Peripheral blockers for central nervous system-selective drug activity

Abstract

Aspects of the disclosure related to peripheral blocker compounds for use in reducing peripheral side effects of anti-CNS disease drugs.

Description

[0001] PERIPHERAL BLOCKERS FOR CENTRAL NERVOUS SYSTEM-SELECTIVE DRUG ACTIVITY

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application U.S.S.N. 63 / 693,126, filed September 10, 2024, U.S. Provisional Patent Application U.S.S.N. 63 / 693,144, filed September 10, 2024, and U.S. Provisional Patent Application U.S.S.N. 63 / 807,236, filed May 16, 2025, the entire disclosure of each of which is incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] Therapeutics for many diseases associated with the central nervous system (CNS) must penetrate the blood-brain barrier and be active against a target at the disease site. However, many promising drug candidates fail to advance due to dose-limiting on-target off-tissue peripheral side effects or toxicities that compromise both safety and efficacy. These CNS diseases remain among the most significant unmet medical needs with many important targets still considered undruggable.

[0006] SUMMARY OF THE PRESENT DISCLOSURE

[0007] Aspects of the disclosure relate to novel peripheral blocker compounds for use in Brain- Only™ pharmacology technology. Compounds disclosed herein can be used to reduce peripheral side effects of anti -CNS disease drugs.

[0008] In one aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein the compound is of Formula I:

[0009] wherein:

[0010] LAis optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted C2-12 alkylene, or C2-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-6 alkyl);

[0011] RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5- membered heteroaryl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, - ORA1, -SCN, -SRA1, -SSRA1, -N3, -NO, -N(RA1)2, -NO2, -N=S(=O)(RA1)2, - N=S(=O)(RA1)ORA1, -N=S(=O)(RA1)SRA1, -N=S(=O)(RA1)N(RA1)2, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -C(=O)N(RA1)S(=O)RA1, -C(=O)N(RA1)S(=O)ORA1, - C(=O)N(RA1)-S(=O)SRA1, -C(=O)N(RA1)S(=O)N(RA1)2, -C(=O)N(RA1)S(=O)2RA1, - C(=O)N(RA1)S(=O)2ORA1, -C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, - C(=NRA1)RA1, -C(=NRA1)ORA1, -C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, - S(=O)ORA1, -S(=O)SRA1, -S(=O)N(RA1)2, -S(=O)(=NRA1)RA1, -S(=O)(=NRA1)ORA1, - S(=O)(=NRA1)SRA1, -S(=O)(=NRA1)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, - S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, - S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)SRA1, -OC(=O)N(RA1)2, - OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, -OC(=NRA1)N(RA1)2, -OS(=O)RA1, - OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, - SC(=NRA1)RA1, -SC(=NRA1)ORA1, -SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, - NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, - NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, -NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, - NRA1S(=O)ORA1, -NRA1S(=O)SRA1, -NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, - NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, -NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, - Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, -OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, - B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, -P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, - OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; each instance of RA1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided that -LA-RAis not any one of-(CH2)3-(unsubstituted pyridinyl), -(CH2)3- (unsubstituted pyridine- 1 -oxide), -CH2CH=CH-(unsubstituted pyridinyl), -CH2CH=CH- (unsubstituted pyridine- 1 -oxide), -(CH2)3-C(=O)NH-(unsubstituted pyridinyl), -(CH2)3- C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3-hydroxy-oxetan-3-yl), and -(CH2)3-S-( substituted Ci-3alkyl);

[0012] ™RBis =O or -ORB1;

[0013] RB1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0014] Rcis -ORC1or hydrogen;

[0015] RC1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0016] RDis -ORD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -NO2, -N=S(=O)(RD1)2, - N=S(=O)(RD1)ORD1, -N=S(=O)(RD1)SRD1, -N=S(=O)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=O)N(RD1)2, -S(=O)(=NRD1)RD1, -S(=O)(=NRD1)ORD1, -S(=O)(=NRD1)SRD1, - S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, - NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, -OP(=O)(ORD1)2, -CN, halogen, or optionally substituted heteroaryl; each instance of RD1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;

[0017] = REis =0 or -0RE1; and

[0018] RE1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

[0019] In another aspect, the present disclosure provides pharmaceutical compositions comprising: the compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.

