PPARG modulators

Abstract

The present disclosure provides compounds of the formulas described herein (e.g., Formula (I)), and pharmaceutically acceptable salts and prodrugs thereof, which are non-agonist modulators of peroxisome proliferator-activated receptor gamma (PPARγ). The present disclosure also provides pharmaceutical compositions and kits comprising the compounds, or pharmaceutically acceptable salts or prodrugs thereof, and methods of treating or preventing diseases or disorders by administering the compounds, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof to a subject in need of treatment or prevention.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 437,891, filed January 9, 2023, entitled PPARG Modulators, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Peroxisome proliferator-activated receptor γ (PPARγ) is implicated in carcinogenesis initiation and tumor progression in several major cancers, including colorectal and pancreatic cancer. Because PPARγ plays both tumor suppressor and oncogenic roles, tumor type and genetic background are relevant factors. Gene signatures of PPARγ phosphorylation have been shown to be associated with worse outcomes in response to chemotherapy in human patients. Previous studies have demonstrated that PPARγ phosphorylation at S273 occurs in cancer cells exposed to DNA-damaging agents, and inhibition of this phosphorylation increases the accumulation of DNA damage and leads to apoptotic cell death. Furthermore, a subset of bladder cancer cell lines, accounting for approximately 10–20% of human bladder cancers, along with esophageal and prostate cancer cell lines, that overexpress PPARγ have been identified, potentially representing a more targeted translational pathway in oncology. Summary of the Invention

[0003] Compounds that are non-activating (non-agonist) peroxisome proliferator-activated receptor gamma (PPARγ) modulators are useful for treating conditions where non-regulation of PPARγ activity is medically necessary, such as the treatment of progressive bone disease and / or selected cancers. Such compounds can inhibit the phosphorylation of PPARγ at serine 273, but are not agonists of the receptor itself. By avoiding agonism of the receptor, the compounds may minimize or reduce the side effects associated with the administration of full and partial PPARγ agonists, such as significant weight gain, edema, impaired bone growth or formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, and / or hepatotoxicity. Non-agonist PPARγ modulators can be used to treat progressive bone diseases such as osteoporosis, Paget's disease, multiple myeloma, and hyperparathyroidism.

[0004] The compounds disclosed herein may be antagonists or inverse agonists of PPARγ modulators and have numerous potential applications in a variety of disease conditions. These include potential intractable diseases, particularly in the therapeutic areas of bone marrow, stem cells, obesity metabolism, and reproductive endocrinology. The compounds may also be useful in a subset of bladder cancer, esophageal cancer, and prostate cancer, which overexpress PPARγ and may represent a more targeted translational pathway in oncology.

[0005] Thus, in one embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or prodrug thereof, wherein A 1 , A 2 , Y., L. 1 , L 2 , L 3 , R 1 , R 2A , R 2B , R B , and p is as defined herein.

[0006] In another aspect, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein. In some embodiments, the pharmaceutical compositions comprise an excipient.

[0007] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a provided compound or pharmaceutical composition. In certain embodiments, the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease).

[0008] In another aspect, the present disclosure provides a method for modulating (e.g., upregulating, downregulating, increasing, decreasing) peroxisome proliferator-activated receptor gamma (PPARγ) in a subject in need of treatment or in a cell, tissue, or biological sample, comprising administering an effective amount of a provided compound or pharmaceutical composition to a subject in need of treatment or contacting the cell, tissue, or biological sample with the cell, tissue, or biological sample. In some embodiments, the cell, tissue, or biological sample is in vivo. In some embodiments, the cell, tissue, or biological sample is in vitro.

[0009] In another aspect, the present disclosure provides a kit comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.

[0010] It should be understood that the above concepts and additional concepts discussed below may be arranged in any suitable combination, and that the disclosure is not limited in this respect. Furthermore, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0011] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide those skilled in the art with general definitions for many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The HarperCollins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to the references unless otherwise specified.

[0012] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in accordance with the Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry and specific functional groups and reactivities are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7 thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0013] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, such as a racemic mixture or a mixture enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses compounds as individual isomers substantially free of other isomers or as mixtures of various isomers. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. All such isomers of the compounds herein are expressly included in the present invention.

[0014] When a range of values ​​("range") is listed, each value and subrange within that range is encompassed therein. Unless otherwise specified, a range includes both endpoints of the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It includes alkyl.

[0015] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0016] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), n-octyl (C10), n-isopropyl (C11), n-isopropyl (C12), n-isopropyl (C13), n-isopropyl (C14), n-isopropyl (C15), n-isopropyl (C16), n-isopropyl (C17), n-isopropyl (C18), n-isopropyl (C19), n-isopropyl (C20), n-isopropyl (C21), n-isopropyl (C22), n-isopropyl (C23), n-isopropyl (C24), n-isopropyl (C25), n-isopropyl (C26), n-isopropyl (C27), n-isopropyl (C28), n-isopropyl (C29 ... 12 ), and the like. Unless otherwise specified, each alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In some embodiments, an alkyl group is an unsubstituted C 1-12 unsubstituted C alkyl (e.g., —CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu), etc. 1-6 In some embodiments, the alkyl group is a substituted C 1-12 alkyl (e.g., -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, or substituted C such as benzyl (Bn) 1-6 alkyl).

[0017] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C 1-20 In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a "perfluoroalkyl" group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0018] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur in the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain and / or located at one or more terminal positions of the parent chain). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-20 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, heteroalkyl groups are saturated groups having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-11 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-12 In some embodiments, the heteroalkyl group is a substituted heteroC 1-12 It is alkyl.

[0019] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms ("C 2-20 In some embodiments, the alkenyl group has 2 to 12 carbon atoms ("C 2-12 In some embodiments, the alkenyl group has 2 to 11 carbon atoms ("C 2-11 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-20 In some embodiments, the alkenyl group is a substituted C 2-20 In an alkenyl group, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH3 or [ka] ) can be in the (E)- or (Z)-configuration.

[0020] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur in the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain and / or located at one or more terminal positions of the parent chain). In certain embodiments, a heteroalkenyl group refers to a group having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroalkenyl"). 2-20 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 12 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-12 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 11 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-11 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC alkenyl"). In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or two heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-20 In some embodiments, the heteroalkenyl group is a substituted heteroC 2-20 It is alkenyl.

[0021] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 1-20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-20 In some embodiments, the alkynyl group is a substituted C 2-20 It is alkynyl.

[0022] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur in the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain and / or located at one or more terminal positions of the parent chain). In certain embodiments, a heteroalkynyl group refers to a group having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroalkynyl"). 2-20 In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3In some embodiments, heteroalkynyl groups have 2 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC alkynyl"). In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or two heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-20 In some embodiments, the heteroalkynyl group is a substituted heteroC 2-20 It is alkynyl.

[0023] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the carbocyclyl group has 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, the carbocyclyl group has 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Representative C 3-6 Carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Representative C 3-8 The carbocyclyl group includes the C 3-6 Included are carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Representative C 3-10 The carbocyclyl group includes the C 3-8 Carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. Representative C 3-8 The carbocyclyl group includes the C 3-10 Carbocyclyl group and cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14), and the like. As the above examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), may be saturated, and may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the carbocyclyl ring), in which case the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 In one embodiment, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0024] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, cycloalkyl groups include unsubstituted C 3-14 In some embodiments, the cycloalkyl group is a substituted C 3-14 In certain embodiments, a carbocyclyl contains, valence permitting, 0, 1, or 2 C=C double bonds in the carbocyclic ring system.

[0025] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system ("3- to 14-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")), can be saturated, and can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups (where the point of attachment is on the carbocyclyl ring or the heterocyclyl ring) or to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring), in which case the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl (wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, valence permitting).

[0026] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system ("5- to 10-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system ("5- to 8-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system ("5- to 6-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0027] Representative 3-membered heterocyclyl groups containing one heteroatom include aziridinyl, oxiranyl, and thiiranyl. Representative 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Representative 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Representative 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiolanyl. Representative 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Representative 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Representative 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Representative 6-membered heterocyclyl groups containing three heteroatoms include triazinyl. Representative 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Representative 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl.Representative bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5 ,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0028] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared among the rings) having 6 to 14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups (where the radical or point of attachment is on the aryl ring), in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0029] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group (where the point of attachment is on the alkyl portion).

[0030] The term "heteroaryl" refers to a radical ("5-14-membered heteroaryl") of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared around the ring) having ring carbon atoms and 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) in the aromatic ring system. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups (where the point of attachment is on the heteroaryl ring), in which case the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups (where the point of attachment is on either the aryl or heteroaryl ring); in such cases, the number of ring members refers to the number of ring members in the fused polycyclic ring system (aryl / heteroaryl ring system). In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, for example, on a ring containing a heteroatom (e.g., 2-indolyl) or on a ring containing no heteroatoms (e.g., 5-indolyl). In some embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl (wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur). In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0031] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system ("5- to 10-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system ("5- to 8-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system ("5- to 6-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0032] Representative 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Representative 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Representative 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Representative 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Representative 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Representative 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Representative 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Representative 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Representative 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Representative 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Representative tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0033] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group (wherein the point of attachment is on the alkyl portion).

[0034] The term "unsaturated bond" refers to a double or triple bond.

[0035] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0036] The terms "saturated" or "fully saturated" refer to a moiety that does not contain any double or triple bonds, e.g., the moiety contains only single bonds.

[0037] The addition of the suffix "-ene" indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0038] Unless otherwise expressly specified, a group may be optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. "Optionally substituted" refers to a group that is substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position is substituted in a given structure, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is not limited in any way by the representative substituents described herein.

[0039] In certain embodiments, a "substituted" group (e.g., a "substituted" alkyl, a "substituted" alkenyl, a "substituted" alkynyl, a "substituted" heteroalkyl, a "substituted" heteroalkenyl, a "substituted" heteroalkynyl, a "substituted" carbocyclyl, a "substituted" heterocyclyl, a "substituted" aryl, or a "substituted" heteroaryl group) can be selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A , -OC(=NRA )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NRA S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, and / or -B(OR A ) substituted with one or more of two groups.

[0040] Representative carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(Rbb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(Rcc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group, wherein X - is the counterion, Alternatively, the two geminal hydrogens on the carbon atom can be ═O, ═S, ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb, or =NOR cc is substituted with a group During the ceremony, R aa are each independently 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb are each independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc are each independently hydrogen, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+ X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(OR ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2、C 1-10 アルキル、C 1-10Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd The substituents may be bonded to form =O or =S, and X - is the counterion, R ee are each independently 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff are each independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10Carbocyclyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are joined to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently contain 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, or two geminal R gg the substituents may be linked to form =O or =S; X - are counter ions, respectively.

[0041] In some embodiments, the carbon atom substituents are each independently halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb In some embodiments, the carbon atom substituents are each independently a halogen, a substituted (e.g., substituted with one or more halogens), or an unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb)2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, if attached to an oxygen atom, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or if attached to a sulfur atom, a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and R bb are each independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In some embodiments, the carbon atom substituents are each independently a halogen, a substituted (e.g., substituted with one or more halogens) or an unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb In certain embodiments, the carbon atom substituents are each independently a halogen, a substituted (e.g., substituted with one or more halogen moieties) or an unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, if attached to an oxygen atom, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or if attached to a sulfur atom, a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and R bbare each independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0042] In some embodiments, the molecular weight of the carbon atom substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0043] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0044] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)Raa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb ))2, wherein X - , R aa , R bb , and R cc is as defined herein).

[0045] The term "thiol" or "thio" refers to the group -SH. The term "substituted thiol" or "substituted thio" by extension refers to a thiol group in which the sulfur atom directly attached to the parent molecule is replaced with a group other than hydrogen, such as -SR aa , -S=SR cc , -SC(=S)SR aa , -SC(=S)OR aa , -SC(=S)N(R bb )2, -SC(=O)SR aa , -SC(=O)OR aa , -SC(=O)N(R bb )2, and -SC(=O)R aa wherein R aa and R cc is as defined herein).

[0046] The term "amino" refers to the group -NH. The term "substituted amino" extends to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0047] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, and includes -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2)2)2, wherein R aa , R bb , and R cc is as defined herein, where —NH(R bb ) group R bb is not hydrogen).

[0048] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two non-hydrogen groups, such as -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2)2, wherein R aa , R bb , and R cc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen).

[0049] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, such as -N(Rbb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein).

[0050] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein).

[0051] The term "sulfinyl" refers to -S(=O)R aa (wherein R aa is as defined herein).

[0052] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, and -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, wherein R X1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 The groups together form a 5- to 6-membered heterocycle. Representative acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acid halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, which result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0053] The term "carbonyl" refers to the carbon directly bonded to the parent molecule being sp 2 Groups that are hybridized and substituted with oxygen, nitrogen, or sulfur atoms, such as ketones (-C(=O)R aa ), carboxylic acid (-CO2H), aldehyde (-CHO), ester (-CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amide (-C(=O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imine (-C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb ) 2) (wherein R aa and R bb is as defined herein).

[0054] The term "silyl" refers to -Si(R aa )3, where R aa is as defined herein).

[0055] The term "phosphino" refers to -P(R cc )2, where R cc is as defined herein).

[0056] The term "phosphono" refers to -(P=O)(OR cc )2, where R aa and R cc is as defined herein).

[0057] The term "phosphoramide" refers to -O(P=O)(N(R bb )2)2, where R bbare each as defined herein).

[0058] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0059] Nitrogen atoms may be substituted or unsubstituted, valence permitting, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Representative nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R ccThe groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd group, wherein R aa , R bb , R cc , and R dd is as defined above.

[0060] In certain embodiments, the nitrogen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group. In certain embodiments, the nitrogen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or, when attached to an oxygen atom, an oxygen protecting group, R bb are each independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In some embodiments, the nitrogen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group.

[0061] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(Rcc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd group, wherein R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0062] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a nitrogen protecting group (e.g., —C(═O)R aa ) is a moiety containing a nitrogen atom to which ) is directly bonded. In such embodiments, the nitrogen protecting groups, taken together with the nitrogen atom to which they are attached, are each independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0063] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., —C(═O)OR aaIn such embodiments, the nitrogen protecting groups, taken together with the nitrogen atom to which they are attached, are each independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), ), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl t-butylcarbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc ), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-Dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate mate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-di Methoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N -dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0064] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a nitrogen protecting group (e.g., —S(═O)R aa In such embodiments, the nitrogen protecting groups, taken together with the nitrogen atom to which they are attached, are each independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 4-methoxybenzenesulfonamide (Mtb ... Selected from the group consisting of methylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0065] In certain embodiments, the nitrogen protecting groups, taken together with the nitrogen atom to which they are attached, are each independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyl Cyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, the two nitrogen protecting groups, taken together with the nitrogen atom to which they are attached, are N,N'-isopropylidenediamine.

[0066] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0067] In certain embodiments, the oxygen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group. In some embodiments, the oxygen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10alkyl, or, when attached to an oxygen atom, an oxygen protecting group, R bb are each independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In some embodiments, the oxygen atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or oxygen protecting group.

[0068] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein X - , R aa , R bb , and R ccis as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0069] In certain embodiments, the oxygen protecting groups, taken together with the oxygen atom to which they are attached, are each selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl (SOM), methyl ... 2-Methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[ (2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoro Ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyl 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl)carbamoyl]trityl ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl ether (IETr-OR), 1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloro Acetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methan Benzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethyl)benzoate (E)-isobutyrate, (E)-isopropyl methyl ... The alkyl group is selected from the group consisting of 2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0070] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0071] In certain embodiments, the sulfur atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, the sulfur atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or, when attached to an oxygen atom, an oxygen protecting group; R bb are each independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In some embodiments, the sulfur atom substituents are each independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or sulfur protecting group.

[0072] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). In some embodiments, the sulfur protecting group is each -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(Rcc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0073] In certain embodiments, the molecular weight of the substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, the substituent includes 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, the substituent includes 0, 1, 2, or 3 hydrogen bond acceptors.

[0074] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (e.g., containing a formal negative charge of one). Anionic counterions can also be multivalent, such as divalent or trivalent (e.g., containing two or more formal negative charges). Representative counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - 、 HSO4 - , sulfonates (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, and the like), carboxylates (e.g., acetic acid, propionic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, and the like), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Representative counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- 、 B4O7 2- , SO4 2- , S2O3 2-, carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, and the like), and carboranes.

[0075] "Leaving group" (LG) is an art-recognized term that refers to an atomic or molecular fragment that departs with an electron pair in a heterolytic bond cleavage (where the molecular fragment is an anion or a neutral molecule). As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, e.g., Smith, March, Advanced Organic Chemistry 6th ed. (501-502). Representative leaving groups include halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc(wherein R is as defined herein). Further examples of suitable leaving groups include, but are not limited to, halogen, alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is a brosylate such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0076] Use of the phrase "at least one example" refers to 1, 2, 3, 4, or more examples, but also encompasses ranges (e.g., 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 examples, inclusive).

[0077] A "non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0078] These and other representative substituents are described in more detail in the detailed description, examples, and claims. The present invention is not limited in any way by the above list of representative substituents.

[0079] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. The term "salt" refers to an ionic compound resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), and therefore is electrically neutral (has no net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, and lactate. Salts derived from appropriate bases include salts of alkali metals, alkaline earth metals, ammonium, and N-methyl-N ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0080] The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable risk-benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, etc.) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, etc.), or formed using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobacillus acid salts, and benzoates. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations, where appropriate, formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0081] The term "solvate" refers to a compound or salt form thereof that is associated with a solvent, typically through solvolysis. This physical association may involve hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0082] The term "hydrate" refers to a compound associated with water. Generally, the number of water molecules contained in a hydrate of a compound is proportional to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, such as a monohydrate (x is 1), a hypohydrate (x is a number greater than 0 but less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0083] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may favor one crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0084] The term "cocrystal" refers to a crystal structure comprising at least two different components (e.g., a compound and an acid), where each component is independently an atom, ion, or molecule. In certain embodiments, neither of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound and an acid differs from a salt formed from the compound and an acid. In a salt, the compound is complexed with the acid in a manner such that proton transfer from the acid to the compound (e.g., complete proton transfer) occurs readily at room temperature. However, in a cocrystal, the compound is complexed with the acid in a manner such that proton transfer from the acid to the compound does not occur readily at room temperature. In certain embodiments, in a cocrystal, there is substantially no proton transfer from the acid to the compound. In certain embodiments, there is partial proton transfer from the acid to the compound. Cocrystals can be useful for improving the properties of a compound (e.g., solubility, stability, and ease of formulation).

[0085] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, such as temperature, solvent, and pH. Tautomerization (i.e., the reaction providing a pair of tautomers) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0086] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0087] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of one another are called "enantiomers." When a compound has an asymmetric center, e.g., when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral centers, described by the Cahn-Prelog R,S ordering rules, or designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively) depending on how the molecule rotates the plane of polarized light. Chiral compounds can exist as either individual enantiomers or as mixtures of them. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0088] The term "isotopically labeled compound" refers to a derivative of a compound that differs structurally from the compound only in that at least one atom of the derivative contains at least one isotope enriched above its natural abundance (e.g., 3-fold, 10-fold, 30-fold, 100-fold, 300-fold, 1,000-fold, 3,000-fold, or greater than 10,000-fold enrichment), while each atom of the compound contains the isotope at their natural abundance. In certain embodiments, the isotope enriched above its natural abundance is 2 H. In certain embodiments, the isotope enriched above its natural abundance is 13 C. 15 N, or 18 It is O.

[0089] The term "prodrug" refers to a compound having a cleavable group that becomes a pharmaceutically active compound described herein in vivo by solvolysis or under physiological conditions. Examples include choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, for example, esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.

[0090] The terms "pharmaceutical composition," "composition," and "formulation" are used interchangeably.

[0091] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or geriatric adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic or genetically modified animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0092] The term "biological sample" refers to any sample, including tissue samples (e.g., tissue sections and needle biopsies of tissue), cell samples (e.g., cell smears (such as Pap smears or blood smears) or samples of cells obtained by microdissection), samples of whole organisms (e.g., yeast or bacterial samples), or cell fractions, debris, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any material containing biomolecules derived from an initial biological sample.

[0093] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, into or onto a subject.

[0094] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed. In other embodiments, treatment may be administered when there are no signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., taking into account symptom history and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0095] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not currently have a disease, has not previously had the disease, but is at risk of developing the disease, or who has previously had the disease, but does not currently have the disease, and is at risk of developing a recurrence of the disease. In certain embodiments, the subject is at higher risk of developing a disease or a recurrence of the disease than the average healthy person in the population. In some embodiments, the subject is at risk of developing a disease or condition due to an environmental factor (e.g., sun exposure).

[0096] The terms "condition," "disease," and "disorder" are used interchangeably.

[0097] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. An effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the method, route, and desired or required frequency of administration, the species, age, and health or general condition of the subject, etc. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of a compound described herein in a single administration. In some embodiments, the effective amount is the combined amount of a compound described herein in multiple administrations. In some embodiments, the desired dosage is delivered three times a day, twice a day, once a day, every other day, every third day, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0098] In certain embodiments, an effective amount of the compound for one or more daily administrations to a 70 kg adult contains from about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the compound per unit dosage form.

[0099] It is understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount to be administered to children or adolescents can be determined by a physician or person skilled in the art and may be lower than or the same as the amount administered to adults.

[0100] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic effect in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic effect in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of treatment. In some embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of treatment, and reduces side effects experienced by the subject (e.g., weight gain, edema, impaired bone growth or bone formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, hepatotoxicity) compared to administration of a PPARγ agonist. In some embodiments, a therapeutically effective amount is an amount sufficient to modulate (e.g., upregulate, downregulate, increase, decrease) PPARγ (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject in need of treatment or in a cell, tissue, or biological sample.In certain embodiments, a therapeutically effective amount is an amount sufficient to act as an antagonist PPARγ (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject in need of treatment or in a cell, tissue, or biological sample. In certain embodiments, a therapeutically effective amount is an amount sufficient to act as an inverse agonist of PPARγ (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject in need of treatment or in a cell, tissue, or biological sample. In some embodiments, a therapeutically effective amount is an amount that is not sufficient to activate PPARγ. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce the phosphorylation of PPARγ at serine 273 (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In some embodiments, a therapeutically effective amount is an amount sufficient to normalize the functional remodeling activity of osteocytes, osteoblasts, and / or osteoclasts to produce healthy bone structure and / or bone strength. In some embodiments, the functional remodeling activity is measured by an increase in cortical bone area, a decrease in intramedullary fat, an increase in bone material strength, and / or an increase in bone metabolic markers and circulating osteocyte progenitor cells. See, for example, LA Stechschulte et al., EBioMedicine 2016, 10, 174-184.In some embodiments, a therapeutically effective amount is an amount sufficient to reduce marrow adiposity (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In some embodiments, a therapeutically effective amount is an amount sufficient to increase cancellous and / or cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In one embodiment, the therapeutically effective amount is an amount sufficient to improve metabolic parameters by reducing fasting plasma glucose to the normal range of less than 100 mg / dl and HbA1c to less than 6%.

[0101] A "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a condition, or one or more signs and / or symptoms associated with a condition. In some embodiments, a prophylactically effective amount is an amount that improves overall prevention and / or enhances the prophylactic effect of another prophylactic agent. In some embodiments, a prophylactically effective amount is an amount sufficient to prevent a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of prevention. In some embodiments, a prophylactically effective amount is an amount effective to reduce the risk of developing a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of prevention. In some embodiments, the prophylactically effective amount is an amount sufficient to prevent or reduce the risk of developing a disease or disorder associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., progressive bone disease, proliferative disease, metabolic disease) in a subject in need of prevention, and to reduce the side effects experienced by the subject (e.g., weight gain, edema, impaired bone growth or bone formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, hepatotoxicity) compared to administration of a PPARγ agonist. In some embodiments, the prophylactically effective amount is an amount sufficient to modulate (e.g., upregulate, downregulate, increase, decrease) PPARγ (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject in need of prevention, or in a cell, tissue, or biological sample.In certain embodiments, a prophylactically effective amount is an amount sufficient to act as an antagonist PPARγ (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject or cell, tissue, or biological sample in need of prevention. In certain embodiments, a prophylactically effective amount is an amount sufficient to act as an inverse agonist of PPARγ (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%) in a subject or cell, tissue, or biological sample in need of prevention. In some embodiments, a prophylactically effective amount is an amount that is insufficient to activate PPARγ. In some embodiments, a prophylactically effective amount is an amount sufficient to reduce the phosphorylation of PPARγ at serine 273 (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In some embodiments, a prophylactically effective amount is an amount sufficient to normalize the functional remodeling activity of osteocytes, osteoblasts, and / or osteoclasts to result in healthy bone structure and / or bone strength. In some embodiments, the functional remodeling activity is measured by an increase in cortical bone area, a decrease in intramedullary fat, an increase in bone material strength, and / or an increase in bone metabolic markers and circulating osteocyte progenitor cells. See, for example, LA Stechschulte et al., EBioMedicine 2016, 10, 174-184.

[0102] In certain embodiments, a prophylactically effective amount is an amount sufficient to decrease intramedullary fat (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, a prophylactically effective amount is an amount sufficient to increase cancellous and / or cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In one embodiment, the prophylactically effective amount is an amount sufficient to improve metabolic parameters by reducing fasting plasma glucose to the normal range of less than 100 mg / dl and HbA1c to less than 6%.

[0103] The terms "metabolic disease" and "metabolic disorder" refer to any disorder involving an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. Metabolic disorders are associated with either a deficiency or excess in metabolic pathways, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors that affect metabolism include, but are not limited to, endocrine (hormonal) regulatory systems (e.g., insulin pathways, enteroendocrine hormones such as GLP-1 and PYY), neuroregulatory systems (e.g., brain GLP-1), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, metabolic syndrome, hyperinsulinemia, acidemia, and obesity. In some embodiments, the metabolic disease is obesity, hypertriglyceridemia, metabolic syndrome, insulin resistance, hyperinsulinemia, diabetes, or acidemia. DETAILED DESCRIPTION OF THE INVENTION

[0104] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or arrangements, as such may, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting, unless specifically defined herein.

[0105] compound In one embodiment, the present disclosure provides a compound of formula (I): [ka] [In the formula, A 1 is a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; A 2 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L 1 , L 2 , and L 3 are each independently a bond or substituted or unsubstituted alkylene; Y is C or N; R 1 each independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NRA C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)SR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )R A , -NR A C(=NR A ) OR A , -NR A C(=NR A )SR A , -NR A C(=NR A )N(R A )2, -NR A S(=O)R A , -NR A S(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2; R 2A is absent, hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group, except that when Y is N, R2A does not exist; R 2B is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A , -OC(=NR A )SR A , -OC(=NR A )N(R A )2, -OS(=O)R A、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR AS(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2; R A are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, if attached to a nitrogen atom, a nitrogen protecting group, if attached to an oxygen atom, an oxygen protecting group, or if attached to a sulfur atom, a sulfur protecting group; or R A two of which join with the atom between them to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; R B is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; p is 0, 1, 2, or 3] or a pharmaceutically acceptable salt or prodrug thereof.

[0106] In certain embodiments, the compound of formula (I) has the formula (Ia): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0107] In certain embodiments, the compound of formula (I) has the formula (Iai): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0108] In certain embodiments, the compound of formula (I) has the formula (Ia-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0109] In certain embodiments, the compound of Formula (I) has the formula (Ia-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0110] In certain embodiments, the compound of formula (I) has the formula (Ib): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0111] In certain embodiments, the compound of formula (I) has the formula (Ibi): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0112] In certain embodiments, the compound of formula (I) has the formula (Ib-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0113] In certain embodiments, the compound of Formula (I) has the formula (Ib-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0114] In certain embodiments, the compound of Formula (I) has the formula (Ic): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0115] In certain embodiments, the compound of formula (I) has the formula (Ici): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0116] In certain embodiments, the compound of formula (I) has the formula (Ic-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0117] In certain embodiments, the compound of Formula (I) has the formula (Ic-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0118] In certain embodiments, the compound of formula (I) has the formula (Id): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0119] In certain embodiments, the compound of formula (I) has the formula (Idi): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0120] In certain embodiments, the compound of formula (I) has the formula (Id-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0121] In certain embodiments, the compound of formula (I) has the formula (Id-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0122] In certain embodiments, the compound of formula (I) has the formula (Iei): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0123] In certain embodiments, the compound of formula (I) has the formula (Ie-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0124] In certain embodiments, the compound of formula (I) has the formula (Ie-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0125] In some embodiments, the compound of formula (I) has the formula (Ie-iv): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0126] In certain embodiments, the compound of formula (I) has the formula (Ifi): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0127] In certain embodiments, the compound of formula (I) has the formula (If-ii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0128] In some embodiments, the compound of formula (I) has the formula (If-iii): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0129] In some embodiments, the compound of formula (I) has the formula (If-iv): [ka] or a pharmaceutically acceptable salt or prodrug thereof.

[0130] A 1 In one embodiment, A 1 is a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0131] In one embodiment, A 1 is substituted or unsubstituted carbocyclyl. 1 is a substituted or unsubstituted monocyclic carbocyclyl (e.g., a substituted or unsubstituted monocyclic 3- to 10-membered carbocyclyl). 1 is a substituted or unsubstituted polycyclic carbocyclyl (e.g., a substituted or unsubstituted bicyclic or tricyclic 3- to 14-membered carbocyclyl). 1 is a substituted or unsubstituted saturated carbocyclyl. 1 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclononyl, or substituted or unsubstituted cyclodecyl. 1 is substituted carbocyclyl. 1 is a substituted saturated carbocyclyl. 1 is substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, substituted cycloheptyl, substituted cyclooctyl, substituted cyclononyl, or substituted cyclodecyl.

[0132] In one embodiment, A 1 is substituted or unsubstituted heterocyclyl. 1 is a substituted or unsubstituted monocyclic heterocyclyl (e.g., a substituted or unsubstituted monocyclic 3- to 10-membered heterocyclyl).1 is a substituted or unsubstituted polycyclic heterocyclyl (e.g., a substituted or unsubstituted, bicyclic or tricyclic 3-14 membered heterocyclyl). 1 is a substituted or unsubstituted saturated heterocyclyl. 1is substituted or unsubstituted aziridinyl, substituted or unsubstituted oxiranyl, substituted or unsubstituted thiiranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted thietanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted tetrahydrothiophenyl, substituted or unsubstituted dihydrothiophenyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted dihydropyrrolyl, substituted or unsubstituted pyrrolyl-2,5-dithiophenyl substituted or unsubstituted dioxolanyl, substituted or unsubstituted oxathiolanyl, substituted or unsubstituted dithiolanyl, substituted or unsubstituted triazolinyl, substituted or unsubstituted oxadiazolinyl, substituted or unsubstituted thiadiazolinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyridinyl, substituted or unsubstituted thianyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted dithianyl, substituted or unsubstituted Substituted dioxanyl, substituted or unsubstituted triazinyl, substituted or unsubstituted azepanyl, substituted or unsubstituted oxepanyl, substituted or unsubstituted thiepanyl, substituted or unsubstituted azocanyl, substituted or unsubstituted oxecanyl, substituted or unsubstituted thiocanyl, substituted or unsubstituted indolinyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted dihydrobenzofuranyl, substituted or unsubstituted dihydrobenzothienyl, substituted or unsubstituted tetrahydrobenzothienyl, substituted or unsubstituted tetrahydrobenzothienyl, benzofuranyl, substituted or unsubstituted tetrahydroindolyl, substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted tetrahydroisoquinolinyl, substituted or unsubstituted decahydroquinolinyl, substituted or unsubstituted decahydroisoquinolinyl, substituted or unsubstituted octahydrochromenyl, substituted or unsubstituted octahydroisochromenyl, substituted or unsubstituted decahydronaphthyridinyl, substituted or unsubstituted decahydro-1,8-naphthyridinyl, substituted or unsubstituted octahydropyrrolo[3,2-b]pyrrole, substituted or unsubstituted indolinyl, substituted or unsubstituted phthalimidyl, substituted or unsubstituted naphthalimidyl, substituted or unsubstituted chromanyl, substituted or unsubstituted chromenyl, substituted or unsubstituted 1H-benzo[e][1,4]diazepinyl, substituted or unsubstituted 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, substituted or unsubstituted 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, substituted or unsubstituted 6,7-dihydro-5H-furo[3,2-b]pyranyl, substituted or unsubstituted 5,7-dihydro-4 In one embodiment, A is substituted or unsubstituted 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, substituted or unsubstituted 2,3-dihydrofuro[2,3-b]pyridinyl, substituted or unsubstituted 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, substituted or unsubstituted 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, substituted or unsubstituted 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, or substituted or unsubstituted 1,2,3,4-tetrahydro-1,6-naphthyridinyl. 1 is substituted heterocyclyl. 1 is a substituted saturated heterocyclyl.

[0133] In one embodiment, A 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 1 is substituted or unsubstituted aryl. 1 is a substituted or unsubstituted C 6-14 In one embodiment, A is aryl. 1 is substituted or unsubstituted phenyl. 1 is substituted phenyl. 1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, -CN, and / or -OR A In one embodiment, A is phenyl substituted with 1is phenyl substituted with -F, -Cl, -Br, -I, -OMe, -OCF3, and / or -CN. 1 is phenyl substituted with -F, -Cl, -Br, and / or -I. 1 is phenyl substituted with -OMe, -OCF3, and / or -CN. 1 is phenyl substituted with substituted or unsubstituted alkyl. 1 is a substituted or unsubstituted C 1-12 In one embodiment, A is phenyl substituted with alkyl. 1 is a substituted or unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 1 is the unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 1 is a substitution C 1-6 In one embodiment, A is phenyl substituted with alkyl. 1 is phenyl substituted with substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 1 is phenyl substituted with methyl or trifluoromethyl. 1 is phenyl substituted with methyl, trifluoromethyl, ethyl, isopropyl, or tert-butyl. 1 is phenyl substituted with substituted or unsubstituted carbocyclyl. 1 is C 1-6In one embodiment, A is phenyl substituted with cycloalkyl. 1 is phenyl substituted with substituted or unsubstituted monocyclic carbocyclyl (e.g., substituted or unsubstituted monocyclic 3- to 10-membered carbocyclyl). 1 is phenyl substituted with a substituted or unsubstituted polycyclic carbocyclyl (e.g., a substituted or unsubstituted, bicyclic or tricyclic 3- to 14-membered carbocyclyl). 1 is phenyl substituted with a substituted or unsubstituted saturated carbocyclyl. 1 is phenyl substituted with substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclononyl, or substituted or unsubstituted cyclodecyl. 1 is phenyl substituted with substituted or unsubstituted cyclopropyl. 1 is phenyl substituted with substituted cyclopropyl. 1 is phenyl substituted with unsubstituted cyclopropyl. 1 is unsubstituted phenyl.

[0134] In one embodiment, A 1 is the expression: [ka] wherein: R 3 each independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A、-SCN、-SR A 、-SSR A 、-N3、-NO、-N(R A )2、-NO2、-C(=O)R A 、-C(=O)OR A 、-C(=O)SR A 、-C(=O)N(R A )2、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SR A 、-NR A S(=O)2N(R A )2、-Si(R A )3、-Si(R A )2OR A 、-Si(R A )(OR A )2、-Si(OR A )3、-OSi(R A)3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2; m is 0, 1, 2, 3, 4, or 5.

[0135] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0136] In one embodiment, A 1 is an expression [ka] In one embodiment, A 1 is an expression [ka] It is expressed as:

[0137] In one embodiment, R 3 At least one of R is halogen. 3 At least one of R is substituted or unsubstituted alkyl. 3 At least one of R is substituted or unsubstituted alkenyl. 3 and at least one of R is substituted or unsubstituted alkynyl. 3 At least one of R is substituted or unsubstituted heteroalkyl. 3 In some embodiments, at least one of R 3 At least one of R is substituted or unsubstituted heteroalkynyl. 3At least one of R is substituted or unsubstituted carbocyclyl. 3 At least one of R is substituted or unsubstituted heterocyclyl. 3 At least one of R is substituted or unsubstituted aryl. 3 At least one of R is substituted or unsubstituted heteroaryl. 3 In some embodiments, at least one of R 3 At least one of the is -OR A In one embodiment, R 3 In one embodiment, at least one of R 3 At least one of the is -SR A In one embodiment, R 3 At least one of the -SSR A In one embodiment, R 3 In one embodiment, at least one of R 3 In some embodiments, at least one of R 3 At least one of the -N(R A )2. In one embodiment, R 3 At least one of R 3 At least one of the groups is -C(=O)R A In one embodiment, R 3 At least one of the is -C(=O)OR A In one embodiment, R 3 At least one of the groups is -C(=O)SR A In one embodiment, R 3 At least one of the groups is -C(=O)N(R A )2. In one embodiment, R 3 At least one of the -C(=NR A )R AIn one embodiment, R 3 At least one of the -C(=NR A ) OR A In one embodiment, R 3 At least one of the -C(=NR A )SR A In one embodiment, R 3 At least one of the -C(=NR A )N(R A )2. In one embodiment, R 3 At least one of the is -S(=O)R A In one embodiment, R 3 At least one of the is -S(=O)OR A In one embodiment, R 3 At least one of the following is -S(=O)SR A In one embodiment, R 3 At least one of the following is -S(=O)N(R A )2. In one embodiment, R 3 At least one of the groups is -S(=O)R A In one embodiment, R 3 At least one of the groups is -S(=O)2OR A In one embodiment, R 3 At least one of the following is -S(=O)2SR A In one embodiment, R 3 At least one of the groups is -S(=O)2N(R A )2. In one embodiment, R 3 At least one of the groups is -OC(=O)R A In one embodiment, R 3 At least one of the is -OC(=O)OR A In one embodiment, R 3 At least one of the groups is -OC(=O)SR A In one embodiment, R 3 At least one of the groups is -OC(=O)N(R A)2. In one embodiment, R 3 At least one of the following is -OC(=NR A )R A In one embodiment, R 3 At least one of the following is -OC(=NR A ) OR A In one embodiment, R 3 At least one of the following is -OC(=NR A )SR A In one embodiment, R 3 At least one of the following is -OC(=NR A )N(R A )2. In one embodiment, R 3 At least one of the following is -OS(=O)R A In one embodiment, R 3 At least one of the is -OS(=O)OR A In one embodiment, R 3 At least one of the following must be -OS(=O)SR A In one embodiment, R 3 At least one of the following is -OS(=O)N(R A )2. In one embodiment, R 3 At least one of the following is -OS(=O)2R A In one embodiment, R 3 At least one of the following is -OS(=O)2OR A In one embodiment, R 3 At least one of the following must be -OS(=O)2SR A In one embodiment, R 3 At least one of the following is -OS(=O)2N(R A )2. In one embodiment, R 3 At least one of -ON(R A )2. In one embodiment, R 3 At least one of the groups is -SC(=O)R A In one embodiment, R 3At least one of the is -SC(=O)OR A In one embodiment, R 3 At least one of the groups is -SC(=O)SR A In one embodiment, R 3 At least one of the groups is -SC(=O)N(R A )2. In one embodiment, R 3 At least one of the -SC(=NR A )R A In one embodiment, R 3 At least one of the -SC(=NR A ) OR A In one embodiment, R 3 At least one of the -SC(=NR A )SR A In one embodiment, R 3 At least one of the -SC(=NR A )N(R A )2. In one embodiment, R 3 At least one of the is -NR A C(=O)R A In one embodiment, R 3 At least one of the is -NR A C(=O)OR A In one embodiment, R 3 At least one of the is -NR A C(=O)SR A In one embodiment, R 3 At least one of the is -NR A C(=O)N(R A )2. In one embodiment, R 3 At least one of the is -NR A C(=NR A )R A In one embodiment, R 3 At least one of the is -NR A C(=NR A ) OR A In one embodiment, R3 At least one of the is -NR A C(=NR A )SR A In one embodiment, R 3 At least one of the is -NR A C(=NR A )N(R A )2. In one embodiment, R 3 At least one of the is -NR A S(=O)R A In one embodiment, R 3 At least one of the is -NR A S(=O)OR A In one embodiment, R 3 At least one of the is -NR A S(=O)SR A In one embodiment, R 3 At least one of the is -NR A S(=O)N(R A )2. In one embodiment, R 3 At least one of the is -NR A S(=O)2R A In one embodiment, R 3 At least one of the is -NR A S(=O)2OR A In one embodiment, R 3 At least one of the is -NR A S(=O)2SR A In one embodiment, R 3 At least one of the is -NR A S(=O)2N(R A )2. In one embodiment, R 3 At least one of the groups is -Si(R A )3. In one embodiment, R 3 At least one of the groups is -Si(R A )2OR A In one embodiment, R 3 At least one of the groups is -Si(R A)(OR A )2. In one embodiment, R 3 At least one of -Si(OR A )3. In one embodiment, R 3 At least one of -OSi(R A )3. In one embodiment, R 3 At least one of -OSi(R A )2OR A In one embodiment, R 3 At least one of -OSi(R A )(OR A )2. In one embodiment, R 3 At least one of -OSi(OR A )3. In one embodiment, R 3 At least one of -B(OR A )2.

[0138] In one embodiment, R 3 are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, —CN, or —OR A In one embodiment, R 3 At least one of R is -F, -Cl, -Br, -I, -OMe, -OCF, or -CN. 3 At least one of R is -F, -Cl, -Br, or -I. 3 At least one of R is substituted or unsubstituted alkyl. 3 At least one of 1-12 In one embodiment, R 3 At least one of 1-6 In one embodiment, R 3 At least one of 1-6 In one embodiment, R 3 At least one of the1-6 In one embodiment, R 3 At least one of R is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 3 At least one of R is methyl or trifluoromethyl. 3 At least one of R is methyl, trifluoromethyl, ethyl, isopropyl, or tert-butyl. 3 At least one of R is substituted or unsubstituted carbocyclyl. 3 At least one of 1-6 In one embodiment, R 3 At least one of R is a substituted or unsubstituted monocyclic carbocyclyl (e.g., a substituted or unsubstituted monocyclic 3- to 10-membered carbocyclyl). 3 At least one of R is a substituted or unsubstituted polycyclic carbocyclyl (e.g., a substituted or unsubstituted, bicyclic or tricyclic 3- to 14-membered carbocyclyl). 3 At least one of R is a substituted or unsubstituted saturated carbocyclyl. 3 At least one of R is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclononyl, or substituted or unsubstituted cyclodecyl.3 At least one of R is substituted or unsubstituted cyclopropyl. 3 At least one of R is substituted cyclopropyl. 3 At least one of is unsubstituted cyclopropyl.

[0139] In one embodiment, A 1 is substituted or unsubstituted heteroaryl. 1 is a substituted or unsubstituted 5-14 membered heteroaryl. 1 is a substituted or unsubstituted monocyclic heteroaryl. 1 is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. 1 is substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted tetrazolyl. 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted tetrazinyl, substituted or unsubstituted oxepinyl, or substituted or unsubstituted thiepinyl. 1 is a substituted or unsubstituted bicyclic heteroaryl (e.g., a substituted or unsubstituted bicyclic 9- or 10-membered heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur). 1is substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted isobenzothiophenyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzisofuranyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzthiadiazolyl, substituted or unsubstituted indolizinyl, substituted or unsubstituted purinyl. 1 is substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pteridinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted phthalazinyl, or substituted or unsubstituted quinazolinyl. 1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, -CN, and / or -OR A In one embodiment, A is heteroaryl substituted with 1 is a substituted or unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 1 is heteroaryl substituted with methyl, trifluoromethyl, ethyl, isopropyl, or tert-butyl. 1 is a substituted or unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with cycloalkyl. 1 is heteroaryl substituted with substituted or unsubstituted cyclopropyl. 1 is heteroaryl substituted with -F, -Cl, -Br, -OMe, -OCF3, or -CN. 1 is an unsubstituted heteroaryl.

[0140] A 2 In one embodiment, A 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0141] In one embodiment, A 2 is substituted or unsubstituted aryl. 2 is a substituted or unsubstituted C 6-14 In one embodiment, A is aryl. 2 is substituted or unsubstituted phenyl. 2 is substituted phenyl. 2 is halogen, substituted or unsubstituted alkyl, and / or -OR A In one embodiment, A is phenyl substituted with 2 is phenyl substituted with -F, -Cl, -Br, and / or -I. 2 is phenyl substituted with substituted or unsubstituted alkyl. 2 is a substituted or unsubstituted C 1-12 In one embodiment, A is phenyl substituted with alkyl. 2 is a substituted or unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2 is the unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2 is a substitution C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2is phenyl substituted with substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 2 is phenyl substituted with -O (substituted or unsubstituted alkyl). 2 is -O(substituted or unsubstituted C 1-12 In one embodiment, A is phenyl substituted with alkyl. 2 is -O(substituted or unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2 is -O(unsubstituted C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2 is -O(substitution C 1-6 In one embodiment, A is phenyl substituted with alkyl. 2 is phenyl substituted with -O(substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl). 2 teeth, [ka] In one embodiment, A is phenyl substituted with2 is unsubstituted phenyl.

[0142] In one embodiment, A 2 is the expression: [ka] wherein: R 4 each independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A)R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR AS(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2; n is 0, 1, 2, 3, 4, or 5.

[0143] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 0, 1, or 2.

[0144] In one embodiment, A 2 is an expression [ka] In one embodiment, A 2 is an expression [ka] It is expressed as:

[0145] In one embodiment, R 4 At least one of R is halogen. 4 At least one of R is substituted or unsubstituted alkyl. 4 At least one of R is substituted or unsubstituted alkenyl. 4 and at least one of R is substituted or unsubstituted alkynyl. 4 At least one of R is substituted or unsubstituted heteroalkyl. 4 In some embodiments, at least one of R 4 At least one of R is substituted or unsubstituted heteroalkynyl. 4 At least one of R is substituted or unsubstituted carbocyclyl. 4 At least one of R is substituted or unsubstituted heterocyclyl. 4 At least one of R is substituted or unsubstituted aryl. 4 At least one of R is substituted or unsubstituted heteroaryl. 4 In some embodiments, at least one of R 4 At least one of the is -OR A In one embodiment, R 4 In one embodiment, at least one of R 4 At least one of the is -SR A In one embodiment, R 4 At least one of the -SSR A In one embodiment, R 4 In one embodiment, at least one of R 4 In some embodiments, at least one of R 4At least one of the -N(R A )2. In one embodiment, R 4 At least one of R 4 At least one of the groups is -C(=O)R A In one embodiment, R 4 At least one of the is -C(=O)OR A In one embodiment, R 4 At least one of the groups is -C(=O)SR A In one embodiment, R 4 At least one of the groups is -C(=O)N(R A )2. In one embodiment, R 4 At least one of the -C(=NR A )R A In one embodiment, R 4 At least one of the -C(=NR A ) OR A In one embodiment, R 4 At least one of the -C(=NR A )SR A In one embodiment, R 4 At least one of the -C(=NR A )N(R A )2. In one embodiment, R 4 At least one of the is -S(=O)R A In one embodiment, R 4 At least one of the is -S(=O)OR A In one embodiment, R 4 At least one of the following is -S(=O)SR A In one embodiment, R 4 At least one of the following is -S(=O)N(R A )2. In one embodiment, R 4 At least one of the groups is -S(=O)R A In one embodiment, R 4At least one of the groups is -S(=O)2OR A In one embodiment, R 4 At least one of the following is -S(=O)2SR A In one embodiment, R 4 At least one of the groups is -S(=O)2N(R A )2. In one embodiment, R 4 At least one of the groups is -OC(=O)R A In one embodiment, R 4 At least one of the is -OC(=O)OR A In one embodiment, R 4 At least one of the groups is -OC(=O)SR A In one embodiment, R 4 At least one of the groups is -OC(=O)N(R A )2. In one embodiment, R 4 At least one of the following is -OC(=NR A )R A In one embodiment, R 4 At least one of the following is -OC(=NR A ) OR A In one embodiment, R 4 At least one of the following is -OC(=NR A )SR A In one embodiment, R 4 At least one of the following is -OC(=NR A )N(R A )2. In one embodiment, R 4 At least one of the following is -OS(=O)R A In one embodiment, R 4 At least one of the is -OS(=O)OR A In one embodiment, R 4 At least one of the following must be -OS(=O)SR A In one embodiment, R 4 At least one of the following is -OS(=O)N(R A)2. In one embodiment, R 4 At least one of the following is -OS(=O)2R A In one embodiment, R 4 At least one of the following is -OS(=O)2OR A In one embodiment, R 4 At least one of the following must be -OS(=O)2SR A In one embodiment, R 4 At least one of the following is -OS(=O)2N(R A )2. In one embodiment, R 4 At least one of -ON(R A )2. In one embodiment, R 4 At least one of the groups is -SC(=O)R A In one embodiment, R 4 At least one of the is -SC(=O)OR A In one embodiment, R 4 At least one of the groups is -SC(=O)SR A In one embodiment, R 4 At least one of the groups is -SC(=O)N(R A )2. In one embodiment, R 4 At least one of the -SC(=NR A )R A In one embodiment, R 4 At least one of the -SC(=NR A ) OR A In one embodiment, R 4 At least one of the -SC(=NR A )SR A In one embodiment, R 4 At least one of the -SC(=NR A )N(R A )2. In one embodiment, R 4 At least one of the is -NR A C(=O)R A In one embodiment, R4 At least one of the is -NR A C(=O)OR A In one embodiment, R 4 At least one of the is -NR A C(=O)SR A In one embodiment, R 4 At least one of the is -NR A C(=O)N(R A )2. In one embodiment, R 4 At least one of the is -NR A C(=NR A )R A In one embodiment, R 4 At least one of the is -NR A C(=NR A ) OR A In one embodiment, R 4 At least one of the is -NR A C(=NR A )SR A In one embodiment, R 4 At least one of the is -NR A C(=NR A )N(R A )2. In one embodiment, R 4 At least one of the is -NR A S(=O)R A In one embodiment, R 4 At least one of the is -NR A S(=O)OR A In one embodiment, R 4 At least one of the is -NR A S(=O)SR A In one embodiment, R 4 At least one of the is -NR A S(=O)N(R A )2. In one embodiment, R 4 At least one of the is -NR A S(=O)2R A In one embodiment, R4 At least one of the is -NR A S(=O)2OR A In one embodiment, R 4 At least one of the is -NR A S(=O)2SR A In one embodiment, R 4 At least one of the is -NR A S(=O)2N(R A )2. In one embodiment, R 4 At least one of the groups is -Si(R A )3. In one embodiment, R 4 At least one of the groups is -Si(R A )2OR A In one embodiment, R 4 At least one of the groups is -Si(R A )(OR A )2. In one embodiment, R 4 At least one of -Si(OR A )3. In one embodiment, R 4 At least one of -OSi(R A )3. In one embodiment, R 4 At least one of -OSi(R A )2OR A In one embodiment, R 4 At least one of -OSi(R A )(OR A )2. In one embodiment, R 4 At least one of -OSi(OR A )3. In one embodiment, R 4 At least one of -B(OR A )2.

[0146] In one embodiment, R 4 are each independently halogen, substituted or unsubstituted alkyl, or -OR A In one embodiment, R 4At least one of R is -F, -Cl, -Br, or -I. 4 At least one of R is substituted or unsubstituted alkyl. 4 At least one of 1-12 In one embodiment, R 4 At least one of 1-6 In one embodiment, R 4 At least one of 1-6 In one embodiment, R 4 At least one of the 1-6 In one embodiment, R 4 At least one of R is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 4 At least one of the is -OR A In one embodiment, R 4 At least one of R is -O(substituted or unsubstituted alkyl). 4 At least one of the groups is -O (substituted or unsubstituted C 1-12 In one embodiment, R 4 At least one of the groups is -O (substituted or unsubstituted C 1-6 In one embodiment, R 4 At least one of the -O(unsubstituted C 1-6 In one embodiment, R 4At least one of the -O(substituted C 1-6 In one embodiment, R 4 At least one of is -O(substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl).

[0147] In one embodiment, R 4 At least one of the formulas [ka] where R 4A are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 4A At least one of R is hydrogen. 4 At least one of the formulas [ka] In one embodiment, R 4A are hydrogen atoms.

[0148] In one embodiment, R 4A At least one of R is substituted or unsubstituted alkyl. 4A At least one of 1-12 In one embodiment, R 4A At least one of 1-6 In one embodiment, R 4AAt least one of 1-6 In one embodiment, R 4A At least one of the 1-6 In one embodiment, R 4A At least one of R is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 4A At least one of R is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, or trifluoromethyl. 4A At least one of R is unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 4A At least one of is a substituted methyl, substituted ethyl, or substituted isopropyl.

[0149] In one embodiment, R 4A At least one of R is substituted or unsubstituted carbocyclyl. 4A At least one of 1-6 In one embodiment, R 4A At least one of R is a substituted or unsubstituted monocyclic carbocyclyl (e.g., a substituted or unsubstituted monocyclic 3- to 10-membered carbocyclyl). 4A At least one of R is a substituted or unsubstituted polycyclic carbocyclyl (e.g., a substituted or unsubstituted, bicyclic or tricyclic 3- to 14-membered carbocyclyl). 4AAt least one of R is a substituted or unsubstituted saturated carbocyclyl. 4A At least one of R is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, substituted or unsubstituted cyclooctyl, substituted or unsubstituted cyclononyl, or substituted or unsubstituted cyclodecyl. 4A At least one of R is substituted or unsubstituted cyclopropyl. 4A At least one of R is substituted cyclopropyl. 4A At least one of is unsubstituted cyclopropyl.

[0150] In one embodiment, R 4 At least one of the formulas [ka] In one embodiment, R 4 At least one of the formulas [ka] In one embodiment, R 4 At least one of the formulas [ka] In one embodiment, R 4 At least one of the formulas [ka] In one embodiment, R 4 At least one of the formulas [ka] It is expressed as:

[0151] In one embodiment, A 2 is substituted or unsubstituted heteroaryl. 2 is a substituted or unsubstituted 5-14 membered heteroaryl. 2 is a substituted or unsubstituted monocyclic heteroaryl. 2 is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. 2 is substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted tetrazolyl. 2 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted tetrazinyl, substituted or unsubstituted oxepinyl, or substituted or unsubstituted thiepinyl. 2 is a substituted or unsubstituted bicyclic heteroaryl (e.g., a substituted or unsubstituted bicyclic 9- or 10-membered heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur). 2is substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted isobenzothiophenyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzisofuranyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzthiadiazolyl, substituted or unsubstituted indolizinyl, substituted or unsubstituted purinyl. 2 is substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pteridinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted phthalazinyl, or substituted or unsubstituted quinazolinyl. 2 is halogen, substituted or unsubstituted alkyl, and / or -OR A In one embodiment, A is heteroaryl substituted with 2 is heteroaryl substituted with -F, -Cl, -Br, and / or -I. 2 is heteroaryl substituted with substituted or unsubstituted alkyl. 2 is a substituted or unsubstituted C 1-12 In one embodiment, A is heteroaryl substituted with alkyl. 2 is a substituted or unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2 is the unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2 is a substitution C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2is heteroaryl substituted with substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 2 is heteroaryl substituted with -O (substituted or unsubstituted alkyl). 2 is -O(substituted or unsubstituted C 1-12 In one embodiment, A is heteroaryl substituted with alkyl. 2 is -O(substituted or unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2 is -O(unsubstituted C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2 is -O(substitution C 1-6 In one embodiment, A is heteroaryl substituted with alkyl. 2 is heteroaryl substituted with -O(substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl). 2 teeth, [ka] In one embodiment, A is heteroaryl substituted with 2 is an unsubstituted heteroaryl.

[0152] L 1 、L 2 , and L 3 In one embodiment, L 1 , L 2 , and L 3 are each independently a bond or substituted or unsubstituted alkylene.

[0153] In one embodiment, L 1 is a bond or substituted or unsubstituted alkylene. 1 is a bond. 1 is substituted or unsubstituted alkylene. 1 is a substituted or unsubstituted C 1-12 In one embodiment, L is alkylene. 1 is a substituted or unsubstituted C 1-6 In one embodiment, L is alkylene. 1 is the unsubstituted C 1-6 In one embodiment, L is alkylene. 1 is a substitution C 1-6 In one embodiment, L is alkylene. 1 is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. 1is substituted or unsubstituted methylene. 1 is a substituted methylene. 1 is methylene substituted with at least one substituted or unsubstituted alkyl. 1 is at least one substituted or unsubstituted C 1-6 In one embodiment, L is methylene substituted with alkyl. 1 is at least one unsubstituted C 1-6 In one embodiment, L is methylene substituted with alkyl. 1 is at least one substitution C 1-6 In one embodiment, L is methylene substituted with alkyl. 1 is methylene substituted with at least one substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 1 is methylene substituted with at least one substituted or unsubstituted methyl. 1 is methylene substituted with at least one substituted methyl. 1 is methylene substituted with at least one unsubstituted methyl. 1 is —CH(CH)— or —CH(CF)—. In certain embodiments, L 1 is unsubstituted methylene.

[0154] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0155] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0156] In one embodiment, L 2 is a bond or substituted or unsubstituted alkylene. 2is a bond. 2 is substituted or unsubstituted alkylene. 2 is a substituted or unsubstituted C 1-12 In one embodiment, L is alkylene. 2 is a substituted or unsubstituted C 1-6 In one embodiment, L is alkylene. 2 is the unsubstituted C 1-6 In one embodiment, L is alkylene. 2 is a substitution C 1-6 In one embodiment, L is alkylene. 2 is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. 2 is substituted or unsubstituted methylene. 2 is a substituted methylene. 2 is methylene substituted with at least one substituted or unsubstituted alkyl. 2 is at least one substituted or unsubstituted C 1-6 In one embodiment, L is methylene substituted with alkyl. 2 is at least one unsubstituted C 1-6 In one embodiment, L is methylene substituted with alkyl. 2 is at least one substitution C 1-6 In one embodiment, L is methylene substituted with alkyl. 2is methylene substituted with at least one substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 2 is methylene substituted with at least one substituted or unsubstituted methyl. 2 is methylene substituted with at least one substituted methyl. 2 is methylene substituted with at least one unsubstituted methyl. 2 is unsubstituted methylene.

[0157] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0158] In one embodiment, L 3 is a bond or substituted or unsubstituted alkylene. 3 is a bond. 3 is substituted or unsubstituted alkylene. 3 is a substituted or unsubstituted C 1-12 In one embodiment, L is alkylene. 3 is a substituted or unsubstituted C 1-6 In one embodiment, L is alkylene. 3 is the unsubstituted C 1-6 In one embodiment, L is alkylene. 3 is a substitution C 1-6 In one embodiment, L is alkylene. 3 is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. 3 is substituted or unsubstituted methylene. 3 is a substituted methylene. 3 is unsubstituted methylene.

[0159] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0160] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0161] Y, R 1 , and p In some embodiments, Y is C or N.

[0162] In one embodiment, R 1each independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A , -OC(=NR A )SR A , -OC(=NR A )N(R A )2, -OS(=O)R A , -OS(=O)OR A , -OS(=O)SR A、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SRA , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2.

[0163] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0164] In some embodiments, Y is C. In some embodiments, Y is C and L 3 is a bond. In one embodiment, Y is C and A 1 is an expression [ka] In one embodiment, Y is C and A 1 is an expression [ka] and L 3 is a bond. In one embodiment, Y is C and A 2 is an expression [ka] In one embodiment, Y is C and A 2 is an expression [ka] and L 3 is a bond. In one embodiment, Y is C and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is C and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is C and p is 0. In some embodiments, Y is C and p is 0 and L 3 is a bond. In one embodiment, Y is C, p is 0, and A 1 is an expression [ka] In one embodiment, Y is C, p is 0, and A 1 is an expression [ka] and L 3 is a bond. In one embodiment, Y is C, p is 0, and A 2 is an expression [ka] In one embodiment, Y is C, p is 0, and A 2 is an expression [ka] and L3 is a bond. In one embodiment, Y is C, p is 0, and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is C, p is 0, and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is C and p is 1. In some embodiments, Y is C and p is 1 and L 3 is a bond. In one embodiment, Y is C, p is 1, and A 1 is an expression [ka] In one embodiment, Y is C, p is 1, and A 1 is an expression [ka] and L 3 is a bond. In one embodiment, Y is C, p is 1, and A 2 is an expression [ka] In one embodiment, Y is C, p is 1, and A 2 is an expression [ka] and L3 is a bond. In one embodiment, Y is C, p is 1, and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is C, p is 1, and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond.

[0165] In some embodiments, Y is N. In some embodiments, Y is N and R 2A is absent. In one embodiment, Y is N and R 2A does not exist, and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, and A 1 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, and A 1 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A is absent and p is 0. In some embodiments, Y is N and R 2A does not exist, p is 0, and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, p is 0, and A 1 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 0, and A 1 is an expression [ka] and L 3is a bond. In some embodiments, Y is N and R 2A does not exist, p is 0, and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 0, and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, p is 0, and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 0, and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A is absent and p is 1. In some embodiments, Y is N and R 2A does not exist, p is 1, and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, p is 1, and A 1 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 1, and A 1 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, p is 1, and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 1, and A 2 is an expression [ka] and L 3 is a bond. In some embodiments, Y is N and R 2A does not exist, p is 1, and A 1 is an expression [ka] and A 2 is an expression [ka] In one embodiment, Y is N and R 2A does not exist, p is 1, and A 1 is an expression [ka] and A 2 is an expression [ka] and L 3 is a bond.

[0166] In one embodiment, R 1At least one of R is halogen. 1 At least one of R is -F, -Cl, -Br, or -I. 1 At least one of R is -F. 1 At least one of R is substituted or unsubstituted alkyl. 1 At least one of R is substituted or unsubstituted alkenyl. 1 and at least one of R is substituted or unsubstituted alkynyl. 1 At least one of R is substituted or unsubstituted heteroalkyl. 1 In some embodiments, at least one of R 1 At least one of R is substituted or unsubstituted heteroalkynyl. 1 At least one of R is substituted or unsubstituted carbocyclyl. 1 At least one of R is substituted or unsubstituted heterocyclyl. 1 At least one of R is substituted or unsubstituted aryl. 1 At least one of R is substituted or unsubstituted heteroaryl. 1 In some embodiments, at least one of R 1 At least one of the is -OR A In one embodiment, R 1 In one embodiment, at least one of R 1 At least one of the is -SR A In one embodiment, R 1 At least one of the -SSR A In one embodiment, R 1In one embodiment, at least one of R 1 In some embodiments, at least one of R 1 At least one of the -N(R A )2. In one embodiment, R 1 At least one of R 1 At least one of the groups is -C(=O)R A In one embodiment, R 1 At least one of the is -C(=O)OR A In one embodiment, R 1 At least one of the groups is -C(=O)SR A In one embodiment, R 1 At least one of the groups is -C(=O)N(R A )2. In one embodiment, R 1 At least one of the -C(=NR A )R A In one embodiment, R 1 At least one of the -C(=NR A ) OR A In one embodiment, R 1 At least one of the -C(=NR A )SR A In one embodiment, R 1 At least one of the -C(=NR A )N(R A )2. In one embodiment, R 1 At least one of the is -S(=O)R A In one embodiment, R 1 At least one of the is -S(=O)OR A In one embodiment, R 1 At least one of the following is -S(=O)SR A In one embodiment, R 1 At least one of the following is -S(=O)N(R A)2. In one embodiment, R 1 At least one of the groups is -S(=O)R A In one embodiment, R 1 At least one of the groups is -S(=O)2OR A In one embodiment, R 1 At least one of the following is -S(=O)2SR A In one embodiment, R 1 At least one of the groups is -S(=O)2N(R A )2. In one embodiment, R 1 At least one of the groups is -OC(=O)R A In one embodiment, R 1 At least one of the is -OC(=O)OR A In one embodiment, R 1 At least one of the groups is -OC(=O)SR A In one embodiment, R 1 At least one of the groups is -OC(=O)N(R A )2. In one embodiment, R 1 At least one of the following is -OC(=NR A )R A In one embodiment, R 1 At least one of the following is -OC(=NR A ) OR A In one embodiment, R 1 At least one of the following is -OC(=NR A )SR A In one embodiment, R 1 At least one of the following is -OC(=NR A )N(R A )2. In one embodiment, R 1 At least one of the following is -OS(=O)R A In one embodiment, R 1 At least one of the is -OS(=O)OR A In one embodiment, R 1At least one of the following must be -OS(=O)SR A In one embodiment, R 1 At least one of the following is -OS(=O)N(R A )2. In one embodiment, R 1 At least one of the following is -OS(=O)2R A In one embodiment, R 1 At least one of the following is -OS(=O)2OR A In one embodiment, R 1 At least one of the following must be -OS(=O)2SR A In one embodiment, R 1 At least one of the following is -OS(=O)2N(R A )2. In one embodiment, R 1 At least one of -ON(R A )2. In one embodiment, R 1 At least one of the groups is -SC(=O)R A In one embodiment, R 1 At least one of the is -SC(=O)OR A In one embodiment, R 1 At least one of the groups is -SC(=O)SR A In one embodiment, R 1 At least one of the groups is -SC(=O)N(R A )2. In one embodiment, R 1 At least one of the -SC(=NR A )R A In one embodiment, R 1 At least one of the -SC(=NR A ) OR A In one embodiment, R 1 At least one of the -SC(=NR A )SR A In one embodiment, R 1 At least one of the -SC(=NR A )N(R A)2. In one embodiment, R 1 At least one of the is -NR A C(=O)R A In one embodiment, R 1 At least one of the is -NR A C(=O)OR A In one embodiment, R 1 At least one of the is -NR A C(=O)SR A In one embodiment, R 1 At least one of the is -NR A C(=O)N(R A )2. In one embodiment, R 1 At least one of the is -NR A C(=NR A )R A In one embodiment, R 1 At least one of the is -NR A C(=NR A ) OR A In one embodiment, R 1 At least one of the is -NR A C(=NR A )SR A In one embodiment, R 1 At least one of the is -NR A C(=NR A )N(R A )2. In one embodiment, R 1 At least one of the is -NR A S(=O)R A In one embodiment, R 1 At least one of the is -NR A S(=O)OR A In one embodiment, R 1 At least one of the is -NR A S(=O)SR A In one embodiment, R 1 At least one of the is -NR A S(=O)N(R A)2. In one embodiment, R 1 At least one of the is -NR A S(=O)2R A In one embodiment, R 1 At least one of the is -NR A S(=O)2OR A In one embodiment, R 1 At least one of the is -NR A S(=O)2SR A In one embodiment, R 1 At least one of the is -NR A S(=O)2N(R A )2. In one embodiment, R 1 At least one of the groups is -Si(R A )3. In one embodiment, R 1 At least one of the groups is -Si(R A )2OR A In one embodiment, R 1 At least one of the groups is -Si(R A )(OR A )2. In one embodiment, R 1 At least one of -Si(OR A )3. In one embodiment, R 1 At least one of -OSi(R A )3. In one embodiment, R 1 At least one of -OSi(R A )2OR A In one embodiment, R 1 At least one of -OSi(R A )(OR A )2. In one embodiment, R 1 At least one of -OSi(OR A )3. In one embodiment, R 1 At least one of -B(OR A )2.

[0167] R 2A and R 2B In one embodiment, R 2A is absent, hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group, except that when Y is N, R 2A is absent. In one embodiment, R 2A In one embodiment, Y is N and R is not present. 2A is absent. In one embodiment, R 2A is substituted or unsubstituted alkyl. In some embodiments, R 2A is a substituted or unsubstituted C 1-12 In one embodiment, R 2A is a substituted or unsubstituted C 1-6 In one embodiment, R 2A is the unsubstituted C 1-6 In one embodiment, R 2A is a substitution C 1-6 In one embodiment, R 2A is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 2A is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted 2-methylpropyl, substituted or unsubstituted 2,2-dimethylpropyl, substituted or unsubstituted cyclopropylmethyl, or substituted or unsubstituted cyclobutylmethyl. 2Ais substituted methyl, substituted ethyl, substituted isopropyl, substituted 2-methylpropyl, substituted 2,2-dimethylpropyl, substituted cyclopropylmethyl, or substituted cyclobutylmethyl. 2A is unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted 2-methylpropyl, unsubstituted 2,2-dimethylpropyl, unsubstituted cyclopropylmethyl, or unsubstituted cyclobutylmethyl. 2A is a nitrogen protecting group.

[0168] In one embodiment, R 2B is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR AC(=NR A )N(R A )2, -NR A S(=O)R A , -NR A S(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2.

[0169] In one embodiment, R 2B is hydrogen. 2B is substituted or unsubstituted alkyl. In some embodiments, R 2B is a substituted or unsubstituted C 1-12 In one embodiment, R 2B is a substituted or unsubstituted C 1-6 In one embodiment, R 2B is the unsubstituted C 1-6 In one embodiment, R 2B is a substitution C 1-6 In one embodiment, R 2Bis substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl. 2B is substituted or unsubstituted methyl. In some embodiments, R 2B is substituted methyl. In some embodiments, R 2B is unsubstituted methyl.

[0170] R A and R B In one embodiment, R A are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, if attached to a nitrogen atom, a nitrogen protecting group, if attached to an oxygen atom, an oxygen protecting group, or if attached to a sulfur atom, a sulfur protecting group; or R A and two of R are joined to the atom between them to form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl ring. Aat least one of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, if attached to a nitrogen atom, a nitrogen protecting group, if attached to an oxygen atom, an oxygen protecting group, or if attached to a sulfur atom, a sulfur protecting group; or A and two of R are joined to the atom between them to form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl ring. A At least one of R is hydrogen. A At least one of R is substituted or unsubstituted acyl. A At least one of 1-12 In one embodiment, R A At least one of 1-6 In one embodiment, R A At least one of 1-6 In one embodiment, R A At least one of the 1-6 In one embodiment, R A At least one of R is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hexyl.A At least one of 2-12 In one embodiment, R is alkenyl. A At least one of 2-6 In one embodiment, R is alkenyl. A At least one of R is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl. A At least one of 2-12 In one embodiment, R is alkynyl. A At least one of 2-6 In one embodiment, R is alkynyl. A At least one of R is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. A At least one of the groups is a substituted or unsubstituted heterocyclic C 1-12 In one embodiment, R A At least one of the groups is a substituted or unsubstituted heterocyclic C 1-6 In one embodiment, R A At least one of the groups is a substituted or unsubstituted heterocyclic C 1-12 In one embodiment, R is alkenyl. A At least one of the groups is a substituted or unsubstituted heterocyclic C 1-6 In one embodiment, R is alkenyl. A At least one of the groups is a substituted or unsubstituted heterocyclic C 1-12 In one embodiment, R is alkynyl. AAt least one of the groups is a substituted or unsubstituted heterocyclic C 1-6 In one embodiment, R is alkynyl. A At least one of 3-14 In one embodiment, R A At least one of R is a substituted or unsubstituted 5- to 10-membered heterocyclyl. A At least one of R is a substituted or unsubstituted 6- to 14-membered aryl. A At least one of R is a substituted or unsubstituted 5-14 membered heteroaryl. A When attached to a nitrogen atom, at least one of R A When attached to an oxygen atom, at least one of R A At least one of R is a sulfur protecting group when attached to a sulfur atom. A At least two of R are bonded to the atom between them to form a substituted or unsubstituted 5- to 10-membered heterocycle. A At least two of are joined with the atom between them to form a substituted or unsubstituted 5- to 14-membered heteroaryl ring.

[0171] In one embodiment, R B are each hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. B At least one of R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. B At least one of R is hydrogen. B At least one of R is substituted or unsubstituted alkyl. B At least one of 1-10In one embodiment, R B At least one of 1-6 In one embodiment, R B At least one of 1-3 In one embodiment, R B At least one of 1-3 In one embodiment, R B is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, or substituted or unsubstituted isopropyl. B At least one of R is substituted or unsubstituted acyl. B At least one of is a nitrogen protecting group.

[0172] In certain embodiments, the compound of formula (I) is a compound of the following formula: or a pharmaceutically acceptable salt or prodrug thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0173] In some embodiments, the compound is not a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. In some embodiments, the compound is a PPARγ antagonist. In some embodiments, the compound is a PPARγ inverse agonist.

[0174] In some embodiments, the "provided compound (a compound described herein, a compound of the present disclosure)" is a compound of any of the formulas herein (e.g., Formula (I)), or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the provided compound is a compound of any of the formulas herein (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof. In some embodiments, the provided compound is a compound of any of the formulas herein (e.g., Formula (I)), or a salt thereof.

[0175] In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2012 / 170554. In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2012 / 170561. In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2013 / 078233. In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2013 / 078237. In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2013 / 078240. In some embodiments, the compound provided is not a compound of the formula described in PCT application WO2015 / 161108.

[0176] Pharmaceutical Compositions and Kits In one aspect, the present disclosure provides a pharmaceutical composition comprising the provided compound. In some embodiments, the pharmaceutical composition comprises one or more excipients. In some embodiments, the pharmaceutical composition described herein comprises the provided compound and an excipient.

[0177] In some embodiments, the pharmaceutical composition comprises an effective amount of a provided compound. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to treat a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of treatment. In some embodiments, the effective amount is an amount effective to prevent a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of prevention. In some embodiments, the effective amount is an amount effective to reduce the risk of developing a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of risk reduction. In some embodiments, an effective amount is an amount effective to treat, prevent, or reduce the risk of developing a disease or disorder associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, or a metabolic disease) in a subject in need of such treatment, prevention, or risk reduction, and is an amount that reduces side effects experienced by the subject (e.g., weight gain, edema, impaired bone growth or bone formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, hepatotoxicity) compared to administration of a PPARγ agonist. In some embodiments, an effective amount is an amount effective to modulate (e.g., upregulate, downregulate, increase, or decrease) PPARγ in a subject in need of such modulation, or in a cell, tissue, or biological sample. In some embodiments, an effective amount is an amount that is not effective to activate PPARγ. In some embodiments, an effective amount is an amount effective to reduce the phosphorylation of serine 273 of PPARγ. In certain embodiments, an effective amount is an amount effective to normalize the functional remodeling activity of bone cells, osteoblasts, and / or osteoclasts to result in healthy bone structure and / or bone strength.In some embodiments, functional remodeling activity is measured by an increase in cortical bone area, a decrease in intramedullary fat, an increase in bone material strength, and / or an increase in bone metabolic markers and circulating osteocyte progenitor cells. See, e.g., L.A. Stechschulte et al., EBioMedicine 2016, 10, 174-184. In some embodiments, the effective amount is an amount effective to reduce intramedullary fat. In some embodiments, the effective amount is an amount effective to increase cancellous bone and / or cortical bone. In some embodiments, the effective amount is an amount effective to improve metabolic parameters by reducing fasting plasma glucose to the normal range of less than 100 mg / dL and HbA1c to less than 6%.

[0178] In some embodiments, the subject is an animal. In some embodiments, the subject is a human. In some embodiments, the subject is a human aged 18 years or older. In some embodiments, the subject is a human aged 12 to 18 years, inclusive. In some embodiments, the subject is a human aged 2 to 12 years, inclusive. In some embodiments, the subject is a human under the age of 2. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically modified animal. In some embodiments, the animal is a transgenic animal (e.g., a transgenic mouse or a transgenic pig). In some embodiments, the subject is a fish or a reptile.

[0179] In some embodiments, an effective amount is an amount effective to modulate (e.g., upregulate, downregulate, increase, decrease) the activity of PPARγ by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, an effective amount is an amount effective to modulate (e.g., upregulate, downregulate, increase, decrease) the activity of PPARγ by a percentage described in this paragraph to another percentage described in this paragraph (inclusive).

[0180] In certain embodiments, an effective amount is an amount effective to reduce phosphorylation of PPARγ at serine 273 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In certain embodiments, an effective amount is an amount effective to reduce phosphorylation of PPARγ at serine 273 by a percentage recited in this paragraph to another percentage recited in this paragraph, inclusive.

[0181] In some embodiments, the pharmaceutical composition is used to treat a peroxisome proliferator-activated receptor gamma (PPARγ)-associated disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of treatment. In some embodiments, the pharmaceutical composition is used to prevent a peroxisome proliferator-activated receptor gamma (PPARγ)-associated disease or disorder (e.g., a progressive bone disease, a proliferative disease, a metabolic disease) in a subject in need of prevention. In some embodiments, the pharmaceutical composition is used to modulate (e.g., upregulate, downregulate, increase, decrease) PPARγ in a subject in need of modulation, or in a cell, tissue, or biological sample.

[0182] The compounds or pharmaceutical compositions provided herein may be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or pharmaceutical compositions provided herein may be administered in combination with additional pharmaceutical agents that improve their activity in a subject or cell (e.g., activity (e.g., efficacy and / or effectiveness) in treating a peroxisome proliferator-activated receptor gamma (PPARγ)-related disease or disorder in a subject in need of treatment, in preventing a PPARγ-related disease or disorder in a subject in need of prevention, and / or in reducing the risk of developing a PPARγ-related disease or disorder in a subject in need of risk reduction), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution. It is also understood that the additional pharmaceutical agent utilized may achieve a desired effect on the same disorder and / or may achieve a different effect. In some embodiments, the pharmaceutical compositions described herein, comprising the compounds provided herein and the additional pharmaceutical agents, exhibit a synergistic effect that is not present in pharmaceutical compositions comprising one of the provided compounds and the additional pharmaceutical agents but not both. In some embodiments, the additional pharmaceutical agents achieve a desired effect for the same disorder, hi some embodiments, the additional pharmaceutical agents achieve a different effect.

[0183] The provided compound or pharmaceutical composition can be administered simultaneously with, before, or after one or more additional pharmaceutical agents that are different from the compound or pharmaceutical composition and may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use as specified in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing diseases or disorders associated with peroxisome proliferator-activated receptor gamma (PPARγ).

[0184] Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may be administered together with each other and / or with the compounds or pharmaceutical compositions described herein in a single administration, or may be administered separately in different administrations. The particular combination to be used in the regimen will take into account the compatibility of the compounds described herein with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

[0185] Additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, steroidal or nonsteroidal anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular drugs, cholesterol-lowering drugs, antidiabetic drugs, antiallergic drugs, contraceptives, analgesics, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or antihistamine drugs, antigens, vaccines, antibodies, decongestants, sedatives, opioids, analgesics, antipyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent includes, but is not limited to, cardiovascular drugs, cholesterol-lowering drugs, antidiabetic drugs, anticoagulants, steroids, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is a cardiovascular drug. In certain embodiments, the additional pharmaceutical agent is a cholesterol-lowering drug. In certain embodiments, the additional pharmaceutical agent is an antidiabetic drug. In certain embodiments, the additional pharmaceutical agent is an anticoagulant. In certain embodiments, the additional pharmaceutical agent is a steroid. In certain embodiments, the additional pharmaceutical agent is a hormone. In certain embodiments, the additional pharmaceutical agent is a prostaglandin.

[0186] In some embodiments, provided compounds or pharmaceutical compositions are solid. In some embodiments, provided compounds or pharmaceutical compositions are powder. In some embodiments, provided compounds or pharmaceutical compositions can be dissolved in a liquid to provide a solution. In some embodiments, provided compounds or pharmaceutical compositions can be dissolved in water to provide an aqueous solution. In some embodiments, the pharmaceutical composition is a liquid for injection. In some embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for intravenous injection. In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for subcutaneous injection.

[0187] The pharmaceutical compositions described herein can be prepared by methods known in the art of pharmacology. Generally, such methods include combining a composition containing a provided compound (i.e., the "active ingredient") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single or multiple dosage unit.

[0188] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dose (e.g., one-half or one-third of such a dose, etc.).

[0189] The relative amounts of a provided compound, pharmaceutically acceptable excipient, drug, and / or any additional components in the pharmaceutical compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and will further vary depending on the route by which the pharmaceutical composition is administered. The pharmaceutical composition may contain between 0.1% and 100% (w / w), inclusive, of the drug.

[0190] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients and accessory ingredients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the pharmaceutical composition.

[0191] Representative diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0192] Representative granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, aluminum magnesium silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0193] Representative surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (aluminum magnesium silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan, ... fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), ), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate,Triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0194] Representative binders include starches (e.g., cornstarch and starch glue), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of psyllium husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), aluminum magnesium silicate (Veegum®), and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylic acid, waxes, water, alcohol, and / or mixtures thereof.

[0195] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0196] Representative antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0197] Representative chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, and the like), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Representative antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0198] Representative antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0199] Representative alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0200] Representative acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0201] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0202] Representative buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0203] Representative lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0204] Representative natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, palm, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cucumber, and macadamia nut. Nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Representative synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0205] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, peanut, corn, germ, olive, castor, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof).In addition to inert diluents, oral pharmaceutical compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0206] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending agents. For this purpose, tasteless fixed oils, such as synthetic mono- or diglycerides, can be used. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

[0207] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0208] To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a poorly water-soluble crystalline material or an amorphous liquid suspension. The rate of absorption of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0209] Pharmaceutical compositions for rectal or vaginal administration are generally suppositories which can be prepared by mixing a conjugate described herein with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or a suppository wax) which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active ingredient.

[0210] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; (d) agar, calcium carbonate, potato starch, and the like. They are mixed with disintegrating agents such as starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0211] Solid compositions of a similar type can be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, and other coatings well known in the art of pharmacology.They may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner.Examples of encapsulating compositions that can be used include polymeric substances and waxes.

[0212] The active ingredient may be in microencapsulated form with one or more of the excipients mentioned above.Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation arts.In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms may conventionally contain additional substances other than inert diluents, such as tablet lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, the dosage forms may contain buffering agents.They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner.Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0213] Dosage forms for topical and / or transdermal administration of the compounds described herein can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffers, as needed. Furthermore, the present disclosure contemplates the use of transdermal patches, which often have the additional advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively, or additionally, the rate can be controlled by providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0214] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid formulations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions (e.g., creams, ointments, and / or pastes), and / or solutions and / or suspensions. While the concentration of the active ingredient may approach the solubility limit of the active ingredient in the solvent, a formulation for topical administration may contain, for example, about 1% to about 10% (w / w) active ingredient. Formulations for topical administration may further include one or more of the additional ingredients described herein.

[0215] Devices suitable for delivering the injectable pharmaceutical compositions described herein include short-needle devices.The injectable pharmaceutical compositions can be administered by devices that limit the effective penetration length of the needle into the skin.Alternatively, or in addition, conventional syringes can be used for the classic Mantoux administration method.Jet injection devices deliver liquid formulations through a liquid jet injector and / or needle.Ballistic powder / particle delivery devices that use compressed gas to accelerate powdered compounds are suitable.

[0216] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles containing the active ingredient and having diameters of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of a dry powder for administration using a device comprising a dry powder reservoir capable of directing a stream of propellant to disperse the powder, and / or using a self-propelling solvent / powder dispensing container (e.g., a device containing the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container). Such powders comprise particles in which at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent, such as sugar, and are conveniently provided in a unit dose form.

[0217] Generally, low-boiling propellants include liquid propellants having a boiling point below 65 degrees Fahrenheit at atmospheric pressure. Generally, the propellant may comprise 50-99.9% (w / w) of the pharmaceutical composition, and the active ingredient may comprise 0.1-20% (w / w) of the pharmaceutical composition. The propellant may further comprise additional components such as a liquid nonionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size on the same order as the particles containing the active ingredient).

[0218] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, and may be conveniently administered using any inhalation and / or nebulizer device. Such formulations may further comprise one or more additional ingredients, including flavoring agents such as saccharin sodium, volatile oils, buffers, surfactants, and / or preservatives such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter of about 0.1 to about 200 nanometers.

[0219] Formulations described herein as useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of the powder held close to the nostrils.

[0220] Formulations for nasal administration may contain, for example, as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may include one or more of the additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations may be, for example, in the form of tablets and / or lozenges made using conventional methods and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the remainder comprising a composition that dissolves and / or disintegrates in the mouth, and, optionally, one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size of about 0.1 to about 200 nanometers and may further comprise one or more of the additional ingredients described herein.

[0221] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in an ophthalmic formulation. Such formulations may be in the form of eye drops, such as, for example, a 0.1 to 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such eye drops may further comprise one or more buffering agents, salts, and / or other additional ingredients described herein. Other useful ophthalmic formulations include those comprising the active ingredient in microcrystalline form and / or in a liposomal formulation. Ear drops and / or eye drops are also contemplated as being within the scope of the present disclosure.

[0222] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such pharmaceutical compositions are generally suitable for administration to any and all animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0223] Provided compound is generally formulated in the form of dosage unit for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of pharmaceutical compositions described herein is determined by a doctor within the scope of sound medical judgment.The specific therapeutically effective dose level for specific subject or organism depends on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient being used; the specific composition being used; the age, weight, overall health, sex and diet of subject; the administration time, administration route and excretion rate of the specific active ingredient being used; treatment period; the drug that is used in combination with or at the same time as the specific active ingredient being used; and similar factors well known in the medical field.

[0224] The compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (e.g., by powder, ointment, cream, and / or drops), mucosal, nasal, buccal, sublingual, by intratracheal instillation, bronchial instillation, and / or inhalation, and / or as a mouth spray, nasal drops, and / or aerosol. Specifically, possible routes include intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and / or lymphatic supply, and / or direct administration to the affected area. Generally, the most appropriate administration route will depend on various factors, such as the nature of the agent (e.g., stability in the gastrointestinal environment) and / or the subject's condition (e.g., whether the subject can tolerate oral administration).

[0225] The exact amount of a provided compound required to achieve an effective dose will vary depending on the subject, for example, the subject's species, age, and general condition, severity of side effects or disorders, the identity of the particular compound of the present disclosure, the method of administration, and the like. An effective amount can be contained in a single administration (e.g., a single oral administration) or in multiple administrations (e.g., multiple oral administrations). In some embodiments, when multiple administrations are administered to a subject or applied to a biological sample, tissue, or cell, any two administrations of the multiple administrations contain different or substantially the same amount of an agent described herein.

[0226] In certain embodiments, pharmaceutical compositions containing provided compounds are administered orally or parenterally (depending on the method of administration) at dosage levels of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg in one or more administrations over one or more days. In certain embodiments, the effective amount per administration varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of subject body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be administered one or more times daily at a dose level sufficient to achieve the desired therapeutic and / or prophylactic effect, such as from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or more preferably from about 1 mg / kg to about 25 mg / kg of subject body weight per day. Desirable doses may be delivered three times a day, twice a day, once a day, every two days, every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations). In certain embodiments, the pharmaceutical compositions described herein are administered at a dose below the dose at which the agent causes non-specific effects.

[0227] In one embodiment, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In one embodiment, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In one embodiment, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In one embodiment, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In one embodiment, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In one embodiment, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0228] The dosage ranges described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to adults.For example, the amount to be administered to children or adolescents can be determined by a doctor or person skilled in the art, and can be lower than or the same as the amount administered to adults.In some embodiments, the dosages described herein are the dosages for adults with a body weight of 70 kg.

[0229] In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of administering the multiple doses to the subject or the multiple doses to the tissues or cells may be, for example, three times a day, twice a day, once a day, once every two days, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks, or delayed controlled delivery over a period of time using a drug delivery device. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the period from the first administration to the last administration of the multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of the subject, tissue, or cell. In some embodiments, the period from the first administration to the last administration of the multiple doses is 3 months, 6 months, or 1 year. In some embodiments, the period from the first administration to the last administration of the multiple doses is the lifespan of the subject, tissue, or cell.

[0230] Kits (e.g., pharmaceutical packages) are also encompassed by the present disclosure. In some embodiments, the kit comprises a provided compound or pharmaceutical composition described herein and instructions for use of the compound or pharmaceutical composition. In some embodiments, the kit comprises a first container, wherein the first container comprises the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In some embodiments, the second container comprises an excipient (e.g., an excipient for diluting or suspending the compound or pharmaceutical composition). In some embodiments, the second container comprises an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In some embodiments, the third container comprises an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition contained in the first container and the excipient or additional pharmaceutical agent contained in the second container are combined to form a single unit dosage form. In some embodiments, the provided compound or pharmaceutical composition contained in the first container, the excipient contained in the second container, and the additional pharmaceutical agent contained in the third container are combined to form a single unit dosage form. In certain embodiments, the first, second, and third containers are each independently a vial, an ampoule, a bottle, a syringe, a dispenser package, a tube, or an inhaler.

[0231] In some embodiments, the instructions are for administering a provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease or disorder described herein). In some embodiments, the instructions are for contacting a biological sample or cell with a provided compound or pharmaceutical composition. In some embodiments, the instructions include information required by a regulatory authority, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). In some embodiments, the instructions include prescribing information.

[0232] In some embodiments, the kits and instructions provide for the treatment of a disease or disorder associated with peroxisome proliferator-activated receptor gamma (PPARγ) in a subject in need of treatment. In some embodiments, the kits and instructions provide for the prevention of a disease or disorder associated with PPARγ in a subject in need of prevention. In some embodiments, the kits and instructions provide for the reduction of the risk of developing a disease or disorder associated with PPARγ in a subject in need of such risk reduction. In some embodiments, the kits and instructions provide for the modulation (e.g., upregulation, downregulation, increase, decrease) of PPARγ in a subject in need of modulation, or in a cell, tissue, or biological sample.

[0233] The kits described herein may include one or more additional pharmaceutical agents described herein as separate pharmaceutical compositions.

[0234] Another object of the present disclosure is the use of a compound described herein in the manufacture of a medicament for treating a disorder or disease described herein.Another object of the present disclosure is the use of a compound described herein for the treatment of a disorder or disease described herein.

[0235] Treatment and prevention methods In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder in a subject in need of treatment or prevention, comprising administering to the subject a compound or pharmaceutical composition provided therein. In some embodiments, the present disclosure provides a method for treating a disease or disorder in a subject in need of treatment, comprising administering to the subject a compound or pharmaceutical composition provided therein. In some embodiments, the present disclosure provides a method for preventing a disease or disorder in a subject in need of prevention, comprising administering to the subject a compound or pharmaceutical composition provided therein. In some embodiments, the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease).

[0236] In another aspect, the present disclosure provides compounds or pharmaceutical compositions for treating or preventing a disease or disorder in a subject in need of treatment or prevention. In another aspect, the present disclosure provides compounds or pharmaceutical compositions for treating a disease or disorder in a subject in need of treatment. In another aspect, the present disclosure provides compounds or pharmaceutical compositions for preventing a disease or disorder in a subject in need of prevention. In certain embodiments, the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease).

[0237] In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need of treatment or prevention. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treating a disease or disorder in a subject in need of treatment. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for preventing a disease or disorder in a subject in need of prevention. In certain embodiments, the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease).

[0238] In certain embodiments, the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ) (e.g., a progressive bone disease, a proliferative disease, a metabolic disease). In certain embodiments, the disease or disorder is a progressive bone disease (e.g., osteoporosis, Paget's disease). In certain embodiments, the progressive bone disease is osteoporosis. In certain embodiments, the progressive bone disease is Paget's disease. In certain embodiments, the disease or disorder is a proliferative disease (e.g., cancer). In certain embodiments, the proliferative disease is cancer (e.g., colorectal cancer, pancreatic cancer, bladder cancer, esophageal cancer, breast cancer, prostate cancer, blood cancer, bone cancer). In certain embodiments, the proliferative disease is colorectal cancer. In certain embodiments, the proliferative disease is pancreatic cancer. In certain embodiments, the proliferative disease is bladder cancer. In certain embodiments, the proliferative disease is esophageal cancer. In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is prostate cancer. In some embodiments, the proliferative disease is a hematological cancer (e.g., multiple myeloma). In some embodiments, the cancer is multiple myeloma. In some embodiments, the proliferative disease is bone cancer. In some embodiments, the disease or disorder is a metabolic disease (e.g., diabetes, obesity, metabolic syndrome, atherosclerotic vascular disease, non-alcoholic steatohepatitis (NASH), fatty liver disease, weight loss, adipose tissue remodeling, metabolic bone disease, or hyperparathyroidism). In some embodiments, the metabolic disease is diabetes. In some embodiments, the metabolic disease is obesity. In some embodiments, the metabolic disease is metabolic syndrome. In some embodiments, the metabolic disease is atherosclerotic vascular disease. In some embodiments, the metabolic disease is non-alcoholic steatohepatitis (NASH). In some embodiments, the metabolic disease is fatty liver disease. In some embodiments, the metabolic disease is weight loss. In some embodiments, the metabolic disease is adipose tissue remodeling. In some embodiments, the metabolic disease is metabolic bone disease. In certain embodiments, the metabolic disorder is hyperparathyroidism.

[0239] In another aspect, the present disclosure provides methods of treating a condition associated with peroxisome proliferator-activated receptor gamma (PPARγ). In certain embodiments, the condition is metabolic syndrome.

[0240] In some embodiments, side effects (e.g., weight gain, edema, impaired bone growth or bone formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, hepatotoxicity) experienced by the subject are reduced compared to administration of a PPARγ agonist. In some embodiments, weight gain experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, edema experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, impaired bone growth or bone formation experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, cardiac hypertrophy experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, congestive heart failure experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, blood leak syndrome experienced by the subject is reduced compared to administration of a PPARγ agonist. In some embodiments, hepatotoxicity experienced by the subject is reduced compared to administration of a PPARγ agonist.

[0241] In some embodiments, the method includes improving the activity of bone cells, osteoblasts, and / or osteoclasts. In some embodiments, the method includes improving the activity of bone cells. In some embodiments, the method includes improving the activity of osteoblasts. In some embodiments, the method includes normalizing the functional remodeling activity of bone cells, osteoblasts, and / or osteoclasts to result in healthy bone structure and / or bone strength. In some embodiments, the functional remodeling activity is measured by an increase in cortical bone area, a decrease in intramedullary fat, an increase in bone material strength, and / or an increase in bone metabolic markers and circulating osteocyte progenitor cells. See, e.g., L.A. Stechschulte et al., EBioMedicine 2016, 10, 174-184. In some embodiments, the method includes increasing cancellous bone and cortical bone and / or improving metabolic parameters. In certain embodiments, the methods include increasing cancellous bone and cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the methods include increasing cancellous bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the method includes increasing cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).In certain embodiments, the method includes improving metabolic parameters by reducing fasting plasma glucose to the normal range of less than 100 mg / dl and HbA1c to less than 6%. In certain embodiments, the method includes reducing intramedullary fat (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).

[0242] Methods for modulating peroxisome proliferator-activated receptor gamma (PPAR gamma) and inhibiting cell proliferation or promoting apoptosis - Patent Application 20070122999 In another aspect, the present disclosure provides a method of modulating (e.g., upregulating, downregulating, increasing, decreasing) peroxisome proliferator-activated receptor gamma (PPARγ) in a subject in need of treatment or in a cell, tissue, or biological sample, comprising administering to the subject in need of said treatment or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In some embodiments, the present disclosure provides a method of modulating PPARγ in a subject in need of treatment, comprising administering to the subject in need of said treatment an effective amount of a provided compound or pharmaceutical composition. In some embodiments, the present disclosure provides a method of modulating PPARγ in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.

[0243] In another aspect, the present disclosure provides a method of inhibiting cell proliferation in a subject in need of treatment, or in a cell, tissue, or biological sample, comprising administering to the subject in need of treatment or contacting the cell, tissue, or biological sample an effective amount of a provided compound or pharmaceutical composition. In some embodiments, the present disclosure provides a method of inhibiting cell proliferation in a subject in need of treatment, comprising administering to the subject in need of treatment an effective amount of a provided compound or pharmaceutical composition. In some embodiments, the present disclosure provides a method of inhibiting cell proliferation in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In some embodiments, the method comprises inhibiting cell proliferation (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).

[0244] In some embodiments, the method involves antagonism of PPARγ. In some embodiments, antagonism involves maintaining the receptor at basal activity (e.g., neutral activity). In some embodiments, antagonism involves outcompeting and / or preventing agonist binding, preventing receptor activation. In some embodiments, the method involves inverse agonism of PPARγ. In some embodiments, inverse agonism involves binding to the receptor and / or increasing interaction with a co-repressor. In some embodiments, inverse agonism involves reducing receptor activity below basal levels (e.g., neutral levels). In some embodiments, the method does not involve agonism of PPARγ. In certain embodiments, the method includes reducing phosphorylation of serine 273 of PPARγ (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).

[0245] In some embodiments, the method includes improving the activity of bone cells, osteoblasts, and / or osteoclasts. In some embodiments, the method includes improving the activity of bone cells. In some embodiments, the method includes improving the activity of osteoblasts. In some embodiments, the method includes normalizing the functional remodeling activity of bone cells, osteoblasts, and / or osteoclasts to produce healthy bone structure and / or bone strength. In some embodiments, the functional remodeling activity is measured by an increase in cortical bone area, a decrease in intramedullary fat, an increase in bone material strength, and / or an increase in bone metabolic markers and circulating osteocyte progenitor cells. See, e.g., L.A. Stechschulte et al., EBioMedicine 2016, 10, 174-184.

[0246] In some embodiments, the methods include increasing cancellous and cortical bone and / or improving metabolic parameters. In some embodiments, the methods include increasing cancellous and cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In some embodiments, the methods include increasing cancellous bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the methods include increasing cortical bone (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the methods include improving metabolic parameters by reducing fasting plasma glucose to the normal range of less than 100 mg / dl and HbA1c to less than 6%. In certain embodiments, the methods include reducing intramedullary fat (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).

[0247] In certain embodiments, the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro. [Example]

[0248] In order that this disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0249] Example 1: Compound synthesis Compound 1: 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0250] Step 1: Methyl 4-bromo-3-nitrobenzoate. A solution of 4-bromo-3-nitrobenzoic acid (10 g, 0.04 mol) in methanol (50 mL) was treated with 5 mL of concentrated sulfuric acid and refluxed for 4 hours. After cooling, the solvent was removed in vacuo, and the residue was diluted with 100 mL of cold saturated sodium bicarbonate solution and extracted twice with ethyl acetate (100 mL × 2). The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, and concentrated in vacuo to give the title compound as a white powder (10.1 g, yield 97%). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.13 (d, J = 8Hz, 1H), 7.42 (d, J = 8Hz, 1H), 3.95 (s, 3H), 2.65 (s, 3H) [ka]

[0251] Step 2: Methyl 3-nitro-4-(2-oxopropyl)benzoate. Methyl 4-bromo-3-nitrobenzoate (10 g, 0.038 mol) and acetone (12.75 g, 0.22 mol), 4-methoxyphenol (0.94 g, 7.58 mmol), potassium phosphate (17.74 g, 0.083 mol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.6 g, 1.5 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.34 g, 0.4 mmol) were added sequentially to toluene (100 mL) and stirred at 50 °C overnight. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound as a red oil (6.5 g, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.15 (dd, J = 8, 1 Hz, 1H), 7.20 (d, J = 8Hz, 1H), 4.12 (s, 2H), 3.89 (s, 3H), 2.26 (s, 3H) [ka]

[0252] Step 3: Methyl 2-methyl-1H-indole-6-carboxylate. Zinc powder (3.7 g, 0.056 mmol) and glacial acetic acid (2.01 g, 0.168 mmol) were added to a round-bottom flask. EtOH (20 mL) and methyl 3-nitro-4-(2-oxopropyl)benzoate (6.5 g, 0.019 mmol) were added sequentially via syringe at ambient temperature. The mixture was stirred at room temperature for 90 minutes. Water (200 mL) was then added to the reaction mixture, which was subsequently extracted with ethyl acetate (3 × 50 mL). The combined organic layers were then washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / EtOAc, 10:1 (v / v)). The product was isolated as a light brown solid (2.5 g, 71% yield). 1 H NMR (400 MHz, CDCl3): δ 8.23 ​​(s, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 8.3, 1.5 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 6.30 (dd, J = 2.1, 1 Hz, 1H), 3.95 (s, 3H), 2.51 (s, 3H). ESI-MS (m / z): 189. 62 [M] + [ka]

[0253] Step 4: Methyl 1,2-dimethyl-1H-indole-6-carboxylate. To a stirred solution of methyl 2-methyl-1H-indole-6-carboxylate (0.5 g, 2.64 mmol) in dry DMF (10 mL) was added NaH (60% dispersion in oil, 0.129 g, 3.17 mmol) in portions. The mixture was stirred for 30 min, and then iodomethane (246 μL, 3.96 mmol) was added in one portion. The reaction exothermed and was cooled in an ice bath. After 16 h at 90 °C, the reaction mixture was cooled, quenched with water (100 mL), and extracted with diethyl ether (100 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (hexane / EtOAc, 10:1 (v / v)) to afford the title compound (0.52 g, 97%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.75 (dd, J = 8.28 ,1.4 Hz, 1H), 7.51 (d, J = 8.28 Hz, 1H), 6.28 (s, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.44 (d, J = 0.53 Hz, 3H). ESI-MS (m / z): 203. 62 [M] + [ka]

[0254] Step 5: 1,2-Dimethyl-1H-indole-6-carboxylic acid. To a stirred solution of potassium trimethylsilanol (2.56 mL, 2M in THF, 5.12 mmol) in THF was added methyl 1,2-dimethyl-1H-indole-6-carboxylate (0.52 g, 2.56 mmol) in one portion, and the reaction mixture was heated at 60° C. for 10 min. The mixture was cooled, quenched with 5 N aqueous HCl (20 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting yellow solid was used in the next step without further purification (0.48 g, yield >99%). ESI-MS (m / z): 189.51 [M] + [ka]

[0255] Step 6: (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride. 1-(4-tert-Butylphenyl)ethanone (1 g, 5.7 mmol) and (S)-2-methylpropane-2-sulfinamide (1 g, 8.5 mmol) were added to Ti(OiPr) (5.2 mL, 17.11 mmol) under argon. The resulting deep yellow solution was heated at 80 °C overnight. The mixture was quenched with saturated NH Cl solution and diluted with ethyl acetate. The mixture was filtered through a Celite pad and washed with ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated to give (S,E)-N-(1-(4-tert-butylphenyl)ethylidene)-2-methylpropane-2-sulfinamide as a yellow syrup (1.5 g, 94% yield), which was used in the next step without further purification. ESI-MS (m / z): 279.51 [M] +To a cooled solution of the crude imine (1.5 g, 5.35 mmol) in THF / H2O (10 mL, 50:1 (v / v)) at -50 °C was added NaBH4 (0.78 g, 16.07 mmol) in one portion. The resulting mixture was warmed to rt and stirred for 3 h. The mixture was then partitioned between ethyl acetate (100 mL) and water (200 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. 1 Analysis of the residue by H-NMR and analytical HPLC showed complete consumption of the imine and detection of a mixture of diastereomers. The major diastereoisomer was isolated by silica gel chromatography as a white solid (1.1 g, 71% yield). 1 H NMR (400 MHz, CDCl3): δ 7.22 (dd, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.42 (qd, J = 6.6, 4.1 Hz, 1H), 1.42 (d, J = 6.7 Hz, 3H), 1.19(s, 9H), 1.08(s, 9H)

[0256] The corresponding sulfinamide was dissolved in methanol (10 mL) and concentrated HCl (1 mL) was added dropwise to the solution. The reaction was monitored by analytical reverse-phase HPLC until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, and the crude residue was suspended in ethanol (1 mL). The solution was precipitated by the addition of diethyl ether, and the chiral salt was isolated by filtration as a white solid (0.8 g, 95% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 3H), 7.43 - 7.37 (m, 4H), 4.35 (q, J = 5.9 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H) [ka]

[0257] Step 7: Ethyl 2-(4-formylphenoxy)propanoate. To a mixture of 4-hydroxybenzaldehyde (3 g, 24.6 mmol), ethyl bromopropionate (3.2 mL, 24.6 mmol), and K2CO3 (6 g, 49.2 mmol) was added acetonitrile (50 mL). The reaction mixture was refluxed for 3 h. After completion of the reaction, K2CO3 was removed by filtration, and the filtrate was concentrated in vacuo and subjected to column chromatography (hexane / EtOAc) to afford the final product as a clear liquid (5.2 g, yield 94%). 1 H NMR (600 MHz, CDCl3): δ 9.88 (s, 1H), 7.83 (d, J = 8.82 Hz, 2H), 6 .97(d, J = 8.82 Hz, 2H), 4.87 (q, J = 6.84 Hz, 1H), 4.24 (q, J = 7.20 Hz, 2H), 1. 66 (d, J = 6.84 Hz, 3H), 1.25 (t, J = 7.20 Hz, 3H). ESI-MS (m / z): 222. 63 [M] + [ka]

[0258] Step 8: (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. To a mixture of 1,2-dimethyl-1H-indole-6-carboxylic acid (0.385 g, 2.03 mmol) in DCM (10 mL) was added DIEA (1.12 mL, 6.09 mmol) and HATU (1.16 g, 1.9 mmol). The mixture was stirred for 5 min, followed by the addition of (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride (0.403 g, 1.9 mmol). The reaction mixture was stirred at rt for 30 min. The completion of the reaction was monitored by analytical HPLC. The solvent was removed under reduced pressure to give the crude product, which was purified by flash chromatography (hexane / EtOAc, 10:1 (v / v)) to give the title compound (0.7 g, yield 97%). 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.41 (d, J = 8.82 Hz, 1H), 7.33(m, 5H), 6 .34 (d, J = 8.81 Hz, 1H), 6.19 (s, 1H), 5.32 (q, J = 4.1 ESI-MS (m / z): 348.84 [M] + [ka]

[0259] Step 9: Ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. Triethylsilane (11 μL, 0.67 mmol) and trifluoroacetic acid (31 μL, 0.41 mmol) were added dropwise sequentially over 1 min to a stirred solution of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide (45 mg, 0.13 mmol) and ethyl 2-(4-formylphenoxy)propanoate (29 mg, 0.13 mmol) in DCM (1 mL) at 0 °C. The mixture was then warmed to rt and stirred for 2 h. The reaction was monitored by analytical HPLC until complete consumption of the starting material. The resulting mixture was quenched with saturated sodium bicarbonate solution (20 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, dried, and concentrated under reduced pressure. The crude product was used in the next step without further purification (72 mg, yield >99%). 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.25 (m, 6H), 6.96 (d, J = 8.4 Hz, 1H), 6. 65 (m, 2H), 6.51 (d, J = 8.0 Hz, 1H), 5.31 (q, J = 6.8 Hz, 1H), 4.58 (q, J = 7.1 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.90 (s, 2H), 3. 55 (s, 3H), 2.24 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H), 1.13 (t, J = 7.2 Hz, 3H) [ka]

[0260] Step 10: 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. To a stirred solution of potassium trimethylsilanolate in THF (128 μL, 2 M in THF, 0.26 mmol) was added a solution of ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate (72 mg, 0.13 mmol) in THF (1 mL) in one portion, and the reaction mixture was heated at 60° C. for 10 min. The mixture was cooled, quenched with 5 N aqueous HCl (5 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (1) as a yellowish solid. 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.22 (m, 6H), 6.96 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 6.0 Hz, 2H), 5.31 (q, J = 6.7 Hz, 1H), 4.63 (q, J = 6.8 Hz, 1H), 3.92 (s, 2H), 3. 57 (s, 3H), 2.26 (s, 3H), 1.51 (d, J = 6.8 Hz, 6H), 1.21 (s, 9H)

[0261] Compound 2: (S)-2-(4-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0262] Step 1: Ethyl 2-(4-formylphenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 7 of Compound 1, using 3-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde. A clear oil was obtained (1 g, yield 88%). 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.14 (q, J = 8.1 Hz, 2H), 1.58 (s, 6H), 1.14 (t, J = 8.1Hz, 3H) [ka]

[0263] Step 2: Ethyl (S)-2-(4-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol described in Step 9 of compound 1, using ethyl 2-(4-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A pale yellow solid was obtained (75 mg, yield 77%). 1 H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.29 (m, 6H), 6.97 (d, J = 8.4 Hz, 1H), 6.64 (d, 8.4 Hz, 2H), 6.45 (d, J = 8.0 Hz, 1H), 5.30 (q, J = 6.9 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 3.89 (s, 2H), 3.57 (s, 3H), 2.25 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.45 (s, 6H), 1.22 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H) [ka]

[0264] Step 3: (S)-2-(4-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using (ethyl (S)-2-(4-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (50 mg, yield 71%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.3 Hz, 1H), 7.40 - 7.24 (m, 3H), 7.24 - 7.18 (m, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 7.9 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H), 3.94 (s, 2H), 3.61 (s, 3H), 2.28 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H), 1.46 (s, 6H), 1.24 (s, 9H) [ka]

[0265] Compound 3: 2-(3-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0266] Step 1: Ethyl 2-(3-formylphenoxy)propanoate. The title compound was prepared according to the same general protocol as described in Step 7 of Compound 1, using ethyl α-bromoisobutyrate instead of ethyl bromopropionate. A clear oil was obtained (0.95 g, yield 34%). 1 H NMR (400 MHz, CDCl3) δ 9.72 (t, J = 1.2 Hz, 1H), 7.35 - 7.17 (m, 2H), 7.14 (dt, J = 3.1, 1.6 Hz, 1H), 6.97 (ddd, J = 7.9, 2.6, 1.3 Hz, 1H), 4.80 - 4.46 (m, 1H), 4.01 (dddd, J = 8.0, 7.1, 6.1, 1.7 Hz, 2H), 1.43 (dt, J = 6.8, 1.2 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H) [ka]

[0267] Step 2: Ethyl 2-(3-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol as described in Step 9 of compound 1, using ethyl 2-(3-formylphenoxy)propanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (48 mg, yield 88%). [ka]

[0268] Step 3: 2-(3-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using (ethyl 2-(3-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate instead of ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (40 mg, yield 87%). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.7 Hz, 1H), 7.47 - 7.21 (m, 5H), 7.21 - 7.06 (m, 1H), 6.98 (td, J = 7.9, 3.9 Hz, 1H), 6.71 (dd, J = 7.6, 3.1 Hz, 1H), 6.63 - 6.51 (m, 2H), 6.43 (dd, J = 8.0, 4.3 Hz, 1H), 5.27 (t, J = 6.7 Hz, 1H), 4.55 (q, J = 6.8 Hz, 1H), 4.02 - 3.72 (m, 2H), 3.46 (d, J = 2.4 Hz, 3H), 2.19 (d, J = 2.3 Hz, 3H), 1.51 (dd, J = 6.9, 1.4 Hz, 3H), 1.48 (dd, J = 6.9, 2.3 Hz, 3H), 1.23 (s, 9H)

[0269] Compound 4: (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0270] Step 1: Ethyl 2-(3-formylphenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 7 of Compound 1, using ethyl α-bromoisobutyrate instead of ethyl bromopropionate and 3-hydroxybenzaldehyde instead of 4-benzaldehyde. A clear oil was obtained (1.1 g, yield 90%). 1 H NMR (400 MHz, CDCl3) δ 9.85 (d, J = 0.8 Hz, 1H), 7.41 (dq, J = 7.5, 1.1 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.23 (tt, J = 3.0, 1.6 Hz, 1H), 7.04 (ddt, J = 8.1, 2.0, 0.9 Hz, 1H), 4.16 (td, J = 7.1, 0.8 Hz, 2H), 1.54 (d, J = 0.9 Hz, 6H), 0.83 - 0.73 (m, 3H) [ka]

[0271] Step 2: Ethyl (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 9 of compound 1, using ethyl 2-(3-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (30 mg, yield 96%). [ka]

[0272] Step 3: (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of compound 1, using ethyl (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (25 mg, yield 84%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.43 - 7.20 (m, 5H), 6.98 (t, J = 7.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.60 (dd, J = 8.1, 2.6 Hz, 1H), 6.35 (d, J = 7.9 Hz, 1H), 5.29 (p, J = 7.2 Hz, 1H), 3.93 (s, 2H), 3.58 (s, 3H), 2.26 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H), 1.44 (s, 6H), 1.24 (s, 9H)

[0273] Compound 5: (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenyl)-2-methylpropanoic acid [ka]

[0274] Step 1: Ethyl 2-(3-(hydroxymethyl)phenyl)-2-methylpropanoate. To a solution of 3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)benzoic acid (100 mg, 0.24 mmol) in THF (10 mL) was added BH3-THF (0.25 mL). The mixture was stirred at 65 °C for 7 h. The reaction mixture was then cooled to rt and quenched with HO. After removal of the solvent, the crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 7.4, 1.3 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.49 - 7.26 (m, 2H), 4.53 (s, 2H), 4.29 (br, 1H), 4.00 (q, J = 7.1 Hz, 2H), 1.46 (d, J = 0.9 Hz, 6H), 1.07 (t, J = 7.6 Hz, 3H) [ka]

[0275] Step 2: Ethyl 2-(3-formylphenyl)-2-methylpropanoate. To a solution of ethyl 2-(3-(hydroxymethyl)phenyl)-2-methylpropanoate (90 mg, 0.4 mmol) in dichloromethane (10 mL) was added Dess-Martin reagent (203 mg, 0.48 mmol). The mixture was stirred at rt for 4 h. The mixture was filtered, and the solvent was evaporated in vacuo. The crude product was used in the next step without further purification. [ka]

[0276] Step 3: Ethyl (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenyl)-2-methylpropanoate. The title compound was prepared according to the same general protocol described in Step 9 of compound 1, using ethyl 2-(3-formylphenyl)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A pale yellow solid was obtained (20 mg, yield 73%). 1 H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 7.30 - 7.19 (m, 6H), 7.14 - 7.07 (m, 1H), 7.07 - 6.90 (m, 1H), 6.35 (d, J = 7.9 Hz, 1H), 5.40 - 5.22 (m, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.99 - 3.92 (m, 2H), 3.62 (d, J = 1.3 Hz, 3H), 2.30 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H), 1.49 (s, 6H), 1.23 (d, J = 0.5 Hz, 9H), 1.09 (d, J = 7.1 Hz, 3H) [ka]

[0277] Step 4: (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenyl)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(3-((6-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenyl)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A brown solid was obtained (10 mg, yield 53%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.36 - 7.20 (m, 6H), 7.18 - 6.99 (m, 4H), 6.33 (d, J = 7.9 Hz, 1H), 5.30 (t, J = 7.3 Hz, 1H), 3.98 (s, 2H), 3.64 (s, 3H), 2.30 (s, 3H), 1.54 (dd, J = 6.9, 2.2 Hz, 3H), 1.47 (d, J = 2.1 Hz, 6H), 1.24 (s, 9H)

[0278] Compound 6: 2-(3-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0279] Step 1: (S)-1-(3-(tert-butyl)phenyl)ethanamine hydrochloride. The title compound was prepared according to the same general protocol as described in Step 6 of Compound 1, using 1-(3-tert-butylphenyl)ethenone instead of 1-(4-tert-butylphenyl)ethenone. A white solid was obtained (0.87 g, yield 71%). 1H NMR (600 MHz, DMSO-d6) δ 8.35 (s, 3H), 7.50 (t, J = 1.68 Hz, 1H), 7.39 (dd, J = 7.72, 1.74 Hz, 1H), 7.35 (t, J = 7.68 Hz, 1H), 7.26- 7.17 (m, 1H), 4.37 (q, J = 6.8 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H) [ka]

[0280] Step 2: (S)-N-(1-(3-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. The title compound was prepared according to the same general protocol as described in Step 8 of Compound 1, using (S)-1-(3-(tert-butyl)phenyl)ethan-1-amine hydrochloride instead of (S)-1-(4-(tert-butyl)phenyl)ethan-1-amine hydrochloride. A yellow solid was obtained (0.14 g, yield 99%). [ka]

[0281] Step 3: Ethyl 2-(3-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(3-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(3-formylphenoxy)propanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (65 mg, yield 90%). [ka]

[0282] Step 4: 2-(3-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl 2-(3-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (50 mg, yield 81%). 1 H NMR (400 MHz, MeOD) δ 8.52 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.38 (t, J = 3.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.21 - 6.99 (m, 3H), 6.95 (d, J = 6.4 Hz, 2H), 6.64 (s, 2H), 5.29 - 5.03 (m, 1H), 3.89 (s, 2H), 3.63 (s, 3H), 2.29 (s, 3H), 1.48 (d, J = 6.9 Hz, 6H), 1.21 (s, 9H)

[0283] Compound 7: (S)-2-(3-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0284] Step 1: Ethyl (S)-2-(3-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(3-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(3-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (82 mg, yield 84%). [ka]

[0285] Step 2: (S)-2-(3-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(3-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (71 mg, yield 90%). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.23 (td, J = 7.7, 4.0 Hz, 4H), 7.15 (dt, J = 6.8, 1.9 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.81 - 6.70 (m, 1H), 6.64 (s, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H), 3.89 (s, 2H), 3.54 (s, 3H), 2.22 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.42 (s, 6H), 1.24 (s, 9H)

[0286] Compound 8: 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0287] Step 1: Ethyl 2-(4-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(3-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. A yellow solid was obtained (49 mg, yield 96%). [ka]

[0288] Step 2: 2-(4-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. The title compound was prepared according to the same general protocol described in Step 10 of Compound 1, using ethyl 2-(4-((6-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (32 mg, yield 69%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.34 - 7.19 (m, 6H), 7.04 - 6.85 (m, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 8.0 Hz, 1H), 5.29 (p, J = 7.0 Hz, 1H), 4.61 (qd, J = 6.9, 1.4 Hz, 1H), 3.92 (s, 2H), 3.58 (s, 3H), 2.27 (s, 3H), 1.52 (d, J = 6.9 Hz, 6H), 1.23 (s, 9H)

[0289] Compound 9: (S)-2-(4-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0290] Step 1: Ethyl (S)-2-(4-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(3-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(4-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (59 mg, yield 86%). [ka]

[0291] Step 2: (S)-2-(4-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(4-((6-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (39 mg, yield 85%). 1H NMR (400 MHz, CDCl3) δ 7.90 - 7.73 (m, 1H), 7.35 (q, J = 1.6 Hz, 1H), 7.30 - 7.20 (m, 4H), 7.16 (dt, J = 6.6, 2.1 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 5.31 (q, J = 7.1 Hz, 1H), 3.93 (s, 2H), 3.61 (s, 3H), 2.28 (s, 3H), 1.97 (s, 6H), 1.55 (d, J = 6.9 Hz, 3H), 1.46 (s, 6H), 1.25 (s, 9H)

[0292] Compound 10: 2-(3-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0293] Step 1: (S)-1-(4-isopropylphenyl)ethanamine hydrochloride. The title compound was prepared according to the same general protocol as described in Step 6 of Compound 1, using 1-(4-isopropylphenyl)ethenonone instead of 1-(4-tert-butylphenyl)ethenonone. A white solid was obtained (0.5 g, yield 41%). 1 H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 3H), 7.44 (d, J = 8.08 Hz, 2H), 7.29 (d, J = 8.08 Hz, 2H), 4.34 (q, J = 6.72 Hz, 1H), 2.92 (p, J = 6.88 Hz, 1H), 1.52 (d, J = 6.76 Hz, 3H), 1.20 (d, J = 6.8 Hz, 6H) [ka]

[0294] Step 2: (S)-N-(1-(4-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. The title compound was prepared according to the same general protocol as described in Step 8 of Compound 1, using (S)-(S)-1-(4-isopropylphenyl)ethanamine hydrochloride instead of (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride. A yellow solid was obtained (0.17 g, yield 98%). [ka]

[0295] Step 3: Ethyl 2-(3-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(4-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(3-formylphenoxy)propanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (15 mg, yield 84%). [ka]

[0296] Step 4: 2-(3-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. The title compound was prepared according to the same general protocol described in Step 10 of compound 1, using ethyl 2-(3-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (12 mg, yield 84%). 1 H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.38 (dd, J = 8.3, 1.6 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.15 - 7.06 (m, 2H), 6.99 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 6.57 - 6.50 (m, 1H), 5.16 (t, J = 6.5 Hz, 1H), 4.48 (q, J = 6.8 Hz, 1H), 3.94 (s, 2H), 3.65 (s, 3H), 2.77 (p, J = 6.9 Hz, 1H), 2.31 (s, 3H), 1.47 (d, J = 6.9 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.14 (td, J = 7.1, 2.6 Hz, 6H)

[0297] Compound 11: (S)-2-(3-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0298] Step 1: Ethyl (S)-2-(3-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 9 of Compound 1, using (S)—N-(1-(4-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(3-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (14 mg, yield 93%). [ka]

[0299] Step 2: (S)-2-(3-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(3-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (12 mg, yield 90%). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.25 (dd, J = 13.9, 7.2 Hz, 4H), 7.14 (d, J = 8.0 Hz, 2H), 7.02 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 12.8 Hz, 2H), 6.30 (d, J = 7.9 Hz, 1H), 5.29 (t, J = 7.1 Hz, 1H), 3.95 (s, 2H), 3.62 (s, 3H), 2.83 (p, J = 7.0 Hz, 1H), 2.28 (s, 3H), 1.53 (s, 3H), 1.44 (s, 6H), 1.19 (t, J = 7.1 Hz, 6H)

[0300] Compound 12: (S)-2-(4-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0301] Step 1: Ethyl (S)-2-(4-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 9 of Compound 1, using (S)—N-(1-(4-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(4-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (12 mg, yield 80%). [ka]

[0302] Step 2: (S)-2-(4-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(3-((6-((1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (10 mg, yield 87%). 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.48 - 7.22 (m, 4H), 7.14 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H), 6.29 (s, 1H), 5.33 - 5.25 (m, 1H), 3.95 (s, 2H), 3.64 (s, 3H), 2.82 (p, J = 6.9 Hz, 1H), 2.30 (s, 3H), 1.54 (d, J = 6.5 Hz, 3H), 1.44 (s, 6H), 1.17 (d, J = 6.9 Hz, 6H)

[0303] Compound 13: 2-(4-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0304] Step 1: Ethyl 2-(4-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(4-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. A yellow solid was obtained (14 mg, yield 95%). [ka]

[0305] Step 2: 2-(4-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid. The title compound was prepared according to the same general protocol described in Step 10 of compound 1, using ethyl 2-(4-((6-(((S)-1-(4-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (11 mg, yield 82%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.34 - 7.23 (m, 3H), 7.21 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 6.33 (d, J = 7.9 Hz, 1H), 5.33 - 5.25 (m, 1H), 3.95 (s, 2H), 3.63 (s, 3H), 2.83 (p, J = 6.9 Hz, 1H), 2.30 (s, 3H), 1.54 (d, J = 6.8 Hz, 6H), 1.17 (d, J = 6.9 Hz, 6H)

[0306] Compound 14: (S)-2-(3-((6-((1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid [ka]

[0307] Step 1: 1-(3-Isopropylphenyl)ethanone. To a solution of 1-bromo-3-isopropylbenzene (3 g, 16.6 mmol) in THF was added n-BuLi (9 mL, 24.9 mol) dropwise at −60° C. After stirring for 30 min, N-methoxy-N-methylacetamide (2 g, 20 mmol) was added. The mixture was stirred at −30° C. for 3 h. The mixture was then quenched with HO, and the mixture was partitioned between ethyl acetate and water. The layers were separated, washed with water, saturated brine, dried over sodium sulfate, and concentrated. The residue was purified on silica gel (hexane / EtOAc, 20:1 (v / v)) to give the title compound, 1-(3-isopropylphenyl)ethanone, as a clear oil (2.2 g, 81% yield). 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.8 (dt, J = 7.6, 1.4 Hz, 1H), 7.53-7.33 (m, 2H), 3.00 (dt, J = 13.8, 6.9 Hz, 1H),1.30 (d, J = 6.7 Hz, 6H) [ka]

[0308] Step 2: (S)-1-(3-isopropylphenyl)ethanamine hydrochloride. The title compound was prepared according to the same general protocol as described in Step 6 of Compound 1, using 1-(3-isopropylphenyl)ethanone instead of 1-(4-tert-butylphenyl)ethanone. A white solid was obtained (1.5 g, yield 61%). 1 H NMR (600 MHz, DMSO-d6) δ 8.75 (s, 3H), 7.53 (s, 1H), 7.41-7.37 (m, 2H), 7.30 (t, J= 1.32 Hz, 1H), 4.4 (t, J= 5.04 Hz, 1H), 2.97 (p, J = 6.9 Hz, 1H), 1.52 (d, J = 6.84 Hz, 3H), 1.28 (d, J = 6.96 Hz, 6H) [ka]

[0309] Step 3: (S)—N-(1-(3-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide. The title compound was prepared according to the same general protocol as described in Step 8 of Compound 1, using (S)—(S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride. A yellow solid was obtained (0.32 g, yield 95%). [ka]

[0310] Step 4: Ethyl (S)-2-(3-((6-((1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate. The title compound was prepared according to the same general protocol as described in Step 9 of Compound 1, using (S)—N-(1-(3-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide and ethyl 2-(4-formylphenoxy)-2-methylpropanoate instead of ethyl 2-(4-formylphenoxy)propanoate. A yellow solid was obtained (52 mg, yield 94%). [ka]

[0311] Step 5: (S)-2-(3-((6-((1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoic acid. The title compound was prepared according to the same general protocol as described in Step 10 of Compound 1, using ethyl (S)-2-(3-((6-((1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)-2-methylpropanoate instead of (ethyl 2-(4-((6-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. A yellow solid was obtained (45 mg, yield 91%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 1.5 Hz, 1H), 7.28 - 7.11 (m, 5H), 7.07 (dt, J = 7.6, 1.6 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.74 (dt, J = 7.8, 1.1 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 6.58 (ddd, J = 8.1, 2.6, 0.9 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H), 3.90 (s, 2H), 3.53 (s, 3H), 2.83 (p, J = 6.9 Hz, 1H), 2.23 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H), 1.45 (s, 6H), 1.17 (d, J = 6.9 Hz, 6H)

[0312] Compound 15: 2-(3-((6-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoic acid [ka]

[0313] Step 1: Ethyl 2-(3-((6-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-1,2-dimethyl-1H-indol-3-yl)methyl)phenoxy)propanoate. The title compound was prepared according to the same general protocol described in Step 9 of Compound 1, using (S)—N-(1-(3-isopropylphenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamide instead of (S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1,2-dimethyl-1H-indole-6-carboxamid...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, A １ is a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; A ２ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L １ , L ２ , and L ３ are each independently a bond or substituted or unsubstituted alkylene; Y is C or N; R １ are each independently a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heteroalkenyl, a substituted or unsubstituted heteroalkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —CN, —OR Ａ , -SCN, -SR Ａ , -SSR Ａ , -N ３ , -NO, -N(R Ａ ) ２ , -NO ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)SR Ａ , -C(=O)N(R Ａ ) ２ , -C(=NR Ａ ) R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )SR Ａ , -C(=NR Ａ ) N (R Ａ ) ２ , -S(=O)R Ａ , -S(=O)OR Ａ , -S(=O)SR Ａ , -S(=O)N(R Ａ ) ２ , -S(=O) ２ R Ａ , -S(=O) ２ OR Ａ , -S(=O) ２ SR Ａ , -S(=O) ２ N (R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)SR Ａ , -OC(=O)N(R Ａ ) ２ , -OC(=NR Ａ ) R Ａ , -OC(=NR Ａ )OR Ａ 、-OC(=NR Ａ )SR Ａ 、-OC(=NR Ａ )N(R Ａ ) ２ 、-OS(=O)R Ａ 、-OS(=O)OR Ａ 、-OS(=O)SR Ａ 、-OS(=O)N(R Ａ ) ２ 、-OS(=O) ２ R Ａ 、-OS(=O) ２ OR Ａ 、-OS(=O) ２ SR Ａ 、-OS(=O) ２ N(R Ａ ) ２ 、-ON(R Ａ ) ２ 、-SC(=O)R Ａ 、-SC(=O)OR Ａ 、-SC(=O)SR Ａ 、-SC(=O)N(R Ａ ) ２ 、-SC(=NR Ａ )R Ａ 、-SC(=NR Ａ )OR Ａ 、-SC(=NR Ａ )SR Ａ 、-SC(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ C(=O)R Ａ 、-NR Ａ C(=O)OR Ａ 、-NR Ａ C(=O)SR Ａ 、-NR Ａ C(=O)N(R Ａ ) ２ 、-NR Ａ C(=NR Ａ )R Ａ 、-NR Ａ C(=NR Ａ )OR Ａ 、-NR Ａ C(=NR Ａ )SR Ａ 、-NR Ａ C(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ S(=O)R Ａ 、-NR Ａ S(=O)OR Ａ 、-NR Ａ S(=O)SR Ａ 、-NR Ａ S(=O)N(R Ａ ) ２ 、-NR Ａ S(=O) ２ R Ａ 、-NR Ａ S(=O) ２ OR Ａ 、-NR Ａ S(=O) ２ SR Ａ 、-NR Ａ S(=O) ２ N(R Ａ ) ２ 、-Si(R Ａ ) ３ 、-Si(R Ａ ) ２ OR Ａ 、-Si(R Ａ )(OR Ａ ) ２ 、-Si(OR Ａ ) ３ 、-OSi(R Ａ ) ３ 、-OSi(R Ａ ) ２ OR Ａ 、-OSi(R Ａ )(OR Ａ ) ２ 、-OSi(OR Ａ ) ３ 、または-B(OR Ａ ) ２ であり; R ２Ａ is absent, hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group, with the proviso that when Y is N, R ２Ａ does not exist; R ２Ｂ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —OR Ａ , -SCN, -SR Ａ , -SSR Ａ , -N ３ , -NO, -N(R Ａ ) ２ , -NO ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)SR Ａ , -C(=O)N(R Ａ ) ２ , -C(=NR Ａ ) R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )SR Ａ , -C(=NR Ａ ) N (R Ａ ) ２ , -S(=O)R Ａ , -S(=O)OR Ａ , -S(=O)SR Ａ , -S(=O)N(R Ａ ) ２ , -S(=O) ２ R Ａ , -S(=O) ２ OR Ａ , -S(=O) ２ SR Ａ , -S(=O) ２ N (R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)SR Ａ , -OC(=O)N(R Ａ ) ２ , -OC(=NR Ａ ) R Ａ , -OC(=NR Ａ ) OR Ａ 、-OC(=NR Ａ )SR Ａ 、-OC(=NR Ａ )N(R Ａ ) ２ 、-OS(=O)R Ａ 、-OS(=O)OR Ａ 、-OS(=O)SR Ａ 、-OS(=O)N(R Ａ ) ２ 、-OS(=O) ２ R Ａ 、-OS(=O) ２ OR Ａ 、-OS(=O) ２ SR Ａ 、-OS(=O) ２ N(R Ａ ) ２ 、-ON(R Ａ ) ２ 、-SC(=O)R Ａ 、-SC(=O)OR Ａ 、-SC(=O)SR Ａ 、-SC(=O)N(R Ａ ) ２ 、-SC(=NR Ａ )R Ａ 、-SC(=NR Ａ )OR Ａ 、-SC(=NR Ａ )SR Ａ 、-SC(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ C(=O)R Ａ 、-NR Ａ C(=O)OR Ａ 、-NR Ａ C(=O)SR Ａ 、-NR Ａ C(=O)N(R Ａ ) ２ 、-NR Ａ C(=NR Ａ )R Ａ 、-NR Ａ C(=NR Ａ )OR Ａ 、-NR Ａ C(=NR Ａ )SR Ａ 、-NR Ａ C(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ S(=O)R Ａ 、-NR Ａ S(=O)OR Ａ 、-NR Ａ S(=O)SR Ａ 、-NR Ａ S(=O)N(R Ａ ) ２ 、-NR Ａ S(=O) ２ R Ａ 、-NR Ａ S(=O) ２ OR Ａ 、-NR Ａ S(=O) ２ SR Ａ 、-NR Ａ S(=O) ２ N(R Ａ ) ２ 、-Si(R Ａ ) ３ 、-Si(R Ａ ) ２ OR Ａ 、-Si(R Ａ )(OR Ａ ) ２ 、-Si(OR Ａ ) ３ 、-OSi(R Ａ ) ３ 、-OSi(R Ａ ) ２ OR Ａ 、-OSi(R Ａ )(OR Ａ ) ２ 、-OSi(OR Ａ ) ３ 、または-B(OR Ａ ) ２ であり; R Ａ are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, if attached to a nitrogen atom, a nitrogen protecting group, if attached to an oxygen atom, an oxygen protecting group, or if attached to a sulfur atom, a sulfur protecting group; or Ａ two of which join with the atom between them to form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl ring; R Ｂ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; p is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or prodrug thereof.

2. Formula (I-a): 【Chemistry 2】 2. The compound of claim 1, wherein the compound is:

3. Formula (Ib): 【Transformation 3】 2. The compound of claim 1, wherein the compound is:

4. Formula (Ic): 【Chemistry 4】 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt or prodrug thereof.

5. Formula (I-d): 【Transformation 5】 2. The compound of claim 1, wherein the compound is:

6. A １ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

7. A １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted aryl.

8. A １ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted phenyl.

9. A １ But the formula: 【Transformation 6】 wherein: R ３ are each independently a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heteroalkenyl, a substituted or unsubstituted heteroalkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —CN, —OR Ａ , -SCN, -SR Ａ , -SSR Ａ , -N ３ , -NO, -N(R Ａ ) ２ , -NO ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)SR Ａ , -C(=O)N(R Ａ ) ２ , -C(=NR Ａ ) R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )SR Ａ , -C(=NR Ａ ) N (R Ａ ) ２ , -S(=O)R Ａ , -S(=O)OR Ａ , -S(=O)SR Ａ , -S(=O)N(R Ａ ) ２ , -S(=O) ２ R Ａ , -S(=O) ２ OR Ａ , -S(=O) ２ SR Ａ , -S(=O) ２ N (R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)SR Ａ , -OC(=O)N(R Ａ ) ２ , -OC(=NR Ａ ) R Ａ , -OC(=NR Ａ )OR Ａ 、-OC(=NR Ａ )SR Ａ 、-OC(=NR Ａ )N(R Ａ ) ２ 、-OS(=O)R Ａ 、-OS(=O)OR Ａ 、-OS(=O)SR Ａ 、-OS(=O)N(R Ａ ) ２ 、-OS(=O) ２ R Ａ 、-OS(=O) ２ OR Ａ 、-OS(=O) ２ SR Ａ 、-OS(=O) ２ N(R Ａ ) ２ 、-ON(R Ａ ) ２ 、-SC(=O)R Ａ 、-SC(=O)OR Ａ 、-SC(=O)SR Ａ 、-SC(=O)N(R Ａ ) ２ 、-SC(=NR Ａ )R Ａ 、-SC(=NR Ａ )OR Ａ 、-SC(=NR Ａ )SR Ａ 、-SC(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ C(=O)R Ａ 、-NR Ａ C(=O)OR Ａ 、-NR Ａ C(=O)SR Ａ 、-NR Ａ C(=O)N(R Ａ ) ２ 、-NR Ａ C(=NR Ａ )R Ａ 、-NR Ａ C(=NR Ａ )OR Ａ 、-NR Ａ C(=NR Ａ )SR Ａ 、-NR Ａ C(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ S(=O)R Ａ 、-NR Ａ S(=O)OR Ａ 、-NR Ａ S(=O)SR Ａ 、-NR Ａ S(=O)N(R Ａ ) ２ 、-NR Ａ S(=O) ２ R Ａ 、-NR Ａ S(=O) ２ OR Ａ 、-NR Ａ S(=O) ２ SR Ａ 、-NR Ａ S(=O) ２ N(R Ａ ) ２ 、-Si(R Ａ ) ３ 、-Si(R Ａ ) ２ OR Ａ 、-Si(R Ａ )(OR Ａ ) ２ 、-Si(OR Ａ ) ３ 、-OSi(R Ａ ) ３ 、-OSi(R Ａ ) ２ OR Ａ 、-OSi(R Ａ )(OR Ａ ) ２ 、-OSi(OR Ａ ) ３ 、または-B(OR Ａ ) ２ であり; m is 0, 1, 2, 3, 4, or 5; 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or prodrug thereof.

10. Formula (I-ai): 【Transformation 7】 The compound according to any one of claims 1, 2, or 6 to 9, or a pharmaceutically acceptable salt or prodrug thereof, wherein

11. Formula (I-bi): 【Transformation 8】 The compound according to any one of claims 1, 3, or 6 to 9, or a pharmaceutically acceptable salt or prodrug thereof, wherein

12. Formula (I-ci): 【Chemistry 9】 The compound according to any one of claims 1, 4, and 6 to 9, or a pharmaceutically acceptable salt or prodrug thereof, wherein

13. Formula (I-di): 【Chemistry 10】 The compound according to any one of claims 1, 5, and 6 to 9, or a pharmaceutically acceptable salt or prodrug thereof, wherein

14. A １ But the formula: 【Chemistry 11】 The compound according to any one of claims 1 to 13, wherein the compound is represented by the following formula (1): or a pharmaceutically acceptable salt or prodrug thereof.

15. R ３ are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, —CN, or —OR Ａ The compound according to any one of claims 9 to 14, wherein:

16. R ３ At least one of １－６ The compound according to any one of claims 9 to 15, or a pharmaceutically acceptable salt or prodrug thereof, wherein R is alkyl.

17. R ３ 17. The compound of any one of claims 9 to 16, or a pharmaceutically acceptable salt or prodrug thereof, wherein at least one of: is methyl, trifluoromethyl, ethyl, isopropyl, or tert-butyl.

18. R ３ At least one of １－６ 18. The compound of any one of claims 9 to 17, or a pharmaceutically acceptable salt or prodrug thereof, which is cycloalkyl.

19. R ３ 19. The compound of any one of claims 9 to 18, or a pharmaceutically acceptable salt or prodrug thereof, wherein at least one of: is cyclopropyl.

20. R ３ At least one of the following is —F, —Cl, —Br, —OMe, or —OCF ３ 20. The compound according to any one of claims 9 to 19, or a pharmaceutically acceptable salt or prodrug thereof, wherein:

21. R ２Ａ The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or prodrug thereof, wherein

22. R ２Ａ The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted alkyl.

23. R ２Ａ is a substituted or unsubstituted C １－６ 23. The compound of any one of claims 1 to 20 or 22, or a pharmaceutically acceptable salt or prodrug thereof, wherein:

24. R ２Ａ 24. The compound of any one of claims 1 to 20, 22, or 23, or a pharmaceutically acceptable salt or prodrug thereof, wherein is methyl, ethyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, or cyclobutylmethyl.

25. R ２Ｂ The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted alkyl.

26. R ２Ｂ is a substituted or unsubstituted C １－６ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or prodrug thereof, wherein:

27. R ２Ｂ The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or prodrug thereof, wherein is methyl.

28. A ２ The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted aryl.

29. A ２ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted phenyl.

30. A ２ But the formula: 【Chemistry 12】 wherein: R ４ are each independently a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heteroalkenyl, a substituted or unsubstituted heteroalkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —CN, —OR Ａ , -SCN, -SR Ａ , -SSR Ａ , -N ３ , -NO, -N(R Ａ ) ２ , -NO ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)SR Ａ , -C(=O)N(R Ａ ) ２ , -C(=NR Ａ ) R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )SR Ａ , -C(=NR Ａ ) N (R Ａ ) ２ , -S(=O)R Ａ , -S(=O)OR Ａ , -S(=O)SR Ａ , -S(=O)N(R Ａ ) ２ , -S(=O) ２ R Ａ , -S(=O) ２ OR Ａ , -S(=O) ２ SR Ａ , -S(=O) ２ N (R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)SR Ａ , -OC(=O)N(R Ａ ) ２ , -OC(=NR Ａ ) R Ａ , -OC(=NR Ａ )OR Ａ 、-OC(=NR Ａ )SR Ａ 、-OC(=NR Ａ )N(R Ａ ) ２ 、-OS(=O)R Ａ 、-OS(=O)OR Ａ 、-OS(=O)SR Ａ 、-OS(=O)N(R Ａ ) ２ 、-OS(=O) ２ R Ａ 、-OS(=O) ２ OR Ａ 、-OS(=O) ２ SR Ａ 、-OS(=O) ２ N(R Ａ ) ２ 、-ON(R Ａ ) ２ 、-SC(=O)R Ａ 、-SC(=O)OR Ａ 、-SC(=O)SR Ａ 、-SC(=O)N(R Ａ ) ２ 、-SC(=NR Ａ )R Ａ 、-SC(=NR Ａ )OR Ａ 、-SC(=NR Ａ )SR Ａ 、-SC(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ C(=O)R Ａ 、-NR Ａ C(=O)OR Ａ 、-NR Ａ C(=O)SR Ａ 、-NR Ａ C(=O)N(R Ａ ) ２ 、-NR Ａ C(=NR Ａ )R Ａ 、-NR Ａ C(=NR Ａ )OR Ａ 、-NR Ａ C(=NR Ａ )SR Ａ 、-NR Ａ C(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ S(=O)R Ａ 、-NR Ａ S(=O)OR Ａ 、-NR Ａ S(=O)SR Ａ 、-NR Ａ S(=O)N(R Ａ ) ２ 、-NR Ａ S(=O) ２ R Ａ 、-NR Ａ S(=O) ２ OR Ａ 、-NR Ａ S(=O) ２ SR Ａ 、-NR Ａ S(=O) ２ N(R Ａ ) ２ 、-Si(R Ａ ) ３ 、-Si(R Ａ ) ２ OR Ａ 、-Si(R Ａ )(OR Ａ ) ２ 、-Si(OR Ａ ) ３ 、-OSi(R Ａ ) ３ 、-OSi(R Ａ ) ２ OR Ａ 、-OSi(R Ａ )(OR Ａ ) ２ 、-OSi(OR Ａ ) ３ 、または-B(OR Ａ ) ２ であり; n is 0, 1, 2, 3, 4, or 5; 30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or prodrug thereof.

31. Formula (I-a-ii): 【Chemistry 13】 The compound according to any one of claims 1, 2, 6 to 10, and 14 to 30, or a pharmaceutically acceptable salt or prodrug thereof, wherein

32. Formula (I-b-ii): 【Chemistry 14】 The compound according to any one of claims 1, 3, 6 to 9, 11, and 14 to 30, or a pharmaceutically acceptable salt or prodrug thereof, wherein

33. Formula (I-c-ii): 【Chemistry 15】 The compound according to any one of claims 1, 4, 6 to 9, 12, and 14 to 30, or a pharmaceutically acceptable salt or prodrug thereof, wherein

34. Formula (I-d-ii): 【Chemistry 16】 The compound according to any one of claims 1, 5 to 9, or 13 to 30, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

35. Formula (I-a-iii): 【Chemistry 17】 32. The compound according to any one of claims 1, 2, 6 to 10, and 14 to 31, or a pharmaceutically acceptable salt or prodrug thereof, wherein:

36. Formula (I-b-iii): [Chemistry 18] 33. The compound according to any one of claims 1, 3, 6 to 9, 11, 14 to 30, or 32, or a pharmaceutically acceptable salt or prodrug thereof.

37. Formula (I-c-iii): 【Chemistry 19】 34. The compound according to any one of claims 1, 4, 6 to 9, 12, 14 to 30, or 33, or a pharmaceutically acceptable salt or prodrug thereof.

38. Formula (I-d-iii): 【Chemistry 20】 35. The compound according to any one of claims 1, 5 to 9, 13 to 30, or 34, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

39. A ２ But the formula: 【Chemistry 21】 The compound according to any one of claims 1 to 38, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

40. R ４ are each independently halogen, substituted or unsubstituted alkyl, or —OR Ａ 40. The compound according to any one of claims 1 to 39, wherein:

41. R ４ At least one of the groups is -OR Ａ 41. The compound according to any one of claims 1 to 40, wherein:

42. R ４ at least one of which is of the formula: 【Chemistry 22】 wherein: R ４Ａ are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; 42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt or prodrug thereof.

43. R ４ at least one of which is of the formula: 【Chemistry 23】 The compound according to any one of claims 1 to 42, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

44. R ４ at least one of which is of the formula: 【Chemistry 24】 The compound according to any one of claims 1 to 43, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

45. R ４ at least one of which is of the formula: 【Chemistry 25】 The compound according to any one of claims 1 to 44, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

46. R ４ at least one of which is of the formula: 【Chemistry 26】 The compound according to any one of claims 1 to 45, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof.

47. R ４Ａ 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt or prodrug thereof, wherein at least one of: is methyl, ethyl, isopropyl, trifluoromethyl, or cyclopropyl.

48. L １ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted alkylene.

49. L １ is a substituted or unsubstituted C １－６ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt or prodrug thereof, which is alkylene.

50. L １ But -CH(CH ３ )- or -CH(CF ３ 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt or prodrug thereof, wherein:

51. L ２ 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted alkylene.

52. L ２ is a substituted or unsubstituted C １－６ 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt or prodrug thereof, which is alkylene.

53. L ２ 53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt or prodrug thereof, wherein is substituted or unsubstituted methylene.

54. L ３ 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or prodrug thereof, wherein: is a bond.

55. The compound according to any one of claims 1 to 54, which is represented by the following formula: or a pharmaceutically acceptable salt or prodrug thereof: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11

56. 56. A composition comprising a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, and an excipient.

57. 57. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56.

58. 57. A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56, for treating a disease or disorder in a subject in need thereof.

59. 57. A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56, for use in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

60. 60. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 59, wherein the disease or disorder is associated with peroxisome proliferator-activated receptor gamma (PPARγ).

61. 61. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 60, wherein the disease or disorder is a progressive bone disease.

62. 62. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 61, wherein the progressive bone disease is osteoporosis or Paget's disease.

63. 61. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 60, wherein the disease or disorder is a proliferative disease.

64. 64. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 63, wherein the proliferative disease is cancer.

65. 65. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 64, wherein the cancer is colorectal cancer, pancreatic cancer, bladder cancer, esophageal cancer, breast cancer, prostate cancer, blood cancer, or bone cancer.

66. 66. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 64 or 65, wherein the cancer is multiple myeloma.

67. 61. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 60, wherein the disease or disorder is a metabolic disease.

68. 68. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 67, wherein the metabolic disease is diabetes, obesity, metabolic syndrome, atherosclerotic vascular disease, nonalcoholic steatohepatitis (NASH), fatty liver disease, weight loss, adipose tissue remodeling, metabolic bone disease, or hyperparathyroidism.

69. 69. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 68, wherein side effects experienced by the subject are reduced compared to administration of a PPARγ agonist.

70. 70. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 69, wherein the side effects include weight gain, edema, impaired bone growth or formation, cardiac hypertrophy, congestive heart failure, blood leak syndrome, and / or hepatotoxicity.

71. 56. A method of inhibiting cell proliferation or promoting apoptosis in a subject in need of treatment, or in a cell, tissue, or biological sample, said method comprising administering to a subject in need of treatment or contacting with said cell, tissue, or biological sample an effective amount of a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56, wherein said cell, tissue, or biological sample is in vivo.

72. 57. A method for inhibiting cell proliferation or promoting apoptosis in a cell, tissue, or biological sample, said method comprising contacting an effective amount of a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56, with said cell, tissue, or biological sample, wherein said cell, tissue, or biological sample is in vitro.

73. 57. A method for modulating peroxisome proliferator-activated receptor gamma (PPARγ) in a subject in need of treatment, or in a cell, tissue, or biological sample, comprising administering to the subject in need of treatment or contacting with the cell, tissue, or biological sample an effective amount of a compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or a composition according to claim 56.

74. 74. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 73, which does not involve activating PPARγ.

75. 75. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 74, comprising decreasing phosphorylation of serine 273 of PPARγ.

76. 76. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 75, comprising normalizing the functional remodeling activity of bone cells, osteoblasts, and / or osteoclasts to result in healthy bone structure and / or bone strength.

77. 77. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 76, comprising reducing marrow adiposity.

78. 78. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of any one of claims 57 to 77, comprising increasing cancellous and cortical bone and / or improving metabolic parameters.

79. 79. The method, compound, pharmaceutically acceptable salt or prodrug thereof, or composition of claim 78, wherein the improvement in metabolic parameters comprises reducing fasting plasma glucose to the normal range of less than 100 mg / dl and HbA1c to less than 6%.

80. A kit comprising the compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or prodrug thereof, or the composition according to claim 56, and instructions for use thereof.

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