was stirred at room temperature for 24 hrs and the solvent was removed. The residue was diluted with water and extracted with CH2Cl2. Chromatography on alumina eluting with CH2Cl2/EtOAc (9: 1) gave 0.51 g (100% yield) of tert-butyl l-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-lH- benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate: ' Η NMR (CDCb) δ 7.88 (d, J = 8.3 Hz, IH), 7.49 (t, 7HF = 53.6 Hz, IH), 7.32 (t, J = 8.2 Hz, IH), 6.84 (d, J = 8.0 Hz, IH), 4.90 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H), 4.28 (m, IH), 3.88 (m, 4H), 3.78 (m, 4H), 2.96 (m, 2H), 2.72 (s, 3H), 2.51 (t, J = 7.1 Hz, 2H), 2.26 (s, 6H), 2.12 (pentet, 7 = 7.0 Hz, 2H), 1.78 (m, 2H), 1.68 (m, 2H), 1.48 (s, 9H).
[00332] Treatment of the above carbamate with TFA (5 mL) in CH2Cl2 ( 10 mL) gave
0.42 g (98% yield) of l-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-lH- benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-N-methyl-4-piperidinamine: 1H ΝMR (CDCb) δ 7.89 (d, J = 8.3 Hz, IH), 7.51 (t, /HF = 53.6 Hz, IH), 7.31 (t, J = 8.2 Hz, IH), 6.84 (d, J = 8.0 Hz, IH), 4.63 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H), 3.87 (m, 4H), 3.78 (m, 4H), 3.13 (m, 2H), 2.69 (m, IH), 2.52 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H), 2.27 (s, 6H), 2.12 (pentet, J = 7.0 Hz, 2H), 2.00 (m, 2H), 1.35 (dt, J = 14.0, 4.1 Hz, 2H).
[00333] The above amine was reacted with chloroacetyl chloride and K2CO3 in CH2Cl2 at 0 0C, and the product was purified by chromatography on alumina, eluting with EtOAc/MeOH (99:1). The combined product containing fractions were acidified with HCl (1.25 M) in MeOH, and the solvents were removed under vacuum. Recrystallization of the residue from EtOH/EtOAc gave 0.33 g (65% yield) of 2-chloro-N-{ l-[4-{2-(difluoromethyl)- 4-[3-(dimethylamino)-propoxy]- lH-benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]-4-piperidinyl}-N-methylacetamide hydrochloride: mp 245 0C dec; 1H ΝMR (DMSO-^5) δ 10.18 (m, exchangeable with D2O, 1 H), 7.92 (d, J = 8.4 Hz, IH), 7.71 (t, 7HF = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.98 (d, J = 8.1 Hz, IH), 4.85 - 4.72 (m, 2H), 4.57 (m, 0.5H), 4.50 and 4.38 (2s, 2H), 4.33 (t, J = 6.1 Hz, 2H), 4.00 (m, 0.5H), 3.81 (m, 4H), 3.69 (m, 4H), 3.28 (m, 2H), 3.05 (m, 2H), 2.84 and 2.70 (2s, 3H), 2.81 (s, 6H), 2.24 (dt, J = 12.3, 6.1 Hz, 2H), 1.80-1.60 (m, 2H); Anal. Calcd. for C28H39Cl2F2N9O3 H2O: C, 49.7; H, 6.1 ; Cl, 10.5; N, 18.6; Found: 49.95; H, 6.0; Cl, 10.6; N, 18.6%.
Example 25
Synthesis of 2-chloro-N- f (3R)- 1 -r4-r2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yll- 6-(4-moφholinyl)-l,3,5-triazin-2-yllpyrrolidinyl)acetamide
Figure imgf000117_0001
[00334] The compound was prepared according to Scheme 1 using Method A.
[00335] A mixture of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole (420 mg, 1.06 mmol), tørf-butyl (3R)- pyrrolidinylcarbamate (0.24 g, 1.27 mmol), and DIPEA (0.3 mL, 1.6 mmol) in THF (25 mL) was stirred at 20 0C for 20 hrs. The reaction mixture was diluted with water (100 mL), and the resulting precipitate was filtered, washed with water, and recrystallized from CH2Cl2/hexanes, to give 554 mg (96% yield) of tert-butyl (3/?)-l-[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinylcarbamate: mp 151-153 0C; 1H NMR (DMSO-J6) δ 8.01 and 7.98 (2d, J = 8.3, 8.9 Hz, IH), 7.77 and 7.74 (2t, JHF = 53.0 Hz, 1 H) 7.40 and 7.39 (2t, J = 8.2 Hz, IH), 7.20 (br s, exchangeable with D2O, IH), 6.94 (d, J = 8.1 Hz, IH), 4.13 (br, IH), 3.92 (s, 3H), 3.79 (m, 4H), 3.78-3.37 (m, 2H), 3.68 (m, 4H), 3.28 (m, 2 H), 2.20-2.08 and 1.95-1.84 (2m, 2H), 1.40 (s, 9H).
[00336] A solution of tert-butyl (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]pyrrolidinylcarbamate (200 mg, 0.36 mmol) in CH2Cl2 (10 mL) was treated with TFA (5 mL) and stirred for 3 hrs. The solvent and excess TFA was evaporated at 20 0C under vacuum, and the resulting residue was diluted with H2O (50 mL), and basified with aq NH3. The resulting precipitate was filtered, washed with water and dried, to give 143 mg (89% yield) of (3R)- 1 -[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-3-pyrrolidinamine. The amine was dissolved in CH2Cl2 (10 mL) containing a suspension of powdered K2CO3 (3 g), and chloroacetyl chloride (1 mL) was added at 00C. After stirred for 3 hrs at 20 0C, the reaction mixture was diluted with water (20 mL), and the organic layer was separated and dried. Chromatography on silica eluting with CH2Cl2/MeOH (47:3) containing 1% aq. NH3 gave 129 mg (77% yield) of 2-chloro-N-{ (3/?)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl}acetamide as a white solid: mp (CH2Cl2MeOH) 270-275 0C; 1H NMR (DMSO-J15) (rotamers) δ 8.54 (d, J = 6.4 Hz, IH), 8.02 and 7.99 (2d, J = 8.2 Hz, IH), 7.78 and 7.75 (2t, /HF = 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 4.44-4.35 (m, IH), 4.05 (s, 2H), 3.97 (s, 3 ), 3.87- 3.63 (m, 10H), 3.55 and 3.46 (2dd, 7 = 11.6, 4.1, and 12.0, 4.2 Hz, 2H), 2.26-2.14 and 2.01- 1.88 (2m, 2H); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N, 21.4; Found: C, 50.7; H, 5.0; N, 21.2%. Example 26
Synthesis of 2-chloro-N- { (35)- 1 -r4-r2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yll -6- (4-morpholinyl)-l,3,5-triazin-2-yllpyrrolidinvUacetamide
Figure imgf000119_0001
[00337] The compound was prepared according to Scheme 1 using Method A.
[00338] Similarly, reaction of l-[4-chloro-6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with tert-butyl (35)-pyrrolidinylcarbamate as in Example 25 gave terf-butyl (35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l- yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinylcarbamate in 91% yield as a white solid: mp (CΗ2Cl2/MeOΗ) 292 0C dec; 1H ΝMR (DMSCM6) δ 8.01 and 7.98 (2d, J = 8.2, 8.4 Hz, IH), 7.77 and 7.75 (2t, 7HF = 53.0 Hz, IH), 7.40 (2t, J = 8.2 Hz, IH), 7.21 (br, exchangeable with D2O, IH), 6.95 (d, J = 8.0 Hz, IH), 4.15 -411 (m, IH), 3.97 (s, 3H), 3.79-3.37 (m, 12H), 3.00-2.08 and 1.95-1.05 (2m, 2H), 1.40 (s, 9H).
[00339] Deprotection of the carbamate with TFA in CH2Cl2 gave (35)- 1 -[4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-3- pyrrolidinamine in 95% yield. Reaction of the amine with chloroacetyl chloride as in Example 25 gave 2-chloro-N- { (35)- l-[4-[2-(difluoromethyl)-4-methoxy-l H-benzimidazol- 1- yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl}acetamide in 95% yield: 1H ΝMR (DMSO-^5) (rotamers) δ 8.54 (d, J = 6.4 Hz, exchangeable with D2O, IH), 8.02 and 7.99 (2d, J = 8.1, 8.3 Hz, IH), 7.78 and 7.75 (2t, /HF = 53.1 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 4.44-4.33 (m, IH), 4.04 (s, 2H), 3.98 (s, 3H), 3.87-3.44 (m, 12H), 2.26-2.14 and 2.01-1.88 (2m, 2H); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N, 21.4; Found: C, 50.5, H, 4.9, N, 21.4%. Example 27 Synthesis of 2-chloro-N- f (3R)- 1 -14-f 2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yll-
6-(4-moφholinyl)- 1 ,3,5-triazin-2-vUpyrrolidinyl 1 -N-methylacetamide
Figure imgf000120_0001
[00340] The compound was prepared according to Scheme 1 using Method A.
[00341] To a solution of 322 mg (0.59 mmol) of tert-butyl (3/?)-l-[4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2- yl]pyrrolidinylcarbamate (Example 25) in dry DMF (5 mL) at 0 0C was added ΝaΗ (42 mg, 1.77 mmol). The reaction mixture was stirred for 30 min at this temp and then MeI (1 mL) was added. The resulting mixture was allowed to warm to 20 0C over 3 hrs, and was then carefully diluted with water. The precipitate was filtered, washed with water, and dried. Recrystallization from CΗ2Cl2/hexanes gave 290 mg (88% yield) of tert-butyl (3/?)-l-[4-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl]pyrrolidinyl(methyl)carbamate: mp 180-182 0C; 1H ΝMR (DMSO-J6) δ 8.00 (t, J = 8.4 Hz, IH), 7.77 (t, JHF = 53.0 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.9 Hz, IH), 4.76- 4.66 (m, 1 H), 3.98 (s, 3H), 3.87-3.75 (m, 6H), 3.69 (m, 4H), 3.62-3.38 (m, 2H), 2.77 (d, J = 3.5 Hz, 3H), 2.16-2.07 (m, 2H), 1.43 (s, 9H).
[00342] The above carbamate was deprotected with TFA in CH2Cl2 to give (3/?)-l-[4-
[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]- N-methyl-3-pyrrolidinamine in 100% yield: 1H ΝMR (DMSO-J6) (rotamers) δ 8.02 and 8.00 (2d, J = 8.1 Hz, IH), 7.77 (t, 7HF = 53.0 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 3.98 (s, 3H), 3.81-3.80 (m, 4H), 3.79-3.38 (m, 8H), 2.39 (s, 3H), 1.19-2.08 and 1.96- 1.86 (2m, 2H).
[00343] Reaction of the amine with chloroacetyl chloride in similar manner as previous examples gave 2-chloro-N-{(3/?)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl}-N-methylacetamide in 89% yield: mp (CH2Cl2/hexanes) 231-233 0C; 1H ΝMR (DMSO-^6) (rotamers) δ 8.02 and 7.98 (2d, J = 8.3 Hz, IH), 7.78 (br t, JHF = 53.0 Hz, IH), 7.40 (t, J = 8.5 Hz, IH), 6.95 (d, J = 8.8 Hz, IH), 5,14-5.03 and 4.71-4.52 (2m, IH), 4.54-4.52 and 4.44-4.42 (2m, 2H), 3.98 and 3.97 (2s, 3H), 3.90-3.42 (m, 12H), 2.95 and 2.82 (2s, 3H), 2.23-2.09 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: 51.5; H, 5.1 ; N, 20.9; Found: C, 51.3; H, 5.1; N, 2Oi
Example 28
Synthesis of 2-chloro-N-{ (35)- l-r4-r2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-vH-6- (4-moφholinyl)-l,3,5-triazin-2-yllpyrrolidinyll-N-methylacetamide
Figure imgf000121_0001
[00344] The compound was prepared according to Scheme 1 using Method A.
[00345] Similarly to Example 27, tert-buty\ (3S)- 1 -[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]pyrrolidinyl(methyl)carbamate was prepared by methylation of
Figure imgf000121_0002
(3S)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]pyrrolidinylcarbamate (Example 26) in 88 % yield: mp (CΗ2Cl2/hexanes) 182-185 0C; 1H NMR (DMSO-dβ) (rotamers) δ 8.00 and 7.99 (2d, y = 8.1 Hz, IH), 7.61 and 7.60 (2t, /HF = 53.6 Hz, IH), 7.35 and 7.34 (2t, / = 8.1, 8.2 Hz, IH), 5.56 (d, J = 8.0 Hz, IH), 4.87 (m, IH), 4.05 (s, 3H), 3.95-3.82 (m, 10H), 3.64- 3.43 (m, 2H), 2.84 (s, 3H), 2.23-2.06 (m, 2H), 1.49 (s, 9H).