[0020] In another aspect, the present disclosure provides kits comprising: the compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition provided herein; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

[0021] In another aspect, the present disclosure provides methods comprising administering to a subject the compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition provided herein.

[0022] In some embodiments, methods associated with the disclosure further comprise administering to the subject an anti-CNS disease drug. In some embodiments, the subject has, is suspected of having, or is at risk of having a disease of the central nervous system.

[0023] In another aspect, the present disclosure provides methods comprising contacting a cell, tissue, or biological sample with the compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition provided herein.

[0024] Other aspects of the disclosure relate to methods for central nervous system-selective activity of tacrolimus by administering tacrolimus with novel peripheral blocker compounds using Brain-Only™ pharmacology technology. Methods disclosed herein can be used to reduce peripheral side effects of tacrolimus.

[0025] In some aspects, the present disclosure provides methods comprising administering to a subject:

[0026] (a) tacrolimus; and

[0027] (b) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I: wherein:

[0028] LAis optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted C2-12 alkylene, or C2-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-6 alkyl);

[0029] RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5- membered heteroaryl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, - ORA1, -SCN, -SRA1, -SSRA1, -N3, -NO, -N(RA1)2, -NO2, -N=S(=O)(RA1)2, - N=S(=O)(RA1)ORA1, -N=S(=O)(RA1)SRA1, -N=S(=O)(RA1)N(RA1)2, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -C(=O)N(RA1)S(=O)RA1, -C(=O)N(RA1)S(=O)ORA1, - C(=O)N(RA1)-S(=O)SRA1, -C(=O)N(RA1)S(=O)N(RA1)2, -C(=O)N(RA1)S(=O)2RA1, - C(=O)N(RA1)S(=O)2ORA1, -C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, - C(=NRA1)RA1, -C(=NRA1)ORA1, -C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, - S(=O)ORA1, -S(=O)SRA1, -S(=O)N(RA1)2, -S(=O)(=NRA1)RA1, -S(=O)(=NRA1)ORA1, - S(=O)(=NRA1)SRA1, -S(=O)(=NRA1)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, - S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, - S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)SRA1, -OC(=O)N(RA1)2, - OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, -OC(=NRA1)N(RA1)2, -OS(=O)RA1, - OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, - SC(=NRA1)RA1, -SC(=NRA1)ORA1, -SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, - NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, - NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, -NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, - NRA1S(=O)ORA1, -NRA1S(=O)SRA1, -NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, - NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, -NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, - Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, -OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, - B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, -P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, - OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; each instance of RA1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided that -LA-RAis not any one of-(CH2)3-(unsubstituted pyridinyl), -(CH2)3- (unsubstituted pyridine- 1 -oxide), -CH2CH=CH-(unsubstituted pyridinyl), -CH2CH=CH- (unsubstituted pyridine- 1 -oxide), -(CH2)3-C(=O)NH-(unsubstituted pyridinyl), -(CH2)3- C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3-hydroxy-oxetan-3-yl), and -(CH2)3-S-( substituted C1-3 alkyl);

[0030] ™RBis =O or -ORB1;

[0031] RB1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0032] Rcis -ORC1or hydrogen;

[0033] RC1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0034] RDis -ORD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -NO2, -N=S(=O)(RD1)2, - N=S(=O)(RD1)ORD1, -N=S(=O)(RD1)SRD1, -N=S(=O)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=O)N(RD1)2, -S(=O)(=NRD1)RD1, -S(=O)(=NRD1)ORD1, -S(=O)(=NRD1)SRD1, - S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, - NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, -OP(=O)(ORD1)2, -CN, halogen, or optionally substituted heteroaryl; each instance of RD1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;

[0035] = REis =0 or -0RE1; and RE1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

[0036] The details of one or more embodiments of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the Detailed Description, Examples, Figure, and Claims.

[0037] DEFINITIONS

[0038] 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, 75thEd., 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, 7thEdition, 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.

[0039] 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, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are 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 are 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 disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0040] In a formula, the bond is a single bond, the dashed line - is a single bond or absent, and the bond = or is a single or double bond. In a formula, wedged bold ( ) and wedged hash bonds ( -11 1 1) are used to designate absolute configuration, while unwedged bold ( - ) and unwedged hash bonds ( ) are used to designate relative configuration. Alternatively, in the case of molecules with a single stereocenter, an unwedged bold ( - ) or unwedged hash bond ( ) is used to designate a single stereocenter of unknown configuration. For example, if only one type of unwedged bond (either - or > ) appears in compound provided in a scheme, it is used to indicate that the compound is a single enantiomer of unknown absolute configuration.

