WO2014055647A1 - (sulfinyl and sulfonyl benzimidazolyl) pyrimidines and triazines, pharmaceutical compositions thereof, and their use for treating proliferative diseases - Google Patents

(sulfinyl and sulfonyl benzimidazolyl) pyrimidines and triazines, pharmaceutical compositions thereof, and their use for treating proliferative diseases Download PDF

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WO2014055647A1
WO2014055647A1 PCT/US2013/063067 US2013063067W WO2014055647A1 WO 2014055647 A1 WO2014055647 A1 WO 2014055647A1 US 2013063067 W US2013063067 W US 2013063067W WO 2014055647 A1 WO2014055647 A1 WO 2014055647A1
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compound
substituents
optionally substituted
certain embodiments
hydrogen
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French (fr)
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S. David Brown
David J. Matthews
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Mei Pharma, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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

  • Phosphoinositide-3 -kinases are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into at least three classes (classes I, II, and III) and play an important role in cellular signaling (Stephens et al, Curr. Opin. Pharmacol. 2005, 5, 357). Class I enzymes are further classified into classes la and lb based on their mechanism of activation.
  • Class la PI3Ks are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi 10 ⁇ , or pi 10 ⁇ ) in complex with a regulatory p85 subunit, while class-lb PI3K (pi 10 ⁇ ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by ⁇ subunits of heterotrimeric G-proteins (Walker et al, Mol .Cell. 2000, 6, 909).
  • PI3Ks play a variety of roles in normal tissue physiology (Foukas & Shepherd,
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where each R x is independently hydrogen or Ci_ 6 alkyl;
  • R 3 and R 4 are linked together to form (i) a bond; or (ii) Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2 _ 6 alkenylene, or C 2 _ 6 heteroalkenylene;
  • each R 5a and R 5b is independently hydrogen, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or independently, each pair of R 5a and R 5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C 3 _io cycloalkyl or heterocyclyl;
  • R 5z is C 3 _io cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • R 6 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;
  • R 7 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, heterocyclyl, or -NR lb R lc ;
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
  • n is an integer of 1 or 2;
  • n is an integer of 1, 2, 3, 4, 5, 6, or 7;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(0)R a
  • each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 cycloalkyl,
  • compositions comprising a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable excipients.
  • 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 provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for treating, preventing, or ameliorating one or more symptoms of a ⁇ -mediated disorder, disease, or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for modulating PI3K activity comprising contacting a PI3K with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for modulating ⁇ activity comprising contacting ⁇ with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • a method for selectively modulating ⁇ activity comprising contacting ⁇ with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof.
  • 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. In one embodiment, the subject is a human.
  • treat means to include alleviating or abrogating a disorder, disease, or condition, or one or more symptoms of 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 is 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 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 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 disorder, disease, or condition.
  • 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 disorder, disease, or condition.
  • nucleic acid ⁇ e.g., a DNA or RNA
  • polypeptide a polypeptide
  • host cell refers to a material which is found in nature and is not manipulated by man.
  • non-naturally occurring or non-native refers to a material that is not found in nature or that has been structurally modified or synthesized by man.
  • PI3K refers to a phosphoinositide 3-kinase or a variant thereof, which is capable of phosphorylating the inositol ring of a phosphatidylinositol (PI) in the D-3 position.
  • PI3K variant is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions ⁇ e.g., PI3K derivatives, homo logs, and fragments), as compared to the amino acid sequence of a native PI3K.
  • the amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K.
  • PI3K include, but are not limited to, pi 10a, pi 10 ⁇ , ⁇ ⁇ , ⁇ ⁇ , PI3K-C2a, PI3K-C2P, PI3K-C2y, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312.
  • PBKs are classified into at least four classes.
  • Class I includes pi 10a, pi 10 ⁇ , pi 105, and pi 10 ⁇ .
  • Class II includes PI3K-C2a, PI3K-C2p, and PI3K-C2y.
  • Class III includes Vps34.
  • Class IV includes mTOR, ATM, ATR, and DNA-PK.
  • the PI3K is a Class I kinase.
  • the PI3K is pi 10a, pi 10 ⁇ , pi 10 ⁇ , or pi 10 ⁇ .
  • the PI3K is a variant of a Class I kinase.
  • the PI3K is a pi 10a mutant.
  • pi 10a mutants include, but are not limited to, R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, and H1047Y
  • the PI3K is a Class II kinase.
  • the PI3K is PI3K-C2a, PI3K-C2p, or PI3K-C2y.
  • the PI3K is a Class III kinase. In certain embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK.
  • PI3K-mediated disorder, disease, or condition and "a disorder, disease, or condition mediated by PI3K” refer to a disorder, disease, or condition
  • PI3K activity characterized by abnormal or dysregulated, e.g., less than or greater than normal, PI3K activity.
  • Abnormal PI3K functional activity might arise as the result of PI3K overexpression in cells, expression of PI3K in cells which normally do not express PI3K, or dysregulation due to constitutive activation, caused, for example, by a mutation in PI3K.
  • a PI3K-mediated disorder, disease, or condition may be completely or partially mediated by abnormal PI3K activity.
  • PI3K-mediated disorder, disease, or condition is one in which modulation of a PI3K activity results in some effect on the underlying disorder, disease, or condition, e.g., a PI3K inhibitor results in some improvement in at least some of patients being treated.
  • pi ⁇ -mediated disorder, disease, or condition refers to a disorder, disease, or condition characterized by abnormal or dysregulated, e.g., less than or greater than normal, pi 10 ⁇ activity.
  • Abnormal pi 105 functional activity might arise as the result of pi 105 overexpression in cells, expression of pi 105 in cells which normally do not express pi 10 ⁇ , or dysregulation due to constitutive activation, caused, for example, by a mutation in pi 10 ⁇ .
  • a pi ⁇ -mediated disorder, disease, or condition may be completely or partially mediated by abnormal pi 10 ⁇ activity.
  • pi ⁇ -mediated disorder, disease, or condition is one in which modulation of a pi 10 ⁇ activity results in some effect on the underlying disorder, disease, or condition, e.g., a pi 10 ⁇ inhibitor results in some improvement in at least some of patients being treated.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • 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 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10
  • Ci_io or 1 to 6 (C 1-6 ) 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 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3 _ 6 alkyl groups are also referred as "lower alkyl.”
  • 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).
  • 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 is optionally substituted with one or more substituents Q 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 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (Ci_io), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3 _2o), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • linear Ci_ 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), butylene (including all isomeric forms), pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
  • Ci_ 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.
  • heteroalkylene refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms, each of which is independently selected from O, S, and N, in the hydrocarbon chain.
  • Ci_ 6 heteroalkylene 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.
  • the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (Ci_io), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3 _ 2 o), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3 _ 6 heteroalkylene groups are also referred as "lower heteroalkylene.”
  • heteroalkylene groups include, but are not limited to, -CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -CH 2 NH-, -CH 2 NHCH 2 -, -CH 2 CH 2 NH-, -CH 2 S- -CH 2 SCH 2 -, and -CH 2 CH 2 S-.
  • the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). In certain embodiments, the alkenyl is optionally substituted with one or more substituents Q as described herein.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or
  • 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
  • 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 _ 2 o), 3 to 15 (C 3-15 ), 3 to 10 (C 3 _io), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-l-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, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). In certain embodiments, the alkenylene is optionally substituted with one or more substituents Q as described herein.
  • alkenylene also embraces radicals having "cis" and "trans"
  • 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 _ 2 o), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), 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 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, and butenylene.
  • heteroalkenylene refers to a linear or branched divalent
  • heteroalkenylene which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms, each independently selected from O, S, and N, in the hydrocarbon chain.
  • the heteroalkenylene is optionally substituted with one or more substituents Q as described herein.
  • the term “heteroalkenylene” embraces radicals having a "cis” or “trans” configuration or a mixture thereof, or alternatively, a "Z" or "E"
  • C 2 _ 6 heteroalkenylene 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 heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2 _ 2 o), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), 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 (C 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • Examples of heteroalkenylene groups include, but are not limited to,
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon triple bond(s). In certain embodiments, the alkynyl is optionally substituted with one or more substituents Q as described herein. The term “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- 2o), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), 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).
  • 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.
  • cycloalkyl refers to a cyclic saturated or non-aromatic unsaturated, bridged or non-bridged monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl is a cyclic saturated bridged or non-bridged monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl has from 3 to 20 (C 3 _ 2 o), from 3 to 15 (C 3-15 ), from 3 to 10 (C 3-10 ), 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.
  • 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 (C6 -15 ), or from 6 to 10 (C 6 -io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • aryl refers to a bicyclic or tricyclic carbon ring, 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).
  • the aryl is optionally substituted with one or more substituents Q as described herein.
  • aralkyl refers to a monovalent alkyl group substituted with one or more aryl groups.
  • the aralkyl has from 7 to 30 (C 7 _ 3 o), from 7 to 20 (C 7 _2o), or from 7 to 16 (C 7-16 ) carbon atoms.
  • Examples of aralkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, and 3- phenylpropyl.
  • the aralkyl is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, N, and P, in the ring.
  • a heteroaryl group is bonded to the rest of a molecule through its aromatic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P 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, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • the heteroaryl is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl-alkyl refers to a monovalent alkyl group substituted with one or more heteroaryl groups, wherein the terms “alkyl” and “heteroaryl” are each as defined herein. In certain embodiments, the heteroaryl-alkyl is optionally substituted with one or more substituents Q as described herein.
  • heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, N, and P; 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.
  • a heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, 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 groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,
  • heterocyclyl is optionally substituted with one or more substituents Q as described herein.
  • heterocyclylalkyl refers to a monovalent alkyl group substituted with one or more heterocyclyl groups, wherein the terms “alkyl” and “heterocyclyl” are each as defined herein.
  • the heterocyclylalkyl is optionally substituted with one or more substituents Q as described herein.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • a group or substituent such as an alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclyl- alkyl group, may be substituted with one or more substituents Q, each of which is
  • Ci_6 alkyl C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, four, or five, substituents Q a ; and (c) -C(0)R a , -C(0)OR a , -C(0)NR b R c , -C(NR a )NR b R c , -OR a , -OC(0)R a , -OC(0)OR a , -OC(0)NR b R c ,
  • each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two,
  • each substituent Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; and (b) Ci_ 6 alkyl, C 2 _ 6 alkenyl,
  • each R e , R f , R g , and R h is independently (i) hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) R f and R g together with the N atom to which they are attached form heteroaryl or heterocyclyl.
  • 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 two enantiomers in question.
  • the prefixes R and S are used to denote the absolute configuration of the optically active compound about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of an optically active compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that an optically active compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that an optically active 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 a compound, R and S.
  • an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( U C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), oxygen-16 ( 16 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), fiuorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36
  • an "isotopic variant" of a compound is in a stable form, that is, non-radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen- 14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 C1), chlorine-37 ( 37 C1), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( I).
  • an "isotopic variant" of a compound is in an unstable form, that is, radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( U C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine-131 ( 131 I).
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, for example, or any nitrogen can be 15 N, for example, or any oxygen can be 18 0, for example, where feasible according to the judgment of one of skill.
  • an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable. In one
  • the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form.
  • the solvent is water
  • the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein.”
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where each R x is independently hydrogen or Ci_ 6 alkyl;
  • R 3 and R 4 are linked together to form (i) a bond; or (ii) Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2 _ 6 alkenylene, or C 2 _ 6 heteroalkenylene;
  • each R 5a and R 5b is independently hydrogen, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or independently, each pair of R 5a and R 5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C 3 _io cycloalkyl or heterocyclyl;
  • R 5z is C 3 _io cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • R 6 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;
  • R 7 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, heterocyclyl, or -NR lb R lc ;
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
  • n is an integer of 1 or 2;
  • n is an integer of 1, 2, 3, 4, 5, 6, or 7;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(0)R a
  • each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 cycloalkyl,
  • R 5c is hydrogen, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-10 cycloalkyl, C 6 -i4 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and R 5d is halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _6 alkynyl, C 3 _i 0 cycloalkyl, C 6-14 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or R 5c and R 5d together with the carbon atom to which they are attached form C 3 _io cycloalkyl or heterocyclyl;
  • p and q are each independently an integer of 0, 1, 2, or 3;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5z , X, Y, Z, and m are each as defined herein; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined herein.
  • the compound of Formula II has the structure of Formula Ila:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, p, and q are each as defined herein.
  • the compound of Formula II has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, p, and q are each as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and p are each as defined herein.
  • the compound of Formula III has the structure of Formula
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and p are each as defined herein.
  • the compound of Formula III has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and p are each as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and q are each as defined herein.
  • the compound of Formula IV has the structure of Formula
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and q are each as defined herein.
  • the compound of Formula IV has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , X, Y, Z, m, and q are each as defined herein.
  • R 8a , R 8b , R 8c , R 8d , and R 8e that are adjacent to each other form C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R la , R lb , R lc , R ld , R 5c , R 5d , X, Y, Z, and m are each as defined herein.
  • the compound of Formula V has the structure of Formula Va:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • the compound of Formula V has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • the compound of Formula VI has the structure of Formula
  • RR 11 RR 22 ,, RR 33 ,, R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • the compound of Formula VI has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • R 8c , R 8d , and R 8e is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 _i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heterocyclyl, e.g., 5-membered or
  • R 8a , R 8b , R 8c , R 8d , and R 8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophen
  • R a is C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g., 5 -membered or 6-membered
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R 8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluorophenyl,
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 5a and R 5b are each independently hydrogen, halo, or Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6-14 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where R is a hydrogen or C 1-6 alkyl, optionally substituted with one or more substituents Q; and
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are each independently C 6-14 alkyl
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH; and m is 2.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen; R 3 and R 4 are hydrogen;
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • the compound of Formula VII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • the compound of Formula VII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R a , R , R c , R , and R e is heterocyclyl, e.g.
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 _i4 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 5a and R 5b are each independently hydrogen, halo, or Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N;
  • R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 -i4 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are each independently C 6 -i4 alkyl
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen; X, Y, and Z are each independently N or CH; and
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R ? and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen; R 3 and R 4 are hydrogen;
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • the compound of Formula VIII has the structure of
  • the compound of Formula VIII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , X, Y, Z, and m are each as defined herein.
  • one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 _i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heterocyclyl, e
  • R 8a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6 -i 4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g. , 5 -membered or 6-membered
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R 8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluorophenyl,
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N;
  • R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 -i4 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5c and R 5d are each independently C 6 -i4 alkyl;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5c and R 5d are methyl;
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5c and R 5d are methyl
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5c and R 5d are methyl;
  • R a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • X, Y, and Z are each independently N or CH;
  • R 3 and R 4 are linked together to form (i) a bond; or (ii) Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2 _ 6 alkenylene, or C 2 _ 6 heteroalkenylene;
  • each R 5a and R 5b is independently hydrogen, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or
  • each pair of R 5a and R 5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C 3 _io cycloalkyl or heterocyclyl;
  • R 5z is C 3 _io cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • R 6 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl;
  • R 7 is hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7 _i 5 aralkyl, heteroaryl, heterocyclyl, or -NR lb R lc ;
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io cycloalkyl, C 6-14 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
  • n is an integer of 1 or 2;
  • n is an integer of 1, 2, 3, 4, 5, 6, or 7;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more substituents Q as described herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5A , R 5B , R 5C , R 5D , R 5Z , m, p, and q are each as defined herein.
  • the compound of Formula X has the structure of Formula
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5A , R 5B , R 5C , R 5D , R 5Z , m, p, and q are each as defined herein.
  • the compound of Formula X has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, p, and q are each as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and p are each as defined herein.
  • the compound of Formula XI has the structure of Formula
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and p are each as defined herein.
  • the compound of Formula XI has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and p are each as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and q are each as defined herein.
  • the compound of Formula XII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and q are each as defined herein.
  • the compound of Formula XII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 5z , m, and q are each as defined herein.
  • the compound of Formula XIII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • the compound of Formula XIII has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • the compound of Formula XIV has the structure of
  • the compound of Formula XIV has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • one of R a , R , R c , R , and R e is C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d ,
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 _i4 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 5a and R 5b are each independently hydrogen, halo, Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6-14 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are each independently C 6-14 alkyl
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen; R 5c and R 5d are methyl;
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • the compound of Formula XV has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • the compound of Formula XV has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5a , R 5b , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R a , R , R c , R , and R e is heterocyclyl,
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6 -i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 5a and R 5b are each independently hydrogen, halo, Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6-14 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i4 alkyl, optionally substituted with one or more substituents Q;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are each independently C 6-14 alkyl
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 5a and R 5b are hydrogen
  • R 5c and R 5d are methyl;
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5a and R 5b are hydrogen;
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • the compound of Formula XVI has the structure of
  • the compound of Formula XVI has the structure of
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 5c , R 5d , R 8a , R 8b , R 8c , R 8d , R 8e , and m are each as defined herein.
  • one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is C 6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R 8a , R 8b , R 8c , R 8d , and R 8e is heterocyclyl, e
  • R 8a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R 8a is C 6 -i 4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R 8a is heterocyclyl, e.g. , 5 -membered or 6-membered
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R 8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluorophenyl,
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one or more substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 7 is C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 5c is hydrogen or C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 5d is C 6 -i 4 alkyl, optionally substituted with one or more substituents Q;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or C 6-14 alkyl
  • R 7 is C 6 -i4 alkyl, optionally substituted with one or more halo;
  • R 5c and R 5d are each independently C 6-14 alkyl;
  • R 8a is C 6 -i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 5c and R 5d are methyl;
  • R 8a is C 6 -i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl; R is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl;
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl
  • R 5c and R 5d are methyl
  • R 8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is hydrogen or methyl
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl
  • R 5c and R 5d are methyl
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,
  • R 8b , R 8c , R 8d , and R 8e are hydrogen
  • R 1 is hydrogen. In certain embodiments, R 1 is cyano.
  • R 1 is halo. In certain embodiments, R 1 is fluoro, chloro, bromo, or iodo. In certain embodiments, R 1 is nitro. In certain embodiments, R 1 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 1 is C 6 _i4 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is C 7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 1 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 1 is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 1 is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 1 is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 1 is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 1 is -OR la , wherein R la is as defined herein.
  • R 1 is -0-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein..
  • R 1 is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy.
  • R 1 is -OC(0)R la , wherein R la is as defined herein.
  • R 1 is -OC(0)OR la , wherein R la is as defined herein.
  • R 1 is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 1 is -OS(0)R la , wherein R la is as defined herein.
  • R 1 is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 1 is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 1 is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 1 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 1 is -NR la C(0)R ld , wherein R la and R ld are each as defined herein.
  • R 1 is -NR la C(0)OR ld , wherein R la and R ld are each as defined herein.
  • R 1 is -NR la C(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R is -NR la S(0)R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 1 is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 1 is -SR la , wherein R la is as defined herein. In certain embodiments,
  • R 1 is -S(0)R la , wherein R la is as defined herein. In certain embodiments, R 1 is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 1 is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 1 is
  • R 2 is hydrogen. In certain embodiments, R 2 is cyano.
  • R 2 is halo. In certain embodiments, R 2 is fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is nitro. In certain embodiments, R 2 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 2 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 2 is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 2 is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 2 is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 2 is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 2 is -OR la , wherein R la is as defined herein. In certain embodiments, R 2 is -OC(0)R la , wherein R la is as defined herein. In certain embodiments, R 2 is -OC(0)OR la , wherein R la is as defined herein. In certain embodiments, R 2 is -OC(0)OR la , wherein R la is as defined herein. In certain embodiments, R 2 is -C(0)OR la
  • R 2 is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 2 is -OS(0)R la , wherein R la is as defined herein.
  • R 2 is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 2 is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 2 is
  • R 2 is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 2 is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 2 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R is ammo (-NH 2 ).
  • R 2 is -NR la C(0)R ld , wherein R la and R ld are each as defined herein.
  • R 2 is -NR la C(0)OR ld , wherein R la and R ld are each as defined herein.
  • R 2 is -NR la C(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R is -NR la S(0)R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R 2 is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 2 is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 2 is -SR la , wherein R la is as defined herein.
  • R 2 is -S(0)R la , wherein R la is as defined herein. In certain embodiments, R 2 is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 2 is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 2 is
  • R 3 is hydrogen. In certain embodiments, R 3 is cyano.
  • R 3 is halo. In certain embodiments, R 3 is fluoro, chloro, bromo, or iodo. In certain embodiments, R 3 is nitro. In certain embodiments, R 3 is oxo. In certain embodiments, R 3 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is hydrogen, methyl, ethyl, or propyl (e.g. , n- propyl, isopropyl, or 2-isopropyl). In certain embodiments, R 3 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein.
  • R 3 is C 2 _6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 3 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 3 is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 3 is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 3 is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 3 is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 3 is -OR la , wherein R la is as defined herein. In certain embodiments, R 3 is -OC(0)R la , wherein R la is as defined herein. In certain embodiments, R 3 is -OC(0)OR la , wherein R la is as defined herein. In certain embodiments, R 3 is -OC(0)OR la , wherein R la is as defined herein. In certain embodiments, R 3 is -C(0)OR la
  • R 3 is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 3 is -OS(0)R la , wherein R la is as defined herein.
  • R 3 is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 3 is
  • R 3 is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 3 is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 3 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R is ammo (-NH 2 ).
  • R 3 is -NR la C(0)R ld , wherein R la and R ld are each as defined herein.
  • R 3 is -NR la C(0)OR ld , wherein R la and R ld are each as defined herein.
  • R 3 is -NR la C(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R is -NR la S(0)R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R 3 is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 3 is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 3 is -SR la , wherein R la is as defined herein.
  • R 3 is -S(0)R la , wherein R la is as defined herein. In certain embodiments, R 3 is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 3 is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 3 is
  • R 4 is hydrogen. In certain embodiments, R 4 is cyano.
  • R 4 is halo. In certain embodiments, R 4 is fluoro, chloro, bromo, or iodo. In certain embodiments, R 4 is nitro. In certain embodiments, R 4 is oxo. In certain embodiments, R 4 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is hydrogen, methyl, ethyl, or propyl (e.g. , n- propyl, isopropyl, or 2-isopropyl). In certain embodiments, R 4 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein.
  • R 4 is C 2 _6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 4 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 4 is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 4 is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 4 is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 4 is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 4 is -OR la , wherein R la is as defined herein.
  • R 4 is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 4 is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 4 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R is ammo (-NH 2 ).
  • R 4 is -NR la C(0)R ld , wherein R la and R ld are each as defined herein.
  • R 4 is -NR la C(0)OR ld , wherein R la and R ld are each as defined herein.
  • R 4 is -NR la C(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R is -NR la S(0)R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R 4 is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 4 is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 4 is -SR la , wherein R la is as defined herein.
  • R 4 is -S(0)R la , wherein R la is as defined herein. In certain embodiments, R 4 is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 4 is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 4 is
  • R 6 is hydrogen. In certain embodiments, R 6 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 6 is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 6 is heterocyclyl, optionally substituted with one or more substituents Q as described herein. [00152] In certain embodiments, R is hydrogen. In certain embodiments, R is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein.
  • R 7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R 7 is methyl. In certain embodiments, R 7 is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 7 is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 7 is C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 7 is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein.
  • R 7 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein.
  • R 7 is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 7 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 7 is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 7 is -NH 2 .
  • each R 5a is independently hydrogen. In certain embodiments, each R 5a is independently halo. In certain embodiments, each R 5a is independently fluoro, chloro, bromo, or iodo. In certain embodiments, each R 5a is independently Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein.
  • each R 5a is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, each R 5a is independently methyl. In certain embodiments,
  • each R 5a is independently C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently C 3 _io cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently C 7 _i5 aralkyl, optionally substituted with one or more substituents Q as described herein.
  • each R 5a is independently heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5a is independently heterocyclyl, optionally substituted with one or more substituents Q as described herein. [00154] In certain embodiments, each R is independently hydrogen. In certain embodiments, each R 5b is independently halo. In certain embodiments, each R 5b is
  • each R 5b is independently fluoro, chloro, bromo, or iodo.
  • each R 5b is independently fluoro, chloro, bromo, or iodo.
  • each R 5b is independently Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein.
  • each R 5b is independently methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein.
  • each R 5b is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.
  • each R 5b is independently methyl.
  • each R 5b is independently C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5b is independently C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5b is independently C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5b is independently C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5b is independently C 7 _i5 aralkyl, optionally
  • each R 5b is independently heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R 5b is independently heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • each R 5a and R 5b is hydrogen.
  • R 5c is hydrogen. In certain embodiments, R 5c is halo.
  • R 5c is fluoro, chloro, bromo, or iodo. In certain embodiments, R 5c is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, R 5c is methyl.
  • R 5c is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is C 7 _i 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5c is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 5d is halo. In certain embodiments, R 5d is fluoro, chloro, bromo, or iodo. In certain embodiments, R 5d is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, R 5d is methyl.
  • R 5d is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is C 7 _i 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 5c and R 5d together with the carbon atom to which they are attached form C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 5c and R 5d together with the carbon atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 5c and R 5d are methyl.
  • R 5z is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is moncyclic C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with one or more substituents Q as described herein.
  • R 5z is bicyclic C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein.
  • R 5b is C 6-14 aryl substituted at the 2-position with one substituent Q as described herein.
  • R 5z is phenyl or naphthyl, each of which is optionally substituted with one or more substituents Q as described herein.
  • R 5z is phenyl, naphtha- 1-yl, or naphtha-2-yl, each optionally substituted with one or more substituents Q as described herein.
  • R 5z is phenyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is moncyclic heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is 5-membered heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is 6-membered heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is bicyclic heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is heterocyclyl; optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 5z is moncyclic
  • R 5z is 5-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 5z is bicyclic heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is hydrogen. In certain embodiments, R 8a is cyano. In certain embodiments, R 8a is halo. In certain embodiments, R 8a is fluoro, chloro, bromo, or iodo. In certain embodiments, R 8a is nitro. In certain embodiments, R 8a is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is phenyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl.
  • R 8a is C 7 _i5 aralkyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is monocyclic heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is 5-membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is imidazolyl or pyrozolyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8a is imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, or 2-methylpyrozol-3-yl. In certain embodiments, R 8a is 6- membered heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is pyridinyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, or 2-methoxypyridin-4-yl.
  • R 8a is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is 5-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is piperidinyl or piperazinyl, optionally substituted with one or more substituents Q as described herein.
  • R 8a is l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, 4-methylpiperazin- 1 -yl.
  • R 8a is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 8a is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 8a is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8a is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 8a is -OR la , wherein R la is as defined herein.
  • R 8a is -0-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • R 8a is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R 8a is
  • R 8a is -OC(0)R la , wherein R la is as defined herein.
  • R 8a is -OC(0)OR la , wherein R la is as defined herein.
  • R 8a is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R a is
  • R 8a is -OS(0)R la , wherein R la is as defined herein.
  • R 8a is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 8a is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8a is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8a is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8a is amino (-NH 2 ).
  • R a is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8a is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8a is -SR la , wherein R la is as defined herein.
  • R 8a is -S(0)R la , wherein R la is as defined herein.
  • R 8a is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 8a is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8a is -S(0) 2 NR lb R lc ; wherein R lb and R lc are each as defined herein.
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 8a is phenyl, 2-fluorophenyl, 2-chlorophenyl,
  • 2-(4-methylpiperazin-l-yl)pyridin-4-yl 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
  • R 8b is hydrogen. In certain embodiments, R 8b is cyano. In certain embodiments, R 8b is halo. In certain embodiments, R 8b is fluoro, chloro, bromo, or iodo. In certain embodiments, R 8b is nitro. In certain embodiments, R 8b is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain
  • R is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as
  • R is C 2 _ 6 alkynyl, optionally substituted with one
  • R is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R is C 6 -i4 aryl, optionally substituted with one or more substituents Q as
  • R is C 8-15 aralkyl, optionally substituted with one
  • R is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8b is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 8b is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 8b is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8b is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 8b is -OR la , wherein R la is as defined herein.
  • R 8b is -0-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • R 8b is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R 8b is
  • R 8b is -OC(0)R la , wherein R la is as defined herein.
  • R 8b is -OC(0)OR la , wherein R la is as defined herein.
  • R 8b is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R is
  • R 8b is -OS(0)R la , wherein R la is as defined herein.
  • R 8b is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 8b is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8b is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8b is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8b is amino (-NH 2 ).
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8b is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8b is -SR la , wherein R la is as defined herein.
  • R 8b is -S(0)R la , wherein R la is as defined herein.
  • R 8b is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 8b is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8b is
  • R 8b is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 8b is phenyl, 2-fluorophenyl, 2-chlorophenyl,
  • 2-(4-methylpiperazin-l-yl)pyridin-4-yl 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
  • R 8c is hydrogen. In certain embodiments, R 8c is cyano. In certain embodiments, R 8c is halo. In certain embodiments, R 8c is fluoro, chloro, bromo, or iodo. In certain embodiments, R 8c is nitro. In certain embodiments, R 8c is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein.
  • R 8c is C 3 _i 0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is C 6 -i4 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is C 8-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8c is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8c is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 8c is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 8c is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8c is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 8c is -OR la , wherein R la is as defined herein.
  • R 8c is -0-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • R 8c is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R 8c is
  • R 8c is -OC(0)R la , wherein R la is as defined herein.
  • R 8c is -OC(0)OR la , wherein R la is as defined herein.
  • R 8c is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R c is
  • R 8c is -OS(0)R la , wherein R la is as defined herein.
  • R 8c is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 8c is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8c is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8c is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8c is amino (-NH 2 ).
  • R c is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8c is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8c is -SR la , wherein R la is as defined herein.
  • R 8c is -S(0)R la , wherein R la is as defined herein.
  • R 8c is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 8c is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8c is
  • R 8c is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 8c is phenyl, 2-fluorophenyl, 2-chlorophenyl,
  • 2-(4-methylpiperazin-l-yl)pyridin-4-yl 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3 - yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin- 1 -yl.
  • R 8d is hydrogen. In certain embodiments, R 8d is cyano. In certain embodiments, R 8d is halo. In certain embodiments, R 8d is fluoro, chloro, bromo, or iodo. In certain embodiments, R 8d is nitro. In certain embodiments, R 8d is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain
  • R is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as
  • R is C 2 _ 6 alkynyl, optionally substituted with one
  • R is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R is C 6-14 aryl, optionally substituted with one or more substituents Q as
  • R is C 8-15 aralkyl, optionally substituted with one
  • R is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8d is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 8d is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 8d is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8d is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 8d is -OR la , wherein R la is as defined herein. In certain
  • R is -0-Ci_ 6 alkyl, wherein the alkyl is optionally substituted with one or
  • R is methoxy, ethoxy,
  • R isopropoxy, or 3-dimethylaminopropoxy.
  • R isopropoxy, or 3-dimethylaminopropoxy.
  • R 8d is -OC(0)R la , wherein R la is as defined herein.
  • R 8d is -OC(0)OR la , wherein R la is as defined herein.
  • R 8d is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R is
  • R 8d is -OS(0)R la , wherein R la is as defined herein.
  • R 8d is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 8d is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8d is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8d is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8d is amino (-NH 2 ).
  • R is -NR la S(0) 2 R ld , wherein R la and R ld are each as defined herein.
  • R is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8d is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8d is -SR la , wherein R la is as defined herein.
  • R 8d is -S(0)R la , wherein R la is as defined herein.
  • R 8d is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 8d is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8d is
  • R 8d is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 8d is phenyl, 2-fluorophenyl, 2-chlorophenyl,
  • 2-(4-methylpiperazin-l-yl)pyridin-4-yl 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
  • R 8e is hydrogen. In certain embodiments, R 8e is cyano. In certain embodiments, R 8e is halo. In certain embodiments, R 8e is fluoro, chloro, bromo, or iodo. In certain embodiments, R 8e is nitro. In certain embodiments, R 8e is Ci_ 6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R 8e is C 2 _ 6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R e is C 2 _ 6 alkynyl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is C 6-14 aryl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is C 8-15 aralkyl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is heteroaryl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
  • R 8e is -C(0)R la , wherein R la is as defined herein. In certain embodiments, R 8e is -C(0)OR la , wherein R la is as defined herein. In certain embodiments, R 8e is -C(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8e is -C(NR la )NR lb R lc , wherein R la , R lb , and R lc are each as defined herein. In certain embodiments, R 8e is -OR la , wherein R la is as defined herein.
  • R 8e is -0-C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • R 8e is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R 8e is
  • R 8e is -OC(0)R la , wherein R la is as defined herein.
  • R 8e is -OC(0)OR la , wherein R la is as defined herein.
  • R 8e is -OC(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R e is
  • R 8e is -OS(0)R la , wherein R la is as defined herein.
  • R 8e is -OS(0) 2 R la , wherein R la is as defined herein.
  • R 8e is -OS(0)NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8e is -OS(0) 2 NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8e is -NR lb R lc , wherein R lb and R lc are each as defined herein.
  • R 8e is amino (-NH 2 ).
  • R e is -NR la S(0)NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8e is -NR la S(0) 2 NR lb R lc , wherein R la , R lb , and R lc are each as defined herein.
  • R 8e is -SR la , wherein R la is as defined herein.
  • R 8e is -S(0)R la , wherein R la is as defined herein.
  • R 8e is -S(0) 2 R la , wherein R la is as defined herein. In certain embodiments, R 8e is -S(0)NR lb R lc , wherein R lb and R lc are each as defined herein. In certain embodiments, R 8e is
  • R 8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 8e is phenyl, 2-fluorophenyl, 2-chlorophenyl,
  • 2-(4-methylpiperazin-l-yl)pyridin-4-yl 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
  • X is N In certain embodiments, X is CR X , wherein R x is as defined herein. In certain embodiments, X is CH.
  • Y is N In certain embodiments, Y is CR X , wherein R x is as defined herein. In certain embodiments, Y is CH.
  • Z is N In certain embodiments, Z is CR X , wherein R x is as defined herein. In certain embodiments, Z is CH.
  • X, Y, and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.
  • n is 1. In certain embodiments, m is 2. [00185] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7.
  • p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.
  • 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
  • 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.
  • 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. Sci. 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, (+)-(lS)- 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, gluco
  • naphthalene-2-sulfonic acid naphthalene- 1, 5 -disulfonic acid, l-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.
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are 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, but not limited to, 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)-morpholine, methylamine, piperidine, piperazine, propylamine,
  • triethanolamine trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)- 1,3 -propanediol, and tromethamine.
  • 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
  • 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.
  • a compound of Formula II is prepared, as shown in Scheme I, via a first aromatic substitution reaction of a halo-substituted triazine or pyrimidine with compound 1-1 to form compound 1-2, which is subsequently converted to compound 1-4 via a second aromatic substitution reaction with compound 1-3.
  • Compound I- 4 then reacts with HNR 5 R 6 via a third aromatic substitution reaction to form a compound of Formula II.
  • a compound of Formula II is prepared, as shown in Scheme II, first via an aromatic substitution reaction of compound 1-2 with compound 1-6 to form compound 1-7, which is subsequently converted to compound 1-8 via an aromatic substitution reaction with FINR 5 R 6 .
  • Compound 1-8 is then oxidized with an oxidant, e.g., KMn0 4 , to form a sulfonyl compound of Formula II; or e.g., hydrogen peroxide, to form a sulfmyl compound of Formula II.
  • an oxidant e.g., KMn0 4
  • a pharmaceutical composition comprising a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
  • the pharmaceutical composition provided herein is formulated in a dosage form for oral administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition for oral administration is formulated in tablet, capsule, powder, or liquid form.
  • the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition provided herein is formulated in a dosage form for topical administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition provided herein is formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastric retention dosage forms.
  • the pharmaceutical composition provided herein is 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.
  • compositions provided herein further comprise one or more therapeutic agents (e.g., chemotherapeutic agents) as defined herein.
  • therapeutic agents e.g., chemotherapeutic agents
  • compositions provided herein for 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
  • hydroxypropylcellulose HPC
  • HPMC hydroxypropyl methyl cellulose
  • 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
  • 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.
  • 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, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 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
  • 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
  • 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 (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 propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be
  • 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,
  • 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.
  • a pharmaceutically acceptable acetal such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal
  • a water-miscible solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are clear, sweetened, and
  • 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
  • liquid carrier e.g., water
  • 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.
  • 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,
  • 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 are 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 a-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin
  • 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. [00228] In one embodiment, the pharmaceutical compositions for parenteral
  • the pharmaceutical compositions 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.
  • 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 are 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
  • 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

Abstract

Provided herein are (sulfmyl and sulfonyl benzimidazolyl) pyrimidines and triazines, e.g., a compound of Formula I, and their pharmaceutical compositions, and use for treating proliferative diseases.

Description

(SULFINYL AND SULFONYL BENZIMIDAZOLYL) PYRIMIDINES AND TRIAZINES, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR USE
FOR TREATING PROLIFERATIVE DISEASES
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of the priority of U.S. Provisional
Application No. 61/744,821, filed October 3, 2012; the disclosure of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein are (sulfinyl and sulfonyl benzimidazolyl) pyrimidines and triazines, and their pharmaceutical compositions, and use for treating proliferative diseases.
BACKGROUND
[0003] Phosphoinositide-3 -kinases (PI3Ks) are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into at least three classes (classes I, II, and III) and play an important role in cellular signaling (Stephens et al, Curr. Opin. Pharmacol. 2005, 5, 357). Class I enzymes are further classified into classes la and lb based on their mechanism of activation. Class la PI3Ks are heterodimeric structures consisting of a catalytic subunit (pi 10a, pi 10β, or pi 10δ) in complex with a regulatory p85 subunit, while class-lb PI3K (pi 10γ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by βγ subunits of heterotrimeric G-proteins (Walker et al, Mol .Cell. 2000, 6, 909).
[0004] PI3Ks 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 10β in thrombus formation mediated by integrin απβ3 (Jackson et al, Nat. Med. 2005, 11, 507), and pi 10γ in inflammation, rheumatoid arthritis, and other chronic inflammation states (Barber et al, Nat. Med. 2005, 11, 933; Camps et al, Nat. Med. 2005, 11, 936; Rommel et al, Nat. Rev. 2007, 7, 191; and Ito, et al., J. Pharm. Exp. Therap. 2007, 321, 1). Therefore, there is a need for PI3K inhibitors for treating cancer and/or inflammatory diseases. SUMMARY OF THE DISCLOSURE [0005] Provided herein
Figure imgf000003_0001
(I)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where each Rx is independently hydrogen or Ci_6 alkyl;
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc;
R3 and R4 are each independently (a) hydrogen, cyano, halo, nitro, or oxo; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or R3 and R4 are linked together to form (i) a bond; or (ii) Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
each R5a and R5b is independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or independently, each pair of R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl;
R5z is C3_io cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R6 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heterocyclyl, or -NRlbRlc;
each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
m is an integer of 1 or 2; and
n is an integer of 1, 2, 3, 4, 5, 6, or 7;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa,
-OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl,
C6-i4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0006] Also provided herein are pharmaceutical compositions comprising a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable excipients.
[0007] 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 provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0008] Furthermore, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a ΡΒΚδ-mediated disorder, disease, or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0009] Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0010] Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0011] Provided herein is a method for modulating PI3K activity, comprising contacting a PI3K with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0012] Provided herein is a method for modulating ΡΒΚδ activity, comprising contacting ΡΒΚδ with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0013] Provided herein is a method for selectively modulating ΡΒΚδ activity, comprising contacting ΡΒΚδ with an effective amount of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
DETAILED DESCRIPTION
[0014] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0015] 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. [0016] 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. In one embodiment, the subject is a human.
[0017] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more symptoms of the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0018] 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.
[0019] The term "therapeutically effective amount" is 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 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.
[0020] 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 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, 7th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.
[0021] 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.
[0022] 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 disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.
[0023] 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 disorder, disease, or condition.
[0024] The term "naturally occurring" or "native" when used in connection with a biological material, such as a nucleic acid {e.g., a DNA or RNA), a polypeptide, and a host cell, refers to a material which is found in nature and is not manipulated by man. Similarly, "non-naturally occurring" or "non-native" refers to a material that is not found in nature or that has been structurally modified or synthesized by man.
[0025] The term "PI3K" refers to a phosphoinositide 3-kinase or a variant thereof, which is capable of phosphorylating the inositol ring of a phosphatidylinositol (PI) in the D-3 position. The term "PI3K variant" is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions {e.g., PI3K derivatives, homo logs, and fragments), as compared to the amino acid sequence of a native PI3K. The amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K. Examples of PI3K include, but are not limited to, pi 10a, pi 10β, ρΐ ΐθδ, ρΐ ΐθγ, PI3K-C2a, PI3K-C2P, PI3K-C2y, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PBKs are classified into at least four classes. Class I includes pi 10a, pi 10β, pi 105, and pi 10γ. Class II includes PI3K-C2a, PI3K-C2p, and PI3K-C2y. Class III includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is pi 10a, pi 10β, pi 10δ, or pi 10γ. In certain embodiments, the PI3K is a variant of a Class I kinase. In certain embodiments, the PI3K is a pi 10a mutant. Examples of pi 10a mutants include, but are not limited to, R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, and H1047Y
(Ikenoue et ah, Cancer Res. 2005, 65, 4562-4567; and Gymnopoulos et ah, Proc. Natl. Acad. Sci., 2007, 104, 5569-5574). In certain embodiments, the PI3K is a Class II kinase. In certain embodiments, the PI3K is PI3K-C2a, PI3K-C2p, or PI3K-C2y. In certain
embodiments, the PI3K is a Class III kinase. In certain embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK.
[0026] The terms "PI3K-mediated disorder, disease, or condition" and "a disorder, disease, or condition mediated by PI3K" refer to a disorder, disease, or condition
characterized by abnormal or dysregulated, e.g., less than or greater than normal, PI3K activity. Abnormal PI3K functional activity might arise as the result of PI3K overexpression in cells, expression of PI3K in cells which normally do not express PI3K, or dysregulation due to constitutive activation, caused, for example, by a mutation in PI3K. A PI3K-mediated disorder, disease, or condition may be completely or partially mediated by abnormal PI3K activity. In particular, PI3K-mediated disorder, disease, or condition is one in which modulation of a PI3K activity results in some effect on the underlying disorder, disease, or condition, e.g., a PI3K inhibitor results in some improvement in at least some of patients being treated.
[0027] The terms "pi ΙΟδ-mediated disorder, disease, or condition," "a disorder, disease, or condition mediated by pi 105," "ΡΒΚδ-mediated disorder, disease, or condition," and "a disorder, disease, or condition mediated by ΡΙ3Κδ" refer to a disorder, disease, or condition characterized by abnormal or dysregulated, e.g., less than or greater than normal, pi 10δ activity. Abnormal pi 105 functional activity might arise as the result of pi 105 overexpression in cells, expression of pi 105 in cells which normally do not express pi 10δ, or dysregulation due to constitutive activation, caused, for example, by a mutation in pi 10δ. A pi ΙΟδ-mediated disorder, disease, or condition may be completely or partially mediated by abnormal pi 10δ activity. In particular, pi ΙΟδ-mediated disorder, disease, or condition is one in which modulation of a pi 10δ activity results in some effect on the underlying disorder, disease, or condition, e.g., a pi 10δ inhibitor results in some improvement in at least some of patients being treated.
[0028] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q 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 (C1-20), 1 to 15 (C1-15), 1 to 10
(Ci_io), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent 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. 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.
[0029] The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene is optionally substituted with one or more substituents Q 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 (C1-20), 1 to 15 (C1-15), 1 to 10 (Ci_io), or 1 to 6 (C1-6) carbon atoms, or branched saturated 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. As used herein, linear Ci_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), butylene (including all isomeric forms), pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, Ci_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.
[0030] The term "heteroalkylene" refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms, each of which is independently selected from O, S, and N, in the hydrocarbon chain. For example, Ci_6 heteroalkylene 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. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (Ci_io), or 1 to 6 (C1-6) carbon atoms, or branched saturated 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. As used herein, linear Ci_6 and branched C3_6 heteroalkylene groups are also referred as "lower heteroalkylene." Examples of heteroalkylene groups include, but are not limited to, -CH2O-, -CH2OCH2-, -CH2CH2O-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S- -CH2SCH2-, and -CH2CH2S-. In certain embodiments, the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
[0031] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). In certain embodiments, the alkenyl is optionally substituted with one or more substituents Q 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_2o), 3 to 15 (C3-15), 3 to 10 (C3_io), or 3 to 6 (C3_6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
[0032] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). In certain embodiments, the alkenylene is optionally substituted with one or more substituents Q 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_2o), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2_6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3_20), 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, and butenylene.
[0033] The term "heteroalkenylene" refers to a linear or branched divalent
hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms, each independently selected from O, S, and N, in the hydrocarbon chain. In certain embodiments, the heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenylene" embraces radicals having a "cis" or "trans" configuration or a mixture thereof, or alternatively, a "Z" or "E"
configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2_6 heteroalkenylene 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 heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_2o), 2 to 15 (C2-15), 2 to 10 (C2-10), 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 heteroalkenylene groups include, but are not limited to,
-CH=CHO- -CH=CHOCH2- -CH=CHCH20- -CH=CHS- -CH=CHSCH2- -CH=CHCH2S- or -CH=CHCH2NH-.
[0034] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon triple bond(s). In certain embodiments, the alkynyl is optionally substituted with one or more substituents Q 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- 2o), 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 (C3-15), 3 to 10 (C3-10), 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.
[0035] The term "cycloalkyl" refers to a cyclic saturated or non-aromatic unsaturated, bridged or non-bridged monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkyl is a cyclic saturated bridged or non-bridged monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q 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 (C3-10), 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.
[0036] 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 (C6-15), or from 6 to 10 (C6-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. In certain embodiments, the term "aryl" refers to a bicyclic or tricyclic carbon ring, 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, the aryl is optionally substituted with one or more substituents Q as described herein.
[0037] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7_3o), from 7 to 20 (C7_2o), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, and 3- phenylpropyl. In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.
[0038] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, N, and P, in the ring. A heteroaryl group is bonded to the rest of a molecule through its aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P 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, 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, the heteroaryl is optionally substituted with one or more substituents Q as described herein.
[0039] The term "heteroaryl-alkyl" refers to a monovalent alkyl group substituted with one or more heteroaryl groups, wherein the terms "alkyl" and "heteroaryl" are each as defined herein. In certain embodiments, the heteroaryl-alkyl is optionally substituted with one or more substituents Q as described herein.
[0040] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, N, and P; 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. A heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, 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 heterocyclic groups 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, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.
[0041] The term "heterocyclylalkyl" refers to a monovalent alkyl group substituted with one or more heterocyclyl groups, wherein the terms "alkyl" and "heterocyclyl" are each as defined herein. In certain embodiments, the heterocyclylalkyl is optionally substituted with one or more substituents Q as described herein.
[0042] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.
[0043] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclyl- alkyl group, may be substituted with one or more substituents Q, each of which is
independently selected from, e.g., (a) oxo (=0), halo, cyano (-CN), and nitro (-N02);
(b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, four, or five, substituents Qa; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc,
-OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -P(0)RaRd, -P(0)(ORa)Rd,
-P(0)(ORa)(ORd), -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups described herein that can be substituted are "optionally substituted," unless otherwise specified.
[0044] In one embodiment, each substituent Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; and (b) Ci_6 alkyl, C2_6 alkenyl,
C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and
(c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -P(0)ReRh, -P(0)(ORe)Rh,
-P(0)(ORe)(ORh), -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0045] 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 two enantiomers in question.
[0046] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the optically active compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of an optically active compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that an optically active compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that an optically active 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 a compound, R and S.
[0047] The term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (UC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (140), oxygen-15 (150), oxygen-16 (160), oxygen-17 (170), oxygen-18 (180), fiuorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an "isotopic variant" of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen- 14 (14N), nitrogen-15 (15N), oxygen-16 (160), oxygen-17 (170), oxygen-18 (180), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 ( I). In certain embodiments, an "isotopic variant" of a compound is in an unstable form, that is, radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (UC), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (140), oxygen-15 (150), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, for example, or any carbon can be 13C, for example, or any nitrogen can be 15N, for example, or any oxygen can be 180, for example, where feasible according to the judgment of one of skill. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).
[0048] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one
embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
[0049] The phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein." Compounds
[0050] In one embodiment, provided herein is a compound of Formula I:
Figure imgf000019_0001
(I)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where each Rx is independently hydrogen or Ci_6 alkyl;
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc;
R3 and R4 are each independently (a) hydrogen, cyano, halo, nitro, or oxo; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or R3 and R4 are linked together to form (i) a bond; or (ii) Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
each R5a and R5b is independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or independently, each pair of R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl;
R5z is C3_io cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R6 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heterocyclyl, or -NRlbRlc;
each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
m is an integer of 1 or 2; and
n is an integer of 1, 2, 3, 4, 5, 6, or 7;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa,
-OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl,
C6-i4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0051] In another embodiment, provided herein is a compound of Formula II:
Figure imgf000021_0001
(Π)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R5c is hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and R5d is halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or R5c and R5d together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl;
p and q are each independently an integer of 0, 1, 2, or 3; and
R1, R2, R3, R4, R6, R7, R5a, R5b, R5z, X, Y, Z, and m are each as defined herein; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined herein. [0052] In one embodiment, the compound of Formula II has the structure of Formula Ila:
Figure imgf000022_0001
(Ila)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, p, and q are each as defined herein.
[0053] In another embodiment, the compound of Formula II has the structure of
Formula lib:
Figure imgf000022_0002
(lib)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, p, and q are each as defined herein.
[0054] In yet another embodiment, provided herein is a compound of Formula III:
Figure imgf000023_0001
(III)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and p are each as defined herein.
[0055] In one embodiment, the compound of Formula III has the structure of Formula
Ilia:
Figure imgf000023_0002
(Ilia)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and p are each as defined herein.
[0056] In another embodiment, the compound of Formula III has the structure of
Formula Illb:
Figure imgf000024_0001
(Illb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and p are each as defined herein.
[0057] In yet another embodiment, provided herein is a compound of Formula IV:
Figure imgf000024_0002
(IV)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and q are each as defined herein.
[0058] In one embodiment, the compound of Formula IV has the structure of Formula
IVa:
Figure imgf000025_0001
(IVa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and q are each as defined herein.
[0059] In another embodiment, the compound of Formula IV has the structure of
Formula IVb:
Figure imgf000025_0002
(IVb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, X, Y, Z, m, and q are each as defined herein.
[0060] In yet another embodiment, provided herein is a compound of Formula V:
Figure imgf000026_0001
(V)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R8a, R8b, R8c, R8d, and R8e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or
two of R8a, R8b, R8c, R8d, and R8e that are adjacent to each other form C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and
R1, R2, R3, R4, R6, R7, Rla, Rlb, Rlc, Rld, R5c, R5d, X, Y, Z, and m are each as defined herein.
[0061] In one embodiment, the compound of Formula V has the structure of Formula Va:
Figure imgf000027_0001
(Va)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
In another embodiment, the compound of Formula V has the structure of
Figure imgf000027_0002
(Vb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein. [0063] In yet another embodiment, provided herein is a compound of Formula VI:
Figure imgf000028_0001
(VI)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0064] In one embodiment, the compound of Formula VI has the structure of Formula
Via:
Figure imgf000028_0002
(Via)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or pprrooddrruugg tthheerreeooff;; wwhheerreeiinn RR11,, RR22,, RR33,, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0065] In another embodiment, the compound of Formula VI has the structure of
Formula VIb:
Figure imgf000029_0001
(VIb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0066] In Formula V, Va, Vb, VI, Via, or VIb, in one embodiment, one of R8a, R8b,
R8c, R8d, and R8e is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6_i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heterocyclyl, e.g., 5-membered or
6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl. [0067] In Formula V, Va, Vb, VI, Via, or VIb, in one embodiment, R a is C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g., 5 -membered or 6-membered
heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2- methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4- yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[0068] In one embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5a and R5b are each independently hydrogen, halo, or Ci_6 alkyl, optionally substituted with one or more substituents Q;
R5c is hydrogen or C6-14 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where R is a hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q; and
m is 2.
[0069] In another embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo;
R5a and R5b are hydrogen;
R5c and R5d are each independently C6-14 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0070] In yet another embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and m is 2.
[0071] In yet another embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0072] In yet another embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0073] In still another embodiment, in Formula VI, Via, or VIb,
R1 is hydrogen or methoxy;
R2 is hydrogen; R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0074] In yet another embodiment, provided herein is a compound of Formula VII:
Figure imgf000033_0001
(VII)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein. In one embodiment, the compound of Formula VII has the structure of
Figure imgf000034_0001
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0076] In another embodiment, the compound of Formula VII has the structure of
Formula Vllb:
Figure imgf000034_0002
(Vllb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0077] In Formula VII, Vila, or Vllb, in one embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R a, R , R c, R , and R e is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl,
1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[0078] In Formula VII, Vila, or Vllb, in one embodiment, R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2- (3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[0079] In one embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6_i4 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q; R5a and R5b are each independently hydrogen, halo, or Ci_6 alkyl, optionally substituted with one or more substituents Q;
R5c is hydrogen or C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or Ci_6 alkyl, optionally substituted with one or more substituents Q; and
m is 2.
[0080] In another embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-i4 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo;
R5a and R5b are hydrogen;
R5c and R5d are each independently C6-i4 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; X, Y, and Z are each independently N or CH; and
m is 2.
[0081 ] In yet another embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R? and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0082] In yet another embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0083] In yet another embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or methoxy;
R2 is hydrogen; R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0084] In still another embodiment, in Formula VII, Vila, or Vllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2. [0085] In yet another embodiment, provided herein is a compound of Formula VIII:
Figure imgf000039_0001
(VIII)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0086] In one embodiment, the compound of Formula VIII has the structure of
Formula Villa:
Figure imgf000039_0002
(Villa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein. [0087] In another embodiment, the compound of Formula VIII has the structure of
Formula VHIb:
Figure imgf000040_0001
(VHIb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, X, Y, Z, and m are each as defined herein.
[0088] In Formula VIII, Villa, or VHIb, in one embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[0089] In Formula VIII, Villa, or VHIb, in one embodiment, R8a is C6_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g. , 5 -membered or 6-membered
heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2- methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4- yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[0090] In one embodiment, in Formula VIII, Villa, or VHIb,
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-i4 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5c is hydrogen or C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or Ci_6 alkyl, optionally substituted with one or more substituents Q; and
m is 2.
[0091] In another embodiment, in Formula VIII, Villa, or Vlllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-i4 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo; R5c and R5d are each independently C6-i4 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0092] In yet another embodiment, in Formula VIII, Villa, or Vlllb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2. [0093] In yet another embodiment, in Formula VIII, Villa, or VHIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0094] In yet another embodiment, in Formula VIII, Villa, or VHIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5c and R5d are methyl;
R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0095] In still another embodiment, in Formula VIII, Villa, or VHIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5c and R5d are methyl; R a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen;
X, Y, and Z are each independently N or CH; and
m is 2.
[0096] In yet another embodiment, provided herein is a compound of Formula IX:
Figure imgf000044_0001
(IX)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc;
R3 and R4 are each independently (a) hydrogen, cyano, halo, nitro, or oxo; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or R3 and R4 are linked together to form (i) a bond; or (ii) Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
each R5a and R5b is independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or
independently, each pair of R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl;
R5z is C3_io cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R6 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl;
R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, heterocyclyl, or -NRlbRlc;
each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
m is an integer of 1 or 2; and
n is an integer of 1, 2, 3, 4, 5, 6, or 7;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more substituents Q as described herein. [0097] In yet another embodiment, provided herein is a compound of Formula X:
Figure imgf000046_0001
(X)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5A, R5B, R5C, R5D, R5Z, m, p, and q are each as defined herein.
[0098] In one embodiment, the compound of Formula X has the structure of Formula
Xa:
Figure imgf000046_0002
(Xa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5A, R5B, R5C, R5D, R5Z, m, p, and q are each as defined herein.
[0099] In another embodiment, the compound of Formula X has the structure of
Formula Xb:
Figure imgf000047_0001
(Xb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, p, and q are each as defined herein.
[00100] In yet another embodiment, provided herein is a compound of Formula XI:
Figure imgf000047_0002
(XI)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and p are each as defined herein.
[00101] In one embodiment, the compound of Formula XI has the structure of Formula
XIa:
Figure imgf000048_0001
(XIa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and p are each as defined herein.
In another embodiment, the compound of Formula XI has the structure of
Figure imgf000048_0002
(Xlb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and p are each as defined herein.
[00103] In yet another embodiment, provided herein is a compound of Formula XII:
Figure imgf000049_0001
(XII)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and q are each as defined herein.
[00104] In one embodiment, the compound of Formula XII has the structure of
Formula Xlla:
Figure imgf000049_0002
(Xlla)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and q are each as defined herein.
In another embodiment, the compound of Formula XII has the structure of
Figure imgf000050_0001
(Xllb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, m, and q are each as defined herein.
[00106] In yet another embodiment, provided herein is a compound of Formula XIII:
Figure imgf000050_0002
(XIII)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein. [00107] In one embodiment, the compound of Formula XIII has the structure of
Formula Xllla:
Figure imgf000051_0001
(Xllla)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00108] In another embodiment, the compound of Formula XIII has the structure of
Formula XHIb:
Figure imgf000051_0002
(XHIb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein. [00109] In yet another embodiment, provided herein is a compound of Formula XIV:
Figure imgf000052_0001
(XIV)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00110] In one embodiment, the compound of Formula XIV has the structure of
Formula XI Va:
Figure imgf000052_0002
(XlVa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein. [00111] In another embodiment, the compound of Formula XIV has the structure of
Formula XI Vb:
Figure imgf000053_0001
(XlVb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00112] In Formula XIII, XHIa, XHIb, XIV, XlVa, or XlVb, in one embodiment, one of R a, R , R c, R , and R e is C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4- fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4- methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl.
[00113] In Formula XIII, XHIa, XHIb, XIV, XlVa, or XlVb, in one embodiment, R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2- methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4- yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[00114] In one embodiment, in Formula XIV, XlVa, or XlVb,
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6_i4 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, optionally substituted with one or more substituents Q; R5c is hydrogen or C6-14 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00115] In another embodiment, in Formula XIV, XlVa, or XIVb„
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo;
R5a and R5b are hydrogen;
R5c and R5d are each independently C6-14 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00116] In yet another embodiment, in Formula XIV, XlVa, or XlVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2. [00117] In yet another embodiment, in Formula XIV, XlVa, or XlVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00118] In yet another embodiment, in Formula XIV, XlVa, or XlVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00119] In still another embodiment, in Formula XIV, XlVa, or XlVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen; R5c and R5d are methyl;
R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00120] In yet another embodiment, provided herein is a compound of Formula XV:
Figure imgf000057_0001
(XV)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein. [00121] In one embodiment, the compound of Formula XV has the structure of
Formula XVa:
Figure imgf000058_0001
(XVa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00122] In another embodiment, the compound of Formula XV has the structure of
Formula XVb:
Figure imgf000058_0002
(XVb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00123] In Formula XV, XVa, or XVb, in one embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R a, R , R c, R , and R e is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl,
1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[00124] In Formula XV, XVa, or XVb, in one embodiment, R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2- (3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[00125] In one embodiment, in Formula XV, XVa, or XVb
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q; R5a and R5b are each independently hydrogen, halo, Ci_6 alkyl, optionally substituted with one or more substituents Q;
R5c is hydrogen or C6-14 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00126] In another embodiment, in Formula XV, XVa, or XVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo;
R5a and R5b are hydrogen;
R5c and R5d are each independently C6-14 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2. [00127] In yet another embodiment, in Formula XV, XVa, or XVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00128] In yet another embodiment, in Formula XV, XVa, or XVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00129] In yet another embodiment, in Formula XV, XVa, or XVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
R5a and R5b are hydrogen;
R5c and R5d are methyl; R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00130] In still another embodiment, in Formula XV, XVa, or XVb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5a and R5b are hydrogen;
R5c and R5d are methyl;
R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2. [00131] In yet another embodiment, provided herein is a compound of Formula XVI :
Figure imgf000063_0001
(XVI)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00132] In one embodiment, the compound of Formula XVI has the structure of
Formula XVIa:
Figure imgf000063_0002
(XVIa)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein. [00133] In another embodiment, the compound of Formula XVI has the structure of
Formula XVIb:
Figure imgf000064_0001
(XVIb)
or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, R7, R5c, R5d, R8a, R8b, R8c, R8d, R8e, and m are each as defined herein.
[00134] In Formula XVI, XVIa, or XVIb, in one embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, one of R8a, R8b, R8c, R8d, and R8e is C6-14 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is heterocyclyl, e.g., 5-membered or 6- membered heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, one of R8a, R8b, R8c, R8d, and R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2- methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4- yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[00135] In Formula XVI, XVIa, or XVIb, in one embodiment, R8a is C6_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in another embodiment, R8a is C6-i4 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heteroaryl, e.g., 5- membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is heterocyclyl, e.g. , 5 -membered or 6-membered
heterocyclyl, optionally substituted with one or more substituents Q; in yet another embodiment, R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and in still another embodiment, R8a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6- difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2- methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4- yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.
[00136] In one embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or -ORla, where Rla is Ci_6 alkyl, optionally substituted with one or more substituents Q;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-i4 alkyl, optionally substituted with one or more substituents Q;
R7 is C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5c is hydrogen or C6-i4 alkyl, optionally substituted with one or more substituents Q;
R5d is C6-i4 alkyl, optionally substituted with one or more substituents Q; R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00137] In another embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or C6-14 alkyl;
R7 is C6-i4 alkyl, optionally substituted with one or more halo; R5c and R5d are each independently C6-14 alkyl;
R8a is C6-i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00138] In yet another embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R5c and R5d are methyl;
R8a is C6-i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00139] In yet another embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl; R is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl;
R5c and R5d are methyl;
R8a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00140] In yet another embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl;
R5c and R5d are methyl;
R8a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00141] In still another embodiment, in Formula XVI, XVIa, or XVIb,
R1 is hydrogen or methoxy;
R2 is hydrogen;
R3 and R4 are hydrogen;
R6 is hydrogen or methyl;
R7 is methyl, fluoromethyl, difluoromethyl, or trifiuoromethyl;
R5c and R5d are methyl;
R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4- methylpiperazin- 1 -yl;
R8b, R8c, R8d, and R8e are hydrogen; and
m is 2.
[00142] The groups or variables, each R1, R2, R3, R4, R6, R7, R5a, R5b, R5c, R5d, R5z, R8a,
R8b, R8c, R8d, R8e, m, n, p, q, X, Y, and Z in Formulae provided herein, e.g., Formulae I to XVI, Ila to Villa, Xa to XlVa, lib to VHIb, and Xb to XlVb, is further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups and/or variables are within the scope of this disclosure.
[00143] In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is cyano.
In certain embodiments, R1 is halo. In certain embodiments, R1 is fluoro, chloro, bromo, or iodo. In certain embodiments, R1 is nitro. In certain embodiments, R1 is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C6_i4 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00144] In certain embodiments, R1 is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -0-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain embodiments, R1 is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R1 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R1 is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R1 is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R1 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R1 is -SRla, wherein Rla is as defined herein. In certain
embodiments, R1 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R1 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R1 is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00145] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is cyano.
In certain embodiments, R2 is halo. In certain embodiments, R2 is fluoro, chloro, bromo, or iodo. In certain embodiments, R2 is nitro. In certain embodiments, R2 is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00146] In certain embodiments, R2 is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R2 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -ORla, wherein Rla is as defined herein. In certain embodiments, R2 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R2 is
-OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R2 is
-OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R is ammo (-NH2). In certain embodiments, R2 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R2 is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R2 is -SRla, wherein Rla is as defined herein. In certain
embodiments, R2 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R2 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R2 is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein. [00147] In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is cyano.
In certain embodiments, R3 is halo. In certain embodiments, R3 is fluoro, chloro, bromo, or iodo. In certain embodiments, R3 is nitro. In certain embodiments, R3 is oxo. In certain embodiments, R3 is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is hydrogen, methyl, ethyl, or propyl (e.g. , n- propyl, isopropyl, or 2-isopropyl). In certain embodiments, R3 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00148] In certain embodiments, R3 is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R3 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R3 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R3 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R3 is -ORla, wherein Rla is as defined herein. In certain embodiments, R3 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R3 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R3 is
-OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R3 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R3 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R3 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R3 is
-OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R3 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R3 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R is ammo (-NH2). In certain embodiments, R3 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R3 is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R3 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R3 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R3 is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R3 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R3 is -SRla, wherein Rla is as defined herein. In certain
embodiments, R3 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R3 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R3 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R3 is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00149] In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is cyano.
In certain embodiments, R4 is halo. In certain embodiments, R4 is fluoro, chloro, bromo, or iodo. In certain embodiments, R4 is nitro. In certain embodiments, R4 is oxo. In certain embodiments, R4 is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is hydrogen, methyl, ethyl, or propyl (e.g. , n- propyl, isopropyl, or 2-isopropyl). In certain embodiments, R4 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00150] In certain embodiments, R4 is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R4 is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R4 is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R4 is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R4 is -ORla, wherein Rla is as defined herein. In certain embodiments, R4 is -OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R4 is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R4 is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R4 is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R4 is -OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R4 is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R4 is
-OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R4 is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R4 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R is ammo (-NH2). In certain embodiments, R4 is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R4 is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R4 is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R4 is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R4 is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R4 is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R4 is -SRla, wherein Rla is as defined herein. In certain
embodiments, R4 is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R4 is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R4 is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R4 is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00151] In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is methyl. In certain embodiments, R6 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is heterocyclyl, optionally substituted with one or more substituents Q as described herein. [00152] In certain embodiments, R is hydrogen. In certain embodiments, R is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R7 is methyl. In certain embodiments, R7 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is C7-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7 is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R7 is -NH2.
[00153] In certain embodiments, each R5a is independently hydrogen. In certain embodiments, each R5a is independently halo. In certain embodiments, each R5a is independently fluoro, chloro, bromo, or iodo. In certain embodiments, each R5a is independently Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, each R5a is independently methyl. In certain
embodiments, each R5a is independently C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently C3_io cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently C7_i5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5a is independently heterocyclyl, optionally substituted with one or more substituents Q as described herein. [00154] In certain embodiments, each R is independently hydrogen. In certain embodiments, each R5b is independently halo. In certain embodiments, each R5b is
independently fluoro, chloro, bromo, or iodo. In certain embodiments, each R5b is
independently Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, each R5b is independently methyl. In certain
embodiments, each R5b is independently C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently C7_i5 aralkyl, optionally
substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, each R5b is independently heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00155] In certain embodiments, R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached independently form C3_io cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached independently form heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00156] In certain embodiments, each R5a and R5b is hydrogen.
[00157] In certain embodiments, R5c is hydrogen. In certain embodiments, R5c is halo.
In certain embodiments, R5c is fluoro, chloro, bromo, or iodo. In certain embodiments, R5c is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, R5c is methyl. In certain embodiments, R5c is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is C7_i5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00158] In certain embodiments, R5d is halo. In certain embodiments, R5d is fluoro, chloro, bromo, or iodo. In certain embodiments, R5d is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, R5d is methyl. In certain embodiments, R5d is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is C7_i5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00159] In certain embodiments, R5c and R5d together with the carbon atom to which they are attached form C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5c and R5d together with the carbon atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein. [00160] In certain embodiments, R5c and R5d are methyl.
[00161] In certain embodiments, R5z is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is moncyclic C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is bicyclic C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein.
[00162] In certain embodiments, R5z is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is C6-14 aryl substituted at the 2-position with one substituent Q as described herein. In certain embodiments, R5z is phenyl or naphthyl, each of which is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is phenyl, naphtha- 1-yl, or naphtha-2-yl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is phenyl, optionally substituted with one or more substituents Q as described herein.
[00163] In certain embodiments, R5z is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is moncyclic heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is 5-membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is 6-membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is bicyclic heteroaryl, optionally substituted with one or more substituents Q as described herein.
[00164] In certain embodiments, R5z is heterocyclyl; optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is moncyclic
heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is 5-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5z is bicyclic heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00165] In certain embodiments, R8a is hydrogen. In certain embodiments, R8a is cyano. In certain embodiments, R8a is halo. In certain embodiments, R8a is fluoro, chloro, bromo, or iodo. In certain embodiments, R8a is nitro. In certain embodiments, R8a is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is phenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl. In certain embodiments, R8a is C7_i5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is monocyclic heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is 5-membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is imidazolyl or pyrozolyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is imidazol-l-yl, pyrozol-4- yl, l-methyl-pyrozol-4-yl, or 2-methylpyrozol-3-yl. In certain embodiments, R8a is 6- membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is pyridinyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, or 2-methoxypyridin-4-yl. In certain embodiments, R8a is heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is 5-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is piperidinyl or piperazinyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-propylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, 4-methylpiperazin- 1 -yl.
[00166] In certain embodiments, R8a is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8a is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8a is -ORla, wherein Rla is as defined herein. In certain embodiments, R8a is -0-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8a is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R8a is
-OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8a is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R a is
-OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is amino (-NH2). In certain embodiments, R8a is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8a is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8a is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8a is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R8a is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8a is
-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R a is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8a is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8a is -SRla, wherein Rla is as defined herein. In certain embodiments, R8a is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8a is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8a is -S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00167] In certain embodiments, R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R8a is phenyl, 2-fluorophenyl, 2-chlorophenyl,
2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3 - fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin- 1 -yl.
[00168] In certain embodiments, R8b is hydrogen. In certain embodiments, R8b is cyano. In certain embodiments, R8b is halo. In certain embodiments, R8b is fluoro, chloro, bromo, or iodo. In certain embodiments, R8b is nitro. In certain embodiments, R8b is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain
8b
embodiments, R is C2_6 alkenyl, optionally substituted with one or more substituents Q as
8b
described herein. In certain embodiments, R is C2_6 alkynyl, optionally substituted with one
8b
or more substituents Q as described herein. In certain embodiments, R is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain
8b
embodiments, R is C6-i4 aryl, optionally substituted with one or more substituents Q as
8b
described herein. In certain embodiments, R is C8-15 aralkyl, optionally substituted with one
8b
or more substituents Q as described herein. In certain embodiments, R is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain
8b
embodiments, R is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00169] In certain embodiments, R8b is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8b is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8b is -ORla, wherein Rla is as defined herein. In certain embodiments, R 8b is -0-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain embodiments, R 8b is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R 8b is
-OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8b is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R is
-OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is amino (-NH2). In certain embodiments, R8b is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8b is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8b is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8b is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R8b is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8b is
-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8b is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8b is -SRla, wherein Rla is as defined herein. In certain embodiments, R8b is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8b is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8b is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00170] In certain embodiments, R 8b is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 8b is phenyl, 2-fluorophenyl, 2-chlorophenyl,
2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3 - fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin- 1 -yl.
[00171] In certain embodiments, R8c is hydrogen. In certain embodiments, R8c is cyano. In certain embodiments, R8c is halo. In certain embodiments, R8c is fluoro, chloro, bromo, or iodo. In certain embodiments, R8c is nitro. In certain embodiments, R8c is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is C3_i0 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is C6-i4 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is C8-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8c is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00172] In certain embodiments, R8c is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8c is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8c is -ORla, wherein Rla is as defined herein. In certain embodiments, R8c is -0-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain embodiments, R8c is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R8c is
-OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8c is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R c is
-OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is amino (-NH2). In certain embodiments, R8c is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8c is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8c is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8c is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R8c is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8c is
-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R c is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8c is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8c is -SRla, wherein Rla is as defined herein. In certain embodiments, R8c is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8c is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8c is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00173] In certain embodiments, R8c is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R8c is phenyl, 2-fluorophenyl, 2-chlorophenyl,
2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3 - fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3 - yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin- 1 -yl.
[00174] In certain embodiments, R8d is hydrogen. In certain embodiments, R8d is cyano. In certain embodiments, R8d is halo. In certain embodiments, R8d is fluoro, chloro, bromo, or iodo. In certain embodiments, R8d is nitro. In certain embodiments, R8d is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain
8d
embodiments, R is C2_6 alkenyl, optionally substituted with one or more substituents Q as
8d
described herein. In certain embodiments, R is C2_6 alkynyl, optionally substituted with one
8d
or more substituents Q as described herein. In certain embodiments, R is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain
8d
embodiments, R is C6-14 aryl, optionally substituted with one or more substituents Q as
8d
described herein. In certain embodiments, R is C8-15 aralkyl, optionally substituted with one
8d
or more substituents Q as described herein. In certain embodiments, R is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain
8d
embodiments, R is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00175] In certain embodiments, R8d is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8d is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8d is -ORla, wherein Rla is as defined herein. In certain
8d
embodiments, R is -0-Ci_6 alkyl, wherein the alkyl is optionally substituted with one or
8d
more substituents Q as described herein.. In certain embodiments, R is methoxy, ethoxy,
8d
propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R is
-OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8d is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R is
-OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is amino (-NH2). In certain embodiments, R8d is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8d is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8d is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8d is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R8d is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8d is
-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8d is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8d is -SRla, wherein Rla is as defined herein. In certain embodiments, R8d is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8d is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8d is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00176] In certain embodiments, R 8d is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 8d is phenyl, 2-fluorophenyl, 2-chlorophenyl,
2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3 - fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin- 1 -yl.
[00177] In certain embodiments, R8e is hydrogen. In certain embodiments, R8e is cyano. In certain embodiments, R8e is halo. In certain embodiments, R8e is fluoro, chloro, bromo, or iodo. In certain embodiments, R8e is nitro. In certain embodiments, R8e is Ci_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R e is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is C3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is C8-15 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R8e is heterocyclyl, optionally substituted with one or more substituents Q as described herein.
[00178] In certain embodiments, R8e is -C(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -C(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8e is -C(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is -C(NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8e is -ORla, wherein Rla is as defined herein. In certain embodiments, R8e is -0-C1-6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain embodiments, R8e is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R8e is
-OC(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -OC(0)ORla, wherein Rla is as defined herein. In certain embodiments, R8e is -OC(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is -OC(=NRla)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R e is
-OS(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -OS(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -OS(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is -OS(0)2NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is -NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is amino (-NH2). In certain embodiments, R8e is -NRlaC(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8e is -NRlaC(0)ORld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8e is -NRlaC(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8e is -NRlaC(=NRld)NRlbRlc, wherein Rla, Rlb, Rlc, and Rld are each as defined herein. In certain embodiments, R8e is -NRlaS(0)Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R8e is
-NRlaS(0)2Rld, wherein Rla and Rld are each as defined herein. In certain embodiments, R e is -NRlaS(0)NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8e is -NRlaS(0)2NRlbRlc, wherein Rla, Rlb, and Rlc are each as defined herein. In certain embodiments, R8e is -SRla, wherein Rla is as defined herein. In certain embodiments, R8e is -S(0)Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -S(0)2Rla, wherein Rla is as defined herein. In certain embodiments, R8e is -S(0)NRlbRlc, wherein Rlb and Rlc are each as defined herein. In certain embodiments, R8e is
-S(0)2NRlbRlc; wherein Rlb and Rlc are each as defined herein.
[00179] In certain embodiments, R8e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R8e is phenyl, 2-fluorophenyl, 2-chlorophenyl,
2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3 - fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, l-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3- yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin- 1 -yl.
[00180] In certain embodiments, X is N In certain embodiments, X is CRX, wherein Rx is as defined herein. In certain embodiments, X is CH.
[00181] In certain embodiments, Y is N In certain embodiments, Y is CRX, wherein Rx is as defined herein. In certain embodiments, Y is CH.
[00182] In certain embodiments, Z is N In certain embodiments, Z is CRX, wherein Rx is as defined herein. In certain embodiments, Z is CH.
[00183] In certain embodiments, X, Y, and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.
[00184] In certain embodiments, m is 1. In certain embodiments, m is 2. [00185] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7.
[00186] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
[00187] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.
[00188] In one embodiment, provided herein is N-(2 -methyl- l-(2-(l -methylpiperidin-
4-yl)phenyl)propan-2-yl)-4-(2-(methylsulfonyl)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino- 1 ,3,5-triazin-2-amine, or N-(2 -methyl- 1 -(2-(piperidin-4-yl)phenyl)propan-2 -yl)-4-(2- (methylsulfonyl)-lH-benzo[ ]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2-amine; or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00189] 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.
[00190] 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.
[00191] 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. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
[00192] 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, (+)-(lS)- 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, a- 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, l-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.
[00193] Suitable bases for use in the preparation of pharmaceutically acceptable salts, include, but are 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, but not limited to, 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)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,
triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)- 1,3 -propanediol, and tromethamine.
[00194] 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; Asgharnejad 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, Adv. 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, 8, 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. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 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. Methods of Synthesis
[00195] The compound provided herein can be prepared, isolated, or obtained by any methods known to one of skill in the art, and the following examples are only representative and do not exclude other related procedures.
Scheme I
Figure imgf000091_0001
[00196] In one embodiment, for example, a compound of Formula II is prepared, as shown in Scheme I, via a first aromatic substitution reaction of a halo-substituted triazine or pyrimidine with compound 1-1 to form compound 1-2, which is subsequently converted to compound 1-4 via a second aromatic substitution reaction with compound 1-3. Compound I- 4 then reacts with HNR5R6 via a third aromatic substitution reaction to form a compound of Formula II.
[00197] In another embodiment, for example, a compound of Formula II is prepared, as shown in Scheme II, first via an aromatic substitution reaction of compound 1-2 with compound 1-6 to form compound 1-7, which is subsequently converted to compound 1-8 via an aromatic substitution reaction with FINR5R6. Compound 1-8 is then oxidized with an oxidant, e.g., KMn04, to form a sulfonyl compound of Formula II; or e.g., hydrogen peroxide, to form a sulfmyl compound of Formula II.
Scheme II
Figure imgf000092_0001
1-8 II
Pharmaceutical Compositions
[00198] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
[00199] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical composition for oral administration is formulated in tablet, capsule, powder, or liquid form.
[00200] In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
[00201] In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration, which comprises a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
[00202] In certain embodiments, the pharmaceutical composition provided herein is formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and 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).
[00203] In certain embodiments, the pharmaceutical composition provided herein is 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.
[00204] 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.
[00205] In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents (e.g., chemotherapeutic agents) as defined herein.
A. Oral Administration
[00206] 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.
[00207] 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.
[00208] 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.
[00209] 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.
[00210] 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, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 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.
[00211] 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.
[00212] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00213] 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.
[00214] 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.
[00215] 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 propyl-parabens, 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.
[00216] 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.
[00217] 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.
[00218] 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.
[00219] 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.
[00220] Coloring and flavoring agents can be used in all of the above dosage forms.
[00221] 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
[00222] 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.
[00223] 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).
[00224] 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. [00225] 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.
[00226] 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 a-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin
(CAPTISOL®, CyDex, Lenexa, KS).
[00227] 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. [00228] 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.
[00229] 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.
[00230] 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.
[00231] 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.
[00232] 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
[00233] 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.
[00234] 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.
[00235] 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.
[00236] 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).
[00237] 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 (O/W) 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.
[00238] 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 emulsifier, 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 emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
[00239] 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.
[00240] 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.
[00241] 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 yellow 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.
[00242] 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.
[00243] 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.
[00244] 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.
[00245] 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. [00246] 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 /-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.
[00247] 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
[00248] 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).
[00249] 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
[00250] 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).
[00251] 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.
[00252] 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.
[00253] 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.
[00254] 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.
[00255] 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
[00256] 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). [00257] 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.
[00258] 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.
[00259] 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 MA NOGEM™ 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.
[00260] 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.
[00261] 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.
[00262] 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.
[00263] 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.
[00264] 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.
[00265] 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.
[00266] 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, 7-27).
[00267] 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.
[00268] 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
[00269] 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 μιη to about 3 mm, about 50 μιη to about 2.5 mm, or from about 100 μιη 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.
[00270] 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
[00271] 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
[00272] In one embodiment, 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, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00273] In certain embodiments, the PI3K-mediated disorder, disease, or condition is a proliferative disease. In certain embodiments, the PI3K-mediated disorder, disease, or condition is cancer. In certain embodiments, the PI3K-mediated disorder, disease, or condition is hematological cancer. In certain embodiments, the PI3K-mediated disorder, disease, or condition is an inflammatory disease. In certain embodiments, the PI3K-mediated disorder, disease, or condition is an immune disorder. [00274] In certain embodiments, the PI3K is a wild type PI3K. In certain embodiments, the PI3K is a PI3K variant.
[00275] In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is ΡΒΚα, ΡΒΚβ, ΡΒΚδ, or ΡΒΚγ. In certain embodiments, the PBK is pi 10a, pi 10β, pi 105, or pi 10γ. In certain embodiments, the PBK is a wild type of a Class I kinase. In certain embodiments, the PBK is a variant of a Class I kinase.
[00276] In certain embodiments, the PBK is pi 10a. In certain embodiments, the PBK is a wild type of pi 10a. In certain embodiments, the PBK is a pi 10a mutant. In certain embodiments, the pi 10a mutant is R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, Ml 043V, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K, Q546K, I800L, Ml 0431, H1047L, or H1047Y.
[00277] In certain embodiments, the PBK is ΡΒΚγ. In certain embodiments, the PBK is a wild type of ΡΒΚγ. In certain embodiments, the PBK is a variant of ΡΒΚγ.
[00278] In certain embodiments, the compound provided herein selectively targets
ΡΒΚδ. In certain embodiments, the compound provided herein selectively targets a wild type of ΡΒΚδ. In certain embodiments, the compound provided herein selectively targets a variant of ΡΒΚδ.
[00279] In certain embodiments, the compound provided herein is a selective inhibitor οίΡΒΚδ.
[00280] In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over PBKa ranging from about 2 fold to about 100,000 fold, from about 4 fold to about 10,000 fold, from about 8 fold to about 10,000 fold, from about 20 fold to about 5,000 fold, from about 20 fold to about 5,000 fold, from about 50 fold to about 5,000 fold, or from about 100 fold to about 5,000 fold. In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over PBKa of at least about 2 fold, at least about 4 fold, at least about 8 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 200 fold, at least about 500 fold, at least about 1,000 fold, at least about 2,000 fold, at least about 5,000 fold, at least about 10,000 fold, at least about 20,000 fold, at least about 50,000 fold, or at least about 100,000 fold.
[00281] In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over ΡΒΚβ ranging from about 2 fold to about 100,000 fold, from about 4 fold to about 10,000 fold, from about 8 fold to about 10,000 fold, from about 20 fold to about 5,000 fold, from about 20 fold to about 5,000 fold, from about 50 fold to about 5,000 fold, or from about 100 fold to about 5,000 fold. In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over ΡΒΚβ of at least about 2 fold, at least about 4 fold, at least about 8 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 200 fold, at least about 500 fold, at least about 1,000 fold, at least about 2,000 fold, at least about 5,000 fold, at least about 10,000 fold, at least about 20,000 fold, at least about 50,000 fold, or at least about 100,000 fold.
[00282] In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over ΡΒΚγ ranging from about 2 fold to about 100,000 fold, from about 4 fold to about 10,000 fold, from about 8 fold to about 10,000 fold, from about 20 fold to about 5,000 fold, from about 20 fold to about 5,000 fold, from about 50 fold to about 5,000 fold, or from about 100 fold to about 5,000 fold. In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over ΡΒΚγ of at least about 2 fold, at least about 4 fold, at least about 8 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 200 fold, at least about 500 fold, at least about 1,000 fold, at least about 2,000 fold, at least about 5,000 fold, at least about 10,000 fold, at least about 20,000 fold, at least about 50,000 fold, or at least about 100,000 fold.
[00283] In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over mTOR ranging from about 2 fold to about 100,000 fold, from about 4 fold to about 10,000 fold, from about 8 fold to about 10,000 fold, from about 20 fold to about 5,000 fold, from about 20 fold to about 5,000 fold, from about 50 fold to about 5,000 fold, or from about 100 fold to about 5,000 fold. In certain embodiments, the compound provided herein has a selectivity against ΡΒΚδ over mTOR of at least about 2 fold, at least about 4 fold, at least about 8 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 200 fold, at least about 500 fold, at least about 1,000 fold, at least about 2,000 fold, at least about 5,000 fold, at least about 10,000 fold, at least about 20,000 fold, at least about 50,000 fold, or at least about 100,000 fold.
[00284] In certain embodiments, the PI3K is a Class IV kinase. In certain
embodiments, the PI3K is a wild type of a Class IV kinase. In certain embodiments, the PI3K is a variant of a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PI3K is mTOR.
[00285] In another embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00286] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, 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.
[00287] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is hematological cancer. In certain embodiments, the proliferative disease is an inflammatory disease. In certain embodiments, the proliferative disease is an immune disorder.
[00288] 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.
[00289] In certain embodiments, the cancer treatable with a compound 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,
promyelocytic, 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 al., 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).
[00290] 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. [00291] 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.
[00292] 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.
[00293] 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.
[00294] 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 I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PIK3 enzyme is inside a cell.
[00295] In certain embodiments, the PI3K is a wild type PI3K. In certain
embodiments, the PI3K is a PI3K variant. [00296] In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is ΡΒΚα, ΡΒΚβ, ΡΒΚδ, or ΡΒΚγ. In certain embodiments, the PBK is pi 10a, pi 10β, pi 105, or pi 10γ. In certain embodiments, the PBK is a wild type of a Class I kinase. In certain embodiments, the PBK is a variant of a Class I kinase.
[00297] In certain embodiments, the PBK is pi 10a. In certain embodiments, the PBK is a wild type of pi 10a. In certain embodiments, the PBK is a pi 10a mutant. In certain embodiments, the pi 10a mutant is R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, Ml 043V, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K, Q546K, I800L, Ml 0431, H1047L, or H1047Y.
[00298] In certain embodiments, the PBK is ΡΒΚγ. In certain embodiments, the PBK is a wild type of ΡΒΚγ. In certain embodiments, the PBK is a variant of ΡΒΚγ.
[00299] In certain embodiments, the compound provided herein selectively targets
ΡΒΚγ. In certain embodiments, the compound provided herein selectively targets a wild type of ΡΒΚγ. In certain embodiments, the compound provided herein selectively targets a variant of ΡΒΚγ.
[00300] In certain embodiments, the PBK is a Class IV kinase. In certain
embodiments, the PBK is a wild type of a Class IV kinase. In certain embodiments, the PBK is a variant of a Class IV kinase. In certain embodiments, the PBK is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PBK is mTOR.
[00301] In certain embodiments, the compound provided herein, e.g., a compound of
Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a PBK and a variant thereof.
[00302] In certain embodiments, the compound provided herein, e.g., a compound of
Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a wild type of a PBK. In certain embodiments, the PI3K is ΡΒΚγ.
[00303] In certain embodiments, the compound provided herein, e.g., a compound of
Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a PI3K variant. In certain embodiments, the PI3K variant is a pi 10a mutant. In certain embodiments, the pi 10a mutant is C420R, E542K, E545A, E545K, Q546K, I800L, Ml 0431, H1047L, or H1047Y.
[00304] The compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant 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.
[00305] 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 amorolfme, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifme, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafme, 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; (1 1) anti-platelet agents, such as GPIIb/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, fiumethiazide, 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, tadalafil, 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.
[00306] 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).
[00307] 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.
[00308] In certain embodiments, the method provided herein comprises administration of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, 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 provided herein.
[00309] Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, 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.
[00310] 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 NSAID 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.
[00311] 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.
[00312] 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, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00313] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in a container comprising one or more other therapeutic agent(s) described herein.
[00314] 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.
[00315] 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, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00316] The disclosure will be further understood by the following non- limiting examples.
EXAMPLES
[00317] 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); (microliters); M (molar); mM (millimolar); μΜ (micromolar); mol (moles); mmol (millimoles); Hz (Hertz); MHz (megahertz); hr or hrs (hour or hours); min (minutes); MS (mass spectrometry); Cbz
(benzyloxycarbonyl); DMF (N^N-dimethylformamide); HO Ac (acetic acid); MeOH
(methanol); PdCl2(dppf) (l , l '-bis(diphenylphosphino)ferrocene-palladium(II) dichloride); and TFA (trifluoroacetic acid).
[00318] 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 °C (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. Example 1
Synthesis of N-(2 -methyl- 1 -(2-( 1 -methylpiperidin-4-yl)phenyl)propan-2-yl)-4-(2- (methylsulfonyl)- IH-benzo [ Jimidazol- 1 -yl)-6-morpholino- 1 ,3 ,5-triazin-2-amine Al
Figure imgf000126_0001
Al
[00319] N-(2-Methyl- 1 -(2-( 1 -methylpiperidin-4-yl)phenyl)propan-2-yl)-4-(2- (methylsulfonyl)-lH-benzo[(i]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2-amine Al was prepared according to Schemes 1 and 2.
Scheme 1
Figure imgf000126_0002
Scheme 2
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
[00320] Preparation of methyl 2-(2-bromophenyl)acetate 2. Thionyl chloride (5 mL) was added dropwise to a mixture of 2-bromophenylacetic acid 1 (25 g, 0.12 mol) in methanol (125 mL) at 0 °C. The resulting mixture was refluxed for 12 hrs. The volatiles were removed under vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water, dried over sodium sulfate, and concentrated to give methyl 2-(2-bromophenyl)acetate 2 (25 g, 91% yield) as a yellow oil, which was used directly in the next step without further purification: MS m/z: 229 (M+H). [00321] Preparation of l-(2-bromophenyl)-2-methylpropan-2-ol 3. To a solution of methyl 2-(2-bromophenyl)acetate 2 (25 g, 0.11 mol) in tetrahydrofuran (80 mL) was added methylmagnesium bromide (3M in ether, 123 mL, 0.37 mol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The resulting mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give l-(2-bromophenyl)-2-methylpropan-2-ol 3 (15 g, 60% yield) as a yellow oil, which was used directly in the next step without further purification: MS m/z: 229 (M+H).
[00322] Preparation of N-( l-(2-bromophenyl)-2-methylpropan-2-yl)-2- chloroacetamide 4. Cone, sulfuric acid (18 mL) was added dropwise at 0 °C to a solution of l-(2-bromophenyl)-2-methylpropan-2-ol 3 (9.0 g, 39 mmol) and chloroacetonitrile (5.9 g, 78 mmol) in acetic acid (18 mL) at 0 °C, while the reaction temperature was kept below 10 °C. After stirring at room temperature for 2 hrs, the resulting solution was poured onto ice and the pH was increased to >8 by the addition of solid potassium carbonate. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over sodium sulfate, and concentrated under vacuum to give N-(l-(2-bromophenyl)-2- methylpropan-2-yl)-2-chloroacetamide 4 (9.0 g, 76% yield) as a yellow solid.
[00323] Preparation of l-(2-bromophenyl)-2-methylpropan-2-amine 5. A mixture of N-(l-(2-bromophenyl)-2-methylpropan-2-yl)-2-chloroacetamide 4 (9.0 g, 30 mmol), thiourea (4.0 g, 53 mmol), and acetic acid (16 mL) in ethanol (80 mL) was refluxed under nitrogen atmosphere for 16 hrs. The volatiles were removed under vacuum and the residue was diluted with water. The aqueous solution was acidified with cone, hydrochloric acid to pH ~ 2, washed with ethyl acetate, and then basified with sodium bicarbonate to pH > 8. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over sodium sulfate, and concentrated to give l-(2-bromophenyl)-2- methylpropan-2-amine 5 (4.0 g, 58% yield) as a yellow oil: MS m/z: 228 (M+H).
[00324] Preparation of benzyl (l-(2-bromophenyl)-2-methylpropan-2-yl)carbamate 6. To a stirred mixture of l-(2-bromophenyl)-2-methylpropan-2-amine 5 (640 mg, 2.81 mmol) and sodium carbonate (596 mg, 5.62 mmol) in a mixed solvent of water (10 mL) and tetrahydrofuran (10 mL) was added benzyl chloro formate (720 mg, 4.21 mmol) via syringe at 0 °C. The mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic phase was dried with sodium sulfate and concentrated to afford benzyl (l-(2-bromophenyl)-2-methylpropan-2-yl)carbamate 6 (980 mg, 96% yield) as a white solid: MS m/z: 362 (M+H).
[00325] Preparation of tert-butyl 4-(2-(2-( ( (benzyloxy)carbonyl)amino)-2- methylpropyl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate 7. A mixture of benzyl (l-(2- bromophenyl)-2-methylpropan-2-yl)carbamate 6 (980 mg, 2.71 mmol), N-Boc-1,2,5,6- tetrahydropyridine-4-boronic acid pinacol ester (1.25 g, 4.06 mmol), 1,1 '- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (372 mg, 0.271 mmol), and cesium carbonate (2.65 g, 8.13 mmol) in N,A^-dimethylformamide (50 mL) and water (1 mL) was stirred under nitrogen atmosphere at 100 °C for 3 hrs. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)-2- methylpropyl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate 7 (1.08 g, 86%> yield) as a colorless oil: MS m/z: 465 (Μ+Η).
[00326] Preparation of tert-butyl 4-(2-(2-amino-2-methylpropyl)phenyl)piperidine-l- carboxylate 8. A mixture of tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)-2- methylpropyl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate 7 (1.08 g, 2.32 mmol) and 10%> Pd/C (20 mg) in methanol was refluxed under hydrogen atmosphere for 3 hrs. The reaction mixture was filtered through Celite. The filtrate was concentrated to give tert-butyl 4-(2-(2- amino-2-methylpropyl)phenyl)piperidine-l-carboxylate 8 (735 mg, 95% yield) as a white solid: MS m/z: 333 (Μ+Η).
[00327] Preparation of 4-(4-chloro-6-(2-(methylthio)-lH-benzo[d]imidazol-l-yl)- l,3,5-triazin-2-yl)morpholine 9. A mixture of 4-(4,6-dichloro-l,3,5-triazn-2-yl)morpholine (1.4 g, 8.5 mmol), 2-(methylthio)-lH-benzo[d]imidazole (2 g, 8.5 mmol). and potassium carbonate (9.4 g, 68 mmol) was stirred in DMF (40 mL) at room temperature for 1 hr. The reaction mixture was poured into water to form a white precipitate. The solid was collected by filtration, washed with water, and dried to give 4-(4-chloro-6-(2-(methylthio)-lH- benzo[<i]imidazol-l-yl)-l,3,5-triazin-2-yl)morpholine 9 (3.1 g, > 99%> yield) as a white solid. MS m/z: 363 (Μ+Η), which was used directly in the next step without further purification.
[00328] Preparation of tert-butyl 4-(2-(2-methyl-2-((4-(2-(methylthio)-lH- benzo[dJimidazol-l-yl)-6-morpholino-l,3,5-triazin-2-yl)amino)propyl)phenyl)piperidim carboxylate 10. A mixture of 4-(4-chloro-6-(2-(methylthio)-lH-benzo[(i]imidazol-l-yl)- l,3,5-triazin-2-yl)morpholine 9 (830 mg, 2.3 mmol), tert-butyl 4-(2-(2-amino-2-methylpropyl) phenyl)piperidine-l -carboxylate 8 (800 mg, 2.4 mmol), and potassium carbonate (1.1 g, 8 mmol) in dioxane (10 mL) was refluxed overnight. The volatiles were removed under vacuum and the residue was diluted with water. The mixture was extracted with ethyl acetate and the combined organic phase was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to afford fert-butyl 4- (2-(2-methyl-2-((4-(2-(methylthio)-lH-benzo[ ]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2- yl)amino)propyl)phenyl)piperidine-l -carboxylate 10 (470 mg, 30% yield) as a white solid: MS m/z: 659 (Μ+Η).
[00329] Preparation of N-(2-methyl-l-(2-(piperidin-4-yl)phenyl)propan-2-yl)-4-(2- (methylthio)-lH-benzo[d]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2-am 11. A mixture of tert-butyl 4-(2-(2-methyl-2-((4-(2-(methylthio)-lH-benzo[d]imidazol-l-yl)-6-morpholino- l,3,5-triazin-2-yl)amino)propyl)phenyl)piperidine-l-carboxylate 10 (470 mg, 0.71 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred at room temperature for 2 hrs. The solvent was removed under vacuum. The residue was diluted with water and basified at 0 °C by aq. NaHC03 to pH ~ 8 and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated to give N-(2-methyl-l-(2- (piperidin-4-yl)phenyl)propan-2-yl)-4-(2-(methylthio)- lH-benzo[d]imidazol- 1 -yl)-6- morpholino-l,3,5-triazin-2-amine 11 (300 mg, 75% yield) as a white solid: MS m/z: 559 (Μ+Η).
[00330] Preparation of N-(2-methyl-l-(2-( l-methylpiperidin-4-yl)phenyl)propan-2-yl)- 4-(2-(methylthio)- lH-benzo fdj 'imidazol- 1 -yl)-6-morpholino- 1 ,3 ,5-triazin-2-amine 12. A mixture of N-(2 -methyl- l-(2-(piperidin-4-yl)phenyl)propan-2-yl)-4-(2-(methylthio)-lH- benzo[<i]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2-amine 11 (450 mg, 0.8 mmol), aq.
formaldehyde (37%, 18 drops), and sodium cyanoborohydride (53 mg, 0.85 mmol) in methanol (18 mL) was stirred at room temperature for 1 hr. The solution was concentrated and the organic soluble material was extracted into dichloromethane. The combined organic phase was concentrated to give N-(2 -methyl- l-(2-(l -methylpiperidin-4-yl)phenyl)propan-2- yl)-4-(2-(methylthio)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino- 1 ,3,5-triazin-2-amine 12
(300 mg, 46% yield) as a white solid. MS m/z: 573 (Μ+Η). [00331 ] Preparation of N-(2-methyl-l-(2-( l-methylpiperidin-4-yl)phenyl)propan-2-yl)- 4-(2-(methylsulfonyl)- lH-benzo fdj 'imidazol- 1 -yl)-6-morpholino- 1 ,3 ,5-triazin-2-amine Al . A mixture of N-(2 -methyl- 1 -(2-( 1 -methylpiperidin-4-yl)phenyl)propan-2-yl)-4-(2-(methylthio)- lH-benzo[<i]imidazol-l-yl)-6-morpholino-l,3,5-triazin-2-amine 12 (150 mg, 0.26 mmol) and KMn04 (248 mg, 1.57 mmol) in acetone (45 mL) and HOAc (7.5 mL) was stirred at room temperature for 1 hr. The mixture was decolored with aq. Na2S03, and aq. NaHC03 was then added until the mixture was basic (pH ~ 8). The reaction mixture was extracted with dichloromethane and the combined organic phase was concentrated in vacuo. The residue was purified by prep-HPLC to give N-(2 -methyl- l-(2-(l -methylpiperidin-4- yl)phenyl)propan-2-yl)-4-(2-(methylsulfonyl)- lH-benzo[d]imidazol- 1 -yl)-6-morpholino- l,3,5-triazin-2-amine Al (30 mg, 18.9% yield, >99.9% purity (HPLC)) as a white solid: MS m/z: 605 (M+H); 1H NMR (500 MHz, CDC13) δ (ppm) 8.29 (d, J= 8.0 Hz, 1H), 7.8 (d, J = 7.0 Hz, 1H), 7.47-7.40 (m, 2H) , 7.31 (d, J= 8.0 Hz, 1H), 7.23 (m, 1H), 7.21-7.06 (m, 2H), 5.18 (s, 1H), 4.1-3.81 (m, 8H), 3.60 (s, 3H), 3.26 (s, 2H), 2.93-2.95 (m, 2H), 2.80 (m, 1H), 2.29 (s, 3H), 1.93-1.81 (m, 4H), 1.70-1.64 (m, 2H) , 1.50 (s, 6H).
Example I
A luciferase-based luminescence assay
[00332] PI3K catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) and ATP to phosphatidylinositol-3,4,5-trisphosphate (PIP3) and ADP. For all assays, the reaction buffer comprised 50 mM HEPES, pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS and 2 mM DTT. Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted 1 :25 in reaction buffer.
[00333] PI3K alpha and PI3K delta enzymatic activity was determined by measuring the amount of ATP consumed following the kinase reaction using a luciferase-based luminescence assay (Kinase Glo®, Promega Corp., Madison, WI, USA). PI3K enzyme solutions were prepared by diluting PI3K alpha (Invitrogen Corp., Carlsbad, CA, USA) or PI3K delta (Millipore, Billerica, MA, USA ) in reaction buffer, to 4x the final assay concentration (final concentrations of enzymes were 1.65 uM and 6.86 uM for PI3K alpha and PI3K delta, respectively). A substrate solution was prepared by mixing PIP2 and ATP in reaction buffer at 2x the final assay concentration (final concentrations were 50 μΜ and 25 μΜ for PIP2 and ATP respectively). 2.5 each of the compound and kinase mixtures were added to individual wells of white low volume 384-well assay plates and mixed by shaking. The reactions were started by adding 5 μΐ, of substrate mixture per well and shaking. The assay plates were covered and reactions were allowed to proceed for 1 hour (PI3K alpha) or 2 hours (PI3K delta), after which 10 μΐ, of Kinase Glo® reagent was added. The plates were briefly centrifuged and incubated for 10 minutes, after which luminescence was measured using a FlexStation plate reader (Molecular Devices, Sunnyvale, CA, USA). IC50 values were determined by curve fitting using Graphpad Prism software (Graphpad Software, La Jolla, CA, USA).
[00334] PI3K beta and gamma enzymatic activity was determined by measuring the amount of ADP produced following the kinase reaction using a luciferase-based
luminescence assay (ADP Glo®, Promega Corp., Madison, WI, USA). PI3K enzyme solutions were prepared by diluting PI3K beta (Millipore, Billerica, MA, USA) or PI3K gamma (Invitrogen Corp., Carlsbad, CA, USA) in reaction buffer, to 4x the final assay concentration (final concentrations of enzymes were 4.8 nM and 7.6 nM for PI3K beta and PI3K gamma respectively). A substrate solution was prepared by mixing PIP2 and ATP in reaction buffer at 2x the final assay concentration (final concentrations were 50 μΜ and 25 μΜ for PIP2 and ATP respectively). 2.5 μΐ^ each of the compound and kinase mixtures were added to individual wells of white low volume 384-well assay plates and mixed by shaking. The reactions were started by adding 5 μΐ, of substrate mixture per well and shaking. The assay plates were covered and reactions were allowed to proceed for 1 hour. Then, 5 μΐ, of reaction mix was transferred to another white low volume 384-well plate, and 5 μί of ADP- Glo™ reagent was added. The plates were briefly centrifuged and incubated for 40 minutes, after which ΙΟμΙ, of kinase detection buffer was added. The plates then were centrifuged briefly, shaken slowly and equilibrated at room temperature for 30 minutes, after which luminescence was measured using a FlexStation plate reader (Molecular Devices, Sunnyvale, CA, USA). IC50 values were determined by curve fitting using Graphpad Prism software (Graphpad Software, La Jolla, CA, USA).
[00335] The biological results of inhibition of enzymatic activity of PI3Ks are summarized in Table 1 , where Ref. 1 is 4-(2-(difluoromethyl)-lH-benzo[<i]imidazol-l-yl)-N- (2 -methyl- 1 -(2-(l -methylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino- 1 ,3,5-triazin-2- amine. TABLE 1. Biological Activity
Figure imgf000133_0001
Example II
ELISA assay for ΡΒΚβ
[00336] Cellular ΡΙ3Κβ activity was determined by measuring the phosphorylation of
AKT (Ser473) using an in-cell ELISA assay. PC-3 (prostate carcinoma) cells were obtained from ATCC (ATCC # CRL-1435). Growth medium was DMEM (CellGro # CV-10-013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and lx MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KC1, 86 mM Na3P04 (dibasic, anhydrous), 28 mM K3P04 (monobasic, anhydrous), pH 7.2. lOx stimulation mixture contained 50 μΜ LPA (Cayman # 62215) diluted in serum- free DMEM medium (CellGro # CV-10-013-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum-free DMEM to 2x final assay concentration. 2x fixative solution contained 8% formaldehyde (Amresco # Ml 34) diluted in PBS. Permeabilization solution contained PBS supplemented with 0.1% Triton X-100. Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer contained PBS supplemented with 0.1% Tween-20. Primary antibody solution was rabbit anti-pAKTS473 monoclonal antibody (Cell Signaling # 4060) and mouse anti-total S6 (Santa Cruz # 74459) diluted 1 :500 and 1 :2000, respectively, in blocking buffer. Secondary antibody solution was IRDye 800CW-conjugated goat anti-rabbit IgG (LiCor # 926-3221 1) and IRDye 680LT-conjugated goat anti-mouse IgG (LiCor # 926-68020) diluted 1 :2000 and 1 : 1000, respectively, in blocking buffer.
[00337] PC-3 cells were subcultured in growth medium and seeded into flat, clear bottom, 96-well plates (Corning # 3904) at 16000 cells/well, then incubated overnight in a 37 °C, 5% C02 incubator. Growth medium in plates was replaced with 100 μΕΛνεΙΙ serum- free DMEM and incubated overnight in a 37 °C, 5% C02 incubator. 50 μΕΛνεΙΙ of fresh serum- free DMEM was added to plates. Compound treatment was performed by adding 50 μΕΛνεΙΙ of 2x compound mixture to plates and incubating for 2 hrs at 37 °C, 5% C02, after which 11 μΙ^ΛνεΙΙ of lOx stimulation mixture was added and plates were incubated for 10 min at 37 °C, 5% C02. Fixation was performed by adding 110 μΙ,ΛνεΙΙ of 2x fixative solution to plates and incubating for 20 min at room temperature. Permeabilization was performed by replacing fixation solution with 150 μίΛνεΙΙ permeabilization solution and incubating for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times).
Permeabilization solution was replaced with 100 μίΛνεΙΙ blocking buffer and plates were incubated for 1 hr at room temperature, after which 100 μΕ/well of primary antibody solution was added and plates were incubated overnight at 4 °C. Plates were washed with wash buffer, after which 100 μΙ,ΛνεΙΙ of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash buffer, followed by a wash with PBS. After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images quantified using Licor Odyssey application software. IC50 values were determined by curve fitting using a Collaborative Drug Discovery database (www.collaborativedrug.com).
Example III
ELISA assay for ΡΒΚδ
[00338] Cellular PI3K5 activity was determined by measuring the phosphorylation of
AKT (Thr308) using a sandwich enzyme-linked immunosorbant assay (ELISA). Raji (Burkitt's Lymphoma) cells were obtained from ATCC (ATCC # CCL-86). Phosphate buffer saline (PBS) contained 2.7 M NaCl, 54 mM KC1, 86 mM Na3P04 (dibasic, anhydrous), and 28 mM K3P04 (monobasic, anhydrous) at pH 7.2. Wash buffer contained PBS supplemented with 0.05% Tween-20. Blocking buffer contained wash buffer supplemented with 1% BSA. A lOx stimulation mixture contained 5 μg/mL anti-Human IgM antibody (Sigma # 12386) diluted in serum- free RPMI medium (CellGro # CV-10-040-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), and then diluted in serum-free RPMI to 5 x final assay concentration.
[00339] Raji cells were subcultured in RPMI medium supplemented with 10%> fetal bovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and lx MEM non-essential amino acids. Sandwich ELISA plates were prepared by coating 96-well assay plates (Pierce # 15042) with 100 μΕ/well capture antibody (Cell Signaling Technology # 7142 or 7144) diluted in PBS. Plates were incubated overnight at 4 °C, then washed with wash buffer, after which 200 μΙ,ΛνεΙΙ blocking buffer was added to the plates and incubated at room temperature for at least 2 hrs. Raji cells were resuspended in serum-free RPMI medium and seeded into V-bottom, 2-mL 96-well blocks (Corning # 3961) at 106 cells/well, then incubated for 2 hrs in a 37 °C, 5% C02 incubator. Compound treatment was performed by adding the 5 x compound mixture to the cells and incubating for 2 hrs at 37 °C, 5% C02, after which the lOx stimulation mixture was added to the plates and incubated for 30 min at 37 °C, 5% C02. Cells were pelleted by centrifuging plates at 1500 RPM for 5 min at room
temperature. Media was carefully removed and cells were lysed by adding 100 μΙ,ΛνεΙΙ cell lysis buffer (Cell Signaling Technology # 9803) supplemented with protease and phosphatase inhibitors (Thermo Fisher # 78443). Plates were incubated on ice for 30 min, then the lysates (80 μΐ. for pAKTT308, 10 μΐ. for total AKT) were transferred to prepared assay plates and incubated at 4 °C overnight. After washing plates with wash buffer, 100 μΙ,ΛνεΙΙ detection antibody (Cell Signaling Technology # 7142 or 7144) diluted in blocking buffer was added to the plates and incubated for 1 hr at 37 °C. Plates were washed and 100 μΙ^ΛνεΙΙ of HRP- conjugated secondary antibody (Cell Signaling Technology # 7142 or 7144) diluted in blocking buffer was added to plates and incubated for 1 hr at room temperature. Plates were washed with wash buffer and 100 μΙ,ΛνεΙΙ of luminescent substrate was added to plates.
After 1 min on a plate shaker at medium speed, luminescence was read on a Wallac Victor2 plate reader. IC50 values were determined by curve fitting using a Collaborative Drug
Discovery database (www.collaborativedrug.com).
Example IV
ELISA assay for ΡΙ3Κα
[00340] PI3K alpha (PI3Ka) activity was determined by measuring the
phosphorylation of AKT (Thr308) using an in-cell ELISA assay. MDA-MB-453 (breast carcinoma) cells were obtained from ATCC (ATCC # HTB-131). Growth medium was DMEM (CellGro # CV-10-013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and 1 x MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KC1, 86 mM Na3P04 (dibasic, anhydrous), and 28 mM K3P04 (monobasic, anhydrous) at pH 7.2. Stimulation mixture (10 x) was 1000 ng/mL LONG® R3 human IGF-1 (Sigma # 11271) diluted in serum-free DMEM medium (CellGro # CV-10-013-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum- free DMEM to 2 x final assay concentration. Fixative solution (2 x) was 8% formaldehyde (Amresco # Ml 34) diluted in PBS. Permeabilization solution was PBS supplemented with 0.1% Triton X-100. Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer was PBS supplemented with 0.1% Tween-20. Primary antibody solution was rabbit anti-pAKT1308 monoclonal antibody (Cell Signaling # 2965) and mouse anti-total S6 (Santa Cruz # 74459) diluted 1 :500 and 1 :2000, respectively, in the blocking buffer. Secondary antibody solution was IRDye 800CW-conjugated goat anti-rabbit IgG (LiCor # 926-3221 1) and IRDye 680LT- conjugated goat anti-mouse IgG (LiCor # 926-68020) diluted 1 : 1000 and 1 :2000, respectively, in the blocking buffer.
[00341] MDA-MB-453 cells were subcultured in growth medium and seeded into flat, clear bottom, 96-well plates (Corning # 3904) at 40000 cells/well, then incubated overnight in a 5% C02 incubator at 37 °C. Growth medium in plates was replaced with 100 μίΛνεΙΙ serum-free DMEM and incubated overnight at 37 °C in a 5% C02 incubator. Fresh serum- free DMEM (50 μίΛνεΙΙ) was added to plates. Compound treatment was performed by adding 50 μίΛνεΙΙ of 2 x compound mixture to plates and incubating for 1 hr at 37 °C and 5% C02, after which 1 1 μίΛνεΙΙ of 10 x stimulation mixture was added and plates were incubated for 10 min at 37 °C and 5% C02. Fixation was performed by adding 1 10 μίΛνεΙΙ of 2 x fixative solution to the plates and incubating for 20 min at room temperature.
Permeabilization was performed by replacing fixation solution with 150 μίΛνεΙΙ
permeabilization solution and incubating for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times). Permeabilization solution was replaced with 100 μίΛνεΙΙ blocking buffer and plates were incubated for 1 hour at room temperature, after which 100 μίΛνεΙΙ of primary antibody solution was added and plates were incubated overnight at 4 °C. Plates were washed with wash buffer, after which 100 μίΛνεΙΙ of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash buffer, followed by a wash with PBS.
After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images were quantified using Licor Odyssey application software. IC50 values were determined by curve fitting using a Collaborative Drug Discovery database (www.collaborativedrug.com). Example V
ELISA assay for ΡΒΚγ
[00342] PI3K gamma (ΡΙ3Κγ) activity was determined by measuring the
phosphorylation of AKT (Ser473) using an in-cell ELISA assay. RAW 264.7 (mouse macrophage) cells were obtained from ATCC (ATCC # TIB-71). Growth medium was DMEM (CellGro # CV-10-013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and 1 x MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KC1, 86 mM Na3P04 (dibasic, anhydrous), and 28 mM K3P04 (monobasic, anhydrous) at pH 7.2. Stimulation mixture (10 x) was 500 ng/mL recombinant human complement component C5a (R&D systems # 2037- C5-025) diluted in serum-free DMEM medium (CellGro # CV-10-013-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum-free DMEM to 2 x final assay concentration. Fixative solution (2 x) was 8% formaldehyde (Amresco # Ml 34) diluted in PBS. Permeabilization solution was PBS supplemented with 0.1% Triton X-100. Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer was PBS supplemented with 0.1% Tween-20. Primary antibody solution was rabbit anti-pAKTS473 monoclonal antibody (Cell Signaling # 4060) and mouse anti-total S6 (Santa Cruz # 74459) diluted 1 :500 and 1 :2000, respectively, in the blocking buffer. Secondary antibody solution was IRDye 800CW-conjugated goat anti-rabbit IgG (LiCor # 926-3221 1) and IRDye 680LT-conjugated goat anti-mouse IgG (LiCor # 926-68020) diluted 1 : 1000 and 1 :2000, respectively, in the blocking buffer.
[00343] RAW 264.7 cells were subcultured in growth medium and seeded into flat, clear bottom, 96-well plates (Corning # 3904) at 70000 cells/well, then incubated overnight in a 37 °C, 5% C02 incubator. Growth medium in plates was replaced with 100 μΕΛνεΙΙ serum-free DMEM and incubated overnight in a 37 °C, 5% C02 incubator. Fresh serum-free DMEM (50 μΕΛνεΙΙ) was added to plates. Compound treatment was performed by adding 50 μΕΛνεΙΙ of 2 x compound mixture to plates and incubating for 2 hrs at 37 °C, 5% C02, after which 1 1 μΕΛνεΙΙ of 10 x stimulation mixture was added and plates were incubated for 3 min at 37 °C, 5% C02. Fixation was performed by adding 1 10 μΕΛνεΙΙ of 2 x fixative solution to plates and incubating for 20 min at room temperature. Permeabilization was performed by replacing fixation solution with 150 μΕΛνεΙΙ permeabilization solution and incubating for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times). Permeabilization solution was replaced with 100 μίΛνεΙΙ blocking buffer and plates were incubated for 1 hr at room temperature, after which 100 μίΛνεΙΙ of primary antibody solution was added and plates were incubated overnight at 4 °C. Plates were washed with wash buffer, after which 100 μΙ,ΛνεΙΙ of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash buffer, followed by a wash with PBS. After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images were quantified using Licor Odyssey application software. IC50 values were determined by curve fitting using a Collaborative Drug Discovery database (www.collaborativedrug.com).
[00344] The biological results of inhibition of cellular enzymatic activity of PBKs are summarized in Table 2, where Ref. 1 is 4-(2-(difluoromethyl)-lH-benzo[<i]imidazol-l-yl)-N- (2 -methyl- 1 -(2-(l -methylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino- 1 ,3,5-triazin-2- amine.
TABLE 2
Figure imgf000138_0001
[00345] 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:
A compound of Formula I:
Figure imgf000139_0001
(I)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where each Rx is independently hydrogen or Ci_6 alkyl;
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc;
R3 and R4 are each independently (a) hydrogen, cyano, halo, nitro, or oxo; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or R3 and R4 are linked together to form (i) a bond; or (ii) Ci_6 alkylene, Ci_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene;
each R5a and R5b is independently hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or independently, each pair of R5a and R5b that are attached to the same carbon atom together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl;
R5z is C3_io cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R6 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R7 is hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heterocyclyl, or -NRlbRlc;
each Rla, Rlb, Rlc, and Rld is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rlb and Rlc together with the N atom to which they are attached form heterocyclyl;
m is an integer of 1 or 2; and
n is an integer of 1, 2, 3, 4, 5, 6, or 7;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl is optionally substituted with one or more substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_ 6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Qa; and (c) -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, -OC(0)Ra, -OC(0)ORa,
-OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more substituents Qa;
wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl,
C6-i4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe,
-C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg,
-OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS (0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
2. The compound of claim 1 having the structure of Formula II:
Figure imgf000141_0001
(Π)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R5c is hydrogen, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and R5d is halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R5c and R5d together with the carbon atom to which they are attached form C3_io cycloalkyl or heterocyclyl; and
p and q are each independently an integer of 0, 1, 2, or 3;
wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q.
3. The compound of claim 2 having the structure of Formula III:
Figure imgf000142_0001
(III)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
4. The compound of claim 2 having the structure of Formula IV:
Figure imgf000142_0002
(IV)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
5. The compound of any of claims 1 to 4, wherein R5z is C6-14 aryl, optionally substituted with one or more substituents Q.
6. The compound of claim 5, wherein R5z is phenyl, optionally substituted with one or more substituents Q.
7. The compound of claim 5, wherein R5z is naphthyl, optionally substituted with one or more substituents Q.
8. The compound of any of claims 1 to 4, wherein R5z is heteroaryl, optionally substituted with one or more substituents Q.
9. The compound of claim 8, wherein R5z is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
10. The compound of claim 8, wherein R5z is 5-membered heteroaryl, optionally substituted with one or more substituents Q.
11. The compound of claim 8, wherein R5z is 6-membered heteroaryl, optionally substituted with one or more substituents Q.
12. The compound of claim 8, wherein R5z is bicyclic heteroaryl, optionally substituted with one or more substituents Q.
13. The compound of any of claims 1 to 4, wherein R5z is heterocyclyl, optionally substituted with one or more substituents Q.
14. The compound of claim 13, wherein R5z is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
15. The compound of claim 13, wherein R5z is 5-membered heterocyclyl, optionally substituted with one or more substituents Q.
16. The compound of claim 13, wherein R5z is 6-membered heterocyclyl, optionally substituted with one or more substituents Q.
17. The compound of claim 13, wherein R5z is bicyclic heterocyclyl, optionally substituted with one or more substituents Q.
18. The compound of claim 2 having the structure of Formula V:
Figure imgf000143_0001
(V)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R8a, R8b, R8c, R8d, and R8e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or
two of R8a, R8b, R8c, R8d, and R8e that are adjacent to each other form
C3-10 cycloalkenyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
19. The compound of claim 2 having the structure of Formula VI:
Figure imgf000144_0001
(VI)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R8a, R8b, R8c, R8d, and R8e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld, -NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or
two of R8a, R8b, R8c, R8d, and R8e that are adjacent to each other form C3-10 cycloalkenyl, C6-i4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
20. The compound of claim 2 having the structure of Formula VII:
Figure imgf000145_0001
(VII)
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R8a, R8b, R8c, R8d, and R8e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_i0 cycloalkyl, C6_i4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)Rla, -C(0)ORla, -C(0)NRlbRlc, -C(NRla)NRlbRlc, -ORla, -OC(0)Rla, -OC(0)ORla, -OC(0)NRlbRlc, -OC(=NRla)NRlbRlc, -OS(0)Rla, -OS(0)2Rla, -OS(0)NRlbRlc, -OS(0)2NRlbRlc, -NRlbRlc, -NRlaC(0)Rld, -NRlaC(0)ORld,
-NRlaC(0)NRlbRlc, -NRlaC(=NRld)NRlbRlc, -NRlaS(0)Rld, -NRlaS(0)2Rld,
-NRlaS(0)NRlbRlc, -NRlaS(0)2NRlbRlc, -SRla, -S(0)Rla, -S(0)2Rla, -S(0)NRlbRlc, or -S(0)2NRlbRlc; or
two of R8a, R8b, R8c, R8d, and R8e that are adjacent to each other form C3-10 cycloalkenyl, C6-i4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
21. The compound of any of claims 1 to 20, wherein R5a is hydrogen.
22. The compound of any of claims 1 to 21 , wherein R5b is hydrogen. The compound of claim 20 having the structure of Formula VIII
Figure imgf000146_0001
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
24. The compound of any of claims 2 to 23, wherein R5c is hydrogen or Ci_6 alkyl, optionally substituted with one or more substituents Q.
25. The compound of claim 24, wherein R5c is hydrogen.
5c
26. The compound of claim 24, wherein R c is methyl.
27. The compound of any of claims 2 to 26, wherein R5d is Ci_6 alkyl, optionally substituted with one or more substituents Q.
28. The compound of claim 27, wherein R5d is methyl.
29. The compound of any of claims 2 to 28, wherein R5c and R5d are methyl.
30. The compound of any of claims 18 to 29, wherein R8a is hydrogen, halo, Ci_6 alkyl, C6-14 aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more substituents Q.
31. The compound of claim 30, wherein R8a is C6-i4 aryl, optionally substituted with one or more substituents Q.
32. The compound of claim 30, wherein R8a is phenyl, optionally substituted with one or more substituents Q.
33. The compound of claim 30, wherein R a is phenyl, 2-fiuorophenyl,
2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,
2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difiuorophenyl, 4-fiuoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, or
3- morpholin-4-ylmethylphenyl.
34. The compound of claim 30, wherein R8a is heteroaryl, optionally substituted with one or more substituents Q.
35. The compound of claim 34, wherein R8a is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
36. The compound of claim 34 or 35, wherein R8a is 5-membered heteroaryl, each optionally substituted with one or more substituents Q.
37. The compound of claim 34 or 35, wherein R8a is 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
38. The compound of claim 34, wherein R8a is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.
39. The compound of claim 34, wherein R8a is imidazol-l-yl, pyrozol-4-yl,
1- methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl,
2-methoxypyridin-4-yl, pyrimidin-5-yl.
40. The compound of claim 30, wherein R8a is heterocyclyl, optionally substituted with one or more substituents Q.
41. The compound of claim 40, wherein R8a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
42. The compound of claim 40 or 41, wherein R8a is 5-membered heterocyclyl, each optionally substituted with one or more substituents Q.
43. The compound of claim 40 or 41, wherein R8a is 6-membered heterocyclyl, each optionally substituted with one or more substituents Q.
44. The compound of claim 40, wherein R8a is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
45. The compound of claim 40, wherein R8a is pyrrolidin-3-yl,
l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin- 1 -yl.
8b
46. The compound of any of claims 18 to 45, wherein R is hydrogen, halo, or Ci_6 alkyl optionally substituted with one or more substituents Q.
47. The compound of claim 46, wherein R8b is hydrogen.
48. The compound of any of claims 18 to 47, wherein R8c is hydrogen, halo, or Ci_6 alkyl optionally substituted with one or more substituents Q.
49. The compound of claim 48, wherein R8c is hydrogen.
8d
50. The compound of any of claims 18 to 49, wherein R is hydrogen, halo, or Ci_6 alkyl optionally substituted with one or more substituents Q.
8d
51. The compound of claim 50, wherein R is hydrogen.
52. The compound of any of claims 18 to 51 , wherein R8e is hydrogen, halo, or Ci_6 alkyl optionally substituted with one or more substituents Q.
53. The compound of claim 52, wherein R8e is hydrogen.
54. The compound of any of claims 18 to 29, wherein R8a is C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R8b, R8c, R8d, and R8e are hydrogen.
55. The compound of any of claims 1 to 54, wherein R1 is hydrogen.
56. The compound of any of claims 1 to 54, wherein R1 is -ORla.
57. The compound of claim 56, wherein R1 is -0-C1-6 alkyl.
58. The compound of claim 56, wherein R1 is methoxy.
59. The compound of any of claims 1 to 58, wherein R2 is hydrogen.
60. The compound of any of claims 1 to 58, wherein R2 is -NRlbRlc.
61. The compound of claim 60, wherein R2 is amino.
62. The compound of any of claims 1 to 61, wherein R3 is hydrogen.
63. The compound of any of claims 1 to 62, wherein R4 is hydrogen.
64. The compound of any of claims 1 to 63, wherein R6 is hydrogen or Ci_6 alkyl, optionally substituted with one or more substituents Q.
65. The compound of claim 64, wherein R6 is hydrogen.
66. The compound of claim 64, wherein R6 is methyl.
67. The compound of any of claims 1 to 66, wherein R7 is (i) hydrogen; (ii) Ci_6 alkyl, optionally substituted with one or more substituents Q; or (iii) -NRlbRlc.
68. The compound of claim 67, wherein R7 is Ci_6 alkyl, optionally substituted with one or more substituents Q.
69. The compound of claim 67, wherein R7 is methyl, fluoromethyl,
difluoromethyl, or trifluoromethyl.
70. The compound of claim 67, wherein R7 is methyl.
71. The compound of claim 67, wherein R7 is -NH2.
72. The compound of any of claims 1 to 71, wherein m is 1.
73. The compound of any of claims 1 to 71, wherein m is 2.
74. The compound of any of claims 1 to 73, wherein X is N.
75. The compound of any of claims 1 to 73, wherein X is CRX.
76. The compound of claim 75, wherein X is CH.
77. The compound of any of claims 1 to 76, wherein Y is N.
78. The compound of any of claims 1 to 76, wherein Y is CRX.
79. The compound of claim 78, wherein Y is CH.
80. The compound of any of claims 1 to 79, wherein Z is N.
81. The compound of any of claims 1 to 79, wherein Z is CRX.
82. The compound of claim 81, wherein Z is CH.
83. The compound of any of claims 1 to 73, wherein X, Y, and Z are N.
84. The compound of claim 1 selected from the group consisting of N-(2-methyl- 1 -(2-( 1 -methylpiperidin-4-yl)phenyl)propan-2-yl)-4-(2-(methylsulfonyl)- 1H- benzo[<i]imidazol- 1 -yl)-6-morpholino- 1 ,3 ,5-triazin-2-amine, and N-(2 -methyl- 1 -(2- (piperidin-4-yl)phenyl)propan-2-yl)-4-(2-(methylsulfonyl)-lH-benzo[(i]imidazol-l-yl)-6- morpholino-l,3,5-triazin-2-amine; and isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
85. A pharmaceutical composition comprising the compound of any of claims 1 to 84, 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; and one or more pharmaceutically acceptable excipients.
86. The pharmaceutical composition of claim 85, wherein the pharmaceutical composition is formulated for single dose administration.
87. The pharmaceutical composition of claim 85 or 86, wherein the
pharmaceutical composition is formulated as an oral, parenteral, or intravenous dosage form.
88. The pharmaceutical composition of claim 87, wherein the pharmaceutical composition is formulated as an oral dosage form.
89. The pharmaceutical composition of claim 88, wherein the pharmaceutical composition is formulated as a tablet or capsule.
90. The pharmaceutical composition of any of claims 85 to 89, further comprising a second therapeutic agent.
91. A method for the treatment, prevention, or amelioration of one or more symptoms of a PBK-mediated disorder, disease, or condition in a subject, which comprises administering to the subject the compound of any of claims 1 to 84 or the pharmaceutical composition of any of claims 85 to 90.
92. The method of claim 91, wherein the PBK-mediated disorder, disease, or condition is an inflammatory disease.
93. The method of claim 91, wherein the PBK-mediated disorder, disease, or condition is a proliferative disease.
94. The method of any of claims 91 to 93, wherein the compound or the composition is administered in combination with a second therapeutic agent.
95. A method for modulating PI3K enzymatic activity, comprising contacting a PI3K enzyme with the compound of any of claims 1 to 84 or the pharmaceutical composition of any of claims 85 to 90.
96. The method of any of claims 91 to 95, wherein the PBK is a wild type.
97. The method of claim 96, wherein the PBK is a PBK variant.
98. The method of claim 96 or 97, wherein the PBK is a Class I PBK.
99. The method of claim 98, wherein the PBK is pi 10γ.
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