[00346] Deprotection of the above carbamate with TFA in CH2Cl2 gave (35)- 1 -[4-[2-
(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-N- methyl-3-pyrrolidinamine in 100% yield: 1H ΝMR (DMSO-^6) (rotamers) δ 8.08 (br, exchangeable with D2O, IH), 8.01 and 7.99 (2d, J = 8.5 Hz, IH), 7.77 (t, Jw = 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.96 (d, J = 8.1 Hz, IH), 3.98 (s, 3H), 3.96-3.56 (m, 13H), 3.64 (s, 3H), 2.40-2.29 and 2.21-2.10 (2m, 2H). [00347] Reaction of the amine with chloroacetyl chloride gave 2-chloro-N- { (35)- 1 -[4-
[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]pyrrolidinyl}-N-methylacetamide in 83% yield: mp (CΗ2Cl2/hexanes) 230-232 0C; 1H ΝMR (DMSO-J15) (retainers) δ 8.02 and 7.98 (2d, J = 8.3, 8.1 Hz, IH), 7.78 (br t, Jm = 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 5.18-4.99 and 4.71-4.66 (2m, IH), 4.53-4.51 and 4.44-4.42 (2m, 2H), 3.98 (s, 3H), 3.91-3.39 (m, 12H), 2.95 and 2.82 (2s, 3H), 2.23-2.11 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: 51,5; H, 5.1; N, 20.9; Found: C, 51.2; H, 5.1; N, 20.6%.
Example 29
Synthesis of N-I (3R)- 1 -(chloroacetyl)pyrrolidinyll-4-r2-(difluoromethyl)-4-methox v- 1 H- benzimidazol-l-yll-6-(4-morpholinyl)-l,3,5-triazin-2-amine
Figure imgf000122_0001
[00348] The compound was prepared according to Scheme 1 using Method A.
[00349] Reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with tert-buty\ (3Λ)-3-amino-l- pyrrolidinecarboxylate as in previous examples gave tert-butyl (3/?)-3-{ [4-[2- (difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]amino}-l-pyrrolidinecarboxylate in 93% yield: mp (CΗ2Cl2/hexanes) 224-226 0C; 1H ΝMR (DMSO-J6) (retainers) δ 8.16 (d, J = 6.12 Hz, exchangeable with D2O, IH), 8.11 and 7.95 (dd, J = 8.2, 8.4 Hz, IH), 7.87 (t, 7HF = 53.3 Hz, IH), 7.42-7.35 (m, IH), 6.95 and 6.94 (2d, J = 8.0 Hz, IH), 4.49 (m, IH), 3.97 (2s, 3H), 3.78 (m, 4H), 3.70 (m, 4H), 3.65-3.22 (m, 4H), 2.17-2.13 and 1.99-1.92 (2m, 2H), 1.42 (br s, 9H).
[00350] Deprotection of the above carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-l H-benzimidazol- l-yl]-6-(4-moφholinyl)-N-[(35)-pyrrolidinyl]- l,3,5-triazin-2-amine which was reacted with chloroacetyl chloride to give N-[(3/?)-l- (chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-amine in 33% yield: mp (CΗ2Cl2/hexanes) 208-210 0C; 1H NMR (DMSCM6) (rotamers) δ 8.20, 8.18, and 8.15 (3d, J = 6.7, 6.5, 6.7 Hz, exchangeable with D2O, IH), 8.10 and 7.96 (2d, J = 8.3, 8.5 Hz, IH), 7.86, 7.75 and 7.74 (3t, Jw = 53.0 Hz, IH), 7.43-7.36 (m, IH), 6.97-6.93 (m, IH), 4.59-4.46 (m, IH), 4.36-4.22 (m, 2H), 3.97 (br s, 3H), 3.88-3.39 (m, 12H), 2.29-1.93 (m, 2H); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N. 21.4; Found: C, 50.9; H; 5.0; N, 20.9%.
Example 30
Synthesis of N-[(35)-l-(chloroacetyl)pyrrolidinyll-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -vπ-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine
Figure imgf000123_0001
[00351] The compound was prepared according to Scheme 1 using Method A.
[00352] Similarly to Example 29, reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole with ferr-butyl (3S)-3-amino- 1-pyrrolidinecarboxylate gave terf-butyl (3S)-3-[[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l- pyrrolidinecarboxylate in 91% yield: mp (CΗ2Cl2/hexanes) 225-228 0C; 1H ΝMR (DMSO- d6) (rotamers) δ 8.16 (d, J = 6.2 Hz, exchangeable with D2O, IH), 8.11 and 7.96 (2d, J = 8.2, 8.4 Hz, IH), 7.87 (t, 7HF = 53.3 Hz, IH), 7.42-7.36 (m, IH), 6.96 and 6.94 (2d, J = 5.0 Hz, IH), 4.60-4.46 (m, IH), 3.98 (s, 3H), 3.79 (m, 4H), 3.70 (m, 4H), 3.62-3.55 and 4.36-3.40 (2m, 2H), 3.34-3.23 (m, 2H), 2.19-2.11 and 1.98-1.91 (2m, 2H), 1.41 (s, 9H).
[00353] The above carbamate was deprotected with TFA in CH2Cl2 to give 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-[(35)- pyrrolidinyl]-l,3,5-triazin-2-amine in 72% yield. Reaction of the amine with chloacetyl chloride as before gave N-[(35)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-txiazin-2-amine in 51% yield: mp (CΗ2Cl2/MeOΗ) 208-211 0C; 1H NMR (DMSO-^5) (rotomers) δ 8.20, 8.18, and 8.15 (3d, J = 6,6, 6.5, 6.7 Hz, exchangeable with D2O, IH), 8.10 and 8.00 (2d, J = 8.4 Hz, IH) 7.86, 7.75 and 7.74 (3t, 7HF = 53.0 Hz, IH), 7.43-7.36 (m, IH), 6.97-6.93 (m , IH), 4.60- 4.66 (m, IH) 4.33-4.29 (m, 2H), 3.97 (2s, 3H), 3.78 (m, 4H), 3.69 (m, 4H), 3.65-3.37 (m, 2H), 2.29-2.20, 2.18-2.11, and 2.09-1.95 (3m, 2H); Anal. Calcd. FOr C22H25ClF2N8O3: C, 50.5; H, 4.8; N. 21.4; Found: C, 50.55; H; 5.0; N, 21.2%.
Example 31
Synthesis of N-\(3R)- 1 -(chloroacetyl)pyrrolidinyll-4-[2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yll-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine
Figure imgf000124_0001
[00354] The compound was prepared according to Scheme 1 using Method A.
[00355] Methylation of tert-butyl (3/?)-3-{ [4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]amino } - 1 -pyrrolidinecarboxylate (Example 29) with NaH and MeI in DMF as before gave terr-butyl (3Λ)-3-[[4-[2- (difluoromethyl)-4-methoxy-lH-benzirnidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl](methyl)amino]-l -pyrrolidinecarboxylate in 96% yield: 1H NMR (DMSO-d6) δ 7.97-7.58 (m, 2H), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 5.34-5.25 (m, IH), 3.08 (s, 3H), 3.81 (m, 4H), 3.71-3.70 (m, 4H), 3.55-3.45 (m, 2H), 3.28 (m, 2 H), 3.11-3.08 (m, 3H), 2.14- 2.08 (m, 2H), 1.42 (s, 9H).
[00356] Deprotection of the carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-[(3/?)- pyrrolidinyl]-l,3,5-triazin-2-amine in 100% yield: 1H ΝMR (DMSO- 6) δ 7.97-7.58 (m, 2H), 7.41 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 5.33-5.31 (m, IH), 3.98 (s, 3H), 3.81-3.10 (m, 4H), 3.71-3.70 (m, 4H), 3.43-3.07 (m, 5H), 2.97-2.89 (m, 2H), 2.10-1.97 and 1.88-1.79 (2m, 2H).
[00357] Reaction of the amine with chloroacetyl chloride as before gave N-[(3R)-l-
(chloroacetyl)pyrτolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N- methyl-6-(4-morpholinyl)-l,3,5-triazin-2-amine in 85% yield: mp (CΗ2Cl2/hexanes) 219-221 0C; 1H ΝMR (DMSO-^5) (rotomers) δ 7.97-7.59 (m, 2H), 7.43-7.39 (m, IH), 6.95 (d, J = 8.1 Hz, IH), 5.44-5.37 and 5.33-5.30 (2m, IH), 4.39-4.32 (m, 2H), 3.98 (s, 3H), 3.82 (m, 4H), 3.77-3.26 (m, 8H), 3.13-3.10 (m, 3H), 2.24-2.18 and 2.15-2.09 (2m, 2H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.5, H, 5.1 : N, 20.9; Found: C, 51.7; H, 5.1; 21.0%.
Example 32
Synthesis of N-r(35)-l-(chloroacetyl)pyrrolidinvn-4-r2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -vn-N-methyl-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine
Figure imgf000125_0001
[00358] The compound was prepared according to Scheme 1 using Method A.
[00359] Similar methylation of tert-butyl (35)-3-[[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l- pyrrolidinecarboxylate (Example 30) gave tert-butyl (35)-3-[[4-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l- pyrrolidinecarboxylate in 94 % yield: 1H ΝMR (DMSO-^6) (rotamers) δ 7.97-7.58 (m, 2H), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 5.34-5.28 (m, IH), 3.98 (s, 3H), 3.82 (m, 4H), 3.71-3.70 (m, 4H), 3.55-3.45 (m, 2H), 3.28 (m, 2H), 3.11-3.08 (m, 3H), 3.14-2.08 (m, 2H).
[00360] Deprotection of the above carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-[(35)- pyrrolidinyl]-l,3,5-triazin-2-amine in 100% yield: 1H ΝMR (DMSO-^5) δ 8.04-7.55 (m, 2H), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.0 Hz, IH), 5.29 (br, IH), 3.98 (s, 3H), 3.81 (m, 4H), 3.70 (m, 4H), 4.00-2.99 (m, 5H), 2.89-2.81 (m, 2H), 2.06-1.98 and 1.82-1.73 (2m, 2H).
[00361 ] Reaction of the amine with chloroacetyl chloride gave N-[QS)- 1 -
(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N- methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine in 93% yield: mp (CΗ2Cl2/hexanes) 219-221 0C; 1H ΝMR (DMSO-^5) δ 7.97-7.58 (m, 2H), 7.41 (t, J = 8.2 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, 7 = 8.1 Hz, IH), 5.44-5.37 and 5.33-5.29 (2m, IH), 4.9,4.35,4.34 and 4.32 (4s, 2H), 3.81-3.34 (m, 12H), 3.18-3.11 (m, 3H), 2.24-2.18 and 2.15-2.09 (2m, 2H); Anal. Calcd. for C, 51.4; H, 5.1 ; Ν, 20.9; Found: C, 51.6; H, 5.2; Ν, 20.9%.
Example 33
Synthesis of 2-chloro-N-f (3/?)-l-r4-r2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-vn- 6-(4-morpholinyl)- 1 ,3,5-triazin-2- yllpiperidinyl } acetamide
Figure imgf000126_0001
[00362] The compound was prepared according to Scheme 1 using Method A.
[00363] Reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with ter/-butyl (3Λ)-piperidinylcarbamate gave tert-butyl (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]piperidinylcarbamate in 94 % yield: mp (CΗ2Cl2/hexanes) 115-118 0C; 1H ΝMR (DMSO-^6) (retainers) δ 8.00 and 7.89 (2d, J = 8.1, 8.4 Hz, IH), 7.72 and 7.69 (t, JH¥ = 52.6, 52.7 Hz, lH),7.43-7.36 (m, IH), 6.95 (d, J = 7.9 Hz, IH), 6.95 (br, exchangeable with D2O, IH), 4.53-4.43,4.37-4.31 and 4.21-4.13 (3m, IH), 3.97 (s, 3H), 3.79 (m, 4H), 3.69 (m, 4H), 3.42-3.36 (m, 2H), 3.16-3.10 and 3.02-2.96 (2m, 2H) 1.88-1.79 (m, 2H), 1.55-1.40 (m, 2H), 1.40 and 1.38 (2s, 9H). [00364] Deprotection of the above carbamate with TFA in CH2Cl2 gave (3R)- 1 -[4-[2-
(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-3- piperidinamine in 96 % yield: 1H NMR (DMSO-^5) δ 7.88 (d, J = 8.2 Hz, IH), 7.72 and 7.68 (t, JHF = 53.4, 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 7.41 (br, exchangeable with D2O, 2H), 6.96 (d, J = 8.2 Hz, IH), 4.49-4.38 (m, IH), 4.22-4.14 and 3.90 (2m, 2H), 3.98 (s, 3H), 3.81 (m, 4H), 3.70 (m, 4H), 3.94-3.40 (m, 2H)1 2.03-2.00 and 1.81 (2m, 2H), 1.66-1.54 (m, 2H).
[00365] Reaction of the crude amine with chloroacetyl chloride gave 2-chloro-N-
{ (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5- triazin-2-yl]piperidinyl}acetamide in 63% yield: mp (CΗ2Cl2/hexanes) 231-233 0C; 1H ΝMR (DMSO-J6) (rotamers) δ 8.26 and 8.17 (2d, J = 7.2, 7.1 Hz, exchangeable with D2O, IH), 7.94 (2 , J = 8.3, 8.4 Hz, IH), 7.69 (t, /HF = 52.9 Hz, IH), 7.43-7.37 (m, IH), 6.94 (d, J = 8.1 Hz, IH), 4.27-4.24 and 4.12-4.07 (2m, 2H), 4.12-4.05, 4.01 (ABq, J = 12.8 Hz, 2H), 3.98 (s, 3H), 3.79-3.69 (m, 9H), 3.48-3.34 (m, 2H), 1.93-1.88 and 1.82-1.80 (2m, 2H) 1.64-1.53 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.5; H, 5.1 ; N, 20.9; Found: C, 51.7; H, 5.1 ; N, 20.8%.