[0041] 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. 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.

[0042] 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.

[0043] 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, Ci- 2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0044] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0045] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci- 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). 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 (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., / / -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), / / -octyl (Cs), / / -dodecyl (C12), 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 Ci-12 alkyl (such as unsubstituted C1-6 alkyl, e.g, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl ( / -Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl (zz-Bu), unsubstituted tert-butyl (ter / -Bu or t- Bu), unsubstituted sec-butyl (.sec-Bu or s-Bu), unsubstituted isobutyl ( / -Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted C1-6 alkyl, e.g., - CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0046] 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 (“Ci-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“Ci-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 (“C1-8 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 (“C1-6 haloalkyl”). 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.

[0047] 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, or 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 (“heteroCi-20 alkyl”). 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 (“heteroCi-12 alkyl”). 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 (“heteroCi-n alkyl”). 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 (“heteroCi-10 alkyl”). 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 (“heteroCi-9 alkyl”). 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 (“heteroCi-s alkyl”). 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 (“heteroCi-7 alkyl”). 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 (“heteroCi-6 alkyl”). 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 (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). 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 (“heteroC2-6 alkyl”). 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. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl.

[0048] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 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 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Ci-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“Ci-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1-4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). In some embodiments, the one or more carbon-carbon double bonds is internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C1-4 alkenyl groups include methylidenyl (Ci), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1-6 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 certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In some embodiments, in an alkenyl group, a C=C double bond for which the configuration.

[0049] 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, or 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 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-n alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-6 alkenyl”). 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. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCi-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-20 alkenyl.

[0050] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci -20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“Ci-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds is internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 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. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0051] 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, or 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 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-8 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroCi-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroCi- 6 alkynyl”). 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. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroCi-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-20 alkynyl.

[0052] 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.

[0053] Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 177- indenyl (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 is saturated or contains 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 group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0054] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 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 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 (“C5-6 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. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0055] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either 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 is either saturated or contains one or more carbon-carbon 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 group is an unsubstituted 3- 14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. 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 1-4 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.

[0056] 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, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2- b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-lH-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, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0057] 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 % 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 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 (“Ci4 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. In certain embodiments, the aryl group is an unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is a substituted Ce-i4 aryl.

[0058] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0059] 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 % electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is 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. In some embodiments, in polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is 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.

[0060] 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. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0061] 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.

[0062] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0063] The term “unsaturated bond” refers to a double or triple bond.

[0064] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0065] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0066] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenyl ene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0067] 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 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 disclosure is not limited in any manner by the exemplary substituents described herein.

[0068] Exemplary carbon atom substituents include halogen, -CN, -NO2, “Ns, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X , -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -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, “P(RCC)2, -P(ORCC)2, -P(RCC)3+X , -P(ORCC)3+X , -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X , -0P(0RCC)2, “OP(ORCC)3+X , -OP(RCC)4, “OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci 20 alkyl, Ci -20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-2oalkenyl, heteroCi- 2oalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, CI20alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-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, 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, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X , -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -0C(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-io alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-ioalkyl, heteroCi- walkenyl, heteroCi-ioalkynyl, 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; each instance of Reeis, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, 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, Ci-io alkyl, Ci-io perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, 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, -OCi-6 alkyl, -ON(Ci6alkyl)2, -N(CI-6 alkyl)2, -N(CI-6 alkyl ) X , -NH(Ci6alkyl )2X , -NH2(CI_6alkyl) X , -NH3X , -N(OCI-6 alkyl)(Ci-6 alkyl), -N(OH)(CI-6 alkyl), -NH(OH), -SH, -SCi^ alkyl, -SS(Ci^ alkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(C1 6 alkyl), -OC(=O)(Ci6alkyl), -OCO2(Ci6alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(Ci6alkyl), -NHC(=O)( Ci-6alkyl), -N(CI-6 alkyl)C(=O)( Ci-6alkyl), -NHCO2(CI^ alkyl), -NHC(=O)N(Ci6alkyl)2, -NHC(=O)NH(C! 6 alkyl), -NHC(=O)NH2, -C(=NH)O(Ci6alkyl), -OC(=NH)(Ci6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(Ci^ alkyl), -C(=NH)NH2, -OC(=NH)N(C1 6 alkyl)2, -OC(NH)NH(Ci6alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI^ alkyl), -SO2N(CI 6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2C1 6 alkyl, -SO2OC16alkyl, -OSO2C1 6 alkyl, -SOC] 6 alkyl, -Si(Ci-6alkyl)3, -OSi(Ci6alkyl)3-C(=S)N(CI-6 alkyl)2, C(=S)NH(Ci6alkyl), C(=S)NH2, -C(=O)S(CI-6 alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OC1^ alkyl)2, -P(=O)(C1 6 alkyl)2, -OP(=O)(Ci6alkyl)2, -OP(=O)(OCi6alkyl)2, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents are joined to form =0 or =S; and each X is a counterion.

[0069] 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, -SCN, -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 Ci-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -N02, -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 Ci-10 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 Ci-10 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 C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 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 Ci-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0070] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0071] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X , -OP(ORCC)2, -OP(ORCC)3+X , -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X , Raa, Rbb, and Rccare as defined herein.

[0072] The term “thiol” or “thio” refers to the group -SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -SRaa, -S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, -SC(=O)SRaa, - SC(=O)ORaa, -SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0073] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a tri substituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0074] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0075] The term “di substituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0076] The term “tri substituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3 and -N(Rbh).3 X , wherein Rbband X are as defined herein.

[0077] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and - SO2ORaa, wherein Raaand Rbbare as defined herein.

[0078] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0079] 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, and -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. In some embodiments, 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, or -C(=O)N(Rbb)2.

[0080] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0081] The term “silyl” refers to the group -Si(Raa)s, wherein Raais as defined herein.

[0082] Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, CI 20 alkyl, Ci -20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, hetero Ci-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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 Raa, Rbb, Rccand Rddare as defined above.

[0083] 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 C1-10 alkyl, -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 Ci-10 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-10 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 C1-6 alkyl or a nitrogen protecting group.

[0084] 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-IO alkyl (e.g., aralkyl, heteroaralkyl), C 1-20 alkenyl, Ci-20 alkynyl, hetero Ci-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 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.

[0085] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include 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, phenyl acetamide, 3-phenylpropanamide, picolinamide, 3- pyridyl carb oxami de, A-benzoylphenylalanyl derivatives, benzamide, / ?-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (IP - dithiobenzyloxyacylamino)acetamide, 3-( / ?-hydroxyphenyl)propanamide, 3-( - nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, A-acetylmethionine derivatives, o-nitrobenzamide, and o- (b enzoy loxy m ethy l)b enzami de .

[0086] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include 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 -trimethyl silylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3,5-di- t-butylphenyl)-l -methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl 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), p- methoxybenzyl carbamate (Moz), / ?-nitrobenzyl carbamate, / ?-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfmylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-( / ?-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), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro- / ?-acyloxybenzyl carbamate, / ?- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (7>-nitrophenyl)m ethyl carbamate, / -amyl carbamate, 5-benzyl thiocarbamate, -cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1 -di methyl -3 -(N,N-di methyl carb oxami do)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- m ethylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-( / ?-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri- / -butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0087] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include 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 -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),

[0088] 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs),

[0089] 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.

[0090] 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, TV’-p-toluenesulfonylaminoacyl derivatives, TV ’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasuccinimide (Dts), A-2,3- diphenylmaleimide, A-2,5-dimethylpyrrole, A-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, N- allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3 -acetoxypropylamine, A-(l- isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzyl amine, N- di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenyl amine (PhF), A-2,7- dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), N-2 -picolylamino N’- oxide, A- 1,1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p- methoxybenzylideneamine, A-diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, 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-nitropyridinesulfenamide (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, A5-isopropylidenediamine.

[0091] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0092] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -COzRA, -C(=0)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, -C02Raa, -C(=0)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io 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-io 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-6 alkyl or an oxygen protecting group.

[0093] 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, -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)3+X , -P(ORCC)2, -P(ORCC)3+X , -P(=O)(Raa)2, -P(=O)(ORCC)2, and -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.

[0094] 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), / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), / -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- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl 5,5-dioxide, 1 -[(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, / -butyl, allyl, / ?-chlorophenyl, / ?-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), / ?-methoxybenzyl (PMB), 3,4- dimethoxybenzyl, o-nitrobenzyl, / ?-nitrobenzyl, / ?-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, / ?-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl 7V-oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, / ?- methoxyphenyldiphenylmethyl, di( / ?-methoxyphenyl)phenylmethyl, tri( / ?- 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 , 1 -bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl 5,5-dioxido, trimethyl silyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, Z-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- / ?-xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), / -butylmethoxyphenyl silyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenyl sulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), -nitrophenyl carbonate, benzyl carbonate, p- m ethoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, 5-benzyl 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,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2-methyl-2-butenoate, o-(methoxyacyl )benzoate, a-naphthoate, nitrate, alkyl N, N, N ’,7V’- tetramethylphosphorodiamidate, alkyl 7V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0095] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0096] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -C02Raa, -C(=0)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-io alkyl, -C(=O)Raa, -C02Raa, -C(=0)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io 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-io 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-6 alkyl or a sulfur protecting group.

[0097] 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)3+X , -P(ORCC)2, -P(ORCC)3+X , -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.

[0098] In certain embodiments, the molecular weight of a substituent is lower than 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. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0099] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. In some embodiments, an anionic counterion is 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"), NO3, CIO4 , OH", H2PO4, HCO3", HSO4 , sulfonate ions e.g., methansulfonate, trifluoromethanesulfonate, -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), BF4, PF4", PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4]", B(C6FS)4 , BPI14", A1(OC(CF3)3)4", and carborane anions (e.g., CB11H12" or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO32", HPO42, PO43. B4O72, SO42, S2O32, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, mal onate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. 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.

[0100] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0101] A five-digit compound number that is otherwise the same as a four-digit compound number except that the first digit of the five-digit compound number is zero refers to the same compound as does the four-digit compound number.

[0102] 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 this 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, dodecyl sulfate, 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, -toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI 4 alkyl)4 salts. 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.

[0103] 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 this 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, di gluconate, dodecyl sulfate, 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)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0104] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form, and are solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0105] The term “hydrate” refers to a compound, or a salt thereof, that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound, or a salt thereof, is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, in some embodiments, a hydrate of a compound, or a salt thereof, is represented, for example, by the general formula R x H2O, wherein R is the compound, or a salt thereof, and x is a number greater than 0. A given compound, or a salt thereof, may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0106] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (z.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations.

[0107] It is also to be understood that 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”.

[0108] 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. In some embodiments, an enantiomer is characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing 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 (z.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”.

[0109] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. In some embodiments, co-crystals are useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0110] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. In some embodiments, various polymorphs of a compound (or a salt, hydrate, or solvate thereof) are prepared by crystallization under different conditions.

[0111] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. In some embodiments, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein are preferred.

[0112] The terms “composition” and “formulation” are used interchangeably.

[0113] A “subject” to which administration is contemplated refers to a human (z.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. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0114] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0115] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels. In some embodiments, “tissue” is the object to which a compound, particle, and / or composition of the disclosure is delivered. In some embodiments, a tissue is an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.

[0116] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.

[0117] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0118] 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 is administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment is administered in the absence of signs or symptoms of the disease. For example, in some embodiments, treatment is 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.

[0119] 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.

[0120] 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, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0121] 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.

[0122] 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. An “immunophilin” refers to a cytosolic peptidyl-prolyl isomerase that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline. Immunophilins can be classified into two main families: “cyclosporin-binding cyclophilins” and “FK506-binding proteins.” Immunophilins act as receptors for immunosuppressive drugs, such as cyclosporin and tacrolimus (or FK506), which inhibit the prolyl isomerase activity of immunophilins.

[0123] A “cyclophilin” refers to a family of proteins that bind to cyclosporin, which is an immunosuppressant used to suppress rejection after internal organ transplants. Cyclophilins have peptidyl prolyl isomerase activity.

[0124] An “FK506-binding protein” or “FKBP” refers to a family of proteins that has peptidyl prolyl isomerase activity. Non-limiting examples of FKBPs are provided in Cell Mol Life Sci. 2013 Sep;70(18):3243-75. The FKBP FKBP12 in humans binds to tacrolimus (or FK506), which is an immunosuppressant used in treating subjects after organ transplant as well as subjects suffering from autoimmune disorders. Both the FKBP — FK506 complex and the cyclosporin — cyclophilin complex inhibit calcineurin, thus blocking signal transduction in the T-lymphocyte transduction pathway.

[0125] BRIEF DESCRIPTION OF THE DRAWINGS

[0126] FIG. 1 depicts a schematic showing a representative embodiment of the Brain-Only™ pharmacology technology.

[0127] FIGs. 2A and 2B depict graphs showing reduction of everolimus induced immunosuppression (FIG 2A) and reduction of everolimus induced hyperglycemia (FIG. 2B) using peripheral blocker compound 1-046.

[0128] FIGs. 3 A and 3B depict graphs showing reduction of everolimus induced immunosuppression (FIG 3 A) and reduction of everolimus induced hyperglycemia (FIG. 3B) using peripheral blocker compound 1-014.

[0129] FIG. 4 depicts a graph showing relative everolimus tissue concentrations following coadministration of everolimus and peripheral blocker compound 1-014.

[0130] FIG. 5 depicts a graph showing relative everolimus tissue concentrations following coadministration of everolimus and peripheral blocker compound 1-046.

[0131] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE PRESENT DISCLOSURE

[0132] The present disclosure provides novel peripheral blocker compounds for use in Brain- Only™ pharmacology technology. Compounds disclosed herein can be used to reduce peripheral side effects of anti-CNS disease drugs. This technology addresses a fundamental limitation of many current anti-CNS disease therapies — their peripheral toxicities — by leveraging a novel mechanism of action that ensures CNS-specific drug activity.

[0133] Brain-Only™ pharmacology

[0134] Brain-Only™ pharmacology is an innovative approach to developing brain-targeted therapies that mitigate peripheral toxicities and enhance CNS efficacy. Aspects of Brain-Only™ pharmacology are described in WO2020 / 163594, filed on February 6, 2020, entitled “Immunophilin Binding Agents and Uses Thereof;” US Patent Publication No. 2023 / 0063768, filed on July 29, 2021, entitled “Immunophilin Binding Agents and Uses Thereof;” US Patent Publication No. 2025 / 0108052, filed November 22, 2024, entitled “Immunophilin Binding Agents and Uses Thereof;” and Zhang et al. (2022) “Brain-restricted mTOR inhibition with binary pharmacology,” Nature, Sep;609(7928):822-828, each of which is incorporated by reference herein in its entirety. Brain-Only™ pharmacology involves two small-molecule components: a peripheral blocker and a brain-penetrant anti-CNS disease drug, which can, in some embodiments, be a chimera.

[0135] FIG. 1 depicts a schematic showing a representative embodiment of Brain-Only™ pharmacology. In this embodiment, in the periphery, a brain-impermeable peripheral blocker binds to and saturates FKBP12 in the periphery, while an anti-CNS disease drug (depicted in FIG. 1 as part of a chimera that has FKBP12-binding ability) exhibits substantially reduced binding to FKBP12 in the periphery due to competition and so is in an inactive / closed conformation, which leads to no target engagement or reduced target engagement in the periphery. The anti-CNS disease drug (e.g., depicted as a chimera in FIG. 1), but not the peripheral blocker, is capable of crossing the blood-brain barrier (BBB). In the brain, the anti- CNS disease drug (e.g., depicted as a chimera in FIG. 1) binds to FKBP12, resulting in a conformational switch that exposes the functional part (indicated by an arrow) of the chimera. The anti-CNS disease drug (e.g., depicted as a chimera in FIG. 1) is retained in the brain cells due to its FKBP12 binding (intracellular pooling). The FKBP12-chimera complex can engage with target protein in the brain. The anti-CNS disease drug (depicted as a chimera in FIG. 1) can be an inhibitor or an activator of a target in the CNS.

[0136] Aspects of the disclosure relate to novel peripheral blockers for use in Brain-Only™ pharmacology. The terms “peripheral blocker,” “peripheral blocker compound,” “blocker,” and “blocker compound” may be used interchangeably herein. In some embodiment, a peripheral blocker is capable of binding to one or more immunophilins and / or cyclophilins. In some embodiments, a peripheral blocker is capable of binding to one or more FK506-binding proteins. In some embodiments, