Allosteric modulators of FCRN and uses thereof

Abstract

Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I'), Formula (I), Formula (II)), and pharmaceutically acceptable salts thereof. Compounds provided herein are capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful in the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject.

Description

[0001] ALLOSTERIC MODULATORS OF FCRN AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003]

[0001] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 690,179, filed September 3, 2024, the entire contents of which is incorporated herein by reference.

[0004] BACKGROUND

[0005]

[0002] The neonatal fragment crystallizable receptor (FcRn) plays an important role in extending the half-life of immunoglobulin G (IgG) autoantibodies, which are associated with numerous pathological conditions in subjects including autoimmune diseases. Because inhibition of FcRn can modulate IgG half-life, FcRn inhibitors are useful for the treatment of various diseases and conditions, such as IgG-mediated autoimmune and inflammatory conditions. See, e.g., Low and Mezo, “Inhibitors of the FcRnlgG Protein-Protein Interaction” 2009, The AAPS Journal, vol. 11, no. 3, pp. 432-434; Pyzik et al. “The therapeutic age of the neonatal Fc receptor” 2023, Nature Reviews Immunology, vol. 23, pp. 415-432. Examples of peptide inhibitors of FcRn can be found in, e.g. , International PCT Application Publication Nos. WO 2007 / 098420, WO 2009 / 020867, and WO 2010 / 014909. Agents capable of modulating FcRn activity have therapeutic promise in the treatment of various diseases.

[0006] SUMMARY

[0007]

[0003] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I'), Formula (I), Formula (II)), and pharmaceutically acceptable salts thereof. Compounds provided herein are capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful for the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject. Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0008]

[0004] In one aspect, provided herein are compounds of Formula (I'): and pharmaceutically acceptabl herein.

[0009]

[0005] In another aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable herein.

[0006] For example, in certain embodiments, provided herein are compounds of Formula (II): and pharmaceutically acceptable salts thereof, wherein each variable is as defined herein.

[0010]

[0007] In some embodiments, for example, a compound disclosed herein is selected from those recited in Tables 1A- 1C (infra), and pharmaceutically acceptable salts thereof.

[0011]

[0008] In another aspect, provided herein are compounds recited in Table 2 (infra), and pharmaceutically acceptable salts thereof.

[0012]

[0009] In another aspect, provided herein are pharmaceutical compositions comprising a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0013]

[0010] As described, the compounds, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions provided herein are capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful for treating and / or preventing diseases, disorders, and conditions in a subject, including, e.g., indications in which FcRn activity and / or IgG antibodies are implicated.

[0014] [OH] In other aspects, provided herein are methods and uses of the compounds, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions provided herein, including, but not limited to, the following:

[0015] (a) Methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0016] (b) Methods of treating an IgG-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0017] (c) Methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0018] (d) Methods of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] (e) Methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0020]

[0012] Also provided are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in any of the foregoing (a)-(e). In another aspect, provided herein are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use as medicaments and / or for use in the manufacture of medicaments.

[0021]

[0013] In another aspect, provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g. , instructions for using the compound or composition included in the kit).

[0022]

[0014] Also provided herein are methods of preparing compounds disclosed herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds and compositions are also provided herein.

[0023]

[0015] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims.

[0024] DEFINITIONS

[0025] Chemical Definitions

[0026]

[0016] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75* Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March ’s Advanced Organic Chemistry, Edition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0027]

[0017] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0028]

[0018] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0019] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0029]

[0020] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0021] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0030]

[0022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2.6alkyl”). Examples of Ci_6alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n- propyl, isopropyl), butyl (C4) (e.g., / / -butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g. , / / -pentyl. 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., / -hexyl). Additional examples of alkyl groups include / / -heptyl (C7), n-octyl (C8), / / -dodecyl (Ci2), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted Ci-6alkyl, e.g., -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted / / -propyl ( / / -Pr). unsubstituted isopropyl ( / -Pr)). unsubstituted butyl (Bn, e.g. , unsubstituted / / -butyl (n- Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted .sec-butyl (.sec-Bu or s-Bu). unsubstituted isobutyl ( / - Bn)). In certain embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0031]

[0023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g. , fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g. , fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“Ci_6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). 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 -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.

[0032]

[0024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g. , inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-n heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-4 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1-3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“Ci heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.

[0033]

[0025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 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 (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-e alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-e alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g. , -CH=CHCH3or ) may be in the (£)- or (Z)- configuration.

[0034]

[0026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g. , 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2- 12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-e heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.

[0035]

[0027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0036]

[0028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-e heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“C2-4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.

[0037]

[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / / -indcnyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0038]

[0030] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5- e cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0039]

[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g. , a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carboncarbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0040]

[0032] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041]

[0033] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5 -membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary 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, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[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- IH-pyrrolo [2,3 -b]pyridinyl, 2,3 -dihydrofuro [2,3 -b]pyridinyl, 4,5,6,7-tetrahydro- lH-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-l,6-naphthyridinyl, and the like.

[0034] 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 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“Ce-io aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2- naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“CM aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0042]

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g. , 5- indolyl). In certain embodiments, the heteroaryl is 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 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.

[0043]

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0044]

[0037] Exemplary 5 -membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5 -membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6- membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0045]

[0038] The term “acyl” refers to a group having the general formula -C(=O)Raa, -C(=O)ORaa, -C(=O)-O-C(=O)Raa, -C(=O)SRaa, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0046]

[0039] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0047]

[0040] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0048]

[0041] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g. , “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 or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments described herein are not limited in any manner by the exemplary substituents described herein.

[0049]

[0042] Exemplary substituents (e.g. , carbon atom substituents) include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, Ci-2o perhaloalkyl, C2-20 alkenyl, C2-20 alkynyl, Ci-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, C2-20alkenyl, C2-20alkynyl, Ci-20 heteroalkyl, C2-20heteroalkenyl, C2-20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI-20 alkyl, Ci-20 perhaloalkyl, C2-2o alkenyl, C2-2o alkynyl, Ci-20 heteroalkyl, C2-2o heteroalkenyl, C2-2o heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, C220 alkenyl, C2-20 alkynyl, Ci-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3- 14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalky nyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S, and wherein X is a counterion; each instance of Reeis, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3- 10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6 alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X , -NH(CI-6alkyl)2+X , -NH2(CI-6alkyl) X . -NH3X . -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)( C1-6 alkyl), -N(CI-6alkyl)C(=O)( Ci-6alkyl), -NHCOztCj6alkyl), -NHC(=O)N(CI_6alkyl)2, -NHC(=O)NH(Cj6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6 alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6 alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(CI-6alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2Ci-6alkyl, -SO2OCi6alkyl, -OSO2Ci6alkyl, -SOC1-6 alkyl, -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6alkyl), -C(=S)SCi-6 alkyl, -SC(=S)SCi_6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci_6alkyl)2, -OP(=O)(Ci_6alkyl)2, -OP(=O)(OCi-6 alkyl)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and each X is a counterion.

[0050]

[0043] In certain embodiments, the molecular weight of a substituent (e.g. , carbon atom substituent) is lower than

[0051] 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0052]

[0044] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -N(Rbb)2, -N(Rbb)3+X , -SH, -SRaa, -C(=O)Raa, -CO2H, -CHO, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), C O alkyl, C O perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, CMO heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, wherein X is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from CMO alkyl, CMO perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, CMO heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, -OH, -0Raa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CMO alkyl, CMO perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, CMO heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of Rccis, independently, selected from hydrogen, CMO alkyl, CMO perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, CMO heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0053]

[0045] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g. , substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C IO alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g. , substituted with one or more halogen) or unsubstituted C 6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t- Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g. , acetamidomethyl, / -Bn, 3 -nitro-2 -pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-6 alkyl, -OR33, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group (e.g. , silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3 -nitro-2 -pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0054]

[0046] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci.6alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci.6alkyl or a nitrogen protecting group.

[0055]

[0047] 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, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-10 alkyl (e.g., aralkyl, heteroaralkyl), C220 alkenyl, C2-20alkynyl, Ci_20heteroalkyl, C2-20heteroalkenyl, C2-20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0048] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g. , -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, V-bcnzoy Iphcnvlalanvl derivatives, benzamide, -phcnv Ibenzamide, o-nitophenylacetamide, o- nitrophenoxy acetamide, acetoacetamide, (\ '-di thiobenzyl oxyacyl amino )acctamidc. 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-nitrocinnamide, N- acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0056]

[0049] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g. , a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g. , -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is 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), l-(l-adamantyl)-! -methylethyl carbamate (Adpoc), 1, 1-dimethy 1-2 -haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl- 2,2,2-trichloroethyl carbamate (TCBOC), l-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3,5-di-t- butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(20- and 4c-pyridyl)cthyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4- nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), -mcthoxybcnzyl carbamate (Moz), -nitobcnzy I carbamate, -bromobcnzy I 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-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1, 1-dimethy 1-2 -cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, j>-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), / w-nitrophcnvl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S- benzyl thiocarbamate, -cyanobcnzy I carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, -dccy loxybcnzy I carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A,A- dimethylcarboxamido)benzyl carbamate, 1, 1-dimethy 1-3 -(N, A-dimethylcarboxamido)propyl carbamate, 1,1- dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1-methyl-l- (3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, j>-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0057]

[0050] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g. , -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of -tohicncsulfonamidc (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-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0058]

[0051] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, A ’-phenylaminothioacyl derivatives, V-bcnzoylphcnvIalanvl derivatives, V-acctvImcthioninc derivatives, 4,5-diphenyl-3-oxazolin-2-one, \ -phthalimide. V-dithiasuccinimidc (Dts), \-2.3-diphcnylmalcimidc. \-2.5-dimcthylpyrrolc. \-l. 1.4.4-tctramcthyldisilylazacyclopcntanc adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, V-mcthvlaminc. V-allylaminc. A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3 -acetoxypropylamine, A-( 1 -isopropyl-4-nitro-2-oxo-3 -pyroolin-3 - yl)amine, quaternary ammonium salts, \ -bcnzylaminc. A-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, \ -triphcnylmcthylaininc (Tr), A-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (PhF), \-2.7-dichloro-9-fluorcnylnicthylcncaminc. \ -fcrroccnylmcthylamino (Fem), N-2- picolylamino A ’-oxide, A- 1,1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A’-dimethylaminomethylene)amine, A- -nitrobcnzylidcncaininc. A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A- borane derivatives, A-diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A- copper chelate, A-zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A, A’ -isopropylidenediamine.

[0059]

[0052] In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), -nicthoxybcnzvl (PMB), 3,4-dimethoxybenzyl (DMPM), -mcthoxyphcnyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0060]

[0053] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0061]

[0054] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CCER33, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2R". -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci.6alkyl or an oxygen protecting group.

[0062]

[0055] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -P(=O)(N(Rbb)2)2, wherein X , Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0063]

[0056] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-mcthoxybcnzy loxy methyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t- butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl .S'.,S'-dioxidc. l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,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 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1- methyl-1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy -2 -fluoroethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophcny I. -mcthoxy phenyl, 2,4-dinitrophenyl, benzyl (Bn), p-mcthoxybcnzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, -nitrobcnzyl. p-halobcnzyl. 2,6- dichlorobenzyl, p-cyanobcnzyl. p-phcnylbcnzyl. 2-picolyl, 4-picolyl, 3 -methy 1-2 -picolyl \-oxido. diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthy Idiphcny Imcthy I. - 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(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1, l-bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3- benzodithiolan-2-yl, benzisothiazolyl .S'.,S'-dioxido. 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, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phcny Ibcnzoatc. 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-nitrophcnyl carbonate, benzyl carbonate, p-mcthoxybcnzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobcnzy I carbonate, .S'-bcnzyl thiocarbonate, 4-ethoxy-l- napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6- dichloro-4-(l , 1 ,3 ,3 -tetramethylbutyl)phenoxy acetate, 2,4-bis( 1 , 1 -dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a- naphthoate, nitrate, alkyl \ . \. \ ’. \ ’-tctramcthylphosphorodiamidatc. alkyl V-phcnvIcarbamatc. borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0064]

[0057] In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), / -butyldimcthylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1- ethoxyethyl (EE), 2-methyoxy-2 -propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, -mcthoxybcnzy I (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0065]

[0058] 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.

[0066]

[0059] In certain embodiments, each sulfur atom substituent is independently substituted (e.g. , substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci.6alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g. , substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci.6alkyl or a sulfur protecting group.

[0067]

[0060] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3X . -P(ORCC)2, -P(ORCC)3X . -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0068]

[0061] In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3 -nitro-2 -pyridine sulfenyl, 2- pyridine-sulfenyl, or triphenylmethyl.

[0069]

[0062] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F ", Cl", Br, I"), NO;, , CIO i . OH , H2PO I . HCO3HSO I . sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid- 5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF i . PF4", PFe", AsFe", SbFe", B|3.5-(CF;,);GH;,| i| . B(C6F5)4. BPh4. A1(OC(CF3)3)4", and carborane anions (e.g., CB, | H,2or (HCBi i Mc3Br6) ). Exemplary counterions which may be multivalent include CO;,2. HPO r . PO43B4O-2. SOr . S2O32. carboxylate anions (e.g. , tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0070]

[0063] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above exemplary listing of substituents. Other Definitions

[0071]

[0064] The following definitions are more general terms used throughout the present application.

[0072]

[0065] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result 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) so that the salt is electrically neutral (without a 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 an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -tohicncsulfonatc. undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Cj i alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0073]

[0066] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alky 1 ) i salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0067] 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”.

[0074]

[0068] “Stereoisomers” that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and .S'-scqucncing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory ( / . e. , as (+)- or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0075]

[0069] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts thereof. Stereoisomers and isotopically labeled derivatives are also included.

[0076]

[0070] The terms “composition” and “formulation” are used interchangeably.

[0077] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0078]

[0071] Provided herein are compounds, including compounds of any of the formulae described herein (e.g. , Formula (I'), Formula (I)), and pharmaceutically acceptable salts thereof. Compounds provided herein are capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins and can therefore be used for treating and / or preventing diseases and conditions associated with FcRn activity in a subject, including diseases and conditions associated with immunoglobulin G (IgG) autoantibody levels (e.g., autoimmune diseases, inflammatory diseases). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0079] Compounds

[0080]

[0072] Provided herein are compounds of Formula (I'): and pharmaceutically acceptable salts thereof, wherein:

[0081] R1is -OH, -ORla, or optionally substituted C2-3 alkynyl, wherein Rlais optionally substituted C1-3 alkyl;

[0082] Y1is -C(=O)- or -OC(RY1)2C(=O)-; each instance of RY1is independently hydrogen, C1-6 alkyl, C1-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0083] R2a, R2b, and R2care each independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -(L’j-Cs-s carbocyclyl, -(L' )-(3-8 membered heterocyclyl), -(L’j-Ce-io aryl, -(L1)-(5- l() membered heteroaryl), )R . -(LI)-C(=O)OR '. -(L1)-C(=O)N(RN)2, -(L1)-S(=O) or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L1is independently a bond, Ci-e alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; each instance of RAis independently C3-8 carbocyclylene, 3-8 membered heterocyclylene, Ce-io arylene, or 5-10 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted; each instance of L2is independently a bond, -C(=O)-, Ci-e alkylene, C1-6 haloalkylene, or CMO heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted, or an instance of L2is joined with an instance of R4to form a macrocycle, or an instance of L2is joined with an -N(RN)- or -C(RY2)2- instance of Y2to form a macrocycle; each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-11 membered heterocyclyl, Ce-io aryl, 5- 10 membered heteroaiyl, -OR0, -N(RN)2, -SRS, -C(=O)RC, -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2ORO, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1; each instance of RB1is independently halogen, Ci.6alkyl, Ci.6haloalkyl, C2-e alkenyl, C2-e alkynyl, -(L3)-C3. carbocyclyl, -(L3)-(3-10 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)-CN, - (L3)-OR°, -(L3)-N(RN)2, -(L3)-SRS, -(L3)-C(=O)RC, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, -(L3)-C(=O)N(RN)OR°, -(L3)-C(=O)N(RN)S(=O)2R°, -(L3)-S(=O)2RC, -(L3)-S(=O)2ORO, or - (L3)-S(=O)2N(RN)2, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L3is independently a bond or Ci.6alkylene, wherein the alkylene is optionally substituted; m is 0 or 1; n is 0 or 1; each instance of R3is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits;

[0084] Y2is -O-, -N(RN)-, -S-, -C(=O)-, or -C(RY2)2-; each instance of RY2is independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two RY2attached to the same carbon atom are joined together to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of R4is independently halogen, Ci.6alkyl, Ci.6haloalkyl, C2-e alkenyl, C2-e alkynyl, -(L4)-C3-s carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-Ce-io aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-N3, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)R°, -(L4)-SRS, -(L4)-C(=O)R°, -(L4)-C(=O)OR°, -(L4)- C(=O)N(RN)2, -(L4)-S(=O)R°, -(L4)-S(=O)2RC, -(L4)-S(=O)2OR°, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L4is independently a bond, Ci-e alkylene, C1-6 haloalkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; s is 0, 1, 2, 3, 4, or 5; each instance of R° is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or an oxygen protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atoms are joined to form 3-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of Rsis independently hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a sulfur protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; and each instance of Rcis independently Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0085]

[0073] Also provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0086] R1is -OH, -ORla, or optionally substituted C2-3 alkynyl, wherein Rlais optionally substituted C1-3 alkyl;

[0087] Y1is -C(=O)- or -OC(RY1)2C(=O)-; each instance of RY1is independently hydrogen, C1-6 alkyl, C1-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

[0088] R2a, R2b, and R2care each independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -(L’j-Cs-s carbocyclyl, -(Uj-CS-S membered heterocyclyl), -(L’j-Ce-io aryl, -(L’XS-IO membered heteroaryl), -(Uj-CN, -(L’j-OR0, -(L1)-N(RN)2, -(L’j-SR3, -(Uj-C^OjR0, -(L'j-C^OjOR0, -(L1)-C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)-S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L1is independently a bond, Ci-e alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; each instance of RAis independently C3-8 carbocyclylene, 3-8 membered heterocyclylene, Ce-io arylene, or 5-10 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted; each instance of L2is independently a bond, -C(=O)-, Ci-e alkylene, Ci-6 haloalkylene, or Ci-6 heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5- 10 membered heteroaiyl, -OR0, -N(RN)2, -SRS, -C(=O)RC, -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2ORO, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1; each instance of RB1is independently halogen, Ci-e alkyl, C1-6 haloalkyl, -(L3)-C3-s carbocyclyl, -(L3)-(3-8 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)-CN, -(L3)-OR°, -(L3)-N(RN)2, -(L3)-SRS, -(L3)-C(=O)RC, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, -(L3)-S(=O)2RC, -(L3)-S(=O)2ORO, or -(L3)-S(=O)2N(RN)2, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L3is independently a bond or Ci.6alkylene, wherein the alkylene is optionally substituted; m is 0 or 1; n is 0 or 1; each instance of R3is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits;

[0089] Y2is -O-, -N(RN)-, -S-, -C(=O)-, or -C(RY2)2-; each instance of RY2is independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two RY2attached to the same carbon atom are joined together to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of R4is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, -(L4)-C3-s carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-Ce-io aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)R°, -(L4)-SRS, -(L4)-C(=O)R°, -(L4)-C(=O)OR°, -(L4)- C(=O)N(RN)2, -(L4)-S(=O)R°, -(L4)-S(=O)2RC, -(L4)-S(=O)2OR°, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, C6aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L4is independently a bond, Ci-e alkylene, C1-6 haloalkylene, C1-6 heteroalkylene, C2.e alkenylene, or C2.e alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; s is 0, 1, 2, 3, 4, or 5; each instance of R° is independently hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or an oxygen protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atoms are joined to form 3-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of Rsis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a sulfur protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; and each instance of Rcis independently C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0090]

[0074] In certain embodiments, the compound of Formula (F) is of Formula (I), or a pharmaceutically acceptable salt thereof.

[0091]

[0075] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt thereof.

[0092]

[0076] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-a-1): or a pharmaceutically acceptable salt thereof.

[0093]

[0077] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-a-2): or a pharmaceutically acceptable salt thereof.

[0094]

[0078] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt thereof.

[0095]

[0079] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-b- 1) : or a pharmaceutically acceptable salt thereof.

[0096]

[0080] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-b-2): or a pharmaceutically acceptable salt thereof.

[0097]

[0081] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof.

[0098]

[0082] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-c-1): or a pharmaceutically acceptable salt thereof.

[0099]

[0083] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-c-2): or a pharmaceutically acceptable salt thereof.

[0100]

[0084] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-d-1) or (I-d-2): or a pharmaceutically acceptable salt thereof.

[0101]

[0086] In certain embodiments, a compound of Formula (I') or Formula (I) is of Formula (I-d-3) or (I-d-4): or a pharmaceutically acceptable salt thereof, wherein each instance of RB2is independently halogen or C1-3 alkyl; and b is 0, 1, 2, 3, 4, or 5. In some embodiments, b is 0. In some embodiments, b is 1 and RB2is halogen. In some embodiments, b is 1 and RB2is chloro.

[0102]

[0087] In certain embodiments, a compound provided herein is a compound of Formula (I') or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, a compound provided herein is a compound of Formula (I') or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (I') or any subgenus or species thereof, as a free base.

[0103]

[0088] In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, as a free base.

[0104]

[0089] In some embodiments, a compound provided herein is of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0105] LAis absent or is optionally substituted C1-3 alkylene;

[0106] RN2and RN3are each independently hydrogen, Ci.6alkyl, Ci.6haloalky 1, C3-s carbocyclyl, or Ci.6acyl, or RN2and RN3are joined to form 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, acyl, or heterocyclyl is optionally substituted; each instance of Ry, R6, R7, R8a, and R8bis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-8 carbocyclyl, wherein the alkyl, haloalkyl, or carbocyclyl is optionally substituted;

[0107] RN1is hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, or Ci.6acyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; or wherein RN1and R8aare joined together to form optionally substituted 5-6 membered heterocyclyl; each instance of R3, R5, and R9is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, -CN, - OR0, -N(RN)2, or -SRs, or any two instances of R3, R5, or R9attached to the same carbon atom are joined to form C3- 8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, or heterocyclyl is optionally substituted; each of R2a, R2b, R4a, and R10ais independently hydrogen, halogen, Ci.6alkyl, Ci.6haloalkyl, C2.6alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, -CN, -OR0, - N(RN)2, -SRS, or Ci-e acyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of R4band R10bis independently halogen, Ci-e alkyl, C1-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, or 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRs, or Ci-eacyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of R° is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, or two RNattached to the same nitrogen atom are joined to form 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, acyl, or heterocyclyl is optionally substituted; each instance of Rsis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; p is 0, 1, 2, 3, 4, or 5; each of w and q are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; and each of z and s is independently 0, 1, 2, 3, or 4.

[0090] In some embodiments, a compound of Formula (II) is of Formula (Il-a): or a pharmaceutically acceptable salt thereof.

[0108]

[0091] In some embodiments, a compound of Formula (II) is of Formula (II-a-i): or a pharmaceutically acceptable salt thereof.

[0109]

[0092] In certain embodiments, a compound provided herein is a compound of Formula (II) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, a compound provided herein is a compound of Formula (II) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (II) or any subgenus or species thereof, as a free base.

[0110]

[0093] In the various aspects and embodiments disclosed herein, express reference to a compound of Formula (I'), Formula (I), or Formula (II) is understood to alternatively refer to a compound of any disclosed subgenus or species thereof, for example, to a compound of Tables 1A-1C.

[0111]

[0094] In certain embodiments, a compound disclosed herein is selected from the compounds recited in Tables 1A- 1C, and pharmaceutically acceptable salts, stereoisomers, and isotopically labeled derivatives thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Tables 1A-1C, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Tables 1A-1C, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Tables 1A-1C, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Tables 1A-1C (in free base form).

[0112] Table 1A

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] Table IB

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0095] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formula (I'), Formula (I), or any subgeneric formula thereof) provided herein. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0142]

[0096] As defined herein, R1is -OH, -ORla, or optionally substituted C2.3alkynyl, wherein Rlais optionally substituted C1-3 alkyl.

[0143]

[0097] In some embodiments, R1is -OH.

[0144]

[0098] In some embodiments, R1is -ORla, wherein Rlais optionally substituted C1-3 alkyl. In some embodiments, R1is -ORla, wherein Rlais unsubstituted C1-3 alkyl. In some embodiments, R1is -OCH3.

[0145]

[0099] In some embodiments, R1is optionally substituted C2.3alkynyl. In some embodiments, R1is -C=CH.

[0146]

[0100] In some embodiments, R1is -OH, -OCH3, or -C=CH.

[0147]

[0101] As defined herein, R2a, R2b, and R2care each independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalky 1, C2.e alkenyl, C2.e alkynyl, -(L’j-Cs-s carbocyclyl, -(L’XS-S membered heterocyclyl), -(L’j-Ce-io aryl, -(L’XS-IO membered heteroaiyl), -(L’j-CN, -(L’j-OR0, -(L^-N / R^z, -(L’j-SR3, -(L1)-C(=O)Rc, -(L'j-C^OjOR0, -(L1)- C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)-S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, C6aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0148]

[0102] In some embodiments, R2a, R2b, and R2care each independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -(L’j-Cs-e carbocyclyl, -(Uj-CS-b membered heterocyclyl),

[0149] -(L'j-Ce aryl, -(L^-CS-e membered heteroaiyl), -(L’j-CN, -(L’j-OR0, -(L1)-N(RN)2, -(L’j-SR3, -(L1)-C(=O)RC, -(L1)- C(=O)OR°, -(L1)-C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)-S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0150]

[0103] In some embodiments, R2a, R2b, and R2care each independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -(L’j-Cs-e carbocyclyl, -(L’j' / S-b membered heterocyclyl),

[0151] -(L1)-Ce aryl, -(L1)-(5-6 membered heteroaryl), -(L’j-OR0, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0152]

[0104] In some embodiments, at least one of R2a, R2b, and R2cis hydrogen.

[0153]

[0105] In some embodiments, at least one of R2a, R2b, and R2cis halogen. In some embodiments, at least one of R2a, R2b, and R2cis -F. In some embodiments, at least one of R2a, R2b, and R2cis -Cl. In some embodiments, at least one of R2a, R2b, and R2cis -Br. In some embodiments, at least one of R2a, R2b, and R2cis -I.

[0154]

[0106] In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted Ci.6alkyl. In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted C1.3 alkyl. In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted Ci alkyl. In some embodiments, at least one of R2a, R2b, and R2cis

[0155]

[0107] In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted C1-6 haloalkyl.

[0156]

[0108] In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted C2-6 alkenyl. In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted C2 alkenyl. In some embodiments, at least one

[0157]

[0109] In some embodiments, at least one of R2a, R2b, and R2cis optionally substituted C2-6 alkynyl.

[0158] [HO] In some embodiments, at least one of R2a, R2b, and R2cis -(Uj-Cs-s carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, at least one of R2a, R2b, and R2cis -(C1.3 alkylene)-C4-6 carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, at least one of R2a, R2b, and R2cis [Hl] In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-(3-8 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, at least one of R2a, R2b, and R2cis -(C1-3 alkylene)-(4-6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, at least one of

[0159]

[0112] In some embodiments, at least one of R2a, R2b, and R2cis -(Uj-Ce-io aryl, wherein the aryl is optionally substituted. In some embodiments, at least one of R2a, R2b, and R2cis -(C1-3 alkylene)-phenyl, wherein the phenyl is optionally substituted. In some embodiments, at least one

[0160]

[0113] In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-(5- 10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, at least one of R2a, R2b, and R2cis -(C2.3alkenylene)-(5-6 membered heteroaryl), wherein the alkenylene or heteroaryl is optionally substituted. In some embodiments, at least one

[0161]

[0114] In some embodiments, at least one of R2a, R2b, and R2cis -(L’j-CN.

[0162]

[0115] In some embodiments, at least one of R2a, R2b, and R2cis -(L’j-OR0. In some embodiments, at least one of R2a, R2b, and R2cis -OR0. In some embodiments, at least one of R2a, R2b, and R2cis -OH. In some embodiments, at least one of R2a, R2b, and R2cis -OCH3.

[0163]

[0116] In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-N(RN)2. In some embodiments, at least one of R2a, R2b, and R2cis -(L’j-SR3. In some embodiments, at least one of R2a, R2b, and R2cis

[0164] -(L1)-C(=O)Rc. In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-C(=O)OR°. In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-C(=O)N(RN)2. In some embodiments, at least one of R2a, R2b, and R2cis -(L1)- S(=O)2RC. In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-S(=O)2OR°. In some embodiments, at least one of R2a, R2b, and R2cis -(L1)-S(=O)2N(RN)2.

[0165]

[0117] In some embodiments, at least one of R2a, R2b, and R2cis -RA-L2-RB.

[0166]

[0118] In some embodiments, any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In some embodiments, any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form optionally substituted phenyl. In some embodiments, any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form phenyl.

[0167]

[0119] In some embodiments, at least one of R2a, R2b, and R2cis hydrogen, -F, -Cl, -Br, -I, -OH, -OCH3, r any two of R2a, R2b, and R2care joined to form phenyl.

[0168]

[0120] In some embodiments, R2a, R2b, and R2care each independently hydrogen or -RA-L2-RB.

[0169]

[0121] In some embodiments, R2ais hydrogen. In some embodiments, R2ais halogen. In some embodiments, R2ais optionally substituted Ci-6 alkyl. In some embodiments, R2ais optionally substituted Ci-6 haloalkyl. In some embodiments, R2ais optionally substituted C2-6 alkenyl. In some embodiments, R2ais optionally substituted C2-6 alkynyl. In some embodiments, R2ais -(L'j-Cs-s carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, R2ais -(L1)-(3 -8 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, R2ais -(L’j-Ce-io aryl, wherein the aryl is optionally substituted. In some embodiments, R2ais - (L1)-(5- 10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, R2ais - (L1)-CN. In some embodiments, R2ais -(L1)-OR°. In some embodiments, R2ais -(L1)-N(RN)2. In some embodiments, R2ais -(L1)-SRs. In some embodiments, R2ais -(L1)-C(=O)Rc. In some embodiments, R2ais -(L1)-C(=O)OR°. In some embodiments, R2ais -(L1)-C(=O)N(RN)2. In some embodiments, R2ais -(L1)-S(=O)2RC. In some embodiments, R2ais -(L1)-S(=O)2OR°. In some embodiments, R2ais -(L1)-S(=O)2N(RN)2. In some embodiments, R2ais -RA-L2-RB.

[0170]

[0122] In some embodiments, R2bis hydrogen. In some embodiments, R2bis halogen. In some embodiments, R2bis optionally substituted C1-6 alkyl. In some embodiments, R2bis optionally substituted C1-6 haloalkyl. In some embodiments, R2bis optionally substituted C2-6 alkenyl. In some embodiments, R2bis optionally substituted C2-6 alkynyl. In some embodiments, R2bis -(L'j-Cs-s carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, R2bis -(L1)-(3-8 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, R2bis -(Uj-Ce-io aryl, wherein the aryl is optionally substituted. In some embodiments, R2bis - (L1)-(5- 10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, R2bis - (L1)-CN. In some embodiments, R2bis -(L1)-OR°. In some embodiments, R2bis -(L1)-N(RN)2. In some embodiments, R2bis -(L1)-SRs. In some embodiments, R2bis -(L1)-C(=O)Rc. In some embodiments, R2bis -(L1)-C(=O)OR°. In some embodiments, R2bis -(L1)-C(=O)N(RN)2. In some embodiments, R2bis -(L1)-S(=O)2RC. In some embodiments, R2bis -(L1)-S(=O)2OR°. In some embodiments, R2bis -(L1)-S(=O)2N(RN)2. In some embodiments, R2bis -RA-L2-RB.

[0171]

[0123] In some embodiments, R2cis hydrogen. In some embodiments, R2cis halogen. In some embodiments, R2cis optionally substituted Ci.6alkyl. In some embodiments, R2cis optionally substituted Ci.6haloalkyl. In some embodiments, R2cis optionally substituted C2-6 alkenyl. In some embodiments, R2cis optionally substituted C2-6 alkynyl. In some embodiments, R2cis -(L'j-Cs-s carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, R2cis -(L1)-(3 -8 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, R2cis -(L’j-Ce-io aryl, wherein the aryl is optionally substituted. In some embodiments, R2cis - (L1)-(5- 10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, R2cis - (L1)-CN. In some embodiments, R2cis -(L1)-OR°. In some embodiments, R2cis -(L1)-N(RN)2. In some embodiments, R2cis -(L1)-SRs. In some embodiments, R2cis -(L1)-C(=O)Rc. In some embodiments, R2cis -(L1)-C(=O)OR°. In some embodiments, R2cis -(L1)-C(=O)N(RN)2. In some embodiments, R2cis -(L1)-S(=O)2RC. In some embodiments, R2cis -(L1)-S(=O)2OR°. In some embodiments, R2cis -(L1)-S(=O)2N(RN)2. In some embodiments, R2cis -RA-L2-RB.

[0172]

[0124] In some embodiments, R2aand R2bare joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0173]

[0125] In some embodiments, R2band R2care joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, C6aryl, or 5-6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0126] As defined herein, each instance of L1is independently a bond, C1-6 alkylene, C1-6 haloalkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted.

[0174]

[0127] In some embodiments, at least one instance of L1is a bond.

[0175]

[0128] In some embodiments, at least one instance of L1is optionally substituted C1-6 alkylene. In some embodiments, at least one instance of L1is optionally substituted C1-3 alkylene. In some embodiments, at least one instance of L1is optionally substituted Ci alkylene. In some embodiments, at least one instance of L1is -CH2-.

[0176]

[0129] In some embodiments, at least one instance of L1is optionally substituted C1-6 haloalkylene.

[0177]

[0130] In some embodiments, at least one instance of L1is optionally substituted C1-6 heteroalkylene.

[0178]

[0131] In some embodiments, at least one instance of L1is optionally substituted C2-6 alkenylene. In some embodiments, at least one instance of L1is optionally substituted C2-3 alkenylene. In some embodiments, at least one instance of L1is -CH=CH-.

[0179]

[0132] In some embodiments, at least one instance of L1is optionally substituted C2-e alkynylene.

[0180]

[0133] As defined herein, each instance of RAis independently C3-8 carbocyclylene, 3-8 membered heterocyclylene, Ce-io arylene, or 5-10 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted.

[0181]

[0134] In some embodiments, at least one instance of RAis optionally substituted C3-8 carbocyclylene. In some embodiments, at least one instance of RAis optionally substituted C5-8 carbocyclylene. In some embodiments, at least one instance of RAis optionally substituted cyclohexenylene. In some embodiments, at least one instance of RAis

[0182]

[0135] In some embodiments, at least one instance of RAis optionally substituted 3-8 membered heterocyclylene. In some embodiments, at least one instance of RAis optionally substituted 5-8 membered heterocyclylene. In some embodiments, at least one instance of RAis optionally substituted 1,2,3,6-tetrahydropyridinylene. In some embodiments, at least one instance

[0183]

[0136] In some embodiments, at least one instance of RAis optionally substituted Ce-io arylene. In some embodiments, at least one instance of RAis optionally substituted Ce arylene.

[0184]

[0137] In some embodiments, at least one instance of RAis optionally substituted 5-10 membered heteroarylene. In some embodiments, at least one instance of RAis optionally substituted 5-6 membered heteroarylene.

[0185]

[0138] In some embodiments, at least one instance of RAis C5-8 carbocyclylene, 5-8 membered heterocyclylene, Ce arylene, or 5-6 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted. In some embodiments, at least one instance of RAis optionally substituted cyclohexenylene or optionally substituted 1,2,3,6-tetrahydropyridinylene. In some embodiments, at least one instance of RAis

[0186]

[0139] As defined herein, each instance of L2is independently a bond, -C(=O)-, Ci.6alkylene, Ci.6haloalkylene, or Ci-io heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted, or an instance of L2is joined with an instance of R4to form a macrocycle, or an instance of L2is joined with an -N(RN)- or -C(RY2)2- instance of Y2to form a macrocycle.

[0187]

[0140] In some embodiments, each instance of L2is independently a bond, -C(=O)-, Ci-6 alkylene, Ci-6 haloalkylene, or Ci-6 heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted.

[0188]

[0141] In some embodiments, at least one instance of L2is a bond.

[0189]

[0142] In some embodiments, at least one instance of L2is -C(=O)-.

[0190]

[0143] In some embodiments, at least one instance of L2is optionally substituted Ci-6 alkylene.

[0191]

[0144] In some embodiments, at least one instance of L2is optionally substituted Ci-6 haloalkylene.

[0192]

[0145] In some embodiments, at least one instance of L2is optionally substituted Ci-io heteroalkylene. In some embodiments, at least one instance of L2is optionally substituted Ci-6 heteroalkylene.

[0193]

[0146] In some embodiments, an instance of L2is joined with an instance of R4to form a macrocycle.

[0194]

[0147] In some embodiments, an instance of L2is joined with an -N(RN)- or -C(RY2)2- instance of Y2to form a macrocycle.

[0195]

[0148] As defined herein, each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-11 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -OR0, -N(RN)2, -SRS, -C(=O)RC,

[0196] -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2ORO, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1.

[0197]

[0149] In some embodiments, each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -OR0, -N(RN)2, -SRs, -C(=O)R°,

[0198] -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2OR°, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1.

[0199]

[0150] In some embodiments, at least one instance of RBis hydrogen.

[0200]

[0151] In some embodiments, at least one instance of RBis C3-8 carbocyclyl, wherein the carbocyclyl is optionally substituted with one or more instances of RB1.

[0201]

[0152] In some embodiments, at least one instance of RBis 3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more instances of RB1. In some embodiments, at least one instance of RBis 3-8 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more instances of RB1.

[0202]

[0153] In some embodiments, at least one instance of RBis Ce-io aryl, wherein the aryl is optionally substituted with one or more instances of RB1.

[0203]

[0154] In some embodiments, at least one instance of RBis 5-10 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more instances of RB1.

[0204]

[0155] In some embodiments, at least one instance of RBis -OR0.

[0205]

[0156] In some embodiments, at least one instance of RBis -N(RN)2.

[0206]

[0157] In some embodiments, at least one instance of RBis -SRs.

[0207]

[0158] In some embodiments, at least one instance of RBis -C(=O)R°.

[0208]

[0159] In some embodiments, at least one instance of RBis -C(=O)OR°.

[0209]

[0160] In some embodiments, at least one instance of RBis -C(=O)N(RN)2.

[0210]

[0161] In some embodiments, at least one instance of RBis -S(=O)2R°.

[0211]

[0162] In some embodiments, at least one instance of RBis -S(=O)2OR°.

[0212]

[0163] In some embodiments, at least one instance of RBis -S(=O)2N(RN)2.

[0213]

[0164] As defined herein, each instance of RB1is independently halogen, Ci.6alkyl, Ci.6haloalky 1, C2.6alkenyl, C2.6 alkynyl, -(L3)-C3-IO carbocyclyl, -(L3)-(3-10 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)-CN, -(L3)-OR°, -(L3)-N(RN)2, -(L3)-SRS, -(L3)-C(=O)RC, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, - (L3)-C(=O)N(RN)OR°, -(L3)-C(=O)N(RN)S(=O)2RC, -(L3)-S(=O)2RC, -(L3)-S(=O)2ORO, or -(L3)-S(=O)2N(RN)2, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0214]

[0165] In some embodiments, each instance of RB1is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl,

[0215] -(L3)-C3-8 carbocyclyl, -(L3)-(3-8 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)- CN, -(L3)-OR°, -(L3)-N(RN)2, -(L3)-SRS, -(L3)-C(=O)RC, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, -(L3)-S(=O)2RC, - (L3)-S(=O)2OR°, or -(L3)-S(=O)2N(RN)2, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0216]

[0166] In some embodiments, at least one instance of RB1is halogen.

[0217]

[0167] In some embodiments, at least one instance alkyl.

[0218]

[0168] In some embodiments, at least one instance haloalkyl.

[0219]

[0169] In some embodiments, at least one instance alkenyl.

[0220]

[0170] In some embodiments, at least one instance alkynyl.

[0221]

[0171] In some embodiments, at least one instance )-C3-IO carbocyclyl. In some embodiments, at least one instance of RB1is -(L3)-C3-s carbocyclyl.

[0222]

[0172] In some embodiments, at least one instance of RB1is -(L3)-(3-10 membered heterocyclyl). In some embodiments, at least one instance of RB1is -(L3)-(3-8 membered heterocyclyl).

[0223]

[0173] In some embodiments, at least one instance of RB1is -(L3)-Ce-io aryl.

[0224]

[0174] In some embodiments, at least one instance of RB1is -(L3)-(5-10 membered heteroaryl).

[0225]

[0175] In some embodiments, at least one instance of RB1is -(L3)-CN.

[0226]

[0176] In some embodiments, at least one instance of RB1is -(L3)-OR°.

[0227]

[0177] In some embodiments, at least one instance of RB1is -(L3)-N(RN)2.

[0228]

[0178] In some embodiments, at least one instance of RB1is -(L3)-SRs.

[0229]

[0179] In some embodiments, at least one instance of RB1is -(L3)-C(=O)Rc.

[0230]

[0180] In some embodiments, at least one instance of RB1is -(L3)-C(=O)OR°.

[0231]

[0181] In some embodiments, at least one instance of RB1is -(L3)-C(=O)N(RN)2.

[0232]

[0182] In some embodiments, at least one instance of RB1is -(L3)-C(=O)N(RN)OR°.

[0233]

[0183] In some embodiments, at least one instance of RB1is -(L3)-C(=O)N(RN)S(=O)2RC.

[0234]

[0184] In some embodiments, at least one instance of RB1is -(L3)-S(=O)2RC.

[0235]

[0185] In some embodiments, at least one instance of RB1is -(L3)-S(=O)2OR°.

[0236]

[0186] In some embodiments, at least one instance of RB1is -(L3)-S(=O)2N(RN)2.

[0237]

[0187] As defined herein, each instance of L3is independently a bond or Ci-6 alkylene, wherein the alkylene is optionally substituted. In some embodiments, at least one instance of L3is a bond.

[0238]

[0188] In some embodiments, at least one instance of L3is optionally substituted Ci-6 alkylene.

[0239]

[0189] In some embodiments, -RA-L2-RBis of formula:

[0240]

[0241]

[0191] As defined herein, each instance of R3is independently halogen, Ci-e alkyl, Ci-6 haloalky 1, C3-8 carbocyclyl, 3- 8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0242]

[0192] In some embodiments, at least one instance of R3is C1.3 alkyl, C1.3 haloalkyl, C3-6 carbocyclyl, 3-6 membered heterocyclyl, Ce aryl, 5-6 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In some embodiments, at least one instance of R3is C1-3 alkyl, or two R3attached to the same carbon atom are joined to form C3-4 carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted.

[0193] In some embodiments, at least one instance of R3is C1-3 alkyl substituted with 0 or 1 -OR0, or two R3attached to the same carbon atom are joined to form unsubstituted C3-4 carbocyclyl.

[0243]

[0194] In some embodiments, at least one instance of R3is halogen.

[0244]

[0195] In some embodiments, at least one instance of R3is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R3is optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R3is C1-3 alkyl substituted with 0 or 1 -OR0. In some embodiments, at least one instance of R3is unsubstituted C1-3 alkyl. In some embodiments, at least one instance of R3is -CH3. In some embodiments, at least one instance of R3is C1-3 alkyl substituted with 1 -OR0. In some embodiments, at least one instance of R3is -CH2OH, -CH2OCH3,

[0245]

[0196] In some embodiments, at least one instance of R3is optionally substituted Ci.6haloalkyl. In some embodiments, at least one instance of R3is optionally substituted C1.3 haloalkyl. In some embodiments, at least one instance of R3is optionally substituted C3-8 carbocyclyl. In some embodiments, at least one instance of R3is optionally substituted C3-6 carbocyclyl. In some embodiments, at least one instance of R3is optionally substituted 3-8 membered heterocyclyl. In some embodiments, at least one instance of R3is optionally substituted 3-6 membered heterocyclyl. In some embodiments, at least one instance of R3is optionally substituted Ce-io aryl. In some embodiments, at least one instance of R3is optionally substituted C6aryl. In some embodiments, at least one instance of R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one instance of R3is optionally substituted 5-6 membered heteroaryl. In some embodiments, at least one instance of R3is -CN. In some embodiments, at least one instance of R3is -OR0. In some embodiments, at least one instance of R3is -N(RN)2. In some embodiments, at least one instance of R3is -SRs.

[0246]

[0197] In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted C3-8 carbocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted C3-6 carbocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted C3-4 carbocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form unsubstituted C3-4 carbocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form .

[0247]

[0198] In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted 3-8 membered heterocyclyl. In some embodiments, two R3attached to the same carbon atom are joined to form optionally substituted 3-6 membered heterocyclyl.

[0248]

[0199] As defined herein, m is 0 or 1.

[0249]

[0200] In some embodiments, m is 0. In some embodiments, m is 1.

[0250]

[0201] As defined herein, n is 0 or 1;

[0251]

[0202] In some embodiments, n is 0. In some embodiments, n is 1.

[0252]

[0203] In some embodiments, m is 0 and n is 0. In some embodiments, m is 1 and n is 1.

[0253]

[0204] As defined herein, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits.

[0254]

[0205] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0255] In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is

[0256]

[0257]

[0208] As defined herein, Y1is -C(=O)- or -OC(RY1)2C(=O)-.

[0258]

[0209] In some embodiments, Y1is -C(=O)-.

[0210] In some embodiments, Y1is -OC(RY1)2C(=O)-. In some embodiments, Y1is -OCH2C(=O)-. In some embodiments, Y1is -OCH(RY1)C(=O)-. In some embodiments,

[0259]

[0211] As defined herein, each instance of RY1is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl,

[0260] 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0261]

[0212] In some embodiments, at least one instance of RY1is hydrogen. In some embodiments, two instances of RY1are hydrogen.

[0262]

[0213] In some embodiments, at least one instance of RY1is optionally substituted Ci-6 alkyl. In some embodiments, at least one instance of RY1is optionally substituted Ci-6 haloalkyl. In some embodiments, at least one instance of RY1is optionally substituted C3-s carbocyclyl. In some embodiments, at least one instance of RY1is optionally substituted 3-8 membered heterocyclyl.

[0263]

[0214] In some embodiments, at least one instance of RY1is optionally substituted Ce-io aryl. In some embodiments, at least one instance of RY1is optionally substituted Ce aryl. In some embodiments, at least one instance of RY1is phenyl.

[0264]

[0215] In some embodiments, at least one instance of RY1is optionally substituted 5-10 membered heteroaryl.

[0265]

[0216] As defined herein, Y2is -O-, -N(RN)-, -S-, -C(=O)-, or -C(RY2)2-.

[0266]

[0217] In some embodiments, Y2is -O-.

[0267]

[0218] In some embodiments, Y2is -N(RN)-. In some embodiments, Y2is -N(CH3)-.

[0268]

[0219] In some embodiments, Y2is -S-. In some embodiments, Y2is -C(=O)-.

[0269]

[0220] In some embodiments, Y2is -C(RY2)2-. In some embodiments, Y2is -CH2-.

[0270]

[0221] As defined herein, each instance of RY2is independently hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two RY2attached to the same carbon atom are joined together to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0271]

[0222] In some embodiments, at least one instance of RY2is hydrogen. In some embodiments, two instances of RY2are hydrogen.

[0272]

[0223] In some embodiments, at least one instance of RY2is halogen. In some embodiments, at least one instance of Y2is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of Y2is optionally substituted C1-6 haloalkyl. In some embodiments, at least one instance of RY2is optionally substituted C3-8 carbocyclyl. In some embodiments, at least one instance of RY2is optionally substituted 3-8 membered heterocyclyl. In some embodiments, at least one instance of RY2is optionally substituted Ce-io aryl. In some embodiments, at least one instance of RY2is optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one instance of RY2is -CN. In some embodiments, at least one instance of RY2is -OR0. In some embodiments, at least one instance of RY2is -N(RN)2. In some embodiments, at least one instance of RY2is -SRs. In some embodiments, two RY2attached to the same carbon atom are joined together to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. In some embodiments, two RY2attached to the same carbon atom are joined together to form optionally substituted C3-8 carbocyclyl. In some embodiments, two RY2attached to the same carbon atom are joined together to form optionally substituted 3-8 membered heterocyclyl.

[0273] the substituent on the oxygen atom and at least one substituent on the terminal nitrogen atom are joined to form a macrocycle. In certain embodiments, the substituents are joined to form Cie heterocyclyl. In certain embodiments, the substituents are joined to form 18-22 membered macrocycle. In certain embodiments, the substituents are joined to form 20 membered macrocycle.

[0274]

[0227] As defined herein, each instance of R4is independently halogen, Ci-6 alkyl, Ci-6 haloalky 1, C2-6 alkenyl, C2-6 alkynyl, -(L4)-C3.s carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-Ce-io aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)-NO2, -(L4)-N3, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-SRS, -(L4)- C(=O)RC, -(L4)-C(=O)OR°, -(L4)-C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, -(L4)-S(=O)2ORO, or -(L4)- S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0275]

[0228] In some embodiments, each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- e alkynyl, -(L4)-C3-8 carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-C6-IO aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)-NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-SRS, -(L4)-C(=O)RC, -(L4)- C(=O)OR°, -(L4)-C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, -(L4)-S(=O)2ORO, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0276]

[0229] In some embodiments, each instance of R4is independently halogen, C1.4 alkyl, C1.4 haloalkyl, C2.4alkenyl, C2. 4 alkynyl, -(L4)-C3.e carbocyclyl, -(L4)-(3-6 membered heterocyclyl), -(L4)-Ce aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)-NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-SRS, -(L4)-C(=O)RC, -(L4)- C(=O)OR°, -(L4)-C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, -(L4)-S(=O)2ORO, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C5-6 carbocyclyl, 5-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0277]

[0230] In some embodiments, each instance of R4is independently halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2- 4 alkynyl, -(L4)-C3-e carbocyclyl, -(L4)-(3-6 membered heterocyclyl), -(L4)-Ce aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)-NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-C(=O)RC, -(L4)-C(=O)OR°, - (L4)-C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, or -(L4)-S(=O)2OR°, or any two instances of R4attached to adjacent carbon atoms are joined to form C5-6 carbocyclyl, 5-6 membered heterocyclyl, or Ce aryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0278]

[0231] In some embodiments, at least one instance of R4is halogen. In some embodiments, at least one instance of R4is -F, -Cl, or -I. In some embodiments, at least one instance of R4is -F. In some embodiments, at least one instance of R4is -Cl. In some embodiments, at least one instance of R4is -I.

[0279]

[0232] In some embodiments, at least one instance of R4is optionally substituted Ci.6alkyl. In some embodiments, at least one instance of R4is optionally substituted C1-4 alkyl. In some embodiments, at least one instance of R4is

[0280]

[0233] In some embodiments, at least one instance of R4is optionally substituted Ci.6haloalkyl. In some embodiments, at least one instance of R4is optionally substituted C1.4 haloalkyl. In some embodiments, at least one instance of R4is optionally substituted C1-4 fluoroalkyl. In some embodiments, at least one instance of R4is -CF3.

[0281]

[0234] In some embodiments, at least one instance of R4is optionally substituted C2-6 alkenyl. In some embodiments, at least one instance of R4is optionally substituted C2-4 alkenyl. In some embodiments, at least one instance of R4is -

[0235] In some embodiments, at least one instance of R4is optionally substituted C2-6 alkynyl. In some embodiments, at least one instance of R4is optionally substituted C2-4 alkynyl. In some embodiments, at least one instance of R4is

[0282]

[0236] In some embodiments, at least one instance of R4is -(L4)-C3-s carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, at least one instance of R4is -(L4)-C3-e carbocyclyl, wherein the carbocyclyl is optionally substituted. In some embodiments, at least one instance of R4is optionally substituted C3-6 carbocyclyl. In some embodiments, at least one instance of R4is unsubstituted C3-6 carbocyclyl. In some

[0283]

[0237] In some embodiments, at least one instance of R4is -(L4)-(3-8 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, at least one instance of R4is -(L4)-(3-6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, at least one instance of R4is optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N. In some embodiments, at least one instance some embodiments, at least one instance of R4is -(C1.4 alkylene)-(5-6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted. In some embodiments, at least one instance

[0284]

[0238] In some embodiments, at least one instance of R4is -(L4)-Ce aryl, wherein the aryl is optionally substituted. In some embodiments, at least one instance of R4is optionally substituted Ce aryl. In some embodiments, at least one some embodiments, at least one instance of R4is -(C1-4 alkylene)-Ce aryl, wherein the aryl is optionally substituted. some embodiments, at least one instance of R4is -(C2-4 alkenylene)-C6aryl, wherein the aryl is optionally substituted. In some embodiments, at least one instance of R4is

[0285]

[0239] In some embodiments, at least one instance of R4is -(L4)-(5-10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, at least one instance of R4is optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one instance of R4is optionally substituted monocyclic 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from O, N, and S. In some embodiments, at least one instance some embodiments, at least one instance of R4is optionally substituted bicyclic 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from O, N, and S. In some embodiments, at least one instance of R4is some embodiments, at least one instance of R4is -(C1-4 alkylene)-(5-10 membered heteroaryl), wherein the heteroaryl is optionally substituted. In some embodiments, at least one instance

[0286]

[0240] In some embodiments, at least one instance of R4is -(L4)-CN. In some embodiments, at least one instance of R4is -(C1.4 alkylene)-CN. In some embodiments, at least one instance of R4is -CH2CN. In some embodiments, at least one instance of R4is -CN.

[0287]

[0241] In some embodiments, at least one instance of R4is -(L4)-NO2. In some embodiments, at least one instance of R4is -NO2.

[0288]

[0242] In some embodiments, at least one instance of R4is -(L4)-N3.

[0289]

[0243] In some embodiments, at least one instance of R4is -(L4)-OR°. In some embodiments, at least one instance of R4is -OR0. In some embodiments, at least one instance of R4is -OCH3,

[0290] -OCH2CH2CH3, -OCHF2, -OCF3, -OCH2CF3, . In some embodiments, at least one instance of R4is -(Ci-4 alkylene)-OR°. In some embodiments, at least one instance of R4is -CH2OH, -CH2CH2OH, or -CH2CH2OCH3. In some embodiments, at least one instance of R4is -(C2-4 alkenylene)-OR°. In some embodiments, at least one instance

[0291]

[0244] In some embodiments, at least one instance of R4is -(L4)-N(RN)2. In some embodiments, at least one instance of R4is -(Ci-4 alkylene)-N(RN)2. In some embodiments, at least one instance of R4is some embodiments, at least one instance of R4is -(C2-4 alkynylene)-N(RN)2. In some embodiments, at least one instance of R4is

[0292]

[0245] In some embodiments, at least one instance of R4is -(L4)-N(RN)C(=O)Rc. In some embodiments, at least one instance of R4is -N(RN)C(=O)Rc. In some embodiments, at least one instance of R4is -NHC(=O)Rc. In some embodiments, at least one instance of R4is -NHC(=O)CH3.

[0293]

[0246] In some embodiments, at least one instance of R4is -(L4)-SRs.

[0294]

[0247] In some embodiments, at least one instance of R4is -(L4)-C(=O)Rc. In some embodiments, at least one instance of R4is -C(=O)RC. In some embodiments, at least one instance of R4is -C(=O)H,

[0295]

[0248] In some embodiments, at least one instance of R4is -(L4)-C(=O)OR°. In some embodiments, at least one instance of R4is -C(=O)OR°. In some embodiments, at least one instance of R4is

[0296] -C(=O)OCH3,

[0297]

[0249] In some embodiments, at least one instance of R4is -(L4)-C(=O)N(RN)2. In some embodiments, at least one instance of R4is -C(=O)N(RN)2. In some embodiments, at least one instance

[0298]

[0250] In some embodiments, at least one instance of R4is -(L4)-S(=O)RC. In some embodiments, at least one instance of R4is -S(=O)CH3.

[0299]

[0251] In some embodiments, at least one instance of R4is -(L4)-S(=O)2RC. In some embodiments, at least one instance of R4is -S(=O)2CH3.

[0300]

[0252] In some embodiments, at least one instance of R4is -(L4)-S(=O)2OR°. In some embodiments, at least one instance of R4is -(L4)-S(=O)2N(RN)2.

[0301]

[0253] In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted C4-8 carbocyclyl. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted C5-6 carbocyclyl. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted 4- 8 membered heterocyclyl. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted 5-6 membered heterocyclyl. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted Ce aryl. In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form optionally substituted 5-6 membered heteroaryl.

[0302] In some embodiments, any two instances of R4attached to adjacent carbon atoms are joined to form

[0303]

[0254] In some embodiments, at least one instance of R4is -F, -Cl, -I, -CN, -NO2, -S(=O)CH3, -S(=O)2CH3, CH3,

[0304] -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2OH, -CH2CN, -CH2CH2OH, -CH2CH2OCH3,

[0305] -CH2CH2CH2N(CH3)2, -(CH2)4NHCH3, -CH=CH2, -CH2CH=CH2, -C(=O)H, -C(=O)CH3, -C(=O)OCH3, -OCH3,

[0306] , or any two instances of R4attached to adjacent carbon atoms are joined to form

[0307]

[0255] As defined herein, each instance of L4is independently a bond, Ci-6 alkylene, Ci-6 haloalkylene, Ci-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted.

[0308]

[0256] In some embodiments, each instance of L4is independently a bond, C1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, or C2-4 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted.

[0309]

[0257] In some embodiments, at least one instance of L4is a bond.

[0310]

[0258] In some embodiments, at least one instance of L4is optionally substituted C1-6 alkylene. In some embodiments, at least one instance of L4is optionally substituted C1-4 alkylene.

[0311]

[0259] In some embodiments, at least one instance of L4is optionally substituted C1-6 haloalkylene. In some embodiments, at least one instance of L4is optionally substituted C1-4 haloalkylene.

[0312]

[0260] In some embodiments, at least one instance of L4is optionally substituted Ci.6heteroalkylene. In some embodiments, at least one instance of L4is optionally substituted C1.4 heteroalkylene.

[0313]

[0261] In some embodiments, at least one instance of L4is optionally substituted C2-6 alkenylene. In some embodiments, at least one instance of L4is optionally substituted C2-4 alkenylene.

[0314]

[0262] In some embodiments, at least one instance of L4is optionally substituted C2-6 alkynylene. In some embodiments, at least one instance of L4is optionally substituted C2-4 alkynylene.

[0315]

[0263] As defined herein, s is 0, 1, 2, 3, 4, or 5.

[0316]

[0264] In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5.

[0317] the substituent on the phenyl ring and at least one substituent on a terminal nitrogen or carbon atom are joined to form a macrocycle. In certain embodiments, the substituents are joined to form C16-22 heterocyclyl. In certain embodiments, the substituents are joined to form C18-20 heterocyclyl. In certain embodiments, the substituents are joined to form Cis heterocyclyl. In certain embodiments, the substituents are joined to form C19 heterocyclyl. In certain embodiments, the substituents are joined to form C20 heterocyclyl. In certain embodiments, the substituents are joined to form a 20-27 membered macrocycle. In certain embodiments, the substituents are joined to form a 22- 25 membered macrocycle. In certain embodiments, the substituents are joined to form a 22 membered macrocycle. In certain embodiments, the substituents are joined to form a 24 membered macrocycle. In certain embodiments, the substituents are joined to form a 25 membered macrocycle.

[0318]

[0267] As defined herein, each instance of R° is independently hydrogen, Ci.6alkyl, Ci.6haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, Ci.6acyl, or an oxygen protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0319]

[0268] In some embodiments, at least one instance of R° is hydrogen.

[0320]

[0269] In some embodiments, at least one instance of R° is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R° is optionally substituted C1-3 alkyl.

[0321]

[0270] In some embodiments, at least one instance of R° is optionally substituted Ci.6haloalkyl. In some embodiments, at least one instance of R° is optionally substituted C1.3 haloalkyl.

[0322]

[0271] In some embodiments, at least one instance of R° is optionally substituted C3-8 carbocyclyl.

[0323]

[0272] In some embodiments, at least one instance of R° is optionally substituted 3-8 membered heterocyclyl.

[0324]

[0273] In some embodiments, at least one instance of R° is optionally substituted Ce-io aryl.

[0325]

[0274] In some embodiments, at least one instance of R° is optionally substituted 5-10 membered heteroaryl.

[0326]

[0275] In some embodiments, at least one instance of R° is optionally substituted Ci.6acyl.

[0327]

[0276] In some embodiments, at least one instance of R° is an oxygen protecting group.

[0328]

[0277] As defined herein, each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atoms are joined to form 3-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0329]

[0278] In some embodiments, at least one instance of RNis hydrogen.

[0330]

[0279] In some embodiments, at least one instance of RNis optionally substituted Ci.6alkyl. In some embodiments, at least one instance of RNis optionally substituted C1-3 alkyl.

[0331]

[0280] In some embodiments, at least one instance of RNis optionally substituted C1-6 haloalkyl. In some embodiments, at least one instance of RNis optionally substituted C1-3 haloalkyl.

[0332]

[0281] In some embodiments, at least one instance of RNis optionally substituted C3-8 carbocyclyl.

[0282] In some embodiments, at least one instance of RNis optionally substituted 3-8 membered heterocyclyl.

[0333]

[0283] In some embodiments, at least one instance of RNis optionally substituted Ce-io aryl.

[0334]

[0284] In some embodiments, at least one instance of RNis optionally substituted 5-10 membered heteroaryl.

[0335]

[0285] In some embodiments, at least one instance of RNis optionally substituted Ci-6 acyl.

[0336]

[0286] In some embodiments, at least one instance of RNis a nitrogen protecting group.

[0337]

[0287] In some embodiments, two RNattached to the same nitrogen atoms are joined to form optionally substituted 3- 8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.

[0338]

[0288] As defined herein, each instance of Rsis independently hydrogen, Ci-6 alkyl, Ci-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a sulfur protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0339]

[0289] In some embodiments, at least one instance of Rsis hydrogen.

[0340]

[0290] In some embodiments, at least one instance of Rsis optionally substituted Ci.6alkyl.

[0341]

[0291] In some embodiments, at least one instance of Rsis optionally substituted Ci.6haloalkyl.

[0342]

[0292] In some embodiments, at least one instance of Rsis optionally substituted C3-8 carbocyclyl.

[0343]

[0293] In some embodiments, at least one instance of Rsis optionally substituted 3-8 membered heterocyclyl.

[0344]

[0294] In some embodiments, at least one instance of Rsis optionally substituted Ce-io aryl.

[0345]

[0295] In some embodiments, at least one instance of Rsis optionally substituted 5-10 membered heteroaryl.

[0346]

[0296] In some embodiments, at least one instance of Rsis optionally substituted Ci.6acyl.

[0347]

[0297] In some embodiments, at least one instance of Rsis a sulfur protecting group.

[0348]

[0298] As defined herein, each instance of Rcis independently C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0349]

[0299] In some embodiments, at least one instance of Rcis optionally substituted Ci.6alkyl.

[0350]

[0300] In some embodiments, at least one instance of Rcis optionally substituted Ci.6haloalkyl.

[0351]

[0301] In some embodiments, at least one instance of Rcis optionally substituted C3-8 carbocyclyl.

[0352]

[0302] In some embodiments, at least one instance of Rcis optionally substituted 3-8 membered heterocyclyl.

[0353]

[0303] In some embodiments, at least one instance of Rcis optionally substituted Ce-io aryl.

[0354]

[0304] In some embodiments, at least one instance of Rcis optionally substituted 5-10 membered heteroaryl.

[0355]

[0305] In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 2, and pharmaceutically acceptable salts, stereoisomers, and isotopically labeled derivatives thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 2, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 2, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 2, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 2 (in free base form).

[0356] Pharmaceutical Compositions, Kits, and Administration

[0357]

[0306] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I') or Formula (I), or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0358]

[0307] The terms “composition” and “formulation” are used interchangeably herein.

[0359]

[0308] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0360]

[0309] 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 the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0361]

[0310] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0362]

[0311] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0363]

[0312] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0364]

[0313] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0365]

[0314] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0366]

[0315] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0367]

[0316] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g. , therapeutically and / or prophy lactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0368]

[0317] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0369]

[0318] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0370] Methods of Treatment and Uses

[0371]

[0319] Compounds provided herein can covalently inhibit neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful in treating FcRn-mediated and immunoglobulin G (IgG) -mediated diseases, including autoimmune and inflammatory diseases.

[0372]

[0320] Provided herein are methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are compounds, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an FcRn- mediated disease. In another aspect, provided herein are uses of compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an FcRn-mediated disease.

[0373]

[0321] “FcRn-mediated disease” refers to any disease or condition associated with FcRn protein activity in a subject, including diseases caused or exacerbated by FcRn activity, or for which inhibition of FcRn activity can provide therapeutic benefit. In certain embodiments, the FcRn-mediated disease is an autoimmune disease. In certain embodiments, the FcRn-mediated disease is an inflammatory disease.

[0374]

[0322] Inhibition of FcRn can decrease IgG levels in a subject and can therefore treat diseases and conditions in which autoantibodies are implicated. Provided herein are methods of treating an IgG-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an IgG-mediated disease. In another aspect, provided herein are uses of compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an IgG-mediated disease.

[0375]

[0323] “IgG-mediated disease” refers to any disease or condition associated with IgG autoantibodies in a subject, including diseases caused or exacerbated by IgG antibodies, or for which decreasing levels of IgG antibodies can provide a therapeutic benefit. In certain embodiments, the IgG-mediated disease is an autoimmune disease. In certain embodiments, the IgG-mediated disease is an inflammatory disease.

[0376]

[0324] Provided herein are methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an autoimmune disease. In another aspect, provided herein are uses of compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments (e.g., for treating an autoimmune disease or inflammatory disease).

[0377]

[0325] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. Autoimmune diseases may be restricted to certain organs or involve a particular tissues in different places. The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. However, compounds described herein can provide therapeutic benefit in the treatment of autoimmune diseases.

[0378]

[0326] Autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune hepatitis, Celiac disease, Type 1 diabetes, multiple sclerosis, Sjogren’s syndrome, antiphospholipid syndrome, Wegener’s granulomatosis, polymyositis, dermatomyositis, scleroderma, and autoimmune encephalitis.

[0379]

[0327] Additional exemplary autoimmune diseases include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Behcet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis herpetiformis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, Degos’ disease, dermatomyositis, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves’ disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus (e.g. , pemphigus vulgaris), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis / giant cell arteritis, transplant rejection, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis. In some embodiments, the autoimmune disease is bullous pemphigoid, idiopathic thrombocytopenia purpura, myasthenia gravis, pemphigus (e.g., pemphigus vulgaris), and transplant rejection.

[0380]

[0328] Autoimmune diseases can include inflammatory diseases and conditions. The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[0381]

[0329] Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0382]

[0330] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g. , selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. , eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g. , Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g. , Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, bums, physical injury), vasculitis, vitiligo, and Wegener’s granulomatosis.

[0383]

[0331] In some embodiments, the inflammatory disease is selected from asthma, ulcerative colitis, inflammatory bowel syndrome, allergy (e.g. , allergic rhinitis / sinusitis, skin allergies, food allergies, drug allergies, insect allergies), mastocytosis, arthritis (e.g. , osteoarthritis, rheumatoid arthritis), and spondyloarthropathies. In some embodiments, the skin allergy is chosen from urticaria, angioedema, and atopic dermatitis.

[0384]

[0332] Also provided herein are methods of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in covalently inhibiting FcRn in vitro or in vivo. In another aspect, provided herein are uses of compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for covalently inhibiting FcRn in a subject.

[0385]

[0333] As used herein the term “inhibit,” “inhibition,” or “inhibiting” in the context of proteins, for example, in the context of FcRn proteins, refers to a reduction in the activity of the protein or a downstream effect. In some embodiments, the term refers to a reduction in the level of protein activity (e.g., FcRn activity) to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or reference level of protein activity. In some embodiments, the term refers to a reduction of the level of protein activity (e.g., FcRn activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, of an initial level, which may, for example, be a baseline level of protein activity.

[0386]

[0334] “Covalently inhibiting,” “covalent inhibition,” “covalently inhibit” and the like, refers to inhibition of target protein (e.g. , FcRn) activity resulting from covalent binding of an agent (e.g. , a compound provided herein, or a pharmaceutically acceptable salt thereof) to the target protein. In certain embodiments, the agent binds to an amino acid residue (e.g., an amino acid side chain) of the target protein. Covalent inhibitors can be orthosteric or allosteric. “Orthosteric” inhibitors covalently bind to the active site of the target protein, whereas “allosteric” inhibitors can bind elsewhere on the protein surface.

[0387]

[0335] Also provided herein are methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in decreasing IgG levels in a subject. In another aspect, provided herein are uses of compounds described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for decreasing IgG levels in a subject.

[0388]

[0336] In certain embodiments, the decrease in IgG levels in the subject is a reduction in the level of IgG in the subject which is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of an initial level (e.g., before administration of an FcRn inhibitor).

[0389]

[0337] A “subject” to which administration is contemplated refers to a human ( / . e. , male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0390]

[0338] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0391]

[0339] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0392]

[0340] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0393]

[0341] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0394]

[0342] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG (e.g. , in a subject or in a cell in vitro).

[0395]

[0343] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent, in certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g. , a disease, disorder, or condition associated with FcRn activity) in a subject, in certain embodiments, a therapeutically effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG in a subject.

[0396]

[0344] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with FcRn activity) in a subject, in certain embodiments, a prophylactically effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG.

[0397]

[0345] “Neonatal fragment crystallizable receptor” (also “FcRn”, “IgG receptor FcRn large subunit p51”, or “Brambell receptor' ’) refers to the protein that in humans is encoded by the FCGRT gene. See Uniprot accession number P55899 for human FcRn.

[0398] EXAMPLES

[0399]

[0346] In order that the present 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 in their scope.

[0400]

[0347] The examples provided below include procedures, intermediates, and characterization data useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure. Synthesis of Compounds

[0401] Example 001 - Synthesis of Compound 001

[0402] 001-1 001-2 001-3 001

[0403] Step A: Preparation of tert-butyl 3-(2-ethylphenoxy)azetidine- 1 -carboxylate (001-2)

[0404]

[0348] To a solution of 001-1 (5.0 g, 40.9 mmol, 1 eq) in DMAc (40 mL) was added K2CO3 (10.1 g, 73.6 mmol, 1.8 eq) and tert-butyl 3 -iodoazetidine- 1 -carboxylate (15.0 g, 53.2 mmol, 1.3 eq). After stirring at 120°C for 12 hr, the reaction mixture was quenched by addition H2O (50 mL), extracted with EtOAc (100 mL), dried over Na2SO i. filtered and concentrated to give tert-butyl 3 -(2-ethylphenoxy)azetidine-l -carboxylate (001-2) (12.0 g, crude) as a yellow oil. ' H NMR (400 MHz, CDCb) 5 = 7.20-7.07 (m, 2H), 6.92-6.85 (m, 1H), 6.76 (d, J= 8.0 Hz, 0.5H), 6.45 (d, J= 8.0 Hz, 0.5H), 4.92-4.84 (m, 1H), 4.70-4.60 (m, 1H), 4.34-4.25 (m, 2H), 4.08-3.95 (m, 1H), 2.70-2.60 (m, 2H), 1.44 (s, 9H), 1.30-1.19 (m, 3H). LCMS ESI calcd. For formula CI2HI6NO3[M-56+H]+222.1, found 222.1. Step B: Preparation of 3-(2-ethylphenoxy)azetidine (001-3)

[0405]

[0349] To a solution of 001-2 (12.0 g, 43.27 mmol, 1 eq) in DCM (16 mL) was added TFA (24.7 g, 216.3 mmol, 5 eq) at 0°C. After stirring at 25°C for 12 hr, the reaction mixture was concentrated and purified by silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH in DCM, gradient @80mL / min) to give 3-(2-ethylphenoxy)azetidine (001-3) (5.5 g, 17.9 mmol, 41.4% yield, 98.7% purity, TFA) as a yellow oil.'H NMR (400 MHz, DMSO- g) 5 = 9.00 (brs, 1H), 7.24-7.20 (m, 1H), 7.17-7.12 (m, 1H), 6.95 (t, J= 7.6 Hz, 1H), 6.66 (d, J= 8.0 Hz, 1H), 5.19-4.90 (m, 1H), 4.58-4.35 (m, 2H), 4.10-3.92 (m, 2H), 2.62 (q, J= 7.6 Hz, 2H), 1.16 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula CnHisNO [M+H]+178.1, found 177.8.

[0406] Step C: Preparation of 5-[3-(2-ethylphenoxy)azetidine-l-carbonyl]-2-hydroxy-benzaldehyde (001)

[0407]

[0350] To a solution of 3 -formyl-4-hydroxy -benzoic acid (85.3 mg, 513.42 pmol, 1.3 eq) and 001-3 (70.0 mg, 394.94 pmol, 1 eq) in DMF (1 mL) was added EDCI (113.5 mg, 592.41 pmol, 1.50 eq), HOBt (80.0 mg, 592.41 pmol, 1.5 eq) and TEA (159.8 mg, 1.58 mmol, 219.88 pL, 4 eq). After stirring at 25°C for 12 h, the mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated and purified by reversed-phase HPLC column: Phenomenex Inna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 43%-73% B over 10 min to give 5-[3-(2 -ethylphenoxy) azetidine-l-carbonyl]-2 -hydroxy -benzaldehyde (001) (4.0 mg, 15.14 pmol, 3.83% yield, 100% purity) as an off-white solid.1H NMR (400 MHz, DMSO-<74) 5 = 10.29 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.22-7.10 (m, 2H), 7.01-6.84 (m, 2H), 6.67 (d, J= 8.0 Hz, 1H), 5.17-5.01 (m, 1H), 4.80-4.45 (m, 2H), 4.41-4.04 (m, 2H), 2.63-2.60 (m, 2H), 1.15 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula Ci9H20NO4[M+H]+326.1, found 326.1. HPLC 100.0% purity.

[0408]

[0351] The following further Examples 009 and 028 were prepared analogously to Example 001, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0409] Example 003 - Synthesis of Compound 003

[0410] 003-1 003-2 003-3 003

[0411] Step A: Preparation of methyl 5-fluoro-2-formyl-3-hydroxy-benzoate (003-2)

[0412]

[0352] To a solution of 003-1 (1.0 g, 5.9 mmol) in TFA (20 mL), was added 1, 3, 5, 7-tetrazatricyclo

[0413] [3.3.1.13.7]decane (1.7 g, 11.8 mmol), the mixture was stirred at 80°C for 3 h. The reaction mixture was filtered, concentrated and poured into H2O (20 mL). The mixture was adjusted pH =8 with NaHCCh, and extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated to give methyl 5-fluoro-2-formyl-3-hydroxy-benzoate (003-2) (1 g, 5.1 mmol, 85.9% yield) as yellow oil. ' H NMR (400 MHz, CDCh) 5 = 12.55 (s, 1H), 10.57 (s, 1H), 7.20 (dd, J= 2.4, 9.2 Hz, 1H), 6.84 (dd, J= 2.4, 9.2 Hz, 1H), 3.97 (s, 3H).

[0414] Step B: Preparation of 5-fluoro-2-formyl-3-hydroxy-benzoic acid (003-3)

[0415]

[0353] To a solution of 003-2 (100.0 mg, 504.7 pmol) in THF (6 mL), was added LiOH (12.1 mg, 504 pmol) in H2O (2 mL). After stirring at 25°C for 16 h, the reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined water layers were added IM HC1 to pH = 3, extracted with EtOAc (10 mL x 3), wash with brine (20 mL x 2), dried over Na2SO i. fdtered and concentrated to give 5-fluoro-2-formyl-3-hydroxy-benzoic acid (003-3) (60 mg, 325.9 pmol, 64.6% yield) as a white solid.’H NMR (400 MHz, CDCh) 5 = 12.61 (s 1H), 10.67 (s, 1H), 7.33 (dd, .7 = 2.4. 8.4 Hz, 1H), 6.89 (dd, J = 2.4, 9.6 Hz, 1H).19F NMR (376.5MHz, CDCh) 5 = -97.165, - HO.444, -111.009, -117.275.

[0416] Step C-l: Preparation of2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]-4-fluoro-6-hydroxy-benzaldehyde (003)

[0417]

[0354] To a solution of 003-3 (60.0 mg, 325 pmol) and 3-(2-ethylphenoxy)azetidine (69.3 mg, 391 pmol) in Py (3 mL) was added EDCI (124 mg, 651 pmol). After stirring at 25°C for 16 h, the reaction mixture was filtered, concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water (FA)- ACN]; gradient: 48%-88% B over 9 min) to give 2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]-4-fluoro-6- hydroxy -benzaldehyde (003) (4.0 mg, 11.7 pmol, 3.6% yield) as a yellow solid. ' H NMR (400 MHz, DMSO-cL) 5 = 10.18 (s, 1H), 7.22-7.14 (m, 1H), 7.13-7.07 (m, 1H), 6.94-6.87 (m, 1H), 6.80 (dd, .7 = 2.0, 10.8 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.64 (d, J= 8.0 Hz, 1H), 5.10-4.97 (m, 1H), 4.50-4.49 (m, 1H), 4.25-4.24 (m, 1H), 3.98-3.97 (m, 1H), 3.79-3.78 (m, 1H), 2.60 (q, J= 7.6 Hz, 2H), 1.15 (t, J= 7.6 Hz, 2H).19F NMR (376.5MHz, DMSO-^e) 5 = -100.498, -115.760. LCMS ESI calcd. For formula C19H19FNO4 [M+H]+344.1, found 344.1.HPLC 100.0% purity.

[0418]

[0355] The following further Examples 002 and 024 were prepared analogously to Example 003, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0419] Example 039 - Synthesis of Compound 039

[0420] Step A: Preparation of2-formyl-3-hydroxy-4-iodo-benzoate (039-2)

[0421]

[0356] To a solution of 039-1 (1.0 g, 3.6 mmol, 1 eq) in TFA (10 mL) was added 1, 3, 5, 7-tetrazatricyclo [3.3.1.13, 7] decane (1.0 g, 7.2 mmol, 2 eq). After stirring at 80°C for 16 hr, the reaction mixture was cooled to room temperature, the resulting solution was acidified with HC1 (1 M, 10 mL). The precipitate was removed by filtration and filter cake was washed with H2O (10 mL x 2). The filtrate was extracted with DCM (10 mL x 2), washed with brine (10 mL x 1), dried over anhydrous Na2SO i. filtered, concentrated and purified by prep-TLC (SiO2, MeOH: DCM=1: 10) to give 2-formyl-3-hydroxy-4-iodo-benzoate (039-2) (510.0 mg, 1.67 mmol, 46.3% yield) as a yellow solid. ' H NMR (400 MHz, CDCh) 5 = 13.03 (s, 1H), 10.51 (s, 1H), 8.0 (d, .7 =8.0 Hz, 1H), 7.30-7.27 (m, 1H), 3.89 (s, 3H). LCMS NEG calcd. For formula CsHglCL [M-H]’ 304.9, found 304.9.

[0422] Step B: Preparation of2-formyl-3-hydroxy-4-iodo-benzoic acid (039-3)

[0423]

[0357] To a solution of 039-2 (300.0 mg, 980.2 pmol, 1 eq) in THF (1 mL), H2O (0.5 mL) was added LiOH.H2O (82.2 mg, 1.9 mmol, 2 eq). After stirring at 20°C for 1 hr, the reaction mixture was concentrated, then diluted with HO (1 M, 8 mL) and filtered. The filter cake was concentrated to give 2-formy 1-3 -hydroxy -4-iodo-benzoic acid (039-3) (240.0 mg, crude) as a yellow solid. LCMS NEG calcd. For formula CsH4IO4 [M-H]- 290.9, found 290.9. Step C-2: Preparation of 6-[3-(2-ethylphenoxy) azetidine- 1 -carbonyl]-2-hydroxy-3-iodo-benzaldehyde (039)

[0424]

[0358] To a solution of 039-3 (50.0 mg, 171.2 pmol, 1 eq) in DMF (1 mL) was added HATU (78.1 mg, 205.4 pmol,

[0425] I.2 eq). After string at 25°C for 10 min, 3 -(2 -ethylphenoxy) azetidine (59.8 mg, 205.4 pmol, 1.2 eq, TFA) and DIEA (66.3 mg, 513.6 pmol, 89.4 pL, 3 eq) was added. The mixture was stirred at 25°C for 16 hr. The mixture was stirred with HO (1 M, 2 mL) and quenched with water (5 mL), and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x 1), dried over Na2SO4, filtered, concentrated and purified by prep- HPLC (column: CD01 -Pheno menex Inna C18 150*25*10um; mobile phase: [water(FA)-ACN]; gradient: 60%-80% B over 10 min) to give 6-[3-(2-ethylphenoxy) azetidine-l-carbonyl]-2-hydroxy-3-iodo-benzaldehyde (039) (5.0 mg,

[0426] II.0 pmol, 6.4% yield) as ayellow oil. ' H NMR (400 MHz, CDC13) 5 = 12.72 (s, 1H), 10.12 (s, 1H), 8.02 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.11 (t, J= 7.2 Hz, 1H), 7.01-6.92 (m, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.42 (d, J= 8 Hz, 1H), 5.08-4.99 (m, 1H), 4.69-4.59 (m, 1H), 4.45-4.37 (m, 1H), 4.33-4.27 (m, 1H), 4.16-4.08 (m, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.21 (t, J= 8.0 Hz, 3H). LCMS ESI calcd. For formula C19H19INO4 [M+H]+452.0, found 451.8. HPLC 94.4% purity.

[0427]

[0359] The following further Examples 038, 013, 012, 014, 022, 025, and 285 were prepared analogously to Example 039, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0428] Example 004 - Synthesis of Compound 004

[0429] 004-1 004-2 004-3 004

[0430] Step A: Preparation of methyl 2-formyl-3-hydroxy-5-methoxybenzoate (004-2).

[0431]

[0360] To a solution of 004-1 (1.0 g, 4.4 mmol, 1 eq) in DCM (10 mL) was slowly added BBr3 (559.2 mg, 2.2 mmol, 99.9% purity, 0.5 eq) in DCM (2 mL) at -10°C under N2. After stirring at 25°C for 3 hr, the reaction mixture was quenched by addition H2O (50 mL) at 0°C, extracted with DCM (100 mL), washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5%~8% Ethyl acetate / Petroleum ethergradient @ 60 mL / min) to give methyl 2-formyl-3- hydroxy-5-methoxybenzoate (004-2) (760.0 mg, 3.6 mmol, 81.0% yield) as a white solid. ' H NMR (400 MHz, DMSO-t / 6) 5 = 11.76 (s, 1H), 10.19 (s, 1H), 6.72 (d, J= 2.4 Hz, 1H), 6.64 (d, J= 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H).

[0432] Step B: Preparation of2-formyl-3-hydroxy-5-methoxybenzoic acid (004-3)

[0433]

[0361] To a solution of 004-2 (200.0 mg, 951.5 pmol, 1 eq) in THF (4 mL) and H2O (1 mL) was added LiOH.H2O (119.7 mg, 2.8 mmol, 3 eq) at 25°C. After stirring at 25°C for 3 hr, the reaction mixture was concentrated to give 2- formyl-3-hydroxy-5-methoxy -benzoic acid (004-3) (230.0 mg, crude) as a yellow solid. ' H NMR (400 MHz, DMSO- d6) 5 = 9.54 (s, 1H), 5.68 (d, J= 2.4 Hz, 1H), 5.61 (d, J = 2.4 Hz, 1H), 3.60 (s, 3H).

[0434] Step C: Preparation of2-(3-(2-ethylphenoxy)azetidine-l-carbonyl)-6-hydroxy-4-methoxybenzaldehyde (004)

[0435]

[0362] To a solution of 004-3 (100.0 mg, 509.8 pmol, 1 eq) in DMF (1 mL) was added HATU (213.2 mg, 560.7 pmol, 1.1 eq) and DIEA (197.6 mg, 1.5 mmol, 3 eq). After stirring at 25°C for 30 min, then 3-(2-ethylphenoxy)azetidine (148.4 mg, 509.8 pmol, 1 eq, TFA) was added to the mixture at 25°C. After stirring at 25°C for 16 hr, the reaction mixture was quenched by addition H2O (5 mL), extracted with EtOAc (10 mL), washed with brine (20 mL), dried over Na2SO i. filtered, concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 25mm x 5um; mobile phase: [water(TFA)-ACN]; gradient: 39%-69% B over 10 min) to give 2-(3-(2-ethylphenoxy)azetidine-l- carbonyl)-6-hydroxy-4-methoxybenzaldehyde (004) (10.4 mg, 29.2 pmol, 5.7% yield, 100.0% purity) as a brown solid. ' H NMR (400 MHz, CDC13) 5 = 12.29 (s, 1H), 9.99 (s, 1H), 7.21-7.17 (m, 1H), 7.13-7.07 (m, 1H), 6.94 (t, J= 22 Hz, 1H), 6.52-6.38 (m, 3H), 5.06-4.96 (m, 1H), 4.65-4.56 (m, 1H), 4.42-4.35 (m, 1H), 4.32-4.26 (m, 1H), 4.13- 4.06 (m, 1H), 3.86 (s, 3H), 2.66 (q, J= 7.6 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).LCMS ESI calcd. For formula C20H22NO5[M+H]+356.1, found 355.9.HPLC 100.0% purity.

[0436] Example 005 - Synthesis of Compound 005

[0437] 005-1 005-2 005

[0438] Step A: Preparation of 2-formyl-3,5-dihydroxy-benzoic acid (005-2)

[0439]

[0363] To a solution of 005-1 (500 mg, 2.23 mmol) in DCM (5 mL) was added BBn (2 M, 5.58 mL) carefully under N2at -78°C. The mixture was stirred at -78°C for 2 hr under N2. The reaction mixture was mixture was quenched by aqueous NaHCCL (50 mL), and extracted with DCM (50 mL x 3). The combined organic layers were washed with aqueous NaCl (100 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Which was purified by flash chromatography on silica gel (0-100% of EA in PE) to give 2-formyl-3,5-dihydroxy- benzoic acid (005-2) (200 mg, 1.10 mmol, 49.24% yield) as yellow solid. LCMS ESI calcd. For formula C8H7O5 [M+H]+183.0, found 183.1.

[0440] Step B: Preparation of (E)-l-[4-(3-chloro-2-methyl-phenyl)-l,4-diazepan-l-yl]-4-(dimethylamino)but-2-en-l-one (005)

[0441]

[0364] To a solution of 005-2 (50 mg, 274 pmol) in DMF (5 mL) was added HATU (125 mg, 329 pmol,). After addition, the mixture was stirred at 25°C for 10 min, and then 3-(2-ethylphenoxy)azetidine (48.6 mg, 274 pmol) and DIEA (106 mg, 823 pmol) was added. The resulting mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into H2O (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150 x 30mm x 5um;mobile phase: [water(FA)-ACN]; gradient: 47%-77% B over 9 min) to give 2-[3 -(2 -ethylphenoxy )azetidine-l -carbonyl] -4, 6-dihydroxy -benzaldehyde (005) (5.7 mg, 16.7 pmol, 6.0% yield) as a white solid. ' H NMR (400 MHz, DMSO-t / 6) 5 = 11.49 (s, 1H), 10.94 (s, 1H), 9.96 (s, 1H), 7.19-7.15 (m, 1H), 7.14-7.06 (m, 1H), 6.95-6.86 (m, 1H), 6.64 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 2.4 Hz, 1H), 6.30 (d, J= 2.4 Hz, 1H), 5.11-4.96 (m, 1H), 4.54-4.46 (m, 1H), 4.34-4.26 (m, 1H), 4.01-3.93 (m, 1H), 3.87-3.76 (m, 1H), 2.64-2.56 (m, 2H), 1.15 (t, J= 7.4 Hz, 3H). LCMS ESI calcd. For formula Ci9H20NO5[M+H]+342.1, found 342.2. HPLC 100.0% purity. Example Oil - Synthesis of Compound Oil

[0442] Step A: Preparation of 5-bromo-2-formyl-3-hydroxy-benzoic acid (011-2)

[0443]

[0365] A mixture of 011-1 (300.0 mg, 1.1 mmol, 1 eq), LiOH.H2O (145.7 mg, 3.4 mmol, 3 eq) in THF (3.6 mL) and H2O (1.2 mL) and MeOH (1.2 mL) was stirred at 25°C for 2 hr. The reaction mixture was added HO (1 M, 2 mL), stirred at 25°C for 1 hr, quenched by addition H2O (10 mL), extracted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 5-bromo-2-formyl-3-hydroxy-benzoic acid (011-2) (270.0 mg, 1.1 mmol, 94.3% yield, 99.2% purity) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 12.36 (s, 1H), 10.70 (s, 1H), 7.75 (d, J= 1.6 Hz, 2H), 7.43 (d, J= 2.0 Hz, 2H). LCMS ESI calcd. For formula C8H4O4Br [M-H]’ 243.0, found 242.9.

[0444] Step B: Preparation of 4-bromo-2-[4-(2-ethylphenoxy)piperidine-l-carbonyl]-6-hydroxy-benzaldehyde (011-3)

[0445]

[0366] A mixture of 011-2 (50.0 mg, 204.0 pmol, 1 eq), 4-(2 -ethylphenoxy )piperidine (41.8 mg, 204.0 pmol, 1 eq), HATU (93.1 mg, 244.8 pmol, 1.2 eq), DIEA (79.1 mg, 612.1 pmol, 3 eq) in DMF (1 mL) was stirred at 25°C for 16 hr, quenched by addition H2O (10 mL), extracted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~6% Ethyl acetate / Petroleum ethergradient @ 30 mL / min) to give 4-bromo-2-[4-(2- ethylphenoxy)piperidine-l-carbonyl]-6-hydroxy-benzaldehyde (011-3) (13.0 mg, 28.5 pmol, 14.0% yield, 95.0% purity) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 11.68 (s, 1H), 9.94 (s, 1H), 7.23-7.12 (m, 3H), 7.02 (s, 1H), 6.91 (t, J= 7.2 Hz, 1H), 6.82 (d, J= 8.0 Hz, 1H), 4.66 (s, 1H), 4.13 (q, J= 6.8 Hz, 3H), 3.82-3.74 (m, 1H), 3.61-3.50 (m, 1H), 3.36-3.26 (m, 1H), 2.69-2.62 (m, 2H), 2.04 (s, 5H). LCMS ESI calcd. For formula C2iH25O4BrN [M+H+2]+434.0, found 434.0.

[0446] Step C: Preparation of 4-benzyl-2-[4-(2-ethylphenoxy)piperidine-l-carbonyl]-6-hydroxy-benzaldehyde (Oil)

[0447]

[0367] A mixture of 011-3 (13.0 mg, 30.07 pmol, 1 eq), 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.5 mg, 30.0 pmol, 1 eq), Pd(dppf)Cl2(2.2 mg, 3.0 pmol, 0.1 eq), Cs2CO3(29.3 mg, 90.21 pmol, 3 eq) in dioxane (0.5 mL) and H2O (0.5 mL) was stirred at 120°C for 0.5 hr under N2atmosphere. Then the reaction mixture was quenched by addition H2O (5 mL), extracted with EtOAc (10 mL), washed with H2O (10 mL), concentrated and purified by prep- HPLC (column: CD04-Welch Utimate C18 150*25*7um; mobile phase: [water(TFA)-ACN]; gradient: 61%-91% B over 30 min) to give 4-benzyl-2-[4-(2-ethylphenoxy)piperidine-l-carbonyl]-6-hydroxy -benzaldehyde (Oil) (1.1 mg, 2.4 pmol, 8.2% yield, 100% purity) as a yellow oil. 'H NMR (400 MHz, CDC13) 5 = 11.67-11.56 (m, 1H), 9.98-9.87 (m, 1H), 7.73-7.28 (m, 2H), 7.25-7.22 (m, 1H), 7.20-7.13 (m, 4H), 6.91 (t, J= 12 Hz, 1H), 6.86-6.78 (m, 2H), 6.67 (s, 1H), 4.66-4.58 (m, 1H), 4.11-4.03 (m, 1H), 3.97 (s, 2H), 3.84-3.72 (m, 1H), 3.54-3.45 (m, 1H), 3.29-3.20 (m, 1H), 2.65 (s, 2H), 2.02-1.97 (m, 2H), 1.77-1.70 (m, 2H), 1.22 (s, 3H). LCMS ESI calcd. For formula C28H30NO4[M+H]+444.2, found 444.1. HPLC 100.0% purity.

[0448]

[0368] The following further Examples 006-008 were prepared analogously to Example Oil, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0449] Example 015 - Synthesis of Compound 015

[0450] 015-1 015-2 015

[0451] Step A: Preparation of2-formyl-3-hydroxy-4-phenyl-benzoic acid (015-2)

[0452]

[0369] A mixture of 015-1 (50.0 mg, 193.0 pmol, 1 eq), phenylboronic acid (28.2 mg, 231.6 pmol, 1.2 eq), Pd(dppf)C12 (14.1 mg, 19.3 pmol, 0.1 eq), K2CO3 (80.0 mg, 579.0 pmol, 3 eq) in dioxane (1.6 mL) and H2O (0.4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 85°C for 16 hr under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCF. DCM:MeOH = 10:1) to give 2 -formyl-3 -hydroxy -4-phenyl- benzoic acid (015-2) (35.0 mg, 144.4 pmol, 70.0% yield) as a yellow solid. ' H NMR (400 MHz, DMSO-cL) 5 = 9.94 (s, 1H), 8.01-7.92 (m, 2H), 7.79-7.76 (m, 1H), 7.56-7.51 (m, 3H), 7.35-7.30 (m, 2H), 6.75-6.70 (m, 1H).

[0453] Step B: Preparation of 6-[3-(2-ethylphenoxy)azetidine-l-carbonyl]-2-hydroxy-3-phenyl-benzaldehyde (015)

[0454]

[0370] A solution of 015-2 (35.0 mg, 144.4 pmol, 1 eq) in DMF (2 mL) was added HATU (60.4 mg, 158.9 pmol, 1.1 eq) was stirred at 30°C for 30 min. Then 3-(2-ethylphenoxy)azetidine (46.2 mg, 158.9 pmol, 1.1 eq, TFA) and DIEA (93.3 mg, 722.4 pmol, 5 eq) was added.The mixture was stirred at 30°C for 16 hr. The reaction mixture was quenched by addition water (10 mL) at 25°C, and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD01 -Pheno menex Inna C18 150*25*10um; mobile phase: [water (TFA)-ACN]; gradient: 50%-80% B over 10 min) to give 6-[3-(2-ethylphenoxy)azetidine-l-carbonyl]- 2-hydroxy-3-phenyl-benzaldehyde (015) (3.1 mg, 6.0 pmol, 4.1% yield, 77.8% purity) as a yellow solid. ' H NMR (400 MHz, CDCI3) 5 = 12.39 (s, 1H), 10.28 (s, 1H), 7.60-7.56 (t, .7=8.0 Hz, 3H), 7.48-7.37 (m, 3H), 7.21-7.19 (m, 1H), 7.14-7.10 (m, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.00-6.94 (m, 1H), 6.45 (d, J= 7.6 Hz, 1H), 5.08-5.02 (m, 1H), 4.71- 4.65 (m, 1 H), 4.50-4.46 (m, 1H), 4.36-4.32 (m, 1H), 4.24-4.17 (m, 1 H), 2.71-2.63 (m, 2 H), 1.25-1.20 (m, 3H). LCMS ESI calcd. For formula C25H24CINO4 [M+H]+402.1, found 402.1. HPLC 77.9% purity.

[0455]

[0371] The following further Examples 010, 016, and 026 were prepared analogously to Example 015, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0456] Example 017, 019 - Synthesis of Compound 017, Compound 019

[0457] 017-1 017-2 017 019

[0458] Step A: Preparation of3-bromo-2,6-dihydroxy-benzaldehyde (017-2)

[0459]

[0372] To a solution of 017-1 (1 g, 7.24 mmol) in ACN (10 mL) was added dropwise TsOH.H2O (1.51 g, 7.96 mmol) at 0°C, and then NBS (1.42 g, 7.96 mmol) was added dropwise at 0°C. After stirring at 25°C for 16 h, the reaction mixture was quenched by addition H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried overNa2SO4, filtered and concentrated. The crude product 3-bromo-2,6- dihydroxy-benzaldehyde (017-2) (1.5 g, 6.91 mmol, 95.47% yield) as a yellow solid was used into the next step without further purification.1H NMR (400 MHz, DMSO-t / e) 5 = 12.21 (s, 1H), 11.24 (s, 1H), 10.35-10.05 (m, 1H), 7.64 (d, J= 8.8 Hz, 1H), 6.44 (d, J= 8.8 Hz, 1H).

[0460] Step B: Preparation of 3-bromo-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy-benzaldehyde (017), 3-bromo-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-benzaldehyde (019)

[0461]

[0373] To a solution of 017-2 (200 mg, 788 pmol), 3-bromo-2,6-dihydroxy-benzaldehyde (342 mg, 1.6 mmol) in ACN (10 mL) was added K2CO3(326 mg, 2.36 mmol) and KI (26.2 mg, 157 pmol). After stirring at 80°C for 3 h, the reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water(FA)-ACN]; gradient: 55%-85% B over 9 min) to give 3-bromo-6- [2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy-benzaldehyde (017) (1.5 mg, 3.45 pmol, 4.38e-l% yield) as yellow oil.1H NMR (400 MHz, CDCh) 5 = 12.60 (s, 1H), 10.35 (s, 1H), 7.69-7.57 (m, 1H), 7.20 (d, J= 6.8 Hz, 1H), 7.13 (t, J = 6.8 Hz, 1H), 7.00-6.94 (m, 1H), 6.48-6.40 (m, 1H), 6.34 (d, J= 8.8 Hz, 1H), 5.10-4.92 (m, 2H), 4.70 (d, J= 2.8 Hz, 1H), 4.64-4.57 (m, 1H), 4.51-4.45 (m, 1H), 4.31-4.15 (m, 2H), 2.69-2.61 (m, 2H), 1.22-1.16 (m, 3H). LCMS ESI calcd. For formula C20H2iBrNO5[M+H]+436.1, found 435.9. HPLC 84.8% purity. And 3-bromo-2- [2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-benzaldehyde (019) (9.2 mg, 21.2 pmol, 2.7% yield) as yellow oil. 'H NMR (400 MHz, CDC13) 5 = 11.78 (s, 1H), 10.44 (s, 1H), 7.62 (d, J= 9.2 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.13 (dt, J= 1.6, 8.0 Hz, 1H), 6.99-6.92 (m, 1H), 6.72 (d, J= 9.0 Hz, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.03 (tt, J= 4.0, 6.4 Hz, 1H), 4.79-4.69 (m, 3H), 4.51 (dd, J= 6.8, 10.5 Hz, 1H), 4.38 (dd, J= 3.6, 9.6 Hz, 1H), 4.19 (dd, J= 4.0, 11.2 Hz, 1H), 2.67 (q, J= 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LCMS ESI calcd. For formula C20H2iBrNO5[M+H]+436.1, found 435.9. HPLC 99.8% purity. Example 018 - Synthesis of Compound 018

[0462] 018-1 018-2 018

[0463] Step A: Preparation of 4-bromo-2,6-dihydroxy-benzaldehyde (018-2)

[0464]

[0374] To a solution of 018-1 (200 mg, 816.09 pmol) in DCM (2 mL) was added BBr3(2 M, 4.08 mL) at -78°C for 1 h. After stirring at 25°C for 15 h, the reaction mixture was poured into H2O (10 mL) and NaHCO3(20 mL) and extracted with DCM (30 mL x 3 times). The combined organic layers were washed with brine (30 mL x 3 times), dried over anhydrous Na2SO i. filtered and concentrated to give 4-bromo-2,6-dihydroxy-benzaldehyde (018-2) (55 mg, 253.44 pmol, 31.1% yield) as a brown solid.!H NMR (400 MHz, DMSO-t / 6) 5 = 11.60 (s, 2H), 10.19 (s, 1H), 6.61 (s, 2H).

[0465] Step B: Preparation of 4-bromo-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-benzaldehyde (018)

[0466]

[0375] To a solution of 018-2 (54.74 mg, 252.24 pmol) in ACN (2 mL) was added K2CO3(52.29 mg, 378.36 pmol), KI (4.19 mg, 25.22 pmol) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (40 mg, 126.12 pmol). After stirring at 80°C for 2 h, the reaction mixture was poured into H2O (1 mL), filtered, concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water(FA)-ACN]; gradient: 55%- 85% B over 9 min) to give 4-bromo-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-benzaldehyde (018) (3.7 mg, 8.52 pmol, 6.8% yield) as an off-white solid.1H NMR (400 MHz, CDC13) 5 = 12.06 (s, 1H), 10.33 (s, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.16-7.11 (m, 1H), 7.00-6.93 (m, 1H), 6.83 (d, J= 1.2 Hz, 1H), 6.52 (d, J= 1.6 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 5.07-4.98 (m, 1H), 4.67 (d, J= 2.8 Hz, 2H), 4.65-4.57 (m, 1H), 4.54-4.47 (m, 1H), 4.33-4.26 (m, 1H), 4.23-4.16 (m, 1H), 2.65 (q, J= 7.6 Hz, 2H), 1.20 (t, J= 12 Hz, 3H). LCMS ESI calcd. C20H2iNO5Br, For formula [M+H]+434.1, found 434.1. HPLC 100.0% purity.

[0467] Example 020 - Synthesis of Compound 020

[0468]

[0376] To a solution of 020-1 (480 mg, 2.21 mmol) in DCM (10 mL) was added dropwise DIEA (1.43 g, 11.06 mmol) and bromo(methoxy)methane (1.38 g, 11.06 mmol) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was quenched by addition H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL X 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0~30% of EtOAc in PE) to give 3-bromo-2,6-bis(methoxymethoxy)benzaldehyde (020-2) (270 mg, 885pmol, 40.0% yield) as yellow oil. ' H NMR (400 MHz, CDC13) 5 = 10.51-10.34 (m, 1H), 7.76- 7.63 (m, 1H), 7.01-6.91 (m, 1H), 5.29-5.23 (m, 2H), 5.19-5.09 (m, 2H), 3.67-3.62 (m, 3H), 3.54-3.48 (m, 3H). Step B: Preparation of2,6-bis(methoxymethoxy)-3-phenyl-benzaldehyde (020-3)

[0469]

[0377] To a solution of 020-2 (270 mg, 885 pmol). phenylboronic acid (108 mg, 885 pmol) in dioxane (6 mL) and H2O (2 mL). The mixture was added Na2CO3(563 mg, 5.31 mmol) and Pd(PPh3)4 (205 mg, 177 pmol). After stirring at 110°C for 16 h, the reaction mixture fdtered and concentrated. The crude product was purified by flash chromatography on silica gel (0~30% of EtOAc in PE) to give 2,6-bis(methoxymethoxy)-3-phenyl-benzaldehyde (020-3) (200 mg, 661 pmol, 74.8% yield) as colorless oil.!H NMR (400 MHz, CDC13) 5 = 10.56 (s, 1H), 7.49 (d, J= 8.8 Hz, 3H), 7.41 (t, J= 7.6 Hz, 2H), 7.34 (d, J= 12 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 5.31 (s, 2H), 4.76 (s, 2H), 3.54 (s, 3H), 3.04 (s, 3H).

[0470] Step C: Preparation of2,6-dihydroxy-3-phenyl-benzaldehyde (020-4)

[0471]

[0378] To a solution of 020-3 (200 mg, 662 pmol, 1 eq) in dioxane (2 mL) was added dropwise HCl / dioxane (4 M, 0.2 mL) at 15°C. After stirring at 15°C for 2 h, the reaction mixture was added toluene (10 ml) and concentrated to give 2,6-dihydroxy-3-phenyl-benzaldehyde (020-4) (120 mg, 560 pmol, 84.9% yield) as yellow oil was used into the next step without further purification. ' H NMR (400 MHz, CDCI3) 5 = 10.43 (s, 1H), 7.55-7.48 (m, 2H), 7.44-7.39 (m, 3H), 7.37 (d, J= 8.4 Hz, 1H), 6.54 (d, J= 8.4 Hz, 1H).

[0472] Step D: Preparation of 6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy-3-phenyl-benzaldehyde

[0473] (020)

[0474]

[0379] To a solution of 020-4 (60 mg, 280 pmol), 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (142 mg, 560 pmol) in ACN (2 mL). The mixture was added K2CO3(116 mg, 840 pmol) and KI (9.30 mg, 56.02 pmol). After stirring at 80°C for 3 h, the reaction mixture, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum etherEthyl acetate=3: l) to give 6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy-3- phenyl-benzaldehyde (020) (9 mg, 20.86 pmol, 7.45% yield) as a yellow solid. ' H NMR (400 MHz, CDCI3) 5 = 12.52 (s, 1H), 10.46 (s, 1H), 7.53 (t, J= 12 Hz, 3H), 7.43 (t, J= 7.6 Hz, 2H), 7.38-7.30 (m, 1H), 7.20 (d, J= 12 Hz, 1H), 7.14 (t, J= 7.6 Hz, 1H), 6.96 (t, J= 12 Hz, 1H), 6.45 (t, J= 12 Hz, 2H), 5.05-4.94 (m, 1H), 4.74 (d, J= 2.8 Hz, 2H), 4.69-4.62 (m, 1H), 4.51 (dd, J= 6.4, 10.8 Hz, 1H), 4.33 (dd, J= 3.6, 10.0 Hz, 1H), 4.20 (dd, J= 3.6, 10.8 Hz, 1H), 2.73-2.48 (m, 2H), 1.20 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula C26H26NO5 [M+H]+432.2, found 432.0. HPLC 100.0% purity.

[0475]

[0380] The following further Examples 030 and 064 were prepared analogously to Example 020, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0476] Example 021 - Synthesis of Compound 021

[0477]

[0478]

[0381] To a solution of 021-1 (1 g, 5.64 mmol) in dioxane (10 mL) was added 2-chloroacetyl chloride (955.83 mg, 8.46 mmol). After stirring at 25°C for 2 h, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (30 mL x 3 times). The combined organic layers were washed with brine (50 mL x 3 times), dried over anhydrous Na2SO i. filtered and concentrated to give 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (021-2) (1.6 g, 5.04 mmol, 89.4% yield, 80.0% purity) as a brown oil.!H NMR (400 MHz, CDC13) 5 = 7.22-7.18 (m, 1H), 7.16-7.10 (m, 1H), 7.01-6.93 (m, 1H), 6.45 (d, J= 8.0 Hz, 1H), 5.06-4.97 (m, 1H), 4.78-4.69 (m, 1H), 4.58-4.50 (m, 1H), 4.42-4.34 (m, 1H), 4.23-4.16 (m, 1H), 4.00 (s, 2H), 3.76 (s, 10H), 2.72-2.59 (m, 2H), 1.25-1.14 (m, 3H).

[0479] Step B: Preparation of2,6-dimethoxy-4-phenyl-benzaldehyde (021-4)

[0480]

[0382] To a solution of 021-3 (500.0 mg, 2.04 mmol) in dioxane (10 mL) and H2O (2 mL) was added phenylboronic acid (1.49 g, 12.24 mmol,), Na2CO3(1.30 g, 12.24 mmol) and Pd(PPh3)4(235.76 mg, 204.02 pmol,). After stirring at 100°C for 16 h, the reaction mixture was concentrated and purified by flash chromatography on silica gel (0-15% of EtOAc in PE) to give 2,6-dimethoxy-4-phenyl-benzaldehyde (021-4) (450 mg, 1.86 mmol, 91.0% yield) as a yellow solid. ' H NMR (400 MHz, DMSO-t / s) 5 = 10.38 (s, 1H), 7.81 (d, J= 7.2 Hz, 2H), 7.56-7.44 (m, 3H), 6.98 (s, 2H), 3.93 (s, 6H).

[0481] Step C: Preparation of2,6-dihydroxy-4-phenyl-benzaldehyde (021-5)

[0482]

[0383] To a solution of 021-4 (100 mg, 412.76 pmol) in DCM (3 mL) was added BBr3(2 M, 2.06 mL) at -78°C for 1 h. After stirring at 25°C for 15 h, the reaction mixture was poured into H2O (10 mL) and NaHCO3(20 mL) and extracted with DCM (30 mL x 3 times). The combined organic layers were washed with brine (30 mL x 3 times), dried over anhydrous Na2SO i. filtered and concentrated to give 2,6-dihydroxy-4-phenyl-benzaldehyde (021-5) (88 mg, 410.80 pmol, 99.5% yield) as a brown solid. ' H NMR (400 MHz, DMSO-t / s) 5 = 11.41 (s, 2H), 10.26 (s, 1H), 7.68-7.60 (m, 2H), 7.55-7.41 (m, 3H), 6.65 (s, 2H).

[0483] Step D: Preparation of2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-4-phenyl-benzaldehyde (021)

[0484]

[0384] To a solution of 021-5 (47.28 mg, 220.71 pmol) inACN (2 mL) was added K2CO3(45.76 mg, 331.07 pmol), KI (3.66 mg, 22.07 pmol) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (35.00 mg, 110.36 pmol). After stirring at 80°C for 2 h, the reaction mixture was poured into H2O (1 mL), filtered, concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 40 mm x 5 um; mobile phase: [water(FA)-ACN]; gradient: 50%- 80% B over 9 min) to give 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-4-phenyl-benzaldehyde (021) (3.6 mg, 8.34 pmol, 7.6% yield) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 12.04 (s, 1H), 10.40 (s, 1H), 7.61-7.55 (m, 2H), 7.51-7.41 (m, 3H), 7.21-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.00-6.92 (m, 1H), 6.85 (d, J= 0.8 Hz, 1H), 6.58 (d, J= 1.2 Hz, 1H), 6.43 (d, J= 8.0 Hz, 1H), 5.05-4.96 (m, 1H), 4.78 (d, J= 2.4 Hz, 2H), 4.70-4.60

[0485] (m, 1H), 4.55-4.45 (m, 1H), 4.38-4.30 (m, 1H), 4.25-4.15 (m, 1H), 2.64 (q, J= 7.6 Hz, 2H), 1.18 (t, J= 7.6 Hz, 3H).

[0486] LCMS ESI calcd. For formula C26H26NO5 [M+H]+432.2, found 432.3. HPLC 100.0% purity.

[0487] Example 032 - Synthesis of Compound 032

[0488] Step A: Preparation of3-bromo-2,6-dihydroxy-benzaldehyde (032-2)

[0489]

[0385] To a solution of 032-1 (5.0 g, 36.20 mmol, 1 eq) in ACN (50 mL) was added TsOH (6.86 g, 39.82 mmol, 1.1 eq) and NBS (7.09 g, 39.82 mmol, 1.1 eq) at 0°C. After stirring at 25°C for 16 hr, the reaction mixture was quenched by addition H2O (50 mL) at 25°C, and then diluted with EtOAc (40 mL) and extracted with EtOAc (50 mL x 2), washed with brine, dried, filtered and concentrated to give 3-bromo-2,6-dihydroxy -benzaldehyde (032-2) (8.5 g, crude) as a yellow solid.’H NMR (400 MHz, DMSO-^) 5 = 12.21 (s, 1H), 11.25 (s, 1H), 10.02 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.44 (d, J= 9.2 Hz, 1H).

[0490] Step B: Preparation of 3-bromo-6-hydroxy-2-(methoxymethoxy)benzaldehyde (032-3)

[0491]

[0386] To a solution of 032-2 (4.0 g, 18.43 mmol, 1 eq) in DCM (120 mL) was added DIEA (2.38 g, 18.43 mmol, 3.21 mL, 1 eq), then bromo(methoxy)methane (2.30 g, 18.43 mmol, 1.50 mL, 1 eq) was added dropwise at 0°C. After stirring at 25°C for 16 hr, the reaction mixture was quenched by H2O (50 mL) at 25°C, diluted with DCM (50 mL) and extracted with DCM 100 mL (50 mL x 2), washed with brine, dried, filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethylacetate / Petroleum ethergradient @ 80 mL / min) to give 3-bromo-6-hydroxy-2-(methoxymethoxy)benzaldehyde (032-3) (2.4 g, 9.19 mmol, 49.8% yield) as ayellow oil. ' H NMR (400 MHz, DMSO-tfc) 5 = 11.37 (s, 1H), 10.18 (s, 1H), 7.79 (d, J= 9.2 Hz, 1H), 6.77 (d, J= 8.8 Hz, 1H), 5.15 (s, 2H), 3.53 (s, 3H).

[0492] Step C: Preparation of3-(3-chlorophenyl)-6-hydroxy-2-(methoxymethoxy)benzaldehyde (032-4)

[0493]

[0387] To a solution of 032-3 (200.0 mg, 766.08 pmol, 1 eq) and (3-chlorophenyl)boronic acid (119.8 mg, 766.08 pmol, 1 eq) in H2O (1 mL) and dioxane (1 mL) was added Pd(dppf)Cl2(56.0 mg, 76.61 pmol, 0.1 eq) and Cs2CO2(748.8 mg, 2.30 mmol, 3 eq) at 25°C. After stirring at 120°C for 1 hr, the reaction mixture was filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~6% Ethylacetate / Petroleum ethergradient @ 40 mL / min) to give 3-(3-chlorophenyl)-6-hydroxy-2- (methoxymethoxy)benzaldehyde (032-4) (130.0 mg, 444.12 pmol, 57.9% yield) as a yellow oil.’H NMR (400 MHz, CDC13) 5 = 11.83 (s, 1H), 10.38 (s, 1H), 7.51-7.47 (m, 2H), 7.38-7.33 (m, 3H), 6.83 (d, J= 8.8 Hz, 1H), 4.70 (s, 2H), 3.33 (s, 3H).

[0494] Step D: Preparation of 3-(3-chlorophenyl)-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2- (methoxymethoxy) benzaldehyde ( 032-5)

[0495]

[0388] To a solution of 032-4 (130.0 mg, 444.12 pmol, 1 eq) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l- yl]ethanone (112.6 mg, 444.12 pmol, 1 eq) in MeCN (1 mL) was added KI (14.7 mg, 88.82 pmol, 0.2 eq) and K2COs (184.1 mg, 1.33 mmol, 3 eq). After stirring at 80°C for 16 hr, the reaction mixture was filtered and concentrated to give 3-(3-chlorophenyl)-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-(methoxymethoxy)benzaldehyde (032-5) (200.0 mg, crude) as a yellow oil. LCMS ESI calcd. For formula C2sH28C106NaN [M+Na]+532.1, found 532.2.

[0496] Step E: Preparation of 3-(3-chlorophenyl)-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy- benzaldehyde (032)

[0497]

[0389] A solution of 032-5 (200.0 mg, 392.17 pmol, 1 eq) in HCl / dioxane (2 M, 2 mL) was stirred at 25°C for 2 hr. The reaction mixture was filtered, concentrated and purified by prep-HPLC (column: CD04-Welch Utimate C18

[0498] 150*25 *7um;mobile phase: [column: CD04-Welch Utimate C18 150*25*7um;mobile phase: [water(TFA)- ACN];gradient:67%-97% B over 10 min) to give 3-(3-chlorophenyl)-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2 -oxoethoxy] -2 -hydroxy-benzaldehyde (032) (21.7 mg, 44.39 pmol, 11.3% yield, 95.3% purity) as a yellow solid.1H NMR (400 MHz, CDC13) 5 = 12.55 (s, 1H), 10.45 (s, 1H), 7.56-7.48 (m, 2H), 7.46-7.40 (m, 1H), 7.38-7.30 (m, 2H), 7.19 (d, J= 7.6 Hz, 1H), 7.17-7.09 (m, 1H), 6.96 (t, J= 12 Hz, 1H), 6.45 (t, J= 8.4 Hz, 2H), 5.06-4.97 (m, 1H), 4.75 (d, J= 2.8 Hz, 2H), 4.65 (dd, J= 2.8, 9.2 Hz, 1H), 4.51 (dd, J= 2.4, 10.8 Hz, 1H), 4.33 (dd, J= 4.0, 10.0 Hz, 1H), 4.20 (dd, J= 4.0, 11.2 Hz, 1H), 2.64 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H),. LCMS ESI calcd. For formula C26H25O5CIN [M+H]+466.1, found 466.0. HPLC 95.3% purity.

[0499]

[0390] The following further Examples 034 and 095 were prepared analogously to Example 032, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0500] Example 092 - Synthesis of Compound 092

[0501] 092-1 092-2 092

[0502] Step A: Preparation of3-fluoro-2,6-dihydroxybenzaldehyde (092-2)

[0503]

[0391] To a solution of 092-1 (138.0 mg, 1 mmol, 1 eq) in ACN (15 mL) was added selectfluor (354.2 mg, 1.00 mmol, 1 eq). The mixture was stirred by MW at 70°C for 0.5 hr. The mixture was quenched with water and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3-fluoro-2,6-dihydroxy-benzaldehyde (092-2) (140.0 mg, 896.8 pmol, 89.7% yield) as a yellow oil. ' H NMR (400 MHz, DMSO- g) 5 = 11.27 (s, 1 H), 11.02 (s, 1 H), 10.25 (s, 1 H), 7.47-7.31 (m, 1 H), 6.40-6.32 (m, 1 H)19F NMR (376.5 MHz, DMSO-^e) 5 ppm -148.86.

[0504] Step B: Preparation of 2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3-fluoro-6-hydroxybenzaldehyde (092)

[0505]

[0392] To a solution of 092-2 (40.0 mg, 256.2 pmol, 1 eq) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (65.0 mg, 256.23 pmol, 1 eq) in ACN (1 mL) was added KI (8.5 mg, 51.25 pmol, 0.2 eq) and K2CO3 (70.8 mg, 512.46 pmol, 2 eq). The mixture was stirred at 50°C for 2 hr. The mixture was filtered, concentrated and purified by prep-HPLC (column: CD04-Welch Utimate C18 150*25 *7um;mobile phase: [water(FA)-ACN];gradient:40%-70% B over 10 min) to give 2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3-fluoro-6-hydroxybenzaldehyde (14.0 mg, 37.5 pmol, 14.6% yield) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 11.53 (s, 1 H), 10.46 (s, 1 H), 7.27- 7.23 (m, 1 H), 7.21-7.17 (m, 1 H), 7.13 (t, J= 7.2 Hz, 1 H), 7.00-6.92 (m, 1 H), 6.62 (dd, J = 9.2, 3.2 Hz, 1 H), 6.45 (d, J= 8.0 Hz, 1 H), 5.08-4.97 (m, 1 H), 4.81 (s, 2 H), 4.67-4.57 (m, 1 H), 4.49 (dd, J= 10.4, 6.8 Hz, 1 H), 4.28 (dd, J= 9.2, 3.2 Hz, 1 H), 4.17 (dd, J= 10.8, 3.2 Hz, 1 H), 2.66 (q, J= 7.6 Hz, 2 H), 1.20 (t, J= 7.6 Hz, 3 H).19F NMR (376.5 MHz, CDCI3) 5 ppm -141.45. LCMS ESI calcd. For formula C20H21FNO5 [M+H]+374.1, found 374.0. HPLC 99.4% purity.

[0506] Example 091, 141 - Synthesis of Compound 091, Compound 141

[0507]

[0393] To a solution of 141-1 (1.0 g, 7.24 mmol) in ACN (10 mL) was added dropwise TsOH.H2O (1.51 g, 7.96 mmol) at 0°C, and then NBS (1.42 g, 7.96 mmol) was added dropwise at 0°C. After stirring at 25°C for 16 h, the reaction mixture was quenched by addition H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SC>4, filtered and concentrated. The cmde product 3- bromo-2,6-dihydroxy-benzaldehyde (141-2) (1.5 g, 6.91 mmol, 95.47% yield) as a yellow solid was used into the next step without further purification. ' H NMR (400 MHz, DMSO-cL) 5 = 12.21 (s, 1H), 11.24 (s, 1H), 10.35-10.05 (m, 1H), 7.64 (d, J= 8.8 Hz, 1H), 6.44 (d, J= 8.8 Hz, 1H).

[0508] Step B: Preparation of 3-bromo-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-benzaldehyde (141-3)

[0509]

[0394] To a solution of 141-2 (200.0 mg, 788 pmol), 3-bromo-2,6-dihydroxy -benzaldehyde (342.0 mg, 1.6 mmol) in ACN (10 mL) was added K2CO3 (326.0 mg, 2.36 mmol) and KI (26.2 mg, 157 pmol). After stirring at 80°C for 3 h, the reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water(FA)-ACN]; gradient: 55%-85% B over 9 min) to give 3-bromo-2- [2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy -benzaldehyde (141) (9.2 mg, 21.2 pmol, 2.7% yield) as yellow oil. ' H NMR (400 MHz, CDCL) 5 = 11.78 (s, 1H), 10.44 (s, 1H), 7.62 (d, J= 9.2 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.13 (dt, J= 1.6, 8.0 Hz, 1H), 6.99-6.92 (m, 1H), 6.72 (d, J= 9.0 Hz, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.03 (tt, J= 4.0, 6.4 Hz, 1H), 4.79-4.69 (m, 3H), 4.51 (dd, J= 6.8, 10.5 Hz, 1H), 4.38 (dd, J= 3.6, 9.6 Hz, 1H), 4.19 (dd, J= 4.0, 11.2 Hz, 1H), 2.67 (q, J= 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LCMS ESI calcd. For formula CzoHziBrNOs [M+H]+436.1, found 435.9. HPLC 99.8% purity.

[0510] Step C: Preparation of tert-butyl 4-(2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3-formyl-4-hydroxyphenyl)- 3 ,6-dihydropyridine-l (2H)-carboxylate (141-4)

[0511]

[0395] To a solution of 141-3 (1.0 g, 2.3 mmol, 1 eq) in dioxane (15 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l -carboxylate (712.0 mg, 2.3 mmol, 1 eq), tripotassium;phosphate (1.4 g, 6.9 mmol, 3 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;4-ditert- butylphosphanyl-N,N-dimethyl-aniline (29.2 mg, 46.0 pmol, 0.02 eq) and H2O (3 mL) under N2. After stirring at 110°C for 2 hr under N2, the reaction mixture was filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~3% MeOH / DCM @ 60 mL / min) to give tert-butyl 4-[2-[2-[3 -(2 -ethylphenoxy) azetidin- 1 -yl] -2 -oxo-ethoxy] -3 -formyl-4-hydroxy -phenyl] -3 ,6-dihydro- 2H-pyridine-l -carboxylate (141-4) (770.0 mg, 1.0 mmol, 43.8% yield, 70.3% purity) as a yellow oil.1H NMR (400 MHz, CDC13) 5 = 11.77 (s, 1H), 10.45 (s, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.13 (t, J= 7.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.72 (d, J= 8.8 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 5.84 (s, 1H), 5.03-4.98 (m, 1H), 4.59-4.53 (m, 1H), 4.47 (s, 2H), 4.22-4.12 (m, 2H), 4.05-3.95 (m, 3H), 3.61 (t, J= 4.8 Hz, 2H), 2.65 (q, J= 7.6 Hz, 2H), 2.45 (s, 1H), 2.27 (s, 1H), 1.49-1.47 (m, 9H), 1.20 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C26H29N2O7[M+H-56]+481.2, found 481.0.

[0512] Step D: Preparation of 2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-6-hydroxy-3-(l,2,3, 6-tetrahydropyridin- 4-yl)benzaldehyde (091)

[0513]

[0396] To a solution of 141-4 (770.0 mg, 1.4 mmol, 1 eq) in DCM (7 mL) was added HCl / EtOAc (7 mL). After stirring at 25°C for 2 hr, the reaction mixture was added toluene (10 mL) and concentrated to give 2-[2-[3-(2- ethylphenoxy)azetidin- 1 -yl] -2 -oxo-ethoxy] -6-hydroxy-3 -( 1 ,2,3 ,6-tetrahydropyridin-4-yl)benzaldehyde (091) (680.0 mg, crude, HC1) as a brown solid. ' H NMR (400 MHz, CDC13) 5 = 11.78 (s, 1H), 10.42 (s, 1H), 9.89-9.66 (m, 1H), 7.36-7.28 (m, 1H), 7.20-7.08 (m, 2H), 7.00-6.87 (m, 1H), 6.83-6.68 (m, 1H), 6.51-6.34 (m, 1H), 5.88 (s, 1H), 4.97 (s, 1H), 4.70-4.37 (m, 4H), 4.27-4.06 (m, 2H), 3.84 (s, 2H), 3.43 (s, 2H), 2.88-2.72 (m, 2H), 2.67-2.61 (m, 2H), 1.18 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula C25H29N2O5[M+H]+437.2, found 437.3. HPLC 95.7% purity. Step E-l: Preparation of 2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-6-hydroxy-3-(l-(2-(4-methylpiperazin- 1 -yl) acetyl)- 1,2, 3, 6-tetrahydropyridin-4-yl)benzaldehyde (141)

[0514]

[0397] To a solution of 2-(4-methylpiperazin-l-yl)acetic acid (16.7 mg, 105.7 pmol, 1 eq) in DMF (1 mL) was added HATU (60.3 mg, 158.5 pmol, 1.5 eq) and DIEA (40.9 mg, 317.1 pmol, 3 eq) at 25°C. After stirring at 25°C for 30 min, 091 (50.0 mg, 105.7 pmol, 1 eq, HO) was added to the mixture. After stirring at 25°C for 16 hr, the reaction was quenched by addition H2O (5 mL), extracted with EtOAc (20 mL), washed with brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: CD06-Waters Xbidge C18

[0515] 150*40* 10um;mobile phase: [water(TFA)-ACN];gradient:24%-54% B over 11 min) to give 2-(2-(3-(2- ethylphenoxy)azetidin- 1 -yl)-2-oxoethoxy)-6-hydroxy-3-( 1 -(2-(4-methylpiperazin-l -yl)acetyl)-l ,2,3 ,6- tetrahydropyridin-4-yl)benzaldehyde (141) (19.9 mg, 34.5 pmol, 32.6% yield, 100.0% purity) as a yellow oil. ' H NMR (400 MHz, CDCI3) 5 = 11.71 (s, 1H), 10.36 (s, 1H), 7.31 (d, J= 8.8 Hz, 1H), 7.19 (d, J= 12 Hz, 1H), 7.13 (t, J= 6.8 Hz, 1H), 6.95 (t, J= 8.0 Hz, 1H), 6.75 (d, J= 8.8 Hz, 1H), 6.45 (d, J= 12 Hz, 1H), 5.84 (d, J= 11.2 Hz, 1H), 5.01 (s, 1H), 4.66-4.45 (m, 3H), 4.41 (s, 2H), 4.31-4.17 (m, 3H), 4.15-4.11 (m, 1H), 4.01 (s, 1H), 3.91-3.78 (m, 4H), 3.55 (s, 6H), 2.87 (s, 4H), 2.68-2.63 (m, 2H), 2.47 (s, 1H), 1.20 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula C32H4IN2O6[M+H]+577.3, found 577.1. HPLC 100.0% purity.

[0516]

[0398] The following further Examples 142, 143, 161, 138, 139, 140, 144-160, 163-166, 169-175, 181, 184-188, 192- 196, 201, 167, 168, 179, 197, and 279 were prepared analogously to Examples 091 and 141, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0517] Example 199 - Synthesis of Compound 199

[0518] 199-1 199

[0519] Step A : Preparation of 3-[ 2-[ 4-[ 2-[ 2-[3-(2-ethylphenoxy)azetidin- 1 -yl ]-2-oxo-ethoxy]-3-formyl-4-hydroxy-phenyl ]- 3,6-dihydro-2H-pyridin-l-yl]-2-oxo-ethyl]benzonitrile (199)

[0520]

[0399] A mixture of 2-(3-cyanophenyl)acetic acid (11.0 mg, 68.73 pmol, 1 eq), EDCI (15.8 mg, 82.47 pmol, 1.2 eq), 199-1 (30.0 mg, 68.73 pmol, 1 eq) in Py (1 mL) was stirred at 30°C for 16 hr. The reaction mixture was filtered, concentrated and purified by prep-HPLC (column: CD24-XPT C18 150*25*7um;mobile phase: [water(TFA)- ACN];gradient:48%-78% B over 10 min) to give 3-[2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3- formyl-4-hydroxy -phenyl] -3, 6-dihydro-2H-pyridin-l-yl]-2-oxo-ethyl]benzonitrile (199) (1.1 mg, 1.90 pmol, 27.50% yield, 92.0% purity) as a yellow solid.1H NMR (400 MHz, CDC13) 5 = 11.76-11.72 (m, 1H), 10.40 (s, 1H), 7.61- 4.49 (m, 3H), 7.48-7.43 (m, 1H), 7.31-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.16-7.11 (m, 1H), 7.00-6.94 (m, 1H), 6.78- 6.71 (m, 1H), 6.48-6.41 (m, 1H), 5.91-5.81 (m, 1H), 5.08-4.97 (m, 1H), 4.58-4.10 (m, 9H), 3.86-3.76 (m, 2H), 3.72-

[0521] 3.62 (m, 1H), 2.72-2.59 (m, 2H), 2.49 (s, 2H), 1.23-1.17 (m, 3H). LCMS ESI calcd. For formula C34H34N3O6 [M+H]+580.2, found 580.2. HPLC 92.1% purity.

[0522]

[0400] The following further Example 200 was prepared analogously to Example 199, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative

[0523] HPLC.

[0524] Example 178, 234 - Synthesis of Compound 178, Compound 234

[0525]

[0401] To a solution of 234-1 (1.0 g, 2.3 mmol, 1 eq) in dioxane (15 mL) was added K3PO4 (1.4 g, 6.9 mmol, 3 eq), ethyl 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl]acetate (1.0 g, 3.4 mmol, 1.5 eq), [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;4-ditert-butylphosphanyl-N,N-dimethyl-aniline (43.8 mg, 69.0 pmol, 0.03 eq) and H2O (3 mL) under N2. After stirring at 110°C for 2 hr under N2, the reaction mixture was filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 40.0 g SepaFlash® Silica Flash Column, Eluent of 0~l% MeOH / DCM @ 50 mL / min) to give ethyl 2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo- ethoxy]-3-formyl-4-hydroxy-phenyl]cyclohex-3-en-l-yl]acetate (234-2) (2.2 g, 3.0 mmol, 42.5% yield, 72.3% purity) as a yellow oil. ' H NMR (400 MHz, CDCL) 5 = 11.75 (s, 1H), 10.45 (s, 1H), 7.31-7.26 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.16-7.09 (m, 1H), 6.95 (t, J= 7.2 Hz, 1H), 6.69 (d, J= 8.4 Hz, 1H), 6.45 (d, J= 8.0 Hz, 1H), 5.80 (s, 1H), 5.10-4.94 (m, 1H), 4.64-4.55 (m, 1H), 4.55-4.42 (m, 3H), 4.28-4.19 (m, 1H), 4.19-4.11 (m, 3H), 2.65 (q, J= 7.6 Hz, 2H), 2.46-2.25 (m, 5H), 2.21-2.12 (m, 1H), 1.97-1.81 (m, 2H), 1.50-1.39 (m, 1H), 1.27 (t, J= 6.8 Hz, 3H), 1.20 (t, J= 7.6 Hz, 3H). LCMS Rt= 2.185 min in 3.0 min chromatography, 5-95AB, ESI calcd. For formula C30H36NO7 [M+H]+522.2, found 522.1.

[0526] Step B: Preparation of 2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy-2,3,4,5- tetrahydro-[l,l ’-biphenyl]-4-yl)acetic acid (178)

[0527]

[0402] To a solution of 234-2 (1.0 g, 1.9 mmol, 1 eq) in THF (10 mL), MeOH (10 mL) and H2O (10 mL) was added lithium;hydroxide;hydrate (160.9 mg, 3.8 mmol, 2 eq). After stirring at 25°C for 16 hr, the reaction mixture was concentrated, adjusted pH to 4 by HO (1 M), extracted with DCM (200 mL), dried over Na2SO4, filtered and concentrated to give 2-(2'-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3'-formyl-4'-hydroxy-2,3,4,5- tetrahydro-[l,l'-biphenyl]-4-yl)acetic acid (178) (980 mg, crude) as a yellow oil. ' H NMR (400 MHz, CDCI3) 5 = 11.73 (s, 1H), 10.43 (s, 1H), 7.32-7.28 (m, 1H), 7.21-7.19 (m, 1H), 7.15-7.11 (m, 1H), 6.98-6.93 (m, 1H), 6.75-6.68 (m, 1H), 6.45 (d, J= 8.4 Hz, 1H), 5.86-5.74 (m, 1H), 5.06-4.96 (m, 1H), 4.64-4.56 (m, 1H), 4.54-4.45 (m, 3H), 4.30- 4.22 (m, 1H), 4.20-4.12 (m, 1H), 2.70-2.62 (m, 2H), 2.43-2.35 (m, 5H), 2.23-2.18 (m, 1H), 1.97-1.92 (m, 2H), 1.50- 1.48 (m, 1H), 1.22-1.18 (m, 3H). LCMS ESI calcd. For formula C28H32NO7 [M+H]+494.2, found 494.0.HPLC 97.9% purity.

[0528] Step C: Preparation of 3-(2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy-2,3,4,5- tetrahydro-[l,r-biphenyl]-4-yl)acetamido)-N,N-dimethylpropanamide (234)

[0529]

[0403] To a solution of 234-3 (50.0 mg, 101.3 pmol, 1 eq) in DMF (1 mL) was added HATU (57.7 mg, 151.9 pmol,

[0530] 1.5 eq), DIEA (39.2 mg, 303.9 pmol. 3 eq) and 3-amino-N,N-dimethylpropanamide (11.7 mg, 101.3 pmol, 1 eq). After stirring at 25°C for 2 hr, the reaction mixture was filtered, the mother liquid was purified by prep-HPLC (column: CD02 -Waters Xbidge BEH C18 150*25* 10um;mobile phase: [water(TFA)-ACN];gradient:46%-76% B over 11 min) to give 3-(2-(2'-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3'-formyl-4'-hydroxy-2, 3,4,5- tetrahydro-[l,r-biphenyl]-4-yl)acetamido)-N,N-dimethylpropanamide (234) (13.3 mg, 21.5 pmol, 21.3% yield, 96.0% purity) as a yellow oil.!H NMR (400 MHz, CDCI3) 5 = 11.71 (s, 1H), 10.50-10.28 (m, 1H), 7.28-7.25 (m, 1H), 7.21-7.16 (m, 1H), 7.15-7.10 (m, 1H), 6.94 (t, J= 7.6 Hz, 1H), 6.88 (t, J= 5.2 Hz, 1H), 6.69 (d, J= 8.4 Hz, 1H), 6.45 (d, J= 8.0 Hz, 1H), 5.77 (s, 1H), 5.07-4.97 (m, 1H), 4.65-4.59 (m, 1H), 4.50 (s, 2H), 4.29-4.21 (m, 1H), 4.16-4.10 (m, 1H), 3.85 (s, 2H), 3.59-3.53 (m, 2H), 2.94 (s, 3H), 2.95 (s, 3H), 2.65 (q, J= 7.6 Hz, 2H), 2.55 (t, J=

[0531] 5.6 Hz, 2H), 2.37-2.33 (m, 2H), 2.18 (s, 3H), 1.90-1.80 (m, 2H), 1.46-1.38 (m, 1H), 1.19 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C33H42N3O7 [M+H]+592.3, found 592.1. HPLC 96.0% purity.

[0532]

[0404] The following further Examples 176, 177, 180, 189, 198, 205-223, 225-230, 232, 233, 235-252, 254-263, 266, 268-277, 280, 287, 288, 291, 292, 289, 293-297, 299, 301-314, 317, and 329 were prepared analogously to Examples 178 and 234, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0533] Example 224 - Synthesis of Compound 224

[0534]

[0405] To a solution of 2-(cyclohexylamino)-2-oxo-acetic acid (18.1 mg, 105.7 pmol, 1 eq) in Py (1 mL) was added EDCI (30.4 mg, 158.5 pmol, 1.5 eq) and 224-1 (50.0 mg, 105.7 pmol, 1 eq, HO). The mixture was stirred at 25°C for 16 hr. The reaction mixture was added HO (1 M, 1 ml), stirred at 25°C for 1 hr, quenched by addition H2O (10 mL), extracted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150*25* 10um;mobile phase: [water( NH4HCO3)- ACN];gradient:41%-71% B over 10 min) to give 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy- 3-[4-[2-(4-methylsulfonyl-l,4-diazepan-l-yl)-2-oxo-ethyl]cyclohexen-l-yl]benzaldehyde (5.4 mg, 8.1 pmol, 26.4% yield, 98.1% purity) (224) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 11.73 (s, 1H), 10.43 (s, 1H), 7.30-7.27 (m, 1H), 7.21-7.17(m, 1H), 7.13 (t, .7 = 7.6 Hz. 1H), 6.95 (t, J= 7.2 Hz, 1H), 6.70 (d, J= 8.8 Hz, 1H), 6.48 (d, J= 8.0 Hz, 1H), 5.84-5.77 (m, 1H), 5.07-4.98 (m, 1H), 4.65-4.58 (m, 1H), 4.51 (s, 3H), 4.31-4.22 (m, 1H), 4.20-4.11 (m, 1H), 3.77-3.63 (m, 4H), 3.48-3.34 (m, 4H), 2.87-2.81 (m, 3H), 2.66 (q, J= 7.6 Hz, 2H), 2.48-2.17 (m, 7H), 2.02- 1.88 (m, 4H), 1.20 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C34H44N3O8S [M+H]+654.2, found 654.2. HPLC 98.1% purity.

[0535]

[0406] The following further Examples 265, 267, and 298 were prepared analogously to Example 224, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0536] Example 202, 278, 231 - Synthesis of Compound 202, Compound 278, Compound 231

[0537] 231

[0538] Step A : Preparation of Ethyl 2-[ 4-[ 2-[ 2-[3-(2-ethylphenoxy)azetidin-l-yl ]-2-oxo-ethoxy]-3-formyl-4-hydroxy- phenyl] cyclohexyl] acetate (202)

[0539]

[0407] To a solution of Pd / C (50.0 mg, 46.9 pmol, 10.0% purity, 0.4 eq) in EtOAc (2 mL) was added 231-1 (50.0 mg, 95.8 pmol, 1.0 eq) in EtOAc (2 mL) at 0°C. After stirring at 25°C for 2 hr under H2, the mixture was filtered, concentrated and purified by prep-HPLC (column: CD01 -Pheno menex Inna C18 150 * 25 mm * 5 um; mobile phase: [water(FA)-ACN]; gradient: 20%-50% B over 10 min) to give ethyl 2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2- oxo-ethoxy]-3-formyl-4-hydroxy-phenyl]cyclohexyl]acetate (202) (1.1 mg, 2.1 pmol, 2.1%yield) as ayellow solid. 'H NMR (400 MHz, CDC13) 5 = 11.59 (s, 1H), 10.31 (s, 1H), 7.45-7.40 (m, 1H), 7.23-7.19 (m, 1H), 7.13 (t, J= 7.6 Hz, 1H), 7.02-6.93 (m, 1H), 6.82-6.73 (m, 1H), 6.45 (d, J= 8.4 Hz, 1H), 5.08-5.01 (m, 1H), 4.74-4.67 (m, 1H), 4.58- 4.52 (m, 1H), 4.49-4.45 (m, 2H), 4.39-4.32 (m, 1H), 4.26-4.20 (m, 1H), 4.19-4.11 (m, 2H), 2.90-2.75(m, 1H), 2.69(q, J= 7.6 Hz, 2H), 2.50-2.44 (m, 1H), 2.42-2.32 (m, 1H), 2.29-2.20 (m, 1H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 3H), 1.55-1.35 (m, 2H), 1.25 (t, J= 7.6 Hz, 3H), 1.20 (t, J= 7.6 Hz, 3H), 1.15-1.05 (m, 1H). LCMS ESI calcd. For formula C30H38NO7 [M+H]+524.2, found 524.3. HPLC 98.1% purity.

[0540] Step B: Preparation of 2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3-formyl-4-hydroxy- phenyl] cyclohexyl] acetic acid (278)

[0541]

[0408] To a solution of 202 (30.0 mg, 57.2 pmol, 1 eq) in THF (1 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH.H2O (4.8 mg, 114.5 pmol, 2 eq). After stirring at 25°C for 16 hr, the reaction mixture concentrated and adjusted pH = 3 by HO (I M) and extracted with DCM (10 mL *3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by prep-HPLC (column: CD24-XPT C18 150*25 *7um;mobile phase: [water(FA)-ACN];gradient:45%-75% B over 10 min) to give 2-[4-[2-[2- [3-(2- ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3-formyl-4-hydroxy-phenyl]cyclohexyl]acetic acid (278) (0.9 mg, 1.8 pmol, 3.1% yield) as ayellow oil. ' H NMR (400 MHz, CDC13) 5 = 11.59 (s, 1H), 10.30 (s, 1H), 7.43-7.39 (m, 1H),

[0542] 7.22-7.19 (m, 1H), 7.15-7.11 (m, 1H), 6.99-6.93 (m, 1H), 6.81-6.75 (m, 1H), 6.48-6.43 (m, 1H), 55.07-5.00 (m, 1H),

[0543] 4.74-4.66 (m, 1H), 4.57-4.45 (m, 3H), 4.38-4.32 (m, 1H), 4.28-4.19 (m, 1H), 2.85-2.76 (m, 1H), 2.70-2.64 (m, 2H),

[0544] 2.32-2.27 (m, 2H), 2.24-2.19 (m, 1H), 2.02-1.91 (m, 4H), 1.80-1.74 (m, 4H), 1.22-1.09 (m, 3H). LCMS ESI calcd.

[0545] For formula C28H34NO7 [M+H]+496.2, found 496.0. HPLC 85.3% purity.

[0546] Step C: Preparation ofN-[2-(dimethylamino)ethyl]-2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3- formyl-4-hydroxy-phenyl ] cyclohexyl ] acetamide (231 )

[0547]

[0409] To a solution of 231-3 (35.0 mg, 70.6 pmol, 1.0 eq) and N',N' -dimethylethane- 1,2-diamine (6.2 mg, 70.6 pmol, 7.7 pL, 1.0 eq) in DMF (1 mL) was added HATU (32.2 mg, 84.5 pmol, 1.2 eq) and DIEA (27.3 mg, 211.8 pmol, 36.9 pL, 3.0 eq). After stirring at 25°C for 16 hr, the reaction mixture was filtered and purified by prep-HPLC (column: CD01 -Pheno menex Inna C 18 150*25* 10um;mobile phase: [water(TFA)-ACN];gradient:22%-52% B over 10 min) to give N-[2-(dimethylamino)ethyl]-2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3-formyl- 4-hydroxy-phenyl]cyclohexyl]acetamide (231) (4.3 mg, 7.6 pmol, 10.7% yield, TFA) as a yellow oil. ' H NMR (400 MHz, CDCI3) 5 = 12.57-12.29 (m, 1H), 11.67-11.53 (m, 1H), 10.36-10.25 (m, 1H), 8.33-8.19 (m, 0.5H), 7.96-7.82 (m, 0.5H), 7.62-7.51 (m, 0.5H), 7.44-7.35 (m, 0.5H), 7.22-7.17 (m, 1H), 7.16-7.09 (m, 1H), 7.01-6.90 (m, 1H), 6.84- 6.72 (m, 1H), 6.46 (t, J= 6.8 Hz, 1H), 5.11-4.98 (m, 1H), 4.76-4.67 (m, 1H), 4.61-4.51 (m, 1H), 4.45 (s, 2H), 4.39- 4.30 (m, 1H), 4.26-4.17 (m, 1H), 4.68 (s, 2H), 3.21 (s, 2H), 2.86 (s, 6H), 2.82-2.73 (m, 1H), 2.71-2.62 (m, 2H), 2.38 (s, 2H), 2.17-2.11 (m, 1H), 1.94-1.80 (m, 2H), 1.78-1.72 (m, 1H), 1.71-1.58 (m, 3H), 1.56-1.40 (m, 2H), 1.24-1.18 (m, 3H). LCMS ESI calcd. For formula C32H44N3O6 [M+H]+566.3, found 566.2.19F NMR (376.5 MHz, CDC13) 5 = -75.427. HPLC 100.0% purity.

[0548]

[0410] The following further Example 203 was prepared analogously to Examples 202, 278, and 231, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0549] Example 097 - Synthesis of Compound 097

[0550]

[0411] To a solution of 097-1 (10 g, 46.0 mmol) in DCM (100 mL) was added DIEA (7.74 g, 59.9 mmol, 10.4 mL) and bromo(methoxy) methane (5.76 g, 46.0 mmol, 3.76 mL). After stirring at 25°C for 16 hr, the reaction mixture was quenched by addition H2O (50 mL), extracted with DCM (100 mL), washed with H2O (50 mL), concentrated and purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ethergradient @ 50 mL / min) to give 3-bromo-6-hydroxy-2-(methoxymethoxy)benzaldehyde (097-2) (6.3 g, 24.1 mmol, 52.3% yield) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 11.73 (s, 1H), 10.27 (s, 1H), 7.65 (d, J= 9.2 Hz, 1H), 6.71 (d, J= 9.2 Hz, 1H), 5.21 (s, 2H), 3.61 (s, 3H).

[0551] Step B: Preparation of 3-bromo-6-[2-[3-(2-ethylphenoxy) azetidin- 1 -yl]-2-oxo-ethoxy]-2-hydroxy-benzaldehyde (097-3)

[0552]

[0412] To a solution of 097-2 (4 g, 15.3 mmol) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (1.94 g, 7.66 mmol) in acetonitrile (40 mL) were added K2CO3(3.18 g, 22.9 mmol) and KI (254 mg, 1.53 mmol) at 25°C . The reaction mixture was stirred for 3 h and then HC1 (12 M, 0.638 mL) was added. After stirring at 25°C for 1 hr, the reaction mixture was quenched by addition H2O (10 mL), extracted with EtOAc (20 mL), washed with H2O (10 mL), concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ethergradient @ 60 mL / min) to give 3-bromo-6-[2-[3-(2- ethylphenoxy)azetidin-l-yl] -2 -oxo-ethoxy] -2 -hydroxy -benzaldehyde (097-3) (1.3 g, 2.99 mmol, 39% yield) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 12.60 (s, 1H), 10.35 (s, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.22-7.17 (m, 1H), 7.15-7.09 (m, 1H), 6.99-6.92 (m, 1H), 6.43 (d, J= 8.0 Hz, 1H), 6.34 (d, J= 8.8 Hz, 1H), 5.03-4.95 (m, 1H), 4.69-4.66 (m, 2H), 4.61 (dd, J = 1.2, 9.2 Hz, 1H), 4.49 (dd, J= 6.4, 10.8 Hz, 1H), 4.28 (dd, J = 3.6, 9.6 Hz, 1H), 4.17 (dd, J= 3.6, 11.2 Hz, 1H), 2.64 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H).

[0553] Step C: Preparation of 6-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-2-hydroxy-3-(3-(trifluoromethyl)-lH- pyrazol-4-yl)benzaldehyde (097)

[0554]

[0413] To a solution of 097-3 (50.0 mg, 115 pmol) and [3 -(trifluoromethyl)- lH-pyrazol-4-yl]boronic acid (31.0 mg, 172. pmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added tripotassium;phosphate (73.3 mg, 345 pmol) and [2- (2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;4-ditert-butylphosphanyl-N,N-dimethyl-aniline (7.31 mg, 11.5 pmo), was added to the mixture. After stirring at 110°C for 3 hr, the reaction mixture was quenched by addition H2O (2 mL), extracted with EtOAc (3 mL), washed with H2O (10 mL), concentrated and purified by prep-HPLC (FA condition: column: CD01 -Pheno menex Inna C18 150 x 25 x 10 um; mobile phase: [water(FA)-ACN]; gradient: 45%-75% B over 8 min), to give 6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-hydroxy-3-[3- (trifluoromethyl)-lH-pyrazol-4-yl]benzaldehyde (097) (2.8 mg, 5.72 pmol, 4.9% yield) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 12.52 (s, 1H), 10.44 (s, 1H), 7.86 (s, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.20 (d, J= 7.2 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 7.01-6.92 (m, 1H), 6.44 (dd, J= 3.6, 8.0 Hz, 2H), 5.08-4.95 (m, 1H), 4.79-4.69 (m, 2H), 4.68-4.62 (m, 1H), 4.52 (dd, J= 7.2, 10.8 Hz, 1H), 4.32 (dd, J= 3.6, 10.0 Hz, 1H), 4.20 (dd, J= 3.6, 10.8 Hz, 1H), 2.65 (q, J= 7.6 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H).19F NMR (376.5 MHz, CDC13) 5 = -59.956. LCMS ESI calcd. For formula C24H23F3N3O3[M+H]+490.0, found 490.0. HPLC 94.8% purity.

[0555]

[0414] The following further Examples 107, 116, 122, 135-137, 098-106, 108-115, 117-121, and 123-134 were prepared analogously to Example 097, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0556] Example 182 - Synthesis of Compound 182

[0557] 182-1 182

[0558] Step A: Preparation of 6-[2-[3-(2-ethylphenoxy) azetidin- 1 -yl]-2-oxo-ethoxy]-2-hydroxy-3-tetrahydropyran-4-yl- benzaldehyde (182)

[0559]

[0415] To a solution of 182-1 (50 mg, 114 pmol) in EtOAc (2 mL) was added Pd / C (100 mg, 93.9 pmol, 4.57 pL, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 0°C for 2 hours, the reaction mixture was fdtered and the filter was concentrated and purified by prep-HPLC (FA condition column: CD01 -Pheno menex Inna C18 150 x 25 x 10 um; mobile phase: [water(FA)-ACN]; gradient: 49%-79% B over 10 min), to give 6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo- ethoxy]-2-hydroxy-3-tetrahydropyran-4-yl-benzaldehyde (182) (4.8 mg, 10.9 pmol, 9.5% yield) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 12.36 (s, 1H), 10.40 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 6.98-6.93 (m, 1H), 6.43 (d, J= 8.0 Hz, 1H), 6.34 (d, J= 8.8 Hz, 1H), 5.03-4.95 (m, 1H), 4.68 (d, J = 2.4 Hz, 2H), 4.62 (dd, J = 6.4, 9.2 Hz, 1H), 4.49 (dd, J = 6.4, 10.8 Hz, 1H), 4.30 (dd, J = 4.0, 9.6 Hz, 1H), 4.17 (dd, J= 4.0, 11.2 Hz, 1H), 4.11-4.02 (m, 2H), 3.62-3.53 (m, 2H), 3.22-3.09 (m, 1H), 2.64 (q, J = 1.6 Hz, 2H), 1.77-

[0560] 1.69 (m, 4H), 1.18 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C25H29NO6 [M+H]+440.1, found 440.1. HPLC

[0561] 99.2% purity.

[0562] Example 040 - Synthesis of Compound 040

[0563] 040-1 040

[0564] Step A: Preparation of2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-6-hydroxy-3-(3-(trifluoromethyl)-lH- pyrazol-4-yl)benzaldehyde (040)

[0565]

[0416] To a solution of 040-1 (50 mg, 0.115 mmol) and [3 -(trifluoromethyl)- lH-pyrazol-4-yl]boronic acid (31.1 mg, 0.173 mmol in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;4-ditert-butylphosphanyl-N,N-dimetliyl-aniline (7.3 mg, 11.5 pmol,) and tripotassium;phosphate (73.3 mg, 345pmol), the mixture was stirred at 100°C for 16 h to give yellow solution. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD04-Welch Utimate C18 150*25*7um; mobile phase: [water(FA)-ACN];gradient:47%-77% B over 10 min) to give 2-[2-[3-(2- ethylphenoxy)azetidin- 1 -yl] -2 -oxo-ethoxy] -6-hydroxy-3 -[3 -(trifluoromethyl)-lH-pyrazol-4-yl]benzaldehyde (040) (6.1 mg, 12.5 pmol, 6.1% yield) as a white solid.!H NMR (400 MHz, CDC13) 5 = 11.86 (s, 1H), 10.47 (s, 1H), 7.83 (s, 1H), 7.47 (d, J= 8.8 Hz, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.96 (m, 1H), 6.83 (t, J= 8.8 Hz, 1H), 6.4 (d, J= 8.0 Hz, 1H), 4.94 (m, 1H), 4.39 (m, 1H), 4.32 (m, 1H), 4.17 (s, 2H), 4.07 (m, 1H), 4.00 (m, 1H), 2.64 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C24H23F3N3O5 [M+H]+490.2, found 490.0. HPLC 98.6% purity.

[0566]

[0417] The following further Examples 049, 023, 029, 061, 071, 086, 089, 087, 088, 041-048, 050-055, 058, 060, 062, 063, 065, 067-070, 072-075, 031, 033, 035, 076, 078, 080-085, 066, and 090 were prepared analogously to Example 040, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0567] Example 036 - Synthesis of Compound 036

[0568] 036-1 036 Step A: Preparation of2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-3-[(E)-2-(4- pyridyl)vinyl (benzaldehyde (036)

[0569]

[0418] A mixture of 036-1 (50.0 mg, 115.1 pmol, 1 eq), 4-vinylpyridine (13.3 mg, 126.6 pmol, 1.1 eq), Pd(OAc)2 (2.5 mg, 11.5 pmol, 0.1 eq), TEA (23.3 mg, 230.2 pmol, 2 eq) and tris-o-tolylphosphane (4.2 mg, 13.8 pmol, 0.12 eq) in tol (1 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 120°C for 16 hr under N2atmosphere. The mixture was filtered, concentrated and purified by prep-HPLC (column: CDOl-Phenomenex Inna C18 150*25* 10um;mobile phase: [water(TFA)-ACN];gradient:26%-56% B over 10 min) to give 2-[2-[3-(2- ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-3-[(E)-2-(4-pyridyl)vinyl]benzaldehyde (036) (10.0 mg, 14.1 pmol, 12.3% yield, 89.2% purity) as a yellow oil.’H NMR (400 MHz, CDC13) 5 = 11.94 (s, 1H), 10.40 (s, 1H), 8.69- 8.65 (m, 2H), 7.93-7.89 (m, 1H), 7.86-7.83 (m, 1H), 7.71-7.67 (m, 2H), 7.21-7.18 (m, 2H), 7.14-7.10 (m, 2H), 6.90-

[0570] 6.87 (m, 1H), 6.43-6.39 (m, 1H), 5.35-5.33 (m, 1H), 5.05-4.96 (m, 2H), 4.53 (s, 2H), 4.23-4.19 (m, 2H), 2.65-2.62 (m, 2H), 1.22-1.19 (m, 3H). LCMS ESI calcd. For formula C27H27N2O5 [M+H]+459.1, found 459.1. HPLC 89.2% purity.

[0571] Example 056, 057 - Synthesis of Compound 056, Compound 057

[0572] 056-1 056 057

[0573] Step A: Preparation of 3-(l,4-dioxaspiro[4.5]decan-8-ylmethyl)-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo- ethoxy ]-6-hydroxy-benzaldehyde ( 056)

[0574]

[0419] To a solution of 056-1 (70 mg, 138 pmol) in EtOAc (5 mL) was added Pd / C (147 mg, 138 pmol, 10% purity), the mixture was stirred at 0°C for 2h under H2. The reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 x 30mm x 5um;mobile phase: [water(FA)-ACN]; gradient: 60%-90% B over 9 min) to give 3-(l,4-dioxaspiro[4.5]decan-8-ylmethyl)-2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2- oxo-ethoxy]-6-hydroxy -benzaldehyde (056) (7.4 mg, 15 pmol, 10.5% yield) as an off-white solid. ' H NMR (400 MHz, CDCI3) 5 = 11.63 (s, 1H), 10.33 (s, 1H), 7.32 (d, J= 8.8 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.16-7.10 (m, 1H), 6.99-6.93 (m, 1H), 6.74 (d, J= 8.8 Hz, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.04-5.02 (m, 1H), 4.70-4.69 (m, 1H), 4.53- 4.51 (m, 1H), 4.49 (s, 2H), 4.34-4.33 (m, 1H), 4.22-4.21 (m, 1H), 3.96-3.88 (m, 4H), 2.67 (q, J= 7.6 Hz, 2H), 2.48 (d, J= 7.2 Hz, 2H), 1.76-1.63 (m, 5H), 1.48 (t, J= 12.8 Hz, 2H), 1.37-1.28 (m, 2H), 1.21 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C29H36NO7 [M+H]+510.2, found 510.4. HPLC 97.7% purity.

[0575] Step B: Preparation of 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-hydroxy-3-[ (4- oxocyclohexyl)methyl (benzaldehyde (057)

[0576]

[0420] To a solution of 056 (20 mg, 39 pmol) in THF (1 mL) was added HO (2 M, 0.1 mL), the mixture was stirred at 25°C for 2h. The reaction mixture was poured into aq NaHCCF, to neutralize to pH=8, and extracted with EtOAc (3 mL x2). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, fdtered and concentrated. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150 x 30mm x 5um; mobile phase: [water(FA)-ACN]; gradient: 59%-89% B over 9 min) to give 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo- ethoxy]-6-hydroxy-3-[(4-oxocyclohexyl)methyl]benzaldehyde (057) (1.6 mg, 3.4 gniol. 8.8% yield) as an off-white solid. ' H NMR (400 MHz, CDC13) 5 = 11.63 (s, 1H), 10.34 (s, 1H), 7.35 (d, J= 8.8 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.16-7.10 (m, 1H), 7.00-6.92 (m, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 5.11-4.96 (m, 1H), 4.70-4.62 (m, 1H), 4.53-4.52 (m, 1H), 4.49 (s, 2H), 4.30-4.29 (m, 1H), 4.22-4.21 (m, 1H), 2.66 (q, J= 7.6 Hz, 2H), 2.60-2.55 (m, 2H), 2.42-2.33 (m, 2H), 2.32-2.20 (m, 2H), 2.08-1.95 (m, 3H), 1.45-1.43 (m, 2H), 1.20 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C27H32NO6 [M+H]+466.2, found 466.3. HPLC 100.0% purity.

[0577]

[0421] The following further Examples 059, 077, 079, 093, 094, 183, and 191 were prepared analogously to Examples 056 and 057, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0578] Example 027 - Synthesis of Compound 027

[0579] 027-1 027-2 027-3 027 Step A: Preparation of tert-butyl 3-[2-ethyl-4-(l-piperidyl)phenoxy]azetidine-l-carboxylate (027-2)

[0580]

[0422] To a solution of piperidine (143 mg, 1.68 mmol) tert-butyl 3-(4-bromo-2-ethyl-phenoxy)azetidine-l- carboxylate (300 mg, 842 pmol) in dioxane (10 mL) was added CS2CO3 (823 mg, 2.53 mmol), 027-1 (300 mg, 842 pmol) and RuPhos Pd G3 (70 mg, 84.2 pmol) was added. After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (0-50% of EtOAc in PE) to give tert-butyl 3-[2-ethyl-4-(l-piperidyl)phenoxy]azetidine-l-carboxylate (027- 2) (30 mg, 83.2 pmol, 9.9% yield) as yellow oil. ' H NMR (400 MHZ,CDC13) 5 = 6.92-6.80 (m, 1H), 6.75-6.61 (m, 1H), 6.43-6.34 (m, 1H), 4.88-4.75 (m, 1H), 4.41-4.20 (m, 2H), 4.01-3.94 (m, 2H), 3.18-2.92 (m, 3H), 2.70-2.54 (m,

[0581] 2H), 1.72 (s, 3H), 1.55 (s, 4H), 1.45 (s, 9H), 1.19 (t, J= 7.6 Hz, 3H).

[0582] Step B: Preparation of l-[4-(azetidin-3-yloxy)-3-ethyl-phenyl]piperidine (027-3)

[0583]

[0423] To a solution of 027-2 (30 mg, 83.2 pmol) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol). After stirring at 25°C for 1 h, the reaction mixture was added toluene (5 ml) and concentrated under reduced pressure to give l-[4- (azetidin-3-yloxy)-3-ethyl-phenyl]piperidine (027-3) (40 mg, crude) as yellow oil. LCMS ESI calcd. For formula C16H25N2O [M+H]+261.2, found 261.3.

[0584] Step C: Preparation of2-[3-[2-ethyl-4-(l-piperidyl)phenoxy]azetidine-l-carbonyl]-6-hydroxy-benzaldehyde (027)

[0585]

[0424] To a solution of 2-formy 1-3 -hydroxy -benzoic acid (33 mg, 199 pmol) in DMF (5 mL) was added HATU (70 mg, 184 pmol) and DIEA (59 mg, 460 pmol) and 027-3 (40 mg, 153 pmol). After stirring at 25°C for 12 h, the reaction mixture was quenched by addition H2O (10 mL), and extracted with EtOAC (10 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: C18 100 x 40 mm; mobile phase: [water(TFA)-ACN]; gradient: 10%-40% B over 8 min) to give 2-[3-[2-ethyl-4-(l-piperidyl)phenoxy]azetidine-l- carbonyl]-6-hydroxy-benzaldehyde (027) (2.3 mg, 5.63 pmol, 3.6% yield) as yellow oil. ' H NMR (400 MHz, CDCI3) 5 = 12.09-11.64 (m, 1H), 10.22 (s, 1H), 7.52 (t, J= 7.6 Hz, 1H), 7.46-7.35 (m, 2H), 7.08 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 7.2 Hz, 1H), 6.49 (d, J= 8.8 Hz, 1H), 5.03 (s, 1H), 4.72-4.60 (m, 1H), 4.51-4.38 (m, 1H), 4.34-4.26 (m,

[0586] 1H), 4.14-4.03 (m, 1H), 3.67-3.10 (m, 4H), 2.77-2.60 (m, 2H), 2.33-1.92 (m, 4H), 1.87-1.55 (m, 2H), 1.22 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C24H29N2O4 [M+H]+409.2 found 409.2. HPLC 97.9% purity.

[0587] Example 096 - Synthesis of Compound 096

[0588]

[0425] To a solution of 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]ethanone (607.2 mg, 2.3 mmol, 1 eq) and 096-1 (400.0 mg, 2.3 mmol, 1 eq) in ACN (4 mL) was added KI (79.4 mg, 478.7 pmol, 0.2 eq) and DIEA (928.0 mg, 7.1 mmol, 1.2 mL, 3 eq). After stirring at 80°C for 16 hr, the reaction mixture was quenched by addition water (5 mL) at 25°C, extracted with EtOAc (10 mL), washed with brine (10 mL ), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiCF. Ethyl acetate / Petroleum ether =0% to 50%) to give 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-6-nitro-benzaldehyde (096-2) (311.0 mg, 809.0 pmol, 33.8% yield) as ayellow oil. ' H NMR (400 MHz, CDC13) 5 = 10.39 (s, 1H), 7.68-7.52 (m, 1H), 7.31-7.27 (m, 1H), 7.22-7.16 (m, 1H), 7.16-7.09 (m, 1H), 6.95 (t, J= 12 Hz, 1H), 6.49-6.38 (m, 1H), 5.03-4.94 (m, 1H), 4.78-4.67 (m,

[0589] 2H), 4.52-4.42 (m, 1H), 4.35-4.28 (m, 1H), 4.18-4.07 (m, 3H), 2.69-2.59 (m, 2H), 1.23-1.15 (m, 3H).

[0590] Step B: Preparation of 2-amino-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]benzaldehyde (096)

[0591]

[0426] To a solution of 096-2 (50.0 mg, 130.0 pmol, 1 eq) in THF (1 mL) was added ^28264 (113.2 mg, 650.3 pmol, 141.5 pL, 5 eq) in water (1 mL). After stirring at 25°C for 10 min, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (6 mL), washed with brine (6 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by prep-HPLC (column: CDOl-Phenomenex Inna C18 150*25* 10um;mobile phase: [water(FA)-ACN];gradient:36%-66% B over 10 min) to give 2-amino-6-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo- ethoxy]benzaldehyde (096) (0.3 mg, 2.6 pmol, 2.0% yield, 94.6% purity) as a yellow oil.1H NMR (400 MHz, CDCL) 5 = 10.47 (s, 1H), 7.24-7.17 (m, 2H), 7.15-7.09 (m, 1H), 6.98-6.91 (m, 1H), 6.60-6.39 (m, 3H), 6.28 (t, J= 8.4Hz, 1H), 6.08 (d, J= 8.0 Hz, 1H), 5.03-4.91 (m, 1H), 4.73-4.60 (m, 3H), 4.51-4.44 (m, 1H), 4.32 (dd, J= 4.4, 10.0 Hz, 1H), 4.16 (dd, J= 4.4, 11.6 Hz, 1H), 2.70-2.59 (m, 2H), 1.18 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C20H23N2O4[M+H]+355.2, found 355.1. HPLC 94.6% purity.

[0592] Example 162 - Synthesis of Compound 162

[0593] Step A: Preparation of 4-(2-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3-formyl-4-methoxyphenyl)-3,6- dihydropyri dine- 1( 2H) -carb oxy late (162)

[0594]

[0427] To a solution of 162-1 (50.0 mg, 93.1 pmol, 1 eq) in DMF (1 mL) was added K2CO3 (38.6 mg, 279.5 pmol, 3 eq) and Mel (26.4 mg, 186.3 pmol, 11.6 pL, 2 eq) dropwise at 25 °C. The mixture was stirred at 25°C for 2 hr. The reaction mixture was quenched with H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO i. concentrated and purified by prep-HPLC (column: CD01 -Pheno menex Inna C18 150*25* 10um;mobile phase: [water(FA)-ACN];gradient:56%-86% B over 10 min) to give tert-butyl 4-(2-(2-(3 -(2-ethylphenoxy)azetidin- 1 -yl)-2-oxoethoxy)-3 -formyl-4-methoxyphenyl)-3 ,6- dihydropyridine-l(2H)-carboxylate (162) (10.9 mg, 19.8 pmol, 21.2% yield) as a yellow solid. ' H NMR (400 MHz, CDC13) 5 = 10.46 (s, 1H), 7.32 (d, . / = 8.4 Hz ,1H), 7.18 (d, J= 7.2 Hz, 1H), 7.11 (t, J= 8.0 Hz, 1H), 6.93 (t, J = 1.2 Hz, 1H), 6.76 (d, J= 8.8 Hz, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.75 (s, 1H), 5.06-4.95 (m, 1H), 4.86-4.76 (m, 1H), 4.56- 4.48 (m, 1H), 4.43 (s, 2H), 4.40-4.33 (m, 1H), 4.20-4.13 (m, 1H), 4.02 (s, 2H), 3.90 (s, 3H), 3.64-3.54 (m, 2.H), 2.70-2.63 (m , 2H), 2.50-2.35 (m, 2H), 1.48 (s, 9H), 1.20 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C3iH39N2O7[M+H]+551.3, found 551.1. HPLC 95.7% purity.

[0595]

[0428] The following further Examples 190 was prepared analogously to Example 162, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0596] Example 283 - Synthesis of Compound 283 Step A: Preparation of tert-butyl N-[2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]phenyl]carbamate (283-2)

[0597]

[0429] To a solution of 283-1 (0.6 g, 2.06 mmol, 1 eq, TFA) and 2-(tert-butoxycarbonylamino)benzoic acid (586.5 mg, 2.47 mmol, 1.2 eq) in DMF (5 mL) was added EDCI (592.3 mg, 3.09 mmol, 1.5 eq), HOBt (417.52 mg, 3.09 mmol, 1.5 eq) and TEA (833.8 mg, 1.15 mL, 4 eq). After stirring at 25°C for 12 h, the mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0~10% ethyl acetate in Petroleum ether to give tert-butyl N-[2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]phenyl]carbamate (283-2) (520.0 mg, 1.31 mmol, 63.67% yield) as a yellow oil.!H NMR (400 MHz, CDC13) 5 = 9.58 (s, 1H), 8.31(d, J= 8.0 Hz, 1H), 7.62- 7.48 (m, 1H), 7.44-6.37 (m, 1H), 7.32 (d, J= 7.6 Hz, 1H), 7.19 ( d, J= 12 Hz, 1H), 7.12 (t, J= 8.0 Hz, 1H), 7.02- 6.92 (m, 2H), 5.07-5.00 (m, 1H), 4.75-4.57 (m, 2H), 4.46-4.14 (m, 2H), 2.68 (q, J= 7.6 Hz, 2H), 1.52 (s, 9H), 1.22 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C23H29N2O4 [M+H]+397.2, found 397.1.

[0598] Step B: Preparation of (2-aminophenyl)-[3-(2-ethylphenoxy)azetidin-l-yl]methanone (283-3)

[0599]

[0430] To a solution of 283-2 (0.52 g, 1.26 mmol, 1 eq) in DCM (2 mL) was added TFA (718.9 mg, 6.31 mmol, 468.37 pL, 5 eq) at 0°C. After stirring at 0-25°C for 12h, the reaction mixture was concentrated, diluted with DCM (20 mL), washed with NaHCCF, (10 mL x 3) and concentrated to give (2-aminophenyl)-[3-(2-ethylphenoxy)azetidin- 1-yl] methanone (283-3) (350.0 mg, crude) as a yellow oil. ' H NMR (400 MHz, CDC13) 7.26-7.21 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 2H), 6.91 (t, J= 7.8 Hz, 1H), 6.74-6.66 (m, 2H), 6.49 (d, J= 7.6 Hz, 1H), 6.08 (s, 2H), 5.09-4.97 (m, 1H), 4.70-4.45 (m, 2H), 4.10-4.04 (m, 2H), 2.64-2.58 (m, 2H), 1.20-1.10 (m, 3H). LCMS ESI calcd. For formula C18H21N2O2 [M+H]+297.3, found 296.9.

[0600] Step C: Preparation of 3-[2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]anilino]-4-methoxy-cyclobut-3-ene-l, 2-dione (283).

[0601]

[0431] To a solution of 283-3 (100.0 mg, 337.42 pmol, 1 eq) in MeOH (2 mL) was added 3,4-dimethoxycyclobut-3- ene-1, 2-dione (47.9 mg, 337.42 pmol, 1 eq). After stirring at 25°C for 16 h, the mixture was concentrated and purified by reversed-phase HPLC( 0.1% FA condition). column: Phenomenex Inna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:50%-80% B over 10 min to give 3-[2-[3-(2-ethylphenoxy)azetidine-l- carbonyl]anilino]-4-methoxy-cyclobut-3-ene-l, 2-dione (283) (5.1 mg, 12.55 pmol, 3.7% yield, 100% purity) as a yellow solid. ' H NMR (400 MHz, DMSO-^e) 5 = 10.91 (s, 1H), 7.62-7.48 (m, 3H), 7.23-7.08 (m, 3H), 6.92 (t, J= 7.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.17-5.00 (m, 1H), 4.74-4.50 (m, 2H), 4.38 (s, 3H), 4.32-4.20 (m, 1H), 4.10- 3.99 (m, 1H), 2.61 (q, J= 2.2 Hz, 2H), 1.15 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C23H23N2O5 [M+H]+407.2, found 407.1. HPLC 100.0% purity.

[0602]

[0432] The following further Example 284 was prepared analogously to Example 283, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC. Example 281 - Synthesis of Compound 281

[0603] 283-3 281

[0604] Step A: Preparation ofN-[2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]phenyl]ethenesulfonamide (281)

[0605]

[0433] To a solution of 283-3 (367 mg, 1.24 mmol) and DIEA (320 mg, 2.48 mmol) in DCM (10 mL) was added ethenesulfonyl chloride (157 mg, 1.24 mmol) dropwise at 0°C. After stirring at 25°C for Ihr, the reaction mixture was quenched by addition H2O (1 mL), then concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; gradient: 55%-95% B over 7 min) to afford N-[2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]phenyl]ethenesulfonamide (281) (3.5 mg, 9 pmol, 0.7% yield) as a light yellow solid.!H NMR (400 MHz, CDC13) 5 = 10.12 (s, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.46- 7.36 (m, 2H), 7.20 (d, J= 7.2 Hz, 1H), 7.16-7.04 (m, 2H), 7.00-6.92 (m, 1H), 6.62 (dd, J= 10.0, 16.4 Hz, 1H), 6.45 (d, J= 8.0 Hz, 1H), 6.33 (d, J= 16.4 Hz, 1H), 5.95 (d, J= 10.0 Hz, 1H), 5.07-4.96 (m, 1H), 4.66 (br s, 2H), 4.44- 4.21 (m, 2H), 2.68 (q, J= 7.6 Hz, 2H), 1.22 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For C20H23N2O4S [M+H]+387.1, found 387.2. HPLC 96.1% purity.

[0606]

[0434] The following further Example 282 was prepared analogously to Example 281, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0607] Example 286 - Synthesis of Compound 286

[0608]

[0435] To a solution of 3-(2-ethylphenoxy)azetidine (300.0 mg, 1.69 mmol) and 286-1 (468.0 mg, 2.54 mmol) in THF (6 mL) was added NaOH (812.0 mg, 5.08 mmol). After stirring at 25°C for 12 hr, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-[3-(2-ethylphenoxy)azetidine-l- carbonyl]benzenesulfonic acid (286-2) (350 mg, crude) as an off-white foam, which was used to next step directly without further purification.1H NMR (400 MHz, DMSO-t / s) 5 = 7.77-7.66 (m, 1H), 7.43-7.31 (m, 2H), 7.19-7.05 (m, 3H), 6.92-6.83 (m, 1H), 6.63-6.55 (m, 1H), 5.02-4.92 (m, 1H), 4.40 (dd, J= 6.8, 10.2 Hz, 1H), 4.35-4.26 (m,

[0609] 1H), 3.93-3.87 (m, 1H), 3.85-3.75 (m, 1H), 3.64-3.58 (m, 1H), 2.59 (q, J= 7.6 Hz, 2H), 1.15 (t, J= 7.6 Hz, 3H).

[0610] Step B: Preparation of2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]benzenesulfonyl chloride (286-3)

[0611]

[0436] To a solution of 286-2 (330 mg, 913.09 pmol) and catalytic amount of DMF (3.34 mg, 45.65 pmol) in DCM (20 mL) was added(COCl)2(348 mg, 2.74 mmol) dropwise at 0°C. After stirring at 25°C for 3h, the organic solvent was evaporated in vacuo to give 2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]benzenesulfonyl chloride (286-3) (300 mg, 789pmol, 86.5% yield) as a yellow solid, which was redissolved in anhydrous DCM (10 mL) for further usage without purification.

[0612] Step C: Preparation of2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]benzenesulfonyl fluoride (286)

[0613]

[0437] To a solution of potassium;fluoride;hydrofluoride (105.4 mg, 1.35 mmol) in MeCN (3 mL) was added (286-3) (171 mg, 0.45 mmol) in MeCN (1 mL). After stirring at 25°C for 12hr, the reaction mixture was filtered and purified by prep-HPLC (column: C18 150x40mm; mobile phase: [water(FA)-ACN]; gradient: 40%-80% B over 9 min) to give 2-[3-(2-ethylphenoxy)azetidine-l-carbonyl]benzenesulfonyl fluoride (286) (10.5 mg, 28.9 pmol, 6.4% yield) as colorless gel. ' H NMR (400 MHz, CDC13) 5 = 8.17-8.11 (m, 1H), 7.85-7.77 (m, 1H), 7.72-7.62 (m, 1H), 7.60-7.51 (m, 1H), 7.22-7.16 (m, 1H), 7.14-7.06 (m, 1H), 6.97-6.86 (m, 1H), 6.45-6.36 (m, 1H), 5.08-4.99 (m, 1H), 4.65 (ddd, J= 1.2, 6.8, 10.8 Hz, 1H), 4.32-4.21 (m, 2H), 3.98 (ddd, J= 1.2, 6.8, 10.8 Hz, 1H), 2.67 (q, J= 7.6 Hz, 2H), 1.21 (t, J= 7.6 Hz, 3H).19F NMR (376.5 MHz, CDC13) 5 = 67.832. LCMS ESI calcd. For CI8HI9FNO4S [M+H]+364.1, found 364.0.HPLC 90.1% purity.

[0614] Example 318, 330 - Synthesis of Compound 318, Compound 330

[0615] 318-1 318 330

[0616] Step A: Preparation of tert-butyl 4-(2-(2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy- 2,3,4,5-tetrahydro-[l,l'-biphenyl]-4-yl)-N-methylacetamido)ethyl)piperazine-l-carboxylate (318)

[0617]

[0438] To a solution of 318-1 (150.0 mg, 303.9 pmol, 1 eq) in DMF (3 mL) was added HATU (173.3 mg, 455.8 pmol, 1.5 eq), DIEA (117.8 mg, 911.7 pmol, 3 eq) and tert-butyl 4-(2-(methylamino)ethyl)piperazine-l -carboxylate (73.9 mg, 303.9 pmol, 1 eq). After stirring at 25°C for 16 hr, the reaction mixture was quenched by addition H2O (5 mL), extracted with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO i. filtered, concentrated and purified by prep-HPLC (column: CD24-XPT C18 150*25 *7um;mobile phase: [water(FA)-ACN];gradient:29%-59% B over 10 min) to give tert-butyl 4-(2-(2-(2'-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3'-formyl-4'-hydroxy-2, 3,4,5- tetrahydro-[l,r-biphenyl]-4-yl)-N-methylacetamido)ethyl)piperazine-l-carboxylate (3.6 mg, 4.9 pmol, 1.6% yield, 98.5% purity) (318) as ayellow oil.1H NMR (400 MHz, CD3CN) 5 = 11.69 (br s, 1H), 10.48 (s, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.22-7.16 (m, 1H), 7.16-7.10 (m, 1H), 6.96-6.89 (m, 1H), 6.65 (d, J= 8.4 Hz, 1H), 6.69 (d, J= 8.0 Hz, 1H), 5.81 (s, 1H), 5.06-4.92 (m, 1H), 4.57-4.49 (m, 3H), 4.41-4.34 (m, 1H), 4.15-4.06 (m, 1H), 3.96-3.87 (m, 1H), 3.49- 3.27 (m, 7H), 2.98 (s, 2H), 2.86 (s, 1H), 2.63 (q, J= 7.6 Hz, 2H), 2.51-2.41 (m, 3H), 2.40-2.33 (m, 8H), 2.32-2.29 (m, 2H), 2.14-2.08 (m, 1H), 1.42-1.39 (m, 9H), 1.16 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. Forformula C40H55N4O8 [M+H]+719.4, found 719.2. HPLC 98.6% purity.

[0618] Step B: Preparation of 2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy-2,3,4,5- tetrahydro-[l,l’-biphenyl]-4-yl)-N-methyl-N-(2-(piperazin-l-yl)ethyl)acetamide (330)

[0619]

[0439] To a solution of 318 (70.0 mg, 97.3 pmol, 1 eq) in DCM (1 mL) was added HCl / EtOAc (2 M, 2 mL). After stirring at 25°C for 2 hr, the reaction mixture was concentrated, purified by prep-HPLC (column: CD25-XPT PHS C18 150*25*10um;mobile phase: [water(FA)-ACN];gradient:20%-50% B over 10 min) and purified by prep-HPLC (column: CD24-XPT C18 150*25*7um;mobile phase: [water(TFA)-ACN];gradient:22%-52% B over 10 min) to give 2-[4-[2-[2-[3-(2 -ethylpheno xy)azetidin-l-yl]-2-oxo-ethoxy]-3-formyl-4-hydroxy-phenyl]cyclohex-3-en-l-yl]-N- methyl-N-(2-piperazin-l-ylethyl)acetamide (5.2 mg, 8.1 pmol, 14.5% yield, 96.6% purity) (330) as a yellow oil. ' H NMR (400 MHz, CD3CN) 5 = 11.69 (br s, 1H), 10.45 (s, 1H), 7.33 (d, .7 = 8.8 Hz. 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 6.92 (t, J= 12 Hz, 1H), 6.66 (d, J= 8.8 Hz, 1H), 6.58 (d, J= 8.0 Hz, 1H), 5.80 (s, 1H), 5.05-4.97 (m, 1H), 4.58-4.51 (m, 3H), 4.41-4.35 (m, 1H), 4.15-4.10 (m, 1H), 3.95-3.90 (m, 1H), 3.67-3.61 (m, 2H), 3.49-3.38 (m, 8H), 3.33-3.27 (m, 1H), 3.14-3.07 (m, 3H), 3.05-2.95 (m, 6H), 2.64-2.63 (m, 2H), 2.35-2.31 (m, 4H), 1.46-1.38 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H). LCMS ESI calcd. For formula C35H47N4O6 [M+H]+ 619.3, found 619.1. HPLC 96.6% purity.

[0620]

[0440] The following further Examples 300, 315, and 316 were prepared analogously to Examples 318 and 330, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0621] Example 319 - Synthesis of Compound 319

[0622]

[0441] To a solution of 319-1 (1.0 g, 2.0 mmol, 1 eq) in DMF (10 mL) was added HATU (1.1 g, 3.0 mmol, 1.5 eq), DIEA (785.5 mg, 6.0 mmol, 3 eq) and tert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate (511.1 mg, 2.2 mmol, 1.1 eq). After stirring at 25°C for 16 hr, the reaction mixture was quenched by addition H2O (30 mL), extracted with EtOAc (60 mL), washed with brine (60 mL), dried over Na2SO i. fdtered, concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% MeOH / DCM @ 50 mL / min) to give tert-butyl 4-(2-(2-(2'-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3'-formyl-4'-hydroxy-2,3,4,5- tetrahydro-[l,l'-biphenyl]-4-yl)acetamido)ethyl)piperazine-l-carboxylate (620.0 mg, 703.7 pmol, 34.7% yield, 80.1% purity) (319-2) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 11.71 (s, 1H), 10.41 (s, 1H), 7.30-7.27 (m, 1H), 7.22-7.18 (m, 1H), 7.16-7.10 (m, 1H), 6.95 (t, J= 7.6 Hz, 1H), 6.70 (d, J= 8.8 Hz, 1H), 6.46 (d, J= 7.6 Hz, 1H), 6.39-6.09 (m, 1H), 5.84-5.74 (m, 1H), 5.09-4.97 (m, 1H), 4.66-4.57 (m, 1H), 4.55-4.36 (m, 3H), 4.31-4.21 (m, 1H), 4.18-4.11 (m, 1H), 3.52-3.35 (m, 6H), 2.66 (q, J= 7.6 Hz, 2H), 2.57-2.31 (m, 9H), 2.30-2.17 (m, 3H), 1.96-1.83 (m, 2H), 1.45 (s, 9H), 1.20 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. Forformula C39H53N4O8 [M+H]+705.4, found 705.2.

[0623] Step B: Preparation of 2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy-2,3,4,5- tetrahydro-[l,r-biphenyl]-4-yl)-N-(2-(piperazin-l-yl)ethyl)acetamid (319-3)

[0624]

[0442] To a solution of 319-2 (620.0 mg, 879.6 pmol, 1 eq) in DCM (2 mL) was added HCl / EtOAc (2 M, 6 mL). After stirring at 25°C for 1 hr, the reaction mixture was concentrated and purified by C18 (neutral condition, [water- ACN];gradient:40%-55% B over 20 min) to give 2-[4-[2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-3- formyl-4-hydroxy-phenyl]cyclohex-3-en-l-yl]-N-(2-piperazin-l-ylethyl)acetamide (320.0 mg, 401.6 pmol, 45.6% yield, 75.9% purity) (319-3) as a yellow solid. 'H NMR (400 MHz, DMSO-t / 6) 5 = 11.93 (s, 1H), 10.42 (s, 1H), 7.84-7.58 (m, 1H), 7.23-6.56 (m, 6H), 6.45-6.14 (m, 1H), 5.83-5.53 (m, 1H), 5.04 (s, 1H), 4.76-3.57 (m, 8H), 3.20- 3.07 (m, 3H), 2.82-2.77 (m, 1H), 2.62-2.56 (m, 2H), 2.40-2.21 (m, 8H), 2.10-1.93 (m, 4H), 1.83-1.69 (m, 2H), 1.38- 1.26 (m, 1H), 1.15-1.09 (m, 3H). LCMS ESI calcd. Forformula C34H45N4O6 [M+H]+605.3, found 605.1.

[0625] Step C: Preparation of2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3’-formyl-4’-hydroxy-2,3,4,5- tetrahydro-[ 1, l'-biphenyl]-4-yl)-N-(2-(4-(2-(4-methylpiperazin- 1 -yl) acetyl) piper azin- 1-yl) ethyl) acetamide (319)

[0626]

[0443] To a solution of 2-(4-methylpiperazin-l-yl)acetic acid (5.2 mg, 33.0 pmol, 1 eq) in DMF (1 mL) was added HATU (18.8 mg, 49.6 pmol, 1.5 eq), DIEA (12.8 mg, 99.2 pmol, 3 eq) and 319-3 (20.0 mg, 33.0 pmol, 1 eq). After stirring at 25°C for 16 hr, the reaction mixture was purified by prep-HPLC (column: CD24-XPT C18

[0627] 150*25 *7um;mobile phase: [water(TFA)-ACN];gradient:21%-51% B over 10 min) to give 2-(2'-(2-(3-(2- ethylphenoxy)azetidin- 1 -yl)-2-oxoethoxy)-3 '-formyl-4'-hydroxy-2,3 ,4,5-tetrahydro-[ 1 , 1 '-biphenyl] -4-yl)-N-(2-(4-(2- (4-methylpiperazin-l-yl)acetyl)piperazin-l-yl)ethyl)acetamide (0.7 mg, 2.5% yield, 89.0% purity) (319) as a yellow oil. 'H NMR (400 MHz, CD3CN) 5 = 11.68 (s, 1H), 10.44 (s, 1H), 7.56-7.47 (m, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.21- 7.18 (m, 1H), 7.17-7.12 (m, 1H), 6.97-6.91 (m, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H), 5.83-5.78 (m, 1H), 5.07-4.97 (m, 1H), 4.59-4.51 (m, 3H), 4.42-4.37 (m, 1H), 4.17-4.13 (m, 1H), 3.96-3.92 (m, 1H), 3.59-3.46 (m, 4H), 3.37 (s, 4H), 3.20 (t, J= 5.2 Hz, 4H), 2.77 (s, 4H), 2.64 (q, J= 12 Hz, 3H), 2.39-2.35 (m, 6H), 2.13-2.08 (m, 7H), 1.80-1.74 (m, 2H), 1.54-1.38 (m, 2H), 1.17 (t, J= 7.6 Hz, 3H). LCMS ESI calcd. For formula C41H57N6O7 [M+H]+745.4, found 745.1. HPLC 89.0% purity.

[0628]

[0444] The following further Examples 320-323, 326-328, and 332-334 were prepared analogously to Example 319, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0629] Example 324 - Synthesis of Compound 324 ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)-3-formyl-2’,3’,4’,5’-tetrahydro-[l,r-biphenyl]-4-yl benzoate (324-2)

[0630]

[0445] To a solution of 324-1 (20.0 mg, 33.0 pmol, 1 eq) in DCM (1 mL) was added TEA (10.0 mg, 99.2 pmol, 3 eq) and benzoyl chloride (4.6 mg, 33.0 pmol, 1 eq). After stirring at 25°C for 1 hr, the reaction mixture was concentrated to give [4-[4-[2-[2-(4-benzoylpiperazin-l-yl)ethylamino]-2-oxo-ethyl]cyclohexen-l-yl]-3-[2-[3-(2- ethylphenoxy)azetidin-l-yl]-2-oxo-ethoxy]-2-formyl-phenyl] benzoate (26.8 mg, crude) (324-2) as a yellow solid. LCMS ESI calcd. For formula C48H53N4O8 [M+H]+813.4, found 813.2.

[0631] Step B: Preparation ofN-(2-(4-benzoylpiperazin-l-yl)ethyl)-2-(2’-(2-(3-(2-ethylphenoxy)azetidin-l-yl)-2-oxoethoxy)- 3 ’-formyl-4 ’-hydroxy-2, 3, 4, 5 -tetrahydro- [ 1, 1 ’-biphenyl ]-4-yl)acetamide (324)

[0632]

[0446] To a solution of 324-2 (26.8 mg, 33.0 pmol, 1 eq) in THF (0.5 mL) and MeOH (0.5 mL) was added NaOH (1 M, 66.1 pL). After stirring at 25°C for 2 hr, the reaction mixture was adjusted pH to 7 with 2 M HO, filtered, concentrated and purified by prep-HPLC (column: CD24-XPT C18 150*25*7um;mobile phase: [water(TFA)- ACN];gradient:29%-59% B over 10 min) to give N-[2-(4-benzoylpiperazin-l-yl)ethyl]-2-[4-[2-[2-[3-(2- ethylphenoxyjazetidin- 1 -yl] -2 -oxo-ethoxy] -3 -formyl-4-hydroxy -phenyl] cyclohex-3 -en- 1 -yl]acetamide (2.6 mg, 3.6 pmol, 11.0% yield, 99.4% purity) (324) as a yellow oil.1H NMR (400 MHz, CD3CN) 5 = 11.68 (s, 1H), 10.45 (s, 1H), 7.63-7.54 (m, 1H), 7.54-7.39 (m, 5H), 7.33 (d, J = 8.8 Hz, 1H), 7.23-7.17 (m, 1H), 7.16-7.09 (m, 1H), 6.96- 6.87 (m, 1H), 6.67 (d, J= 8.8 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H), 5.85-5.75 (m, 1H), 5.07-4.96 (m, 1H), 4.62-4.50 (m, 3H), 4.41-4.33 (m, 1H), 4.16-4.11 (m, 1H), 3.95-3.90 (m, 1H), 3.71-3.47 (m, 4H), 3.19 (t, J= 5.2 Hz, 2H), 2.63 (q, J = 7.2 Hz, 2H), 2.36-2.32 (m, 6H), 2.20-2.16 (m, 6H), 1.88-1.80 (m, 2H), 1.47-1.38 (m, 1H), 1.16 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula C41H49N4O7 [M+H]+709.4, found 709.1. HPLC 99.4% purity.

[0633]

[0447] The following further Examples 325, 331, 993-996, 1010-1014, 1039, 1029-1031, 1052-1086, 1110-1114, and 1143 were prepared analogously to Example 324, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0634] Example 418, 419, 420 - Synthesis of Compound 418, Compound 419, Compound 420

[0635] 419 420

[0636] Step A: Preparation of 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]-2-phenyl-ethanone (418-2)

[0637]

[0448] To a mixture of 418-1 (1.8 g, 10.5 mmol, 1 eq) inDCM (20 mL) was added DIEA (4.1 g, 31.7 mmol, 5.5 mL, 3 eq), then 2-chloro-2-phenyl-acetyl chloride (2.0 g, 10.5 mmol, 1.6 mL, 1 eq) in DCM (20 mL) was added at 0°C. After stirring at 25°C for 2 hr, the reaction mixture was quenched with water (20 mL) at 25°C, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SC>4, filtered, concentrated and purified by column chromatography (SiO2, EA / PE= 0% to 9%) to give 2-chloro-l-[3-(2- ethylphenoxy)azetidin-l-yl]-2-phenyl-ethanone (418-2) (800.0 mg, 2.2 mmol, 21.2% yield, 92.6% purity) as a yellow solid. LCMS ESI calcd. For formula C19H21CINO2 [M+H]+330.2, found 330.0.

[0638] Step B: Preparation of 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-l-phenyl-ethoxy]-6-hydroxy-benzaldehyde (418)

[0639]

[0449] To a solution of 418-2 (150.0 mg, 1.0 mmol, l eq) inDMF (2 mL) was added K2CO3 (225.1 mg, 1.6 mmol, 1.5 eq) and 2-chloro-l-[3-(2-ethylphenoxy)azetidin-l-yl]-2-phenyl-ethanone (358.1 mg, 1.0 mmol, 1 eq). After stirring at 50°C for 16 hr, the reaction mixture was quenched by addition H2O (5 mL), and extracted with EtOAc (30 mL), washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by prep-HPLC (column: CD01 -Pheno menex Inna C18 150*25* 10um;mobile phase: [water(FA)-ACN];gradient:55%-85% B over 10 min) to give 2-[2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-l-phenyl-ethoxy]-6-hydroxy-benzaldehyde (1.4 mg, 3.2 pmol, 2.8% yield, 97.5% purity) as a yellow solid.!H NMR (400 MHz, CDC13) 5 = 11.94 (d, J= 10.4 Hz, 1H), 10.51 (d, J = 6.8 Hz, 1H), 7.59-7.50 (m, 2H), 7.49-7.39 (m, 4H), 7.19-7.14 (m, 1H), 7.13-7.06 (m, 1H), 6.98-6.89 (m, 1H), 6.62 (d, J= 8.4 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 6.37 (d, J= 8.0 Hz, 1H), 5.71 (d, J= 8.0 Hz, 1H), 4.96-4.77 (m, 1H), 4.66-4.38 (m, 2H), 4.28-4.06 (m, 2H), 2.68-2.48 (m, 2H), 1.18-1.05 (m, 3H). LCMS ESI calcd. Forformula C26H25NO5Na [M+Na]+454.1, found 454.0. HPLC 97.5% purity.

[0640] Step C: Preparation of 2-[( lR)-2-[3-(2-ethylphenoxy)azetidin- l-yl]-2-oxo-l -phenyl-ethoxy] -6-hydroxy- benzaldehyde(419) , 2-[(lS)-2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-l-phenyl-ethoxy]-6-hydroxy-benzaldehyde (420)

[0450] Compound 418 (140.0 mg, 298.1 pmol, 27.4% yield, 91.9% purity) was purified by prep-SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give 2-[(lR)-2-[3-(2-ethylphenoxy)azetidin-l-yl]-2-oxo-l-phenyl-ethoxy]-6-hydroxy -benzaldehyde

[0641] (419) (1.3 mg, 14.7 pmol, 9.0% yield, 81.3% purity) as a red oil.1H NMR (400 MHz, CDC13) 5 = 11.95 (s, 1H), 10.52 (d, J= 6.0 Hz, 1H), 7.57-7.49 (m, 2H), 7.48-7.38 (m, 4H), 7.19-7.07 (m, 2H), 6.98-6.88 (m, 1H), 6.67-6.58 (m, 1H), 6.47-6.34 (m, 2H), 5.72 (d, J= 8.4 Hz, 1H), 4.96-4.82 (m, 1H), 4.53-4.32 (m, 2H), 4.25-4.05 (m, 2H), 2.63- 2.49 (m, 2H), 1.19-1.04 (m, 3H). LCMS ESI calcd. Forformula C26H26NO5 [M+H]+432.5, found 432.1. HPLC 81.3% purity. And 2-[( 1 S)-2-[3 -(2-ethylphenoxy)azetidin- 1 -yl] -2-oxo- 1 -phenyl-ethoxy] -6-hydroxy -benzaldehyde

[0642] (420) (0.9 mg, 5.3 pmol, 3.3% yield, 89.4% purity) as a red oil.1H NMR (400 MHz, CDCI3) 5 = 11.95 (s, 1H), 10.52 (d, J= 6.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.48-7.38 (m, 4H), 7.17-7.14 (m, 1H), 7.13-7.08 (m, 1H), 6.96-6.90 (m, 1H), 6.65-6.58 (m, 1H), 6.46-6.35 (m, 2H), 5.72 (d, J= 8.4 Hz, 1H), 4.94-4.84 (m, 1H), 4.57-4.35 (m, 2H), 4.25-4.05 (m, 2H), 2.64-2.50 (m, 2H), 1.19-1.04 (m, 3H). LCMS ESI calcd. For formula CAHzeNOs [M+H]+432.2, found 432.0.HPLC 89.4% purity.

[0643] Example 403 - Synthesis of Compound 403

[0644] 403-11 403-12 403-13

[0645] Step A: Preparation of 22-(2-ethylphenoxy)acetyl chloride (403-2)

[0646]

[0451] To a solution of 403-1 (10 g, 55.5 mmol) in DCM (40 mL) and DMF (4 mL) was added SOCL (19.8 g, 166 mmol) at 0°C. After stirring at 25°C for 2 h, the reaction mixture was concentrated to give 2-(2- ethylphenoxy)acetyl chloride (403-2) (11 g, 55.3 mmol, 99.8% yield) as ayellow liquid. ' H NMR (400 MHz, CDCI3) 5 = 7.21-7.10 (m, 2H), 7.01-6.94 (m, 1H), 6.68 (d, J= 8.0 Hz, 1H), 4.96 (s, 2H), 2.67 (q, J= 7.6 Hz, 2H), 1.23-1.16 (m, 3H).

[0647] Step B: Preparation of ethyl 3-(2-ethylphenoxy)-l-[(4-methoxyphenyl)methyl]-4-oxo-azetidine-2-carboxylate (403-3)

[0648]

[0452] To a solution of 403-2 (18 g, 81.4 mmol) in DCM (100 mL) was added TEA (28.0 g, 277 mmol) and 2-(2- ethylphenoxy)acetyl chloride (11 g, 55.4 mmol) at 0°C. After stirring at 40°C for 16 h, the reaction mixture was poured into poured into Na2COs (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel (15-30% of EtOAc in PE) to give ethyl 3-(2-ethylphenoxy)-l-[(4- methoxyphenyl)methyl]-4-oxo-azetidine-2 -carboxylate (403-3) (5.88 g, 15.33 mmol, 27.7% yield) as a brown oil. ' H NMR (400 MHz, CDC13) 5 = 7.18 (d, J= 8.4 Hz, 2H), 7.15-7.11 (m, 2H), 7.10-7.06 (m, 1H), 6.98-6.93 (m, 1H), 6.88 (d, J= 8.8 Hz, 2H), 5.37 (d, J= 4.8 Hz, 1H), 4.88 (d, J= 14.4 Hz, 1H), 4.28 (d, J= 5.2 Hz, 1H), 4.21-4.11 (m, 3H), 3.81 (s, 3H), 2.59 (q, J= 7.6 Hz, 2H), 1.13 (q, J= 7.6 Hz, 6H).

[0649] Step C: Preparation of [3-(2-ethylphenoxy)-l-[(4-methoxyphenyl)methyl]azetidin-2-yl]methanol (403-4)

[0650]

[0453] To a solution of AICI3 (5.22 g, 39.1 mmol) in THF (50 mL) was added LAH (2.5 M, 15.65 mL) slowly and the mixture was stirred at 0°C for 1 h under N2. Then 403-3 (5 g, 13.0 mmol) in THF (20 mL) was added at 0°C under N2. After stirring at 20°C for 1 h, the reaction mixture was quenched by H2O (100 mL) at 0°C and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give [3-(2-ethylphenoxy)-l-[(4-methoxyphenyl)methyl]azetidin-2-yl]methanol (403-4) (2.4 g, 7.33 mmol, 56.2% yield) as yellow oil. ' H NMR (400 MHz, MeOD) 5 = 7.47-7.43 (m, 2H), 7.20-7.16 (m, 1H), 7.02 (d, J= 8.8 Hz, 2H), 6.97-6.91 (m, 2H), 6.63 (d, J= 8.0 Hz, 1H), 5.20-5.14 (m, 1H), 4.47-4.32 (m, 3H), 4.13-4.05 (m, 1H), 3.98-3.88 (m, 2H), 3.83-3.81 (m, 3H), 3.80-3.77 (m, 1H), 3.75-3.64 (m, 1H), 2.71-2.64 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0651] Step D: Preparation of [3-(2-ethylphenoxy)azetidin-2-yl]methanol (403-5)

[0652]

[0454] A solution of 403-4 (2.5 g, 7.64 mmol) in MeOH (37.5 mL) and HO Ac (12.5 mL) was stirred (70°C, granular catalyst 5% Pd / ALO;,. 2.0 Mpa H2) for 3 h. The fixed bed was washed by extra MeOH. The reaction mixture was concentrated and purified by flash chromatography on silica gel (20-80% of MeOH in DCM) to give [3 -(2- ethylphenoxy)azetidin-2-yl]methanol (403-5) (1.17 g, 3.73 mmol, 48.8% yield, 66% purity) as a brown oil. ' H NMR (400 MHz, MeOD) 5 = 7.22-7.14 (m, 2H), 6.98-6.92 (m, 1H), 6.67 (d, J= 8.4 Hz, 1H), 5.27-5.20 (m, 1H), 4.58-4.50 (m, 1H), 4.22-4.13 (m, 1H), 4.10-4.04 (m, 1H), 4.03-3.80 (m, 2H), 2.74-2.64 (m, 2H), 1.24-1.19 (m, 3H).

[0653] Step E: Preparation of tert-butyl 3-(2-ethylphenoxy)-2-(hydroxymethyl)azetidine-l-carboxylate (403-6)

[0654]

[0455] To a solution of 403-5 (1.27 g, 6.13 mmol) in MeOH (6 mL) was added TEA (1.24 g, 12.2 mmol) and tertbutoxycarbonyl tert-butyl carbonate (1.34 g, 6.13 mmol). After stirring at 25°C for 16 h, The reaction mixture was concentrated and purified by flash chromatography on silica gel (0-30% of EtOAc in PE) to give tert-butyl 3-(2- ethylphenoxy)-2-(hydroxymethyl)azetidine-l -carboxylate (403-6) (620 mg, 2.02 mmol, 32.9% yield) as a colorless oil. ' H NMR (400 MHz, CDCfi) 5 = 7.20-7.16 (m, 1H), 7.15-7.09 (m, 1H), 6.99-6.90 (m, 1H), 6.48 (d, J= 8.0 Hz, 1H), 5.06-4.95 (m, 1H), 4.76-4.60 (m, 1H), 4.35-4.26 (m, 1H), 4.22-4.11 (m, 1H), 4.06-3.98 (m, 1H), 3.96-3.90 (m, 1H), 2.63 (q, J= 7.6 Hz, 2H), 1.47 (s, 9H), 1.20 (t, J= 7.6 Hz, 3H).

[0655] Step F: Preparation of tert-butyl 3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine-l-carboxylate (403-7)

[0656]

[0456] To a solution of 403-6 (250 mg, 813 pmol) in THF (3 mL)was added NaH (65 mg, 1.63 mmol, 60% purity) and stirred at 0°C for 0.5 h. The mixture was added Mel (346 mg, 2.44 mmol) at 0°C and stirred at 20°C for 1 h to give a colorless solution. The reaction mixture was added NH4C1 (10 mL) slowly and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO i. filtered, concentrated and purified by flash chromatography on silica gel (0-15% of EtOAc in PE) to give tert-butyl 3-(2- ethylphenoxy)-2-(methoxymethyl)azetidine-l -carboxylate (403-7) (230 mg, 715 pmol, 87.9% yield) as a colorless oil. ' H NMR (400 MHz, CDCfi) 5 = 7.18-7.14 (m, 1H), 7.14-7.08 (m, 1H), 6.94-6.89 (m, 1H), 6.52 (d, J= 8.0 Hz, 1H), 5.02-4.93 (m, 1H), 4.66-4.57 (m, 1H), 4.28-4.19 (m, 1H), 4.00-3.92 (m, 1H), 3.90-3.82 (m, 1H), 3.79-3.70 (m, 1H), 3.33 (s, 3H), 2.68 (q, J= 7.6 Hz, 2H), 1.46 (s, 9H), 1.23 (t, J= 7.6 Hz, 3H).

[0657] Step G: Preparation of3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine (403-8)

[0658]

[0457] To a solution of 403-7 (50 mg, 155 pmol) in DCM (2 mL) was added TFA (307 mg, 2.69 mmol). After stirring at 25°C for 2 h, the reaction mixture was poured into toluene (2 mL) and concentrated to give 3-(2-ethylphenoxy)-2- (methoxymethyl)azetidine (403-8) (40 mg, 119 pmol, 76.7% yield, TFA) as ayellow oil. LCMS ESI calcd. For formula C13H20NO2 [M+H]+222.1, found 222.1

[0659] Step H: Preparation of2-[3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine-l-carbonyl]-6-hydroxy-benzaldehyde (403)

[0660]

[0458] To a solution of 2-formy 1-3 -hydroxy -benzoic acid (20 mg, 120 pmol) in DMF (1 mL) was added HATU (68 mg, 180 pmol), DIEA (155 mg, 1.20 mmol) and 403-8 (36 mg, 108 pmol, TFA). After stirring at 25°C for 2 h, the reaction mixture was poured into H2O (0.5 mL), concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water (FA)-ACN]; gradient: 55%-85% B over 9 min) to give 2-[3-(2- ethylphenoxy)-2-(methoxymethyl)azetidine-l-carbonyl]-6-hydroxy -benzaldehyde (403) (2.4 mg, 6.50 pmol, 5.4% yield) as a gray oil. ' H NMR (400 MHz, CDCL) 5 = 11.80 (d, J= 9.2 Hz, 1H), 10.33-10.06 (m, 1H), 7.54-7.48 (m, 1H), 7.18 (d, J= 7.6 Hz, 1H), 7.14-7.02 (m, 2H), 6.99-6.90 (m, 2H), 6.57-6.45 (m, 1H), 5.20-5.06 (m, 1H), 5.03- 4.64 (m, 1H), 4.58-4.13 (m, 2H), 4.10-3.82 (m, 1H), 3.54-3.39 (m, 2H), 3.27-3.02 (m, 2H), 2.73-2.60 (m, 2H), 1.27- 1.15 (m, 3H). LCMS ESI calcd. For formula C21H24NO5 [M+H]+370.2, found 370.0. HPLC 99.2% purity.

[0661] Step I: Preparation of tert-butyl (2R,3R)-3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine-l-carboxylate (403-9), tertbutyl (2S,3S)-3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine-l -carboxylate (403-10)

[0662]

[0459] Compound 403-7 was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CCL-EtOH (0.1%NH3H2O)]; B%: 15%%, isocratic elution mode) to give tert-butyl (2R,3R)-3-(2- ethylphenoxy)-2-(methoxymethyl)azetidine-l -carboxylate (403-9) (80 mg, 248 pmol, 44.4% yield). ' H NMR (400 MHz, CDCI3) 5 = 7.20-7.07 (m, 2H), 6.96-6.87 (m, 1H), 6.52 (d, J= 8.4 Hz, 1H), 5.20-4.93 (m, 1H), 4.68-4.56 (m, 1H), 4.30-4.20 (m, 1H), 4.00-3.90 (m, 1H), 3.89-3.82 (m, 1H), 3.80-3.71 (m, 1H), 3.34 (s, 3H), 2.68 (q, J= 7.6 Hz, 2H), 1.46 (s, 9H), 1.22 (t, J= 7.6 Hz, 3H). And tert-butyl (2S,3S)-3-(2-ethylphenoxy)-2-(methoxymethyl)azetidine-

[0663] 1 -carboxylate (403-10) (90 mg, 280 pmol, 50.0% yield) as yellow oil.1H NMR (400 MHz, CDCL) 5 = 7.18-7.08 (m, 2H), 6.96-6.87 (m, 1H), 6.52 (d, J= 8.0 Hz, 1H), 5.20-4.93 (m, 1H), 4.68-4.57 (m, 1H), 4.29-4.20 (m, 1H), 3.99- 3.92 (m, 1H), 3.89-3.83 (m, 1H), 3.80-3.72 (m, 1H), 3.34 (s, 3H), 2.68 (q, J= 7.2 Hz, 2H), 1.46 (s, 9H), 1.22 (t, J= 7.6 Hz, 3H).

[0664] Step J: Preparation of ethyl (2E)-2-[(4-methoxyphenyl)methylimino]acetate (403-13)

[0665]

[0460] To a solution of 403-11 (6 g, 43.7 mmol) in DCM (40 mL) was added 4AMS (15 g, 43.74 mmol) and 403-12 (10.7 g, 52.5 mmol). After stirring at 40°C for 2 h, the reaction mixture was concentrated to give ethyl (2E)-2-[(4- methoxyphenyl)methylimino]acetate (403-13) (9 g, 40.7 mmol, 93.0% yield) as brown oil. ' H NMR (400 MHz, CDCL) 5 = 7.22-7.15 (m, 2H), 6.90-6.80 (m, 2H), 4.80 (d, J= 0.8 Hz, 1H), 4.37-4.16 (m, 2H), 3.92-3.57 (m, 5H), 1.37-1.18 (m, 3H).

[0666]

[0461] The following further Examples 404, 405, and 401 were prepared analogously to Example 403, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC.

[0667] Example 402 - Synthesis of Compound 402

[0668] 402-1 402-2 402-3 402

[0669] Step A: Preparation of [(2S,3S)-3-(2-ethylphenoxy)-l-[(4-methoxyphenyl)methyl]azetidin-2-yl]methanol (402-2)

[0670]

[0462] The 402-1 was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, lOum); mobile phase: [CCL-EtOH (0.1%NH3H2O)]; B%:35%%, isocratic elution mode) to give [(2S,3S)-3-(2-ethylphenoxy)-l-[(4- methoxyphenyl)methyl]azetidin-2-yl]methanol 402-2 (180 mg, 549.76 pmol, 30.0% yield) as yellow oil. LCMS ESI calcd. For formula C20H26NO3 [M+H]+328.2, found 328.0.

[0671] Step B: Preparation of [(2S,3S)-3-(2-ethylphenoxy)azetidin-2-yl]methanol (402-3)

[0672]

[0463] To a solution of 402-2 (180 mg, 549.76 pmol) under flow chemistry (5% Pd / Al2O3, 100 V MeOH and 10 V HO Ac, 50°C, 1.5 MPa) to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water (FA)-ACN]; gradient: 14%-44% B over 9 min) to give [(2S,3S)-3-(2-ethylphenoxy)azetidin-2-yl]methanol (402-3) (25 mg, 120.6 pmol, 21.9% yield) as yellow oil. 'H NMR (400 MHz, MeOD) 5 = 8.47 (s, 1H), 7.09-7.24 (m, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.17-5.25 (m, 1H), 4.90-4.80 (m, 1H), 4.40-4.54 (m, 1H), 4.13-4.21 (m, 1H), 3.93-4.09 (m, 2H), 2.62-2.75 (m, 2H), 1.22 (t, J= 7.6 Hz, 3H).

[0673] Step C: Preparation of2-[ (2S,3S)-3-(2-ethylphenoxy)-2-(hydroxymethyl)azetidine-l-carbonyl]-6-hydroxy- benzaldehyde (402)

[0674]

[0464] To a solution of 2-formy 1-3 -hydroxy -benzoic acid (19 mg, 116 pmol) in Py (1 mL) was added 402-3 (20 mg, 96.5 pmol) and EDCI (37 mg, 193 pmol). After stirring at 20°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC(column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water(FA)-ACN]; gradient: 60%-90% B over 9 min) to give 2-[(2S,3S)-3-(2- ethylphenoxy)-2-(hydroxymethyl)azetidine-l-carbonyl]-6-hydroxy -benzaldehyde (402) (0.9 mg, 2.53 pmol, 2.6% yield) as yellow oil.1H NMR (400 MHz, CDC13) 5 =11.80 (s, 1H), 10.22 (s, 1H), 7.50-7.55 (m, 1H), 7.18-7.21 (m, 1H), 7.05-7.13 (m, 2H), 6.93-6.98 (m, 2H), 6.40-6.45 (m, 1H), 5.03-5.16 (m, 2H), 4.38-4.44 (m, 1H), 4.27-4.34 (m, 1H), 4.18-4.26 (m, 1H), 4.03-4.09 (m, 1H), 2.61-2.67 (m, 2H), 1.21 (t, J= 12 Hz, 3H). LCMS ESI calcd. For formula C20H22NO5 [M+H]+356.1, found 356.2. HPLC 91.1% purity.

[0675] Example 406 - Synthesis of Compound 406

[0676] 406-1 406-2 406

[0677] Step A: Preparation of2-(cyclopropylmethoxymethyl)-3-(2-ethylphenoxy)azetidine (406-2)

[0678]

[0465] To a solution of 406-1 (38 mg, 123 pmol) in THF (1 mL) was added NaH (9 mg, 247 pmol, 60% purity) and stirred at 0°C for 0.5 h. The mixture was added bromomethylcyclopropane (50 mg, 370 pmol) at 0°C and stirred at 20°C for 15.5 h to give a colorless solution. The reaction mixture was added H2O (10 mL) slowly and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO i. filtered, concentrated and purified by prep-TLC (Petroleum ether : Ethyl acetate = 0: 1) to give 2- (cyclopropylmethoxymethyl)-3-(2-ethylphenoxy)azetidine (406-2) (6 mg, 22.9 pmol, 18.6% yield) as a yellow oil. ' H NMR (400 MHz, CDC13) 5 = 7.18-7.08 (m, 2H), 6.94-6.87 (m, 1H), 6.54 (d, J= 8.0 Hz, 1H), 5.16-5.06 (m, 1H), 4.45-4.36 (m, 1H), 4.08-4.01 (m, 1H), 3.94-3.86 (m, 1H), 3.84-3.77 (m, 2H), 3.34-3.26 (m, 2H), 2.70-2.59 (m, 2H), 1.20 (t, J= 7.8 Hz, 3H), 1.09-0.97 (m, 1H), 0.56-0.46 (m, 2H), 0.23-0.12 (m, 2H).

[0679] Step B: Preparation of 2-[2-(cyclopropylmethoxymethyl)-3-(2-ethylphenoxy)azetidine-l-carbonyl]-6-hydroxy- benzaldehyde (406)

[0680]

[0466] To a solution of 406-2 (5 mg, 30 pmol) in DMF (0.5 mL) was added HATU (17 mg, 45 pmol), DIEA (19 mg, 150 pmol) and 2-(cyclopropylmethoxymethyl)-3-(2-ethylphenoxy)azetidine (4 mg, 18 pmol). After stirring at 25°C for 16 h, the reaction mixture was poured into H2O (0.5 mL), concentrated and purified by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 um; mobile phase: [water (FA)-ACN]; gradient: 60%-90% B over 9 min) to give 2-[2-(cyclopropylmethoxymethyl)-3-(2-ethylphenoxy)azetidine-l-carbonyl]-6-hydroxy -benzaldehyde (406) (0.5 mg, 1.22 pmol, 4.1% yield) as a colorless oil. ' H NMR (400 MHz, CDC13) 5 = 11.85-11.77 (m, 1H), 10.30- 10.12 (m, 1H), 7.54-7.48 (m, 1H), 7.17 (d, .7 = 7.2 Hz, 1H), 7.14-7.07 (m, 1H), 7.04 (d, J= 8.4 Hz, 1H), 7.01-6.91 (m, 2H), 6.59-6.47 (m, 1H), 5.19-5.06 (m, 1H), 5.05-4.69 (m, 1H), 4.59-4.26 (m, 1H), 4.25-4.19 (m, 1H), 4.13-3.87 (m, 1H), 3.57-3.37 (m, 1H), 3.34 (d, J= 6.8 Hz, 1H), 3.06-2.94 (m, 1H), 2.72-2.59 (m, 2H), 1...

Claims

1. CLAIMSWhat is claimed is:

1. A compound of Formula (I') :or a pharmaceutically acceptable salt thereof, wherein:R1is -OH, -ORla, or optionally substituted C2-3 alkynyl, wherein Rlais optionally substituted C1-3 alkyl;Y1is -C(=O)- or -OC(RY1)2C(=O)-; each instance of RY1is independently hydrogen, C1-6 alkyl, C1-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;R2a, R2b, and R2care each independently hydrogen, halogen, Ci.6alkyl, Ci.6haloalkyl, C2.6alkenyl, C2.6alkynyl, -(L’j-Cs-s carbocyclyl, -(L1)-(3-8 membered heterocyclyl), -(L’j-Ce-io aryl, -(L1)-(5- 10 membered heteroaryl), -(Uj-CN, -(L’j-OR0, -(L^-NCR1^, -(L’j-SR3, -(Uj-C^OjR0, -(Uj-C^OjOR0, -(L1)-C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)-S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L1is independently a bond, Ci-e alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2.e alkenylene, or C2.e alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; each instance of RAis independently C3-8 carbocyclylene, 3-8 membered heterocyclylene, Ce-io arylene, or 5-10 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted; each instance of L2is independently a bond, -C(=O)-, Ci.6alkylene, Ci.6haloalkylene, or CMO heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted, or an instance of L2is joined with an instance of R4to form a macrocycle, or an instance of L2is joined with an -N(RN)- or -C(RY2)2- instance of Y2to form a macrocycle; each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-11 membered heterocyclyl, Ce-io aryl, 5- 10 membered heteroaiyl, -OR0, -N(RN)2, -SRs, -C(=O)RC, -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2ORO, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1; each instance of RB1is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, -(L3)-C3- carbocyclyl, -(L3)-(3-10 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)-CN, -(L3)-OR°, -(L3)-N(RN)2, -(L3)-SRS, -(L3)-C(=O)RC, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, -(L3)-C(=O)N(RN)OR°, -(L3)-C(=O)N(RN)S(=O)2RC, -(L3)-S(=O)2RC, -(L3)-S(=O)2ORO, or -(L3)-S(=O)2N(RN)2, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L3is independently a bond or Ci-e alkylene, wherein the alkylene is optionally substituted; m is 0 or 1;n is 0 or 1; each instance of R3is independently halogen, Ci-e alkyl, Ci-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits;Y2is -O-, -N(RN)-, -S-, -C(=O)-, or -C(RY2)2-; each instance of RY2is independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two RY2attached to the same carbon atom are joined together to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of R4is independently halogen, Ci.6alkyl, Ci.6haloalkyl, C2.6alkenyl, C2.6alkynyl, -(L4)-C3-s carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-C6-IO aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-N3, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)R°, -(L4)-SRS, -(L4)-C(=O)R°, -(L4)-C(=O)OR°, -(L4)- C(=O)N(RN)2, -(L4)-S(=O)R°, -(L4)-S(=O)2RC, -(L4)-S(=O)2OR°, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L4is independently a bond, Ci-e alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2.e alkenylene, or C2.e alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; s is 0, 1, 2, 3, 4, or 5; each instance of R° is independently hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, Ci.6acyl, or an oxygen protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atoms are joined to form 3-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of Rsis independently hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a sulfur protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; and each instance of R° is independently Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

2. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:R1is -OH, -ORla, or optionally substituted C2-3 alkynyl, wherein Rlais optionally substituted C1-3 alkyl;Y1is -C(=O)- or -OC(RY1)2C(=O)-; each instance of RY1is independently hydrogen, C1-6 alkyl, C1-6 haloalky 1, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;R2a, R2b, and R2care each independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -(L’j-Cs-s carbocyclyl, -(L1)-(3-8 membered heterocyclyl), -(L’j-Ce-io aryl, -(L1)-(5- 10 membered heteroaryl), -(Uj-CN, -(L’j-OR0, -(L1)-N(RN)2, -(L’j-SR3, -(Uj-C^OjR0, -(L'j-C^OjOR0, -(L1)-C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)-S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L1is independently a bond, Ci-e alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; each instance of RAis independently C3-8 carbocyclylene, 3-8 membered heterocyclylene, C6-io arylene, or 5-10 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted; each instance of L2is independently a bond, -C(=O)-, Ci-e alkylene, C1-6 haloalkylene, or C1-6 heteroalkylene, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of RBis independently hydrogen, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5- 10 membered heteroaiyl, -OR0, -N(RN)2, -SRS, -C(=O)RC, -C(=O)OR°, -C(=O)N(RN)2, -S(=O)2RC, -S(=O)2OR°, or -S(=O)2N(RN)2, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of RB1; each instance of RB1is independently halogen, Ci-e alkyl, C1-6 haloalkyl, -(L3)-C3-s carbocyclyl, -(L3)-(3-8 membered heterocyclyl), -(L3)-Ce-io aryl, -(L3)-(5-10 membered heteroaryl), -(L3)-CN, -(L3)-OR°, -(L3)-N(RN)2, -(L3)-SRs, -(L3)-C(=O)R°, -(L3)-C(=O)OR°, -(L3)-C(=O)N(RN)2, -(L3)-S(=O)2RC, -(L3)-S(=O)2ORO, or -(L3)- S(=O)2N(RN)2, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L3is independently a bond or Ci.6alkylene, wherein the alkylene is optionally substituted; m is 0 or 1; n is 0 or 1; each instance of R3is independently halogen, Ci-e alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits;Y2is -O-, -N(RN)-, -S-, -C(=O)-, or -C(RY2)2-; each instance of RY2is independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two RY2attached to the same carbon atom are joined together to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted; each instance of R4is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -(L4)-C3-s carbocyclyl, -(L4)-(3-8 membered heterocyclyl), -(L4)-C6-IO aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-SRS, -(L4)-C(=O)RC, -(L4)-C(=O)OR°, -(L4)- C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, -(L4)-S(=O)2ORO, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C4-8 carbocyclyl, 4-8 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; each instance of L4is independently a bond, C1-6 alkylene, C1-6 haloalky lene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted; s is 0, 1, 2, 3, 4, or 5; each instance of R° is independently hydrogen, Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or an oxygen protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, Ci.6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atoms are joined to form 3-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of Rsis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, C1-6 acyl, or a sulfur protecting group, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; and each instance of Rcis independently Ci.6alkyl, Ci.6haloalkyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, or 5-10 membered heteroaryl, wherein the alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

3. The compound of claim 1 or 2, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-1):or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-2):or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 or 2, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1, 2, or 6, wherein the compound is of Formula (I-b- 1 ) :or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1, 2, or 6, wherein the compound is of Formula (I-b-2):or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or 2, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1, 2, or 9, wherein the compound is of Formula (I-c-1):or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1, 2, or 9, wherein the compound is of Formula (I-c-2) :or a pharmaceutically acceptable salt thereof.

12. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein R1is -OH, -OCH3, or -OCH.

13. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein R2a, R2b, and R2care each independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -(L’j-Ca- e carbocyclyl, -(L’XS- membered heterocyclyl), -(L1)-Ce aryl, -(L1)-(5-6 membered heteroaryl), -(L’j-CN, -(L1)- OR°, -(L1)-N(RN)2, -(L'j-SR3, -(L1)-C(=O)RC, -(L^-CC^OR0, -(L1)-C(=O)N(RN)2, -(L1)-S(=O)2RC, -(L1)- S(=O)2ORO, -(L1)-S(=O)2N(RN)2, or -RA-L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

14. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein R2a, R2b, and R2care each independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -(L’j-Cs- e carbocyclyl, -(L’XS-b membered heterocyclyl), -(L1)-Ce aryl, -(L1)-(5-6 membered heteroaryl), -(L1)-OR°, or -RA- L2-RB, or any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

15. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one of R2a, R2b, and R2cis hydrogen, -,any two of R2a, R2b, and R2cattached to adjacent carbon atoms are joined to form phenyl.

16. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one of R2a, R2b, and R2cis -RA-L2-RB.

17. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein R2a, R2b, and R2care each independently hydrogen or -RA-L2-RB.

18. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein R2cis -RA-L2-RB.

19. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one instance of RAis C5-8 carbocyclylene, 5-8 membered heterocyclylene, Ce arylene, or 5-6 membered heteroarylene, wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted.

20. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one instance of RAis optionally substituted cyclohexenylene or optionally substituted 1,2, 3, 6- tetrahydropy ridiny lene .

21. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at22. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein -RA-L2-RBis of formula:

23. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein the24. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3is C1-3 alkyl, C1-3 haloalky 1, C3-6 carbocyclyl, 3-6 membered heterocyclyl, Ce aryl, 5-6 membered heteroaryl, -CN, -OR0, -N(RN)2, or -SRs, or two R3attached to the same carbon atom are joined to form C3-6 carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, haloalky 1, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

25. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3is C1-3 alkyl, or two R3attached to the same carbon atom are joined to form C3-4 carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted.

26. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3is C1-3 alkyl substituted with 0 or 1 -OR0, or two R3attached to the same carbon atom are joined to form unsubstituted C3-4 carbocyclyl.

27. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein the28. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein the29. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein Y1is -C(=O)-.

30. The compound of any one of claims 1-28, or pharmaceutically acceptable salt thereof, wherein Y1is - OCH2C(=O)-.

31. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein Y2is -O-.

34. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein each instance of R4is independently halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -(L4)-C3-e carbocyclyl, -(L4)-(3-6 membered heterocyclyl), -(L4)-Ce aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-SRS, -(L4)-C(=O)RC, -(L4)-C(=O)OR°, -(L4)- C(=O)N(RN)2, -(L4)-S(=O)RC, -(L4)-S(=O)2RC, -(L4)-S(=O)2ORO, or -(L4)-S(=O)2N(RN)2, or any two instances of R4attached to adjacent carbon atoms are joined to form C5-6 carbocyclyl, 5-6 membered heterocyclyl, C6aryl, or 5-6 membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted.

35. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein each instance of R4is independently halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -(L4)-C3.6 carbocyclyl, -(L4)-(3-6 membered heterocyclyl), -(L4)-C6aryl, -(L4)-(5-10 membered heteroaryl), -(L4)-CN, -(L4)- NO2, -(L4)-OR°, -(L4)-N(RN)2, -(L4)-N(RN)C(=O)RC, -(L4)-C(=O)RC, -(L4)-C(=O)OR°, -(L4)-C(=O)N(RN)2, -(L4)- S(=O)RC, -(L4)-S(=O)2RC, or -(L4)-S(=O)2OR°, or any two instances of R4attached to adjacent carbon atoms are joined to form C5-6 carbocyclyl, 5-6 membered heterocyclyl, or Ce aryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

36. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein each instance of L4is independently a bond, C1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, or C2-4 alkynylene, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted.

37. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein each instance of R4is independently -F, -Cl, -I, -CN, -NO2, -S(=O)CH3, -S(=O)2CH3, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2OH, -CH2CN, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2N(CH3)2,, or any two instances of R4attached to adjacent carbon atoms are joined to form38. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein s is 0, 1, 2, or 3.

39. The compound of any one of the preceding claims, or pharmaceutically acceptable salt thereof, wherein the40. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:LAis absent or is optionally substituted C1-3 alkylene;RN2and RN3are each independently hydrogen, C1-6 alkyl, C1-6 haloalky 1, C3-8 carbocyclyl, or C1-6 acyl, or RN2and RN3are joined to form 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, acyl, or heterocyclyl is optionally substituted; each instance of Ry, R6, R7, R8a, and R8bis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-8 carbocyclyl, wherein the alkyl, haloalkyl, or carbocyclyl is optionally substituted;RN1is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or Ci-eacyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; or wherein RN1and R8aare joined together to form optionally substituted 5-6 membered heterocyclyl; each instance of R3, R5, and R9is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, -CN, -OR0, -N(RN)2, or -SRs, or any two instances of R3, R5, or R9attached to the same carbon atom are joined to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, or heterocyclyl is optionally substituted; each of R2a, R2b, R4a, and R10ais independently hydrogen, halogen, Ci.6alkyl, Ci.6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, C6-io aryl, or 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of R4band R10bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, C3-8 carbocyclyl, 3-8 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or Ci-eacyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted; each instance of R° is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, or two RNattached to the same nitrogen atom are joined to form 3-8 membered heterocyclyl, wherein the alkyl, haloalkyl, carbocyclyl, acyl, or heterocyclyl is optionally substituted; each instance of Rsis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, or C1-6 acyl, wherein the alkyl, haloalkyl, carbocyclyl, or acyl is optionally substituted; p is 0, 1, 2, 3, 4, or 5; each of w and q are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; and each of z and s is independently 0, 1, 2, 3, or 4.

41. The compound of claim 40, wherein the compound is of Formula (Il-a) :or a pharmaceutically acceptable salt thereof.

42. The compound of claim 40 or 41, wherein the compound is of Formula (II-a-i):or a pharmaceutically acceptable salt thereof.

43. The compound of any one of the preceding claims, wherein the compound is selected from those in Tables 1A-1C, and pharmaceutically acceptable salts thereof.

44. A compound selected from those in Table 2, and pharmaceutically acceptable salts thereof.

45. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. A method of treating a neonatal fragment crystallizable receptor (FcRn)-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

47. A method of treating an immunoglobulin G (IgG)-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

48. A method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

49. A method of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

50. A method of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

51. A compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in:(a) treating a FcRn-mediated disease in a subject;(b) treating an IgG-mediated disease in a subject;(c) treating an autoimmune disease in a subject;(d) covalently inhibiting an FcRn activity in vitro or in vivo', and / or(e) decreasing IgG levels in a subject.

52. Use of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament.

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