Example 34
Synthesis of 2-chloro-N- f (35)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yll-6- (4-morpholinyl)-l,3,5-triazin-2-vπpiperidinyl}acetamide
Figure imgf000127_0001
[00366] The compound was prepared according to Scheme 1 using Method A.
[00367] Similarly, reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole and terr-butyl (35)-piperidinylcarbamate gave rerΝbutyl (3S)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]piperidinylcarbamate in 100% yield: mp (CΗ2Cl2/hexanes) 119-122 0C; 1H NMR (DMSO-J6) (rotamers) δ 8.00 and 7.89 (2d, J = 8.4, 8.3 Hz, IH), 7.72 and 7.69 (2t, /HF = 52.9 Hz, IH), 7.43-7.36 (m, IH), 6.95 (d, J = 7.9 Hz, IH), 6.96 (br, exchangeable with D2O, IH), 4.51-4.80, 4.37-4.34, and 4.21-4.14 (3m, IH), 3.97 (s, H), 3.79 (m, 4H), 3.69 (m, 4H), 3.42-3.39 and 3.28 (2m, 2H), 3.17-3.10 and 3.02-2.96 (2m, 2H), 1.88- 1.74 (m, 2H), 1.53-1.44 (m, 2H), 1.40 and 1.38 (2s, 9H).
[00368] Deprotection of the above carbamate with TFA in CH2Cl2 gave (35)-l-[4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-ylJ-3- piperidinamine in 100% yield: 1H NMR (DMSO-J6) (rotamers) δ 7.88 (d, J = 8.3 Hz, IH), 7.72 and 7.68 (2t, 7HF = 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 6.96 (d, / = 8.1 Hz, IH), 6.71 (br, exchangeable with D2O, 2H), 4.52-4.35 (m, IH), 4.25-4.16 and 3.10 (2m, 2H), 3.98 (s, 3H), 3.81 (m, 4H), 3.70 (m, 4H), 3.28 (m, 2 H), 1.99 and 1.81 (2m, 2H), 1.55 (m, 2H).
[00369] Reaction of the amine with chloroacetyl chloride as before gave 2-chloro-N-
{ (35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5- triazin-2-yl]piperidinyl}acetamide in 80% yield; mp (CΗ2Cl2/hexanes) 227-229 0C; 1H ΝMR (DMSO-J6) (rotamers) δ 8.26 and 8.17 (2d, J = 7.3, 7.1 Hz, exchangeable with D2O, IH), 7.94 and 7.90 (2d, J = 8.4 Hz, IH), 7.69 (t, JH¥ = 52.9 Hz, IH), 7.43-7.37 (m, IH), 6.94 (d, J = 8.0 Hz, IH), 4.27-4.24 and 4.12-4,00 (2m, 2H), 4.05 and 4.01 (ABq, J = 12.8, 12.9 Hz, 2H), 3.97 (s, 3H), 3.79-3.69 (m, 9H), 3.48-3.37 (m, 2H), 1.92-1.88 and 1.83-1.80 (2m, 2H), 1.64-1.53 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.5; H, 5.1; N, 20.9; Found: C, 51.5; H, 5.1 ; N, 20.8%.
Example 35
Synthesis of 2-chloro-N-((3J?)-l-r4-r2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-vn- 6-(4-moφholinyl)-l,315-triazin-2-yl1piperidinvU-N-methylacetamide
Figure imgf000128_0001
[00370] The compound was prepared according to Scheme 1 using Method A. [00371] Methylation of tert-butyl (3#)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinylcarbamate (Example 33) with NaH and MeI in DMF gave tert-butyl (3Λ)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl(methyl)carbamate in 72% yield: 1H NMR (DMSO-J6) (rotamers) δ 7.89 (d, J = 8.3 Hz, IH), 7.69 and 7.66 (2t, /HF = 52.9, 52.8 Hz, IH), 7.43-7.34 (m, IH), 6.94 (d, J = 8.0 Hz, IH), 4.71 and 4.56 (m, 2H), 3.97 (s, 3H), 3.80-3.69 (m, 9H), 3.07-2.83 (m, 2H), 2.79 and 2.78 (2s, 3H), 1.88-1.80 (m, 3H), 1.52-1.25 (m, IH), 1.41 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.7; H, 6.3; N, 19.5; Found: C, 56.7; H, 6.4; N, 19.7%.
[00372] Deprotection of the above carbamate with TFA in CH2Cl2 gave (35)-l-[4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-N- methyl-3-piperidinamine. 1H ΝMR (DMSO-J6) (rotamers) δ 7.94 and 7.89 (2d, J = 8.3, 8.4 Hz, IH), 7.71 and 7.68 (2t, Jw = 52.9 Hz, IH), 7.42-7.36 (m, IH), 6.94 (d, J = 7.9 Hz, IH), 4.52-4.49, 4.34-4.30 and 4.15-4.10 (m, 2H), 3.97 (s, 3H), 3.79 (m, 4H), 3.69 (m, 4H), 3.43- 3.17 and 2.99-2.94 (2m, 3H), 2.45 (s, 3H), 1.94-1.90 and 1.76-1.74 (2m, 2H), 1.46-1.36 (m, 2H).
[00373] Reaction of the above crude amine with chloroacetyl chloride gave 2-chloro-
N-{(3/?)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)- l,3,5-triazin-2-yl]piperidinyl }-/V-methylacetamide in 95% yield: mp (CΗ2Cl2/hexanes) 201- 203 0C; 1H ΝMR (DMSO-J6) (rotamers) δ 7.90 (t, J = 6.6 Hz, IH), 7.69 and 7.65 (2t, /HF = 53.0 Hz, IH), 6.95 and 6.94 (2d, J = 8.0, 7.9 Hz, IH), 4.74-4.20 (m, 4 H), 3.98 (2s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.22-3.01 (m, IH), 2.98-2.85 (m, 5H), 1.96-151 (m, 4H); Anal. Calcd. for C24H29ClF2N8O3: C, 52.3; H, 5.3; N, 20.3; Found: C, 52.2; H,5.4; N, 20.6%.
Example 36
Synthesis of 2-chloro-N- f (3S)- 1 -r4-r2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yll-6- (4-morpholinvD- 1 ,3,5-triazin-2-vnpiperidinyl ) -N-methylacetamide
Figure imgf000130_0001
[00374] The compound was prepared according to Scheme 1 using Method A.
[00375] Similar methylation of tert-butyl (3S)-l-[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinylcarbamate (Example 34) with ΝaΗ and MeI gave tert-butyl (35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]piperidinyl(methyl)carbamate in 83% yield: 1H ΝMR (DMSO-^6) (rotamers) δ 7.89 (d, J = 8.4 Hz, IH), 7.69 and 7.66 (2t, 7HF = 52.9, 52.8 Hz, IH), 7.43-7.34 (m, IH), 6.94 (d, J = 8.0 Hz, IH), 4.71-4.56 (m, 2H), 3.97 (s, 3H), 3.80-3.69 (m, 9H), 3.07-2.78 (m, 5H), 1.88-1.79 (m, 3H), 1.50-1.25 (m, IH), 1.41 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5; Found: C, 56.5; H, 6.3; N, 19.5%.
[00376] Deprotection of the above carbamate with TFA in CH2Cl2 gave (35)- 1 -[4-[2-
(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-N- methyl-3-piperidinamine in 100% yield: 1H ΝMR (DMSOd6) (rotamers) δ 8.42 (br, exchangeable with D2O, IH), 7.89 (d, J = 8.3 Hz, IH), 7.72 and 7.69 (2t, 7HF = 52.5, 53.1 Hz, IH), 7.42 (t, J = 8.2, IH), 6.96 (d, J = 8.0 Hz, IH), 4.40-4.30, 4.16-4.09 and 3.97-3.92 (m, 2H), 3.98 (s, 3H),3.82-3.49 (m, 10H), 3.22-3.17 (m, IH), 2.64 and 2.60 (2s, 3H), 2.11-2.06 (m, IH), 1.81-1.72 (m, 2H), 1.56-1.55 (m, IH).
[00377] Reaction of the crude amine with chloroacetyl chloride as before gave 2- chloro-N-{ (3S)- 1 -[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl]piperidinyl} -N-methylacetamide in 77% yield: 1H ΝMR (DMSO-d6) (rotamers) δ 7.90 (t, J = 6.8 Hz, IH), 7.69 and 7.65 2 (2t, 7HF = 53.0, 52.6 Hz, IH), 7.43-7.33 (m, IH), 6.95 and 6.94 (2d, J = 7.9 Hz, IH), 4.74-4.49 and 4.33-4.21 (2m, 3H), 4.44 and 4.41 (ABq, J = 13.6, 13.0 Hz, 2H), 3.98 and 3.97 (2s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.20-3.05 (m, IH), 2.98 and 2.96 (2s, 3H), 2.93-2.85 (m, IH), 1.96-1.52 (m, 4H); Anal. Calcd. for C24H29ClF2N8O3: C, 52.3; H, 5.3, N, 20.3; Found C, 52.3, H, 5.6; N, 20.6%.
Example 37
Synthesis of N-\(3R)- 1 -(chloroacetyl)piperidinyll -4-r2-(difluoromethyl)-4-methox v- 1 H- benzimidazol-l-yll-N-methyl-6-(4-morpholinyl)-l,3,5-triazin-2-amine
Figure imgf000131_0001
[00378] Similarly, reaction of l-[4-chloro-6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with
Figure imgf000131_0002
(3/?)-3-amino-l- piperidinecarboxylate gave tert-bu\y\ (3/?)-3-{ [4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]amino } - 1 -piperidinecarboxylate in 88% yield: 1H NMR (DMSO-^6) (rotamers) δ 8.11 and 8.00 (2d, J = 8.1, 8.2 Hz, IH), 7.89 and 7.71 (2t, /HF = 53.1 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 6.95 and 6.94 (2d, J = 8.0, 7.8 Hz, IH), 3.97 (s, 3H), 3.79-3.69 (m, 10H), 3.02-2.80 (m, 2H), 1.97-1.93 (m, IH), 1.76 (m, IH), 1.59-1.20 (m, 2H), 1.35 (s, 9H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1 ; N, 20.0; Found: C, 55.9; H, 6.1; N, 20.1%.
[00379] Deprotection of the above carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)-N-[(3/?)-piperidinyl]- l,3,5-triazin-2-amine in 98 % yield: 1H ΝMR (DMSO-ύfe) (rotamers) δ 8.10 and 7.93 (2d, J = 8.3 Hz, IH), 7.88 and 7.73 (2t, /HF = 53.0 Hz, 1H),7.84 and 7.91 (2d, J = 7.7, 7.9 Hz, IH), 7.43-7.36 (m, IH), 6.95 and 6.94(2d, J = 7.9 Hz, 1 H), 3.98 and 3.97 (2s, 3H), 3.93-3.91 (m, IH), 3.79 (m, 4H), 3.69 (m, 4H), 3.18-3.09 (m, IH), 2.93-2.89 (m, IH), 2.60-2.52 (m, 2H), 1.96-1.94 and 1.73-1.70 (2m, 2H), 1.56-1.42 (m, 2H).
[00380] Reaction of the crude amine with chloroacetyl chloride as before gave N-
[(3R)- 1 -(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-amine in 96 % yield: mp (CH2Cl2/hexanes) 190-192 0C; 1H NMR (DMSO-J6) (rotamers) δ 8.11-7.56 (m, 3H), 7.38 (t, J = 8.2 Hz, IH), 6.94 (d, J = 8.1 Hz, IH), 4,59-4.25 (m, 3H), 4.09-3.69 (m, IH), 3.17-3.03 (m, IH), 2.88-2.79 and 2.60-2.59 (2m, IH), 2.0-1.99 (m, IH), 1.80-1.77 (m, IH), 1.67-1.41 (m, 2H); Anal. Calcd. for C23H27ClF2N8O3: C, 51.5; H, 5.1 ; N, 20.9; Found: C, 51.5; H, 5.2; N, 20.6%.
Example 38
S ynthesis of N-K3S)- 1 -(chloroacetyl)piperidinyll-4-r2-(difluoromethyl)-4-methoxy- 1 H- benzimidazol- 1 -yll-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine
Figure imgf000132_0001
[00381] Similarly, reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with tert-butyl (35)-3-amino- 1 - piperidinecarboxylate gave tert-buty\ (3S)-3-{ [4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]amino}-l-piperidinecarboxylate in 90% yield: 1H NMR (DMSO-J6) (rotamers) δ 8.12-7.58 (m, 3H), 7.38 and 7.38 (2t, J = 8.2 Hz, IH), 6.95 and 6.94 (2d, J = 7.8 Hz, IH), 3.97 (s, 3H), 3.78-3.69 (m, 10H), 2.99-2.94 and 2.85-2.83 (2m, 2H), 1.97-1.93 and 1.78-1.76 (2m, 2H), 1.58-1.19 (m, HH).
[00382] Deprotection of the carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-N-[(35)-piperidinyl]- l,3,5-triazin-2-amine in 100 % yield: 1H ΝMR (DMSO-J6) (rotamers) δ 8.78 (m, 2H), 8.11- 7.59 (m, 3H), 7.43-7.37 (m, IH), 6.98-6.94 (m, IH), 4.20-4.15 (m, IH), 3.99 and 3.97 (2s , 3H), 3.80 (m, 4H), 3,70 (m, 4H), 3.44-3.22 (m, 2H), 2.90-2.76 (m, 2H), 2.04-1.91 (m, 2H), 1.77-1.53 (m, 2H).
[00383] Reaction of the crude amine with chloroacetyl chloride as before gave N-
[(35)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-amine in 83 % yield: mp (CΗ2Cl2/hexanes) 191-192 0C; 1H ΝMR (DMSO-J6) (rotamers) δ 8.1 1-7.56 (m, 3H), 7.38 (t, J = 8.2 Hz, IH), 6.94 (d, J = SA Hz, IH), 4.59-4.25 (m, 3H), 4.09-3.69 (m, 10H), 3.97 (s, 3H), 3.16-3.02, 2.88-2.79 and 2.64- 2.58 (3m, 2H), 2.01-1.98 and 1.80-1.77 (2m, 2H), 1.68-1.41 (m, 2H); Anal. Calcd. for C23H27F2N8O3: C, 51.5; H, 5.1 ; N, 20.9; Found C, 51.4; H, 5.0; N, 20.4%.
Example 39
Synthesis of N-r(3/?)-l-(chloroacetyl)piperidinyll-4-r2-(difluoromethyl)-4-methoxy- IH- benzimidazol- 1 -yll -N-methyl-6-(4-morpholin yl)- 1 ,3,5-triazin-2-amine
Figure imgf000133_0001
[00384] Methylation of terr-butyl (3/?)-3- { [4-[2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]amino}-l-piperidinecarboxylate (Example 37) with NaH and MeI in DMF gave tert-butyl (3Λ)-3-[[4-[2-(difluoromethyl)-4- methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl](methyl)amino]-l - piperidinecarboxylate in 89% yield: mp (CΗ2Cl2/hexanes) 201-203 0C; 1H NMR (DMSOd6) (rotamers) δ 7.97 and 7.89 (2d, J = 8.3, 8.1 Hz, IH), 7.74 and 7.63 (2t, JHF = 52.6, 52.9 Hz, IH), 7.43-7.34 (m, IH), 6.95 and 6.94 (2d, J = 8.1 Hz, IH), 4.55-4.40 (m, IH), 3.97 (s, 3H), 3.82-3.70 (m, 9H), 3.11 and 3.07 (2s, 3H), 2.98-2.81 and 2.71-2.66 (2m, 2H), 1.87-1.76 (3H), 1.45-1.24 (m, IH), 1.40 (s, 9H); Anal. Calcd. for C27H36F2N8O3: C, 56.4; H, 6.4; N, 19.5; Found: C, 56.9: H, 6.3; N, 19.4%.
[00385] Deprotection of the carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-[(3/?)- piperidinyl]-l,3,5-triazin-2-amine in 93% yield: 1H ΝMR (DMSO-J6) (rotamers) δ 7.97 and 7.93 (2d, J = 8.4 Hz, IH), 7.74 and 7.71 (2t, /HF = 52.9, 53.1 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 4.53-4.46 (m, IH), 3.98 (s, 3H), 3.80(m, 4H), 3.70-3.69 (m, 4H), 3.08 and 3.05 (2s, 3H), 2.93-2.88 (m, 2H), 2.72-2.63 (m, IH), 2.43-2.37 (m, IH), 1.80- 1.65 (m, 3H), 1.56-1.47 (m, IH).
[00386] Reaction of the crude amine with chloroacetyl chloride as before gave N-
[(3R)- 1 -(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]- N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine in 97% yield: mp (CH2Cl2/hexanes) 194- 197 0C; 1H NMR (DMSO-J6) (rotamers) δ 8.00 and 7.86 (2d J = 8.2, 8.8 Hz, IH), 7.74 and 7.68 (2t, /HF = 51.5, 52.3 Hz, IH), 7.43-7.35 (m, IH), 6.95-6.94 (m, IH), 4.65-4.24 (m, 4H), 3.98 and 3.97 (2s, 3H), 3.81 (m, 4H), 3.70 (m, 4H), 3.14 and 3.10 (2s, 3H), 3.10-3.02, 2,93- 2.87, 2.83-2.78 and 2.63-2.53 (4m, 2H), 1.93-1.84 (m, 3H), 1.67-1.39 (m, IH); Anal. Calcd. for C22H28F2N8O2: C, 52.3, H, 5.31, N, 20.3; Found C, 52.8; H, 5.5, 20.1%.
Example 40
Synthesis of N-r(35)-l-(chloroacetyl)piperidinvn-4-r2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yl1-N-methyl-6-(4-morpholinyl)-l,3,5-triazin-2-amine
Figure imgf000134_0001
[00387] Similarly, methylation of tert-butyl (3S)-3-{ [4-[2-(difluoromethyl)-4- methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]amino } - 1 - piperidinecarboxylate (Example 38) with NaH and MeI in DMF gave tert-butyl (35)-3-[[4-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl](methyl)amino]-l-piperidinecarboxylate: 1H NMR (DMSO-J6) (rotamers) δ 7.97 and 7.88 (2d, J = 8.3, 8.1 Hz, IH), 7.74 and 7.63 (2t, 7HF = 52.5, 52.9 Hz, IH), 7.43-7.34 (m, IH), 6.95 and 6.95 (2d, J = 8.1 Hz, IH), 4.57-4.40 (m, IH), 3.97 (s, 3H), 3.94-3.67 (m, 10 H), 3.12 and 3.07 (2s, 3H), 2.98-2.94 (m, IH), 2.74-2.66 (m, IH), 1.82-1.76 (m, 3H), 1.40 (s, 9H), 1.45- 1.24 (m, IH); Anal. Calcd. for C27H36F2N8O3: C, 56.4; H, 6.3; N, 19.5; Found C, 56.3, 6.5; N, 19.4%.
[00388] Deprotection of the above carbamate with TFA in CH2Cl2 gave 4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-N-[(35)- piperidinyl]-l,3,5-triazin-2-amine in 99% yield: 1H ΝMR (DMSO-J6) (rotamers) δ 7.96 and 7.92 (2d, J = 8.4 Hz, IH), 7.74 and 7.71 (2t, /HF = 52.9, 53.1 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.1 Hz, IH), 4.61-4.55 (m, IH), 3.98 (s, 3H), 3.80 (m, 4H), 3.70 (m, 4H), 3.09 and 3.05 (2s, 3H), 2.97-2.95 (s, 2H), 2.78-2.67 and 2.52-2.43 (2m, 2H), 1.79-1.52 (m, 4H). [00389] Reaction of the crude amine with chloroacetyl chloride as before gave N-
[(35)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- N-methyl-6-(4-morpholinyl)-l,3,5-triazin-2-amine in 83% yield: 1H ΝMR (DMSO-d6) (rotamers) δ 7.97 and 7.86 (2d, J = 8.4, 8.8 Hz, IH), 7.74 and 7.68 (2t, /HF = 50.8, 52.9 Hz, IH), 7.43-7.35 (m, IH), 6.96-6.92 (m, IH), 4.66-4.79 (m, 4H), 3.98 and 3.99 (2s, 3H), 3.81(m, 4H), 3.70 (m, 4H), 3.40-3.20 and 3.10-3.02 (2m, IH), 3.14 and 3.10 (2s, 3H), 3.95- 2.78 (m, IH), 2.63-2.45 (m, IH), 1.96-1.78 (m, 3H), 1.53-1.40 (m, IH); Anal. Calcd. for C22H29F2N8O2: C, 52.3; H, 5.3; N, 20.3; Found: C, 52.5; H, 5.3; N, 20.3 %.
Example 41
Synthesis of 2-chloro-N-f l-r4-12-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yll-6-(4- morpholinyl)-l,3,5-triazin-2-yll-3-azetidinvl}acetamide
Figure imgf000135_0001
[00390] Reaction of 1 -[4-chloro-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole and tert-bv&y\ 3-azetidinylcarbamate gave 1 -[4- [2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4-morpholinyl)- l,3,5-triazin-2-yl]-3-azetidinylcarbamate in 90% yield: mp (CΗ2Cl2/hexanes) 217-220 0C; 1H NMR (DMSO-40 δ 7.98 (d, J = 8.0 Hz, IH), 7.73 (t, JHF = 53.0 Hz, IH), 8.24 (t, J = 8.2 Hz, IH), 6.95 (d, J - 7.8 Hz, IH), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9 H); Anal. Calcd. for C24H30F2N8O4: C, 54.1 ; H, 5.7; N, 21.0; Found C, 54.4; H, 5.8; N, 21.2%.
[00391] Deprotection of the above carbamate with TFA in CH2Cl2 gave l-[4-[2-
(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-3- azetidinamine in 100% yield: 1H NMR (DMSO-^5) δ 7.99 (d, J = 8.4 Hz, IH), 7.74 (t, 7HF = 53.1 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.94 (d, J = 7.8 Hz, IH), 4.35-4.32 and 4.27-4.23 (2m, 2H), 3.97 (s, 3H), 3.87-3.68 (m, 10H), 2.21 (br, exchangeable with D2O, 2H). [00392] Reaction of the crude amine with chloroacetyl chloride as before gave 2- chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4-morpholinyl)- l,3,5-triazin-2-yl]-3-azetidinyl}acetamide Jn 95% yield: mp (CΗ2Cl2/hexanes) 272-275 0C; 1H ΝMR (DMSO-^5) δ 7.99 (d, J = 8.0 Hz, IH), 7.74 (t, /HF = 53.0 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 4.67-4.59 (m, IH), 4. 49-4.45 and 4.40-4.36 (2m, 2H), 4.10 (s, 2H), 4.10-3.98 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.68 (m, 4H); Anal. Calcd. for C2IH23ClF2N8O3: C, 49.6; H, 4.6: N, 22.0; Found C, 49.8; H, 4.7; N, 21.9%.
Example 42
Synthesis of 2-chloro-N- f 1 -r4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yll-6-(4- morpholinyl)- 1 ,3,5-triazin-2-vπ-3-azetidinyl }-N-methylacetamide
Figure imgf000136_0001
[00393] Methylation of tert-butyl l -[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-3-azetidinylcarbamate (Example 41) with NaH and MeI in DMF gave rerr-butyl l-[4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-3-azetidinyl(methyl)carbamate in 90% yield: mp (CΗ2Cl2/hexanes) 174-177 0C; 1H NMR (DMSO-^6) δ 8.00 (d, J = 8.0 Hz, IH), 7.75 (t, /HF = 53.0 Hz, IH), 7.39 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 4.88 (br, IH), 4.40-4.15 (m, 4H), 3.97 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.89 (s, 3H); Anal. Calcd. for C25H32F2NSO4: C, 54.9, H, 5.9, H, 20.5; Found: C, 55.2; H, 6.0; N, 20.6%.
[00394] Deprotection of the above carbamate with TFA in CH2Cl2 gave l-[4-[2-
(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-N- methyl-3-azetidinamine in 94 % yield: 1H ΝMR (DMSO-^6) δ 7.98 (d, J = 8.3 Hz, IH), 7.74 (t, /HF = 53.0 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 7.17 (br, exchangeable with D2O, IH), 6.96 (d, J = 8.0 Hz, IH), 4.46-4.43 (m, 2H), 4.22-4.06 (m, 3H), 3.98 (s, 3H), 3.82-3.79 (m, 4H), 3.69 (m, 4H), 2.59 (s, 3H). [00395] Reaction of the crude amine with chloroacetyl chloride as before gave 2- chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4-morpholinyl)- l,3,5-triazin-2-yl]-3-azetidinyl}-N-methylacetamide in 85% yield: mp (CΗ2Cl2/hexanes) 233- 236 0C; 1H ΝMR
Figure imgf000137_0001
S 8.00 (d, J =8.3 Hz, IH), 7.75 (t, /HF = 53.0 Hz, IH), 7.40 (t, J = 8.2 Hz, IH), 6.95 (d, J = 8.0 Hz, IH), 5.26-5.20 and 5.08-5.01 (2m, IH), 4.48 and 4.45(2s, 2H), 4.43-4.14 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H) 3.09 and 2.99 (2s, 3H); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N; 21.4; Found: C, 51.2, H, 5.0; N, 21.4%.
Example 43
Synthesis of N-ri-(chloroacetyl)-3-azetidinyl1-4-F2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yll-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine
Figure imgf000137_0002
[00396] Reaction of l-[4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2-
(difluoromethyl)-4-methoxy-lH-benzimidazole with tert-butyl 3-amino-l- azetidinecarboxylate gave ter/-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol- l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]amino}-l-azetidinecarboxylate in 86 % yield: mp (CΗ2Cl2/hexanes) 201-203 0C; 1H NMR (DMSO-^6) (rotamers) δ 8.50 and 8.45 (2d, J = 6.3,6.5 Hz, IH), 8.01 and 7.93 (2d, J = 8.2, 8.3 Hz, IH), 7.83 and 7.44 (2t, /HF = 53.1, 52.9 Hz, IH), 7.44-7.37 (m, IH), 6.96 and 6.95 (2d, J = 8.1, 8.0 Hz, IH), 4.73-4.58 (m, IH), 4.78 (t, J = 7.8 Hz, 2H), 3.97 (s, 3H), 3.87- 3.82 (m, 2H), 3.78 (m, 4H), 3.69, (m, 4H), 1 40 and 1.39 (2 s, 9H); Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5,7; N, 21.0; Found: C, 54.0; 5.8; N, 21.0%.
[00397] Deprotection of the above carbamate with TFA in CH2Cl2 gave N-(3- azetidinyl)-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4-morpholinyl)- l,3,5-triazin-2-amine in 100% yield: 1H NMR (£>MSO-d6) (rotamers) δ 8.58 and 8.54 (2d, J - 5.9, 6.6 Hz, IH), 8.07 and 7.91 (2d, J = 8.4, 8.3 Hz, IH), 7.82 and 7.70 (2t, Jw = 51.3 and 52.9 Hz, IH), 7.44-7.38 (m, IH), 6.97 and 6.96 (2d, 7 =7.9, 8.0 Hz, IH), 4.98-4.88 and 4.88- 4.80 (2m, IH), 4.23-4.16 (m, 2H), 4.06-3.98 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.70 (m, 4H).
[00398] Reaction of the crude amine with chloroacetyl chloride as before gave N-[I-
(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)-l,3,5-triazin-2-amine in 95% yield: mp (CΗ2Cl2/hexanes) 219-221 0C; 1H ΝMR (DMSO-^5) (retainers) δ 8.57 and 8.53 (2d, J = 5.9, 6.4 Hz, IH), 8.09 and 7.95 (2d J = 8.3, 7.1 Hz, 1 H ) 7.82 and 7.71 (2t, 7HF = 41.6, 52.9 Hz, IH), 7.45-7.37 (m, IH), 6.96 and 6.95 (2d, J = 7.9, 8.0 Hz, IH), 4.82-4.70 and 4.72-4.53 (2m, IH), 4.58-4.52 (m, IH), 4.28- 4.11 (m, 4H), 3.98 (s, 3H), 3.79 (m, 4H), 3.69 (m, 4H); Anal. Calcd. for C2IH23ClF2N8O3: C, 49.6; H, 4.6: N, 22.0; Found: C, 49.5; H, 4.5; N, 21.7%.
Example 44
Synthesis of N-F 1 -(chloroacetyD-S-azetidinyll^-^-CdifluoromethvD^-methoxy- 1 H- benzimidazol-l-vn-N-methyl-6-(4-morpholinyl)-K3,5-triazin-2-amine
Figure imgf000138_0001
[00399] Methylation of N-(3-azetidinyl)-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-amine (Example 43) with ΝaΗ and MeI in DMF gave tert-butyl 3-[[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)-l,3,5-triazin-2-yl](methyl)amino]-l-azetidinecarboxylate in 91% yield: mp (CΗ2Cl2/hexanes) 221-223 0C; 1H ΝMR (DMSO-^6) δ 7.97-7.95 (m, 2H), 7.42 (t, J = 8.2 Hz, IH), 6.95 (d, J = 7.9 Hz, IH), 5.52-5.48 and 5.36-5.34 (2m, IH), 4.16-4.06 (m, 4H), 3.98 (s, 3H), 3.81 (m, 4H), 3.70-3.69 (m, 4H), 3.23 (s, 3H), 1.41 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C,54.9; H, 5.9; N, 20.5; Found: C, 55.0, H; 6.0; N, 20.4%.
[00400] Deprotection of the above carbamate with TFA in CH2Cl2 gave N-(3- azetidinyl)-4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-N-methyl-6-(4- morpholinyl)-l,3,5-triazin-2-amine in 96% yield: 1H ΝMR (DMSO-^5) δ 7.95-7.56 (m, 2H), 7.42 (t, J = 8.2 Hz, IH), 6.96 (d, J - 8.0 Hz, IH), 5.60 and 5.38 (2 m, IH), 4.27-4.22 (m, 2H), 4.17 -4.12 (m, 2H), 3.98 (s, 3H), 3.81 (m, 4H), 3.71 (m, 4H), 3.24 (s, 3H).
[00401] Reaction of the crude amine with chloroacetyl chloride as before gave N-[I-
(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-N- methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine in 52% yield: mp (CΗ2Cl2/hexanes) 220-222 0C; 1H ΝMR (DMSO-^5) (rotamers) δ 7.96 and 7.87 (2d, J = 8.2, 7.7 Hz, IH), 7.73 and 7.71 (2t, 7HF = 52.7, 53.6 Hz, IH), 7.42 (t, J = 8.2 Hz, IH), 6.96 (d, J = 7.8 Hz, IH), 5.64-5.61 and 5.46-5.38 (2m, IH), 4.54-4.35 (m, 2H), 4.26-4.12 (m, 2H), 4.21 (s, 2H), 3.97 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.24 (s, 3H); Anal. Calcd. for C22H25ClF2N8O3: C, 50.5; H, 4.8; N; 21.4; Found C, 50.3, H, 4.8; N, 21.1%.
Example 45
Synthesis of 1 -[4- { f 1 -(chloroacetyl)-4-piperidinyπoxy ) -6-(4-morpholinγl)- 1 ,3,5-triazin-2- vH-2-(difluoromethyl)-4-rnethoxv-lH-benzimidazole
Figure imgf000139_0001
[00402] The compound was prepared according to Scheme 1 using Method A.
[00403] A mixture of 0.47 g (2 mmol) of 2,4-dichloro-6-(4-morpholinyl)- 1,3,5- triazine, 0.40 g of teλt-butyl 4-hydroxy- 1 -piperidinecarboxylate (2 mmol) and a small excess of NaH in 20 mL of THF was stirred at room temperature overnight, before being quenched with water and worked up in EtOAc. Chromatography on silica, eluting with CH2Cl2/Et0Ac (9:1) gave 0.65 g (81% yield) of tert-butyl 4-(4-chloro-6-morpholino-l,3,5-triazin-2- yloxy)piperidine-l-carboxylate, as a white solid: mp (/-Pr2O) 150-152 0C; 1H NMR (CDCl3) δ 5.18 (tt, J = 7.7, 3.8 Hz, IH), 3.87 (m, 2H), 3.83 (m, 2H), 3.78 - 3.71 (m, 6H), 3.30 (ddd, J = 13.5, 8.3, 3.8 Hz, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.46 (s, 9H); Anal. Calcd. for C17H26ClN5O4: C, 51.06; H, 6.55; N, 17.51 ; Found: C, 51.21; H, 6.28; N, 17.4%.
[00404] A mixture of 175 mg (0.44 mmol) of the above chloro compound, 100 mg
(0.505 mmol) of 2-(difluoromethyl)-4-methoxy-lH-benzimidazoIe and 0.28 g (2 mmol) of powdered K2CO3 in 10 mL DMSO was stirred at room temperature for 3 days, and diluted with water. The resulting precipitate was collected, washed with water, and dried. Chromatography on silica eluting with CH2Cl2/Et0Ac (4:1) gave 200 mg (81% yield) of tert- butyl 4-(4-(2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl)-6-morpholino- 1 ,3,5- triazin-2-yloxy)piperidine-l-carboxylate: mp (CH2Cl2-MeOH) 191-193 0C; 1H NMR (CDCl3) δ 7.96 (dd, J = 8.4, 0.5 Hz, IH), 7.49 (t, JHF = 53.5 Hz, IH), 7.38 (t, J = 8.3 Hz, IH), 6.85 (d, J = 7.8 Hz, IH), 5.25 (m, IH), 4.06 (s, 3H), 3.96-3.78 (m, 10H), 3.28 (m, 2H), 2.50 (m, 2H), 1.85 (m, 2H), 1.48 (s, 9H); Anal. Calcd. for C26H33F2N7O5: C, 55.61; H, 5.92; N, 17.46; Found: C, 55.77; H, 5.92; N, 17.40%.
[00405] Treatment of 112 mg (0.2 mmol) of the above carbamate with TFA (5 mL) in
CH2Cl2 (10 mL), followed by quenching with aq. NH3 gave 2-(difluoromethyl)-4-methoxy-l- (4-morpholinyl)-6-(4-piperidinyloxy)-l ,3,5-triazin-2-yl]-lH-benzimidazole: 1H NMR (DMSO-J6) δ 7.96 (dd, J = 8.4, 0.5 Hz, IH), 7.71 (t, JHF = 52.8 Hz, IH), 7.44 (t, J = 8.3 Hz, IH), 6.98 (d, J = 7.7 Hz, IH), 5.1 1 (m, IH), 3.98 (s, 3H), 3.83 (m, 4H), 3.71 (m, 4H), 3.00 (m, 2H), 2.62 (m, 2H), 2.00 (m, 2H), 1.58 (m, 2H).
[00406] Treatment of the crude amine with chloroacetyl chloride as before, followed by chromatography on silica eluting with CH2Cl2ZEtOAc (4: 1) gave 61 mg (57% yield) of 1 - [4-{[l-(chloroacetyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy-lH-benzimidazole: mp (aq. MeOH) 170-172 0C; 1H NMR (CDCl3) δ 7.95 (d, J = 8.3 Hz, IH), 7.47 (t, JHF = 53.5 Hz, IH), 7.38 (t, J = 8.3 Hz, IH), 6.85 (d, J = 8.0 Hz, IH), 5.37 (tt, J = 7.1, 3.6 Hz, IH), 4.11 (d, J = 1.6 Hz, 2H), 4.06 (s, 3H), 3.94 (m, 5H), 3.80 (m, 5H), 3.65 (m, IH), 3.53 (m, IH), 2.18-1.92 (m, 4H); Anal. Calcd. for C23H26ClF2N7O4: C, 51.35; H, 4.87; N, 18.23; Found: C, 51.62; H, 4.88; N, 17.99%.
Example 46
Synthesis of 3-f ll-[4-f π-(chloroacetyl)-4-piperidinylloxy}-6-(4-morpholinyl)-l.,3,5-triazin- 2-vn-2-(difluoromethyl)-lH-benzimidazol-4-ylloxy)-NJV-dimethyl-l-propanamine
Figure imgf000140_0001
[00407 J The compound was prepared according to Scheme 1 using Method A.
[00408] A mixture of 7.2 g (46.7 rnmol) of 2-amino-3-nitrophcnol, 6.6 g (70 mrnol) 3- chloro-1 -propanol, and 19.3 g (0.14 mol) dry powdered K2CO-) in 50 mL acetone was heated and stirred under reflux for 20 hrs. The solvent was removed under vacuum and the residue was diluted with water, extracted into ethyl acetate, and dried (Na2S(Xt). Removal of the solvent and chromatography of the residue on silica eiuting with CH2Cl2/Et0Ac (4: 1) gave 10.0 g (100% yield) of 2~(2-amino-3~nitrophenoxy)ethanol as a yellower solid: mp (CH2Cl2/hexanes) 72-74 0C; 1H NMR (CDCl3) S 7.71 (dd, J = 8.9, 1.2 Hz, IH), 6.92 (d, J = 7.7 Hz, I H), 6.60 (dd, J = 8.9, 7.8 Hz, IH), 6.42 (s, exchangeable with D2O, 2H), 4.20 (t, J = 6.1 Hz, 2H), 3.89 (q, J - 5.7 Hz, 2H), 2.12 (pentet, J = 6.1 Hz, 2H), 1.48 (t, J = 5.0 Hz, exchangeable with D2O, IH); Anal. Calcd for C9Hj2N2O4: C, 50.9; H, 5.7; N, 13.3; Found: C, 51.0; H, 5.7; N, 13.3%.
S00409J A solution of 4.3 g (20.26 mmol) of the above alcohol in 50 mL McOH was hydrogcnatcd over 10% Pd on C and then filtered into a solution of 5 mL cone. HCl in MeOH. After removal of the solvents the residue was dissolved in a mixture of 60 mL 4 M HCl and 5 mL of difluoroacetic acid, and the resulting mixture was heated under icflux for 6 hrs. After cooling to 20 0C, the mixture was diluted with 100 mL water, neutralized with aq. NH-;, extracted into EtOAc, and dried (Na2SO.-)). Evaporation of the solvent gave crude 2- { [2-(difluoromclhyl)- l//-benziniidazol-4~yl]oxy}elhanol which was combined with 6.1 g (40 mmol) TBDMSCl in 15 mL pyridine. The mixture was stirred at 20 0C for 3 hrs before being poured into water and extracted with EtOAc. After drying (Na2SO4) and evaporation of the solvent, the residue was purified by chromatography on silica eiuting with GH^Cb/ElOAc (9: 1) to give 5.79 g (84% yield) of 4-(2-( [/e/t-butyl{dimethyl)silyl|oxyj ethoxy)-2- (difluoromethyl)-lH-benzimidazole: mp (CH2Cl2/hcxanes) 133- 135 0C; 1H NMR (DMSO-J6) (tautomers) δ 13.40 and 13.23 (s, exchangeable with D2O, I H), 7.36-7.05 (m, 3H)1 6.86 and 6.75 (2d, J = 7.8 Hz and 7.4 Hz, IH), 4.27 and 4.22 (2 t, J = 6.3 Hz, 211), 3.87 and 3.81 (2t, J = 6.1 Hz, I H), 2.05- 1.95 (m, 2H), 0.85 and 0.84 (2s, 9H), 0.02 and 0.01 (2s, 6H).
[0041 Oj A mixture of 942 mg (2.64 mmol) of the above benzimidazole, 148 mg (0.37 mmol) of ter/-biityl 4-{ [4-chloro-6-(4-morpholinyl)-l,3,5-triazin-2-ylJoxy}-l - pipcridinecarboxylate (Example 45), and 1.09 g (7.92 mmol) K2CO3 in dry DMSO (2 mL) was heated at 130 0C for 2 hrs, before being cooled and diluted with water. The resulting precipitate was filtered, washed with water and dried. Recrystallization from CH2Cl2/hexanes gave 1.47 g (85% yield) of tert-butyl 4-{ [4-[4-(3-{ [tert- butyl(dimethyl)silyl]oxy } propoxy)-2-(difluoromethyl)- 1 H-benzimidazol- 1 -yl] -6-(4- moφholinyl)-l,3,5-triazin-2-yl]oxy}-l-piperidinecarboxylate as a white solid: 1H NMR (CDCl3) δ 7.95 (d, J = 8.1 Hz, exchangeable with D2O, IH), 7.48 (t, 7HF = 53.5 Hz, IH), 7.35 (t, J = 8.3 Hz, IH), 6.89 (d, J = 8.0 Hz, IH), 5.29-5.23 (m, IH), 4.37 (t, J = 6.6 Hz, 2H), 3.93- 3.91 (m, 4H), 3.86 (d, J = 5.9 Hz, 4H), 3.81-3.76 (m, 4H), 3.31-3.25 (m, 2H), 2.15 (q, J = 6.3 Hz, 2H), 2.07-2.03 (m, 2H), 1.88-1.80 (m, 2H), 1.48 (s, 9H), 0.89 (s, 9H) 0.05 (s, 6H).
[00411] To a suspension of the above silyl ether (1.20 g, 1.67 mmol) in CH3CN (15 mL) at 0 0C was added BF3 OEt2 (3.5 mL). The reaction was stirred for 15 min and diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried to give 3-({2-(difluoromethyl)-l-[4-(4-moφholinyl)-6-(4-piperidinyloxy)-l,3,5-triazin- 2-yl]-lH-benzimidazol-4-yl}oxy)-l-propanol as a white solid: 1H NMR (DMSO-J6) δ 8.29 (br s, 1 H, exchangeable with D2O), 7.95 (d, J = 8.3 Hz, IH), 7.72 (t, JHF = 52.8 Hz, IH), 7.42 (t, J = 8.2 Hz, IH), 6.99 (d, J = 8.0 Hz, IH), 5.33-5.28 (m, IH), 4.56 (t, 7 = 5.1 Hz, exchangeable with D2O, IH), 4.29 (t, J = 6.4 Hz, 2H), 3.85 (m, 4H), 3.74-3.71 (m, 4H), 3.65- 3.61 (m, 2H), 3.28 (m, 2H), 3.17-3.11 (m, 2H), 2.21-2.16 (m, 2H), 2.01-1.89 (m, 4H).
[00412] To a mixture of the above amino-alcohol (885 mg, 1.75 mmol) and K2CO3
(483 mg, 3.50 mmol) in THF (15 mL) and H2O (5 mL) was added Boc2O (458 mg, 2.1 mmol). The reaction mixture was stirred at 20 0C for 3 hrs, and then diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried, to give 853 mg (80% yield) of tert-butyl 4-{ [4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-lH-benzimidazol- l-yl]-6-(4-morpholinyl)-l,3,5-triazin-2-yl]oxy}-l-piperidinecarboxylate as a white solid: 1H NMR (DMSO-J6) δ 7.95 (d, J = 8.37 Hz, IH), 7.71 (t, 7HF = 52.8 Hz, IH), 7.42 (t, J = 8.3 Hz, IH), 6.98 (d, J = 8.0 Hz, IH), 4.56 (t, J = 5.1 Hz, IH), 4.29 (t, J = 6.4 Hz, 2H), 3.84 (m, 4H), 3.73-3.60 (m, 6H), 3.64-3.60 (m, 2H), 3.24-3.18 (m, 2H), 2.04-1.92 (m, 4H), 1.69-1.61 (m, 2H), 1.42 (s, 9H).
[00413] Methanesulphonyl chloride (4.2 mmol) was added to a solution of the above alcohol (850 mg, 1.4 mmol) and Et3N (0.4 mL, 2.8 mmol) in THF (10 mL) at 0 0C, and the resulting mixture was stirred at 0 0C for 2 hrs. A 40% aq. solution of dimethylamine (2 mL) was then added and the mixture was stirred at 20 0C for 20 hrs. The solvents were removed under vacuum and the residue was diluted with water to give a precipitate, which was collected by filtration, washed with water, and dried to give 834 mg (94% yield) of terf-butyl 4- { [4- { 2-(difluoromethyl)-4-[3-(dimethylamino)propoxy] - 1 H-benzimidazol- 1 -yl } -6-(4- moφholinyl)-l,3,5-triazin-2-yl]oxy}-l-piperidinecarboxylate as a white solid: 1H NMR (DMSO-^5) δ 7.95 (d, / = 8.1 Hz, IH), 7.72 (t, 7HF = 52.8 Hz, IH), 7.42 (t, J = 8.3 Hz, IH), 6.97 (d, J = 7.9 Hz, IH), 5.26-5.21 (m, IH), 4.26 (t, J = 6.5 Hz, 2H), 3.84 (m, 4H), 3.74-3.70 (m, 6H), 2.26-3.18 (m, 4H), 2.23 (s, 6H), 2.04-1.94 (m, 4H), 1.69-1.57 (m, 2H), 1.42 (s, 9H).
[00414] Deprotection of the above carbamate with TFA in CH2Cl2 in similar manner as before gave N-[3-({2-(difluoromethyl)-l-[4-(4-morpholinyl)-6-(4-piperidinyloxy)-l, 3,5- triazin-2-yl]-lH-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine as a white solid in 97 % yield: 1H ΝMR (DMSO-d6) δ 7.95 (d, J = 8.1 Hz, IH), 7.71 (t, J = 52.8 Hz, IH), 7.41 (t, J = 8.2 Hz, IH), 7.37 (br s, exchangeable with D2O, IH), 6.97 (d, J = 8.0 Hz, IH), 5.14-5.07 (m, IH), 4.25 (t, J = 6.5 Hz, 2H), 3.83 (m, 4H), 3.83-3.70 (m, 4H), 3.01-2.96 (m, 2H), 2.62-2.56 (m, 2H), 2.41 (t, J = 7.1 Hz, 2H), 2.16 (s, 6H), 2.02-1.92 (m, 4H), 1.61-1.52 (m, 2H).
[00415] Reaction of the above amine with chloroacetyl chloride and K2CO3 in CH2Cl2, in a similar manner as before gave 3-{[l-[4-{ [l-(chloroacetyl)-4-piperidinyl]oxy}-6-(4- morpholinyl)- 1 ,3,5-triazin-2-yl]-2-(difluoromethyl)- lH-benzimidazol-4-yl]oxy } -N,N- dimethyl-1-propanamine hydrochloride as a white solid in 49% yield: mp (CΗ2Cl2/MeOΗ/hexanes/EtOAc) 194-197 0C; 1H ΝMR (DMSO-J6) δ 7.99 (d, J = 8.3 Hz, IH), 7.73 (t, JHF = 52.7 Hz, IH), 7.45 (t, J = 8.2 Hz, IH), 7.01 (d, J = 8.0 Hz, IH), 5.35-5.29 (m, IH), 4.42 (s, 2H), 4.33 (t, J = 6.1 Hz, 2H), 3.85 (m, 4H), 3.73-3.71 (m, 4H),3.45-3.34 (m, 2H), 3.28 (m, 2H), 2.82 (s, 6H), 2.28-2.21 (m, 2H), 2.19-1.19 (m, 2H), 1.86-1.67 (m, 2H); Anal. Calcd. for C27H36Cl2F2N8O4. H2O: C, 48.9; H, 5.7; Cl; 10.7; N, 16.9; Found: C, 49.2; H, 5.7; Cl, 10.8; N, 16.9%.
Example 47
Synthesis of 3-( [1-[4-(I l-r(chloromethyl)sulfonyll-4-piperidinylloxy)-6-(4-moφholinyl)- l,3,5-triazin-2-vn-2-(difluoromethyl)-lH-benzimidazol-4-ylloxyl-iV,N-dimethyl-l- propanamine
Figure imgf000143_0001
[00416] The compound was prepared according to Scheme 1 using Method A.
[00417] Reaction of N-[3-( { 2-(difluoromethyl)- 1 -[4-(4-morpholinyl)-6-(4- piperidinyloxy)-l,3,5-triazin-2-yl]-lH-benzimidazol-4-yl}oxy)propyl]-N,N-dimemylamine (Example 46) with chloromethanesulphonyl chloride gave 3-{ [l-[4-({ 1- [(chloromethyl)sulfonyl]-4-piperidinyl}oxy)-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-yl]oxy}-N,N-dimethyl-l-propanamine in 16 % yield: 1H ΝMR (DMSO-J6) δ 7.95 (d, J = 8.4 Hz, IH), 7.72 (t, 7HF = 52.8 Hz, IH), 7.42 (t, J = 8.3 Hz, IH), 6.98 (d, J = 8.0 Hz, IH), 4.25 (t, J = 6.5 Hz, 2H), 3.84 (m, 4H), 3.73-3.70 (m, 4H), 3.63-3.58 (m, 4H), 3.63-3.58 (m, 2H), 3.41-3.34 (m, 2H), 2.41 (t, J = 7.1 Hz, 2H), 2.16 (s, 6H), 2.12-2.07 (m, 2H), 1.99-1.92 (m, 2H), 1.89-1.80 (m, 2H); Anal. Calcd. for C26H35ClF2N8O5S 0.5H2O: C, 47.7; H, 5.55; N, 17.1; Found: C, 47.8; H, 5.5; N, 17.1%.
Example 48
Synthesis of l-( l-r(chloromethyl)sulfonyl1-4-piperidinyll-6-r2-(difluoromethyl)-4-methoxy- lH-benzimidazol-l-yll-4-(4-moipholinyl)-lH-pyrazoloF3,4-J]pyrimidine
Figure imgf000144_0001
[00418] The compound was prepared according to Scheme 1 using Method A.
[00419] A stirred mixture of 0.44 g (2.2 mmol) of 2-(difluoromethyl)-4-methoxy-lH- benzimidazole, 0.47 g (1.1 mmol) of terr-butyl 4-[6-chloro-4-(4-morpholinyl)-lH- pyrazolo[3,4-rf]pyrimidin-l-yl]-l-piperidinecarboxylate (WO 2008/115974), and 0.61 g (4.4 mmol) of powdered K2CO3 in 10 mL of DMSO was heated at 160 0C for 20 hrs. After cooling, the mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried. Chromatography on silica eluting with CΗ2Cl2/EtOAc (17:3) gave 0.20 g (31% yield) of tert-batyl 4-[6-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol- 1 -yl]-4-(4-morpholinyl)- lH-pyrazolo[3,4-<i]pyrimidin- 1 -yl]- 1 -piperidinecarboxylate: mp (MeOH) 245-247 0C; 1H NMR (CDCl3) δ 7.99 (s, IH), 7.84 (dd, J = 8.4, 0.6 Hz, IH), 7.47 (t, JHF = 53.6 HZ, IH), 7.37 (t, 7 = 8.2 Hz, IH), 6.83 (d, J = 7.8 Hz, IH), 4.87 (tt, J = 11.4, 4.1 Hz, IH), 4.32 (m, 2H), 4.07 (s, 3H), 4.06 (m, 4H), 3.91 (m, 4H), 2.99 (m, 2H), 2.23 (dq, J = 12.3, 4.5 Hz, 2H), 2.02 (m, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2; Found: C, 57.2; H, 6.0; N, 19.0%.
[00420] Treatment of the above carbamate with TFA in CH2Cl2 as before gave 6-[2-
(difluoromethyl)-4-methoxy- lH-benzimidazol- 1 -yl]-4-(4-morpholinyl)- 1 -(4-piperidinyl)- IH- pyrazolo[3,4-rf]pyrimidine in 97% yield: 1H NMR (CDCl3) δ 8.00 (s, IH), 7.86 (dd, J = 8.4, 0.6 Hz, IH), 7.51 (t, JHF = 53.6 Hz, IH), 7.38 (t, J = 8.2 Hz, IH), 6.83 (d, J = 7.7 Hz, IH), 4.83 (tt, J = 1 1.6, 4.1 Hz, IH), 4.07 (s, 3H), 4.06 (m, 4H), 3.91 (m, 4H), 3.31 (m, 2H), 2.87 (dt, J = 12.7, 2.5 Hz, 2H), 2.21 (dq, J = 12.3, 4.2 Hz, 2H), 2.04 (m, 2H).
[00421] A mixture of 85 mg (175 mmol) of the above amine and 73 mg (525 mmol) of powdered K2CO3 in CH2Cl2 was cooled to 0 0C and 78 mg (525 mmol) of chloromethanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 3 hrs it was diluted with water and washed with aq. NH3. The organic layer was dried, and removed under vacuum, and the residue was recrystallized from MeOH to give 76 mg (73 % yield) of l-{ l-[(chloromethyl)sulfonyl]-4-piperidinyl}-6-[2- (difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-4-(4-morpholinyl)-lH-pyrazolo[3,4- d]pyrimidine: mp 250-253 0C; 1H NMR (CDCl3) δ 8.01 (s, IH), 7.82 (dd, J = 8.4, 0.6 Hz, IH), 7.45 (t, JHF = 53.6 Hz, IH), 7.39 (t, J = 8.2 Hz, IH), 6.83 (d, J = 7.8 Hz, IH), 4.90 (tt, J = 1 1.1 , 4.1 Hz, 1 H), 4.57 (s, 2H), 4.15 (m, 1 H), 4.12 (m, 1 H), 4.07 (s, 3H), 4.06 (m, 4H), 3.92 (m, 4H), 3.32 (dt J = 12.5, 2.6 Hz, 2H), 2.42 (dq, J = 12.4, 4.3 Hz, 2H), 2.15 (m, 2H); Anal. Calcd. for C24H27ClF2N8O4S: C, 48.3; H, 4.6; N, 18.8; Found: C, 48.1; H, 4.6; N, 18.6%.
Example 49 Biological Activity Determination
A. Reversible inhibition of isolated enzyme
[00422] Compounds were evaluated for their ability to inhibit Class I PI 3-kinase enzymes pi 10δ/p85, pi 10α/p85, and pi 10β/p85. Reaction mixtures comprising 0.1 μg of a recombinant enzyme, 10 μg of L-α-phosphatidylinositol, and 2X Lipid Kinase Buffer (40 mM Tris-HCl, pH 7.4, 200 mM NaCl, 1 mM EDTA), which contains either DMSO only as a control or the test compound in DMSO (the final DMSO concentration is 1%), were activated by the addition of an ATP mix (5 mM MgCl2, 100 μM ATP, and 0.1 μL [γ33P]ATP). Reactions were incubated at room temperature for 1 hr, and then stopped by the addition of IM HCl. The lipids were then extracted using a two step procedure. Firstly, 200 μL of chloroform/methanol (1 :1) was added, the biphasic reactions mixed and centrifuged briefly, and the inorganic phase was removed and discarded. Following this, 80 μL of methanol:HCl (1 :1) was added and the same procedure followed. The organic phase (70 μL) was then transferred to a clean 1.6 mL tube and the reactions were dried using a Speedvac, with no heating, for 30 min. The reactions were spotted onto TLC plates (Merck Ltd) and developed for 1 hr in propanol-1 :2 M acetic acid (13:7). The TLC plates were then dried at room temperature and quantified using a phosphorimager (Stormlmager, Amersham). Nine compound concentrations were used for each test compound to determine its IC50 value. Each experiment was performed twice and the average IC50 value is used herein. The results are summarised in Table 2.
B. Irreversible and selective inhibition of pi 10a isoform
[00423] The compounds were evaluated for their ability to irreversibly inhibit the pi 10a isoform of PI3K in both isolated enzyme and cell culture assays.
a. Isolated enzyme assay:
[00424] Recombinant PI3K (pi 10/p85) was first subjected to immunoprecipitation.
Protein A-Sepharose beads were washed twice with a lysis buffer (20 mM Tris-HCl, 138 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 5% (v/v) glycerol, 1 % (v/v) Nonidet P-40 (NP40), 5 mM EDTA, 20 μM leupeptin, 18 μM pepstatin, 1 mM AEBSF, 4 μg/mL aprotinin, 2 mM Na3VO4, 20 mM NaF, 1 mM DTT (pH7.4)) and then pre-incubated with polyclonal antibodies specific to the N-SH2 domain of p85 alpha (Shepherd et al., J. Biol. Chem. 1997, 272, 19000) for 30 min at 4 0C. Recombinant PI3K (pi 10/p85) was then added for further incubation overnight at 4 0C. The following day, immune complexes were washed twice with the lysis buffer, resuspended in the same buffer, and aliquoted. After incubation with the test compounds (1 μM, 30min at room temperature), immune complexes were then either 1) directly tested for Lipid kinase activity or 2) washed three times with the lysis buffer and then tested for Lipid kinase activity (same protocol as for reversible inhibition of isolated enzyme). Wortmannin (100 nM) and LY 294002 (5 μM) were used as the positive and negative controls, respectively. b. Cellular assay:
[00425] Fully differentiated 3T3L1 adipocytes were starved overnight without serum.
The following day, cells were incubated for 60 min with wortmannin (100 nM) as the positive control, LY 294002 (5 μM) as the negative control, the test compounds (1 μM), or DMSO.
[00426] To test for irreversibility, cells were then either: 1) rinsed 3 times with warm medium and incubated without an inhibitor for 30 min; or 2) maintained in the same medium containing an inhibitor.
[00427] Cells were subsequently stimulated or not with insulin (100 nM, 10 min).
Finally, cells were washed twice with ice-cold Phosphate Buffer Saline (PBS) (140 mM NaCl, 3 mM KCl, 6 mM Na2HPO4, 1 mM KH2PO4 (pH 7.4)) and solubilized with a lysis buffer (20 mM Tris-HCl, 138 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 5% (v/v) glycerol, 1% (v/v) Nonidet P-40 (NP40), 5 mM EDTA, 20 μM leupeptin, 18 μM pepstatin, 1 mM AEBSF, 4 μg/mL aprotinin, 2 mM Na3VO4, 20 mM NaF, 1 mM DTT (pH7.4)). Lysates were kept on ice for 20 min and insoluble material was removed by centrifugation at 14,000 g for 10 min. Protein concentration was determined by colorimetric assay (BCA, Pierce).
[00428] Proteins were separated by SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membranes (Pall Corporation, USA). The membranes were incubated for 1 hr in a blocking buffer (20 mM Tris (pH 7.4), 137 mM NaCl, 0.5% (v/v) Tween 20) containing 3% (w/v) BSA (ICP Bio, Auckland, New Zealand) or non-fat milk, and then incubated overnight in the blocking buffer containing specific antibodies (phosphoSer473 PKB and total PKB). Immunoreactive proteins were detected using horseradish peroxidase- linked secondary antibodies (Dako) and enhanced chemiluminescence (ECL) according to the manufacturer's instructions (GE Healthcare, Inc.). Signals were analyzed and quantified using Fuji LAS-3000 phosphorimager and Fuji Image Gauge software.
[00429] As an example, the results for Compound Example 4 are shown in FIG. 1.
Overnight-starved 3T3L1 adipocytes cells were incubated for 60 min with compound of Example 4 at 1 μM (lanes 7-12). The cells in lanes 10-12 were then rinsed 3 times with warm cell culture medium and incubated without the compound for 30 min, whereas compound of Example 4 was left continuously on the other drug exposed cells (lanes 7-9). Cells were then stimulated (lanes 4-12) or not (lanes 1-3) with insulin (100 nM, 10 min) and then lysed. Whole-cell lysates were then analysed by Western blotting using either an antibody that specifically recognised residue 473 of PKB only when it is phosphorylated (phosphoSer473 PKB) or with an antibody that recognizes all forms of PKB (Total PKB). The results demonstrate that insulin stimulates the phosphorylation of PKB in these cells (lanes 4- 6) and that this is attenuated by compound 4 (lanes 7-12), even when unbound compound 4 had been washed away prior to exposure of the cells to insulin (lanes 10-12). This indicates that compound 4 has irreversibly bound PI 3-kinase in the cells.
C. Cellular growth inhibition
[00430] The compounds were evaluated against two early passage human cell lines
NZB5 and NZOV9 (Marshall et ai, Oncol. Res. 2004, 14, 297). The cells were grown in ITS medium (α-modifϊed minimal essential medium supplemented insulin, transferrin, selenite, and 5% fetal bovine serum) and grown on 96-well tissue culture plates under an atmosphere of 5% O2, 5% CO2, and 90% N2. Individual wells contained 500-1,000 cells (depending on the growth rate) in a volume of 150 μL. Compounds were added at 10-fold concentration steps to a maximum of 20 μM and plates were incubated for five days, with 3H-thymidine being added over the last 6 hrs. Cells were harvested and incorporated radioactivity measured. Duplicate samples were analyzed for each compound dose with multiple control samples. Data were fitted by a least-squares method to an exponential of the form y = yo + ae hx, where y is the radioactivity (corrected for background and normalized to 100% of the control), x is the radiation dose, and yo, a, and b are variables, and the IC50 value defined as the compound concentration reducing 3H-thymidine levels by 50%. The results are summarised in Table 2.
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
*A. < 0.1 μM; B. 0.1-1.0 μM; C. > 1.0 μM
[00431] It is noted that whereas the compounds show both reversible and irreversible inhibition of the pi 10a isoform of PBK, only reversible activity is exhibited against the pi lOβ and pi 105 isoforms.
* * * * *
[00432] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A compound of Formula Ia, Ib, Ic, or Id:
Figure imgf000151_0001
Ib
Ia
Figure imgf000151_0002
Id or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: each Ri is independently Cβ-u aryl, heteroaryl, or heterocyclyl; each R2 is independently Cβ-π aryl, heteroaryl, or heterocyclyl; each R3 and R4 is independently hydrogen, lower alkyl, C2-6 alkenyl, C2-6 alkynyl, or R5; each R5 is independently halogen or -OSO2R7;
R6 is C3_7 cycloalkyl, C6-M aryl, heteroaryl, or heterocyclyl;
R7 is lower alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-I4 aryl, heteroaryl, or heterocyclyl;
Rio is (a) hydrogen, amino, or hydroxyl; or (b) lower alkyl, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or carboxamido; each Q is independently absent or a linker group; each T is independently -CO-, -CS-, or -SO2-;
X, Y, and Z are each independently a nitrogen atom or CRg, with the proviso that at least two of X, Y, and Z are nitrogen atoms; wherein R8 is hydrogen or lower alkyl; and each A, B, D, and E is independently (i) a direct bond; (ii) a nitrogen, oxygen, or sulfur atom; or (iii) CR9, where R9 is hydrogen, halogen, or lower alkyl; wherein the bonds between A, B, D, and E may be saturated or unsaturated; with the proviso that no more than one of A, B, D, and E are a direct bond; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, carboxamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-I4 aryl, C7-i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) -C(O)R3, -C(O)OR3, -C(O)NRbRc, -C(NRa)NRbRc, -OR3, -OC(O)R3, -OC(O)OR3, -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)R3, -OS(O)2R3, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NR3C(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(O)Rd, -NR3S(O)2Rd, -NR3S(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)R3, -S(O)2R3, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Cj-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3.-7 cycloalkyl, C6-H aryl, C7.15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)OR6, -C(O)NR1R8, -C(NRe)NRfRε, -ORe, -OC(O)R6, -OC(O)OR6, -OC(O)NRfR8, -0C(=NRe)NRfR8, -OS(O)R6, -OS(O)2R6, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NR6C(O)Rh, -NReC(O)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(O)Rb, -NR6S(O)2R11, -NReS(O)NRfRg, -NR6S(O)2NR1R8, -SR6, -S(O)Re, -S(O)2R6, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C]-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-H aryl, C7-is aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rε together with the N atom to which they are attached form heterocyclyl.
2. The compound of claim 1, having the structure of Formula IV:
Figure imgf000153_0001
IV ; wherein R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
3. The compound of claim 1 , having the structure of Formula V:
Figure imgf000153_0002
V ; wherein R9 is hydrogen, lower alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, amino, lower alkylamino, hydroxyl, lower alkoxy, or halogen.
4. The compound of claim 1, having the structure of Formula VII:
Figure imgf000153_0003
VII
5. The compound of claim 1, having the structure of Formula VIII:
Figure imgf000153_0004
VIII wherein U is CH or N. The compound of claim 1 , having the structure of Formula IX:
Figure imgf000154_0001
IX wherein:
G and J are each independently a direct bond or -CH2-; and
W is a direct bond; or oxygen, sulfur, or NRn; where Rn is hydrogen, or substituted or unsubstituted lower alkyl.
7. The compound of claim 6, wherein W is NRn.
8. The compound of claim 1 , having the structure of Formula X:
Figure imgf000154_0002
X ; wherein:
Rn is hydrogen, or substituted or unsubstituted lower alkyl; and G and J are each independently a direct bond or -CH2-.
9. The compound of any of claims 6 to 8, wherein G is a direct bond.
10. The compound of any of claims 6 to 8, wherein G is -CH2-.
11. The compound of any of claims 6 to 10, wherein J is a direct bond.
12. The compound of any of claims 6 to 10, wherein J is -CH2-.
13. The compound of claim 1 , having the structure. of Formula XI:
Figure imgf000155_0001
XI ; wherein:
Rn is hydrogen, or substituted or unsubstituted lower alkyl; and V is oxygen or sulfur.
14. The compound of any of claims 6 to 13, wherein Rn is hydrogn or methyl.
15. The compound of claim 1 , having the structure of Formula XII:
Figure imgf000155_0002
XII
16. The compound of claim 1 , having the structure of Formula XIII:
Figure imgf000155_0003
XIII ; wherein R6 is substituted or unsubstituted aryl or heteroaryl.
17. The compound of claim 1, having the structure of Formula XIII:
Figure imgf000155_0004
xrv
18. The compound of claim 17, wherein A is CH.
19. The compound of claim 17 or 18, wherein B is N.
20. The compound of any of claims 17 to 19, wherein D is N.
21. The compound of claim 1 and 13 to 15, wherein R2 is substituted or unsubstituted aryl or substituted heteroaryl.
22. The compound of claim 21, wherein R2 is hydroxyphenyl, hydroxymethylphenyl, aminopyridyl, aminopyrimidyl, indazolyl, difluromethyl-lH- benzimidazolyl, difluromethyl-hydroxy- lH-benzimidazolyl, difluromethyl-methoxy- IH- benzimidazolyl, difluromethyl-ethoxy-lH-benzimidazolyl, or difluromethyl-((N,N- dimethylamino)propoxy)-lH-benzimidazolyl.
23. The compound of claim 22, wherein R2 is 3-hydroxyphenyl, 3- hydroxymethylphenyl, 2-amino-pyrid-5-yl, 2-amino-pyrimid-5-yl, indazol-4-yl, 2- difluromethyl-lH-benzimidazolyl, 2-difluromethyl-4-hydroxy-lH-benzimidazolyl, 2- difluromethyl-4-methoxy- 1 H-benzimidazolyl, 2-difluromethyl-4-ethoxy- 1 H-benzimidazolyl, or 2-difluromethyl-4-(3-(N,N-dimethylamino)propoxy)-lH-benzimidazolyl;
24. The compound of any of claims 1 , 4 to 12, and 17 to 20, wherein Rio is hydrogen, hydroxy, or substituted or unsubstituted lower alkoxy.
25. The compound of claim 24, wherein Rio is hydrogen, hydroxy, methoxy, ethoxy, or 3-(N,N-dimethylamino)propoxy.
26. The compound of any of claims 1 to 25, wherein Ri is substituted or unsubstituted morpholino or pyridyl.
27. The compound of claim 26, wherein Ri is substituted or unsubstituted 4- morpholino or 4-pyridyl.
28. The compound of claim 26, wherein Ri is 4-morpholino or 4-pyridyl.
29. The compound of any of claims 1 to 28, wherein R3 is hydrogen, chloro, or methyl.
30. The compound of any of claims 1 to 29, wherein R4 is hydrogen, chloro, or methyl.
31. The compound of any of claims 1 to 30, wherein R5 is chloro, bromo, or -OSO2-methyl.
32. The compound of any of claims 1 to 4 and 13 to 31 , wherein Q is substituted or unsubstituted heterocyclylene.
33. The compound of claim 32, wherein Q is a divalent linker selected from the group consisting of azetidinyleneamino, azetidinylene(methylamino), piperidyleneoxy, piperazinylene, piperidylene, piperidyleneamino, piperidylene(methylamino), pyrrolidinyleneamino, pyrrolidinylene(methylamino), and piperidylenethio.
34. The compound of claim 33, wherein Q is a divalent linker selected from the group consisting of azetidinylene-4-amino, azetidinylene-4-methylamino, piperidylene-4- oxy, 1 ,4-piperazinylene, 1 ,4-piperidylene, piperidylene-3-amino, (Λ)-piperidylene-3-amino, (S)-piperidylene-3-amino, piperidylene-3-methylamino, (/?)-piperidylene-3-methylamino, (S)-piperidylene-3-methylamino, piperidylene-4-amino, piperidylene -4-methylamino, pyrrolidinylene-3-amino, (Λ)-pyrrolidinylene-3-amino, (5)-pyrrolidinylene-3-amino, pyrrolidinylene-3-methylamino, (/?)-pyrrolidinylene-3-methylamino, (5)-pyrrolidinylene-3- methylamino, and piperidylene-4-thio.
35. The compound of any of claims 1 to34, wherein T is -CO- or -SO2-.
36. The compound of any of claims 1 to 35, wherein X is N or CH.
37. The compound of any of claims 1 to 36, wherein Y is N or CH.
38. The compound of any of claims 1 to 37, wherein Z is N or CH.
39. The compound of claim 1 selected from the group consisting of: 3-[4-[4-(chloroacetyl)- 1 -piperazinyl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2- yl]phenol; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-ethoxy-lH-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol;
1 -[4-[4-(chloroacetyl)- 1 -piperazinyl]-6-(4-pyridinyl)- 1 ,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole; l-[4-[4-(dichloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]- 2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
2-(difluoromethyl)- 1 - { 4-(4-moφholinyl)-6-[4-(trichloroacetyl)- 1 -piperazinyl]- l,3,5-triazin-2-yl}-lH-benzimidazol-4-yl methyl ether;
2- { 4-[4- [2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl] -6-(4- moφholinyl)-l,3,5-triazin-2-yl]-l-piperazinyl}-2-oxoethyl methanesulfonate;
1 -[4-[4-(2-chloropropanoyl)- 1 -piperazinyl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[4- { 4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)- 1 ,3,5- triazin-2-yl] -2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
1 -[4- {4-[(bromomethyl)sulfonyl]-l -piperazinyl }-6-(4-moφholinyl)- 1,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
N-(3-{ [l-[4-{4-[(chloromethyl)sulfonyl]-l-piperazinyl}-6-(4-moφholinyl)- l,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-yl]oxy}propyl)-N,N- dimethylamine;
1 -[4- { 4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -6-(4-moφholinyl)-2- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[6- { 4-[(chloromethyl)sulfonyl]- 1 -piperazinyl } -2-(4-moφholinyl)-4- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole;
1 -[2- {4-[(chloromethyl)sulfonyl]-l -piperazinyl }-6-(4-moφholinyl)-4- pyrimidinyl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-methoxy- 1 H-benzimidazole;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[l-(chloroacetyl)-4-piperidinyl]-4-{2-(difluoromethyl)-4-[3- (dimethylamino)propoxy]-lH-benzimidazol-l-yl}-N-methyl-6-(4-moφholinyl)-l,3,5-triazin- 2-amine;
N-{ l-[(chloromethyl)sulfonyl]-4-piperidinyl}-4-[2-(difluoromethyl)-4- methoxy- 1 H-benzimidazol- 1 -yl]-N-methyl-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
2-chloro-N- { 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]-6-(4- morpholinyl)- 1 ,3,5-triazin-2-yl]-4-piperidinyl } acetamide;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl}-N-methylacetamide;
2-chloro-N- { 1 -[4- { 2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]- IH- benzimidazol- 1 -yl } -6-(4-morpholinyl)- 1 ,3,5-triazin-2-yl]-4-piperidinyl } -N-methylacetamide;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l ,3,5-triazin-2-yl]pyrrolidinyl } acetamide;
2-chloro-N- { (35)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl} acetamide;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl}-N-methylacetamide;
2-chloro-N-{ (35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]pyrrolidinyl} -N-methylacetamide;
N-[(3R)- 1 -(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy- IH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(35)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(3/?)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(35)-l-(chloroacetyl)pyrrolidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl}acetamide;
2-chloro-N- { (35)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 -yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl} acetamide;
2-chloro-N- { (3R)- 1 -[4-[2-(difluoromethyl)-4-methoxy- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl}-N-methylacetamide;
2-chloro-N-{(35)-l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]- 6-(4-moφholinyl)-l,3,5-triazin-2-yl]piperidinyl} -N-methylacetamide;
N-[(3/?)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-/V-methyl-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
N-[(3S)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine;
N-[QR)- 1 -(chloroacetyl)piperidinyl] -4-[2-(difluoromethyl)-4-methoxy- 1 H- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyl)-l,3,5-txiazin-2-arnine;
N-[(35)-l-(chloroacetyl)piperidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol- 1 -yl]-7V-methyl-6-(4-morpholinyl)- 1 ,3,5-triazin-2-amine;
2-chloro-N- { 1 -[4-[2-(difluoromethyl)-4-tnethoxy- lH-benzimidazol- 1 -yl]-6-(4- morpholinyl)- 1 ,3,5-triazin-2-yl] -3-azetidinyl } acetamide;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-methoxy-lH-benzimidazol-l-yl]-6-(4- morpholinyl)- 1 ,3,5-triazin-2-yl]-3-azetidinyl } -Λf-methylacetamide;
N-[ 1 -(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy- 1 H- benzimidazol- 1 -yl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2-amine;
N-[l-(chloroacetyl)-3-azetidinyl]-4-[2-(difluoromethyl)-4-methoxy-lH- benzimidazol-l-yl]-N-methyl-6-(4-moφholinyI)-l,3,5-triazin-2-amine; l-[4-{ [l-(chloroacetyl)-4-piperidinyl]oxy}-6-(4-moφholinyl)-l,3,5-triazin-2- yl]-2-(difluoromethyl)-4-methoxy- 1 H-benzimidazole;
3- { [ 1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)- 1 H-benzimidazol-4-yl]oxy } -Λ^N-dimethyl- 1 -propanamine;
3-{ [l-[4-({ l-[(chloromethyl)sulfonyl]-4-piperidinyl }oxy)-6-(4-moφholinyl)- l,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-yl]oxy}-yV,N-dimethyl-l- propanamine; and
1 - { 1 -[(chloromethyl)sulfonyl]-4-piperidinyl } -6-[2-(difluoromethyl)-4- methoxy-lH-benzimidazol-l-yl]-4-(4-moφholinyl)-lH-pyrazolo[3,4-rf]pyrimidine; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
40. A compound of claim 1 selected from: l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)- 1 Η-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-4-ethoxy- 1 H-benzimidazole; l-[4-[4-(chloroacetyl)-l-piperazinyl]:6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)- 1 H-benzimidazol-4-ol; 3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]phenol;
[3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2- yl] phenyl] methanol ;
[3-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2- y ljphenyl] methanol ;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-mθφholinyl)-l,3,5-triazin-2-yl]-2- pyridinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- pyridinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- pyrimidinamine;
5-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-2- pyrimidinamine;
4-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]- lH-indazole;
4-[4-[4-(chloroacetyl)-l-piperazinyl]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]-lH- indazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazole; l-[4-[l-(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)-l,3,5-triazin-2-yl]-2- (difluoromethyl)-lH-benzimidazol-4-ol;
1 -[4-[ 1 -(chloroacetyl)-4-piperidinyl]-6-(4-moφholinyl)- 1 ,3,5-triazin-2-yl]-2- (difluoromethyl)-4-ethoxy- 1 H-benzimidazole;
N-[I -(chloroacetyl)-4-piperidinyl] -4- [2-(difluoromethyl)- 1 H-benzimidazol- 1 - yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine; l-[4-{[l-(chloroacetyl)-4-piperidinyl]amino}-6-(4-moφholinyl)-l,3,5-triazin- 2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-ol;
N-[l-(chloroacetyl)-4-piperidinyl]-4-[2-(difluoromethyl)-4-ethoxy-lH- benzimidazol-l-yl]-6-(4-moφholinyl)-l,3,5-triazin-2-amine;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-lH-benzimidazole;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)- 1 H-benzimidazol-4-ol;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl]oxy } -6-(4-moφholinyl)- 1 ,3,5-triazin-2- yl]-2-(difluoromethyl)-4-ethoxy- 1 H-benzimidazole;
1 -[4- { [ 1 -(chloroacetyO^-piperidinylJsulfanyl }-6-(4-morpholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)- 1 H-benzimidazole;
1 -[4- { [ 1 -(chloroacetyO^-piperidinylJsulfanyl } -6-(4-morpholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazol-4-ol;
1 -[4- { [ 1 -(chloroacetyl)-4-piperidinyl] sulfanyl } -6-(4-moφholinyl)- 1 ,3,5- triazin-2-yl]-2-(difluoromethyl)-4-methoxy-lH-benzimidazole; l-[4-{ [l-(chloroacetyl)-4-piperidinyl]sulfanyl}-6-(4-morpholinyl)-l,3,5- triazin-2-yl]-2-(difluoromethyl)-4-ethoxy-lH-benzimidazole;
2-chloro-N-{ l-[4-[2-(difluoromethyl)-lH-benzimidazol-l-yl]-6-(4- moφholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl}acetamide;
2-chloro-N- { 1 -[4-[2-(difluoromethyl)-4-hydroxy- lH-benzimidazol- 1 -yl]-6-(4- moφholinyl)- 1 ,3,5-triazin-2-yl]-4-piperidinyl } acetamide; and
2-chloro-N-{ l-[4-[2-(difluoromethyl)-4-ethoxy-lH-benzimidazol-l-yl]-6-(4- moφholinyl)- 1 ,3 ,5-triazin-2-yl] -4-piperidinyl } acetamide; and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
41. A pharmaceutical composition comprising a compound of any of claims 1 to 40, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
42. The pharmaceutical composition of claim 41, further comprising a second therapeutic agent.
43. The pharmaceutical composition of claim 41 or 42, wherein the composition is formulated for single dose administration.
44. The pharmaceutical composition of claim 43, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
45. The pharmaceutical composition of claim 44, wherein the oral dosage form is a tablet or capsule.
46. A method for the treatment, prevention, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of any of claims 1 to 40 or a pharmaceutical composition of any of claims 41 to 45.
47. A method for cancer treatment, which comprises administering to a subject a therapeutically effective amount of the compound of any of claims 1 to 40 or a pharmaceutical composition of any of claims 41 to 45.
48. The method of claim 46 or 47, wherein the compound or the composition is administered in combination with a second therapeutic agent.
49. A method for modulating PBK enzymatic activity, comprising contacting a PI3K enzyme with the compound of any of claims 1 to 40 or a pharmaceutical composition of any of claims 41 to 45.
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WO2023020604A1 (en) * 2021-08-20 2023-02-23 南京大美生物制药有限公司 Five-membered nitrogen-containing heterocyclic and heteroaryl derivative and use thereof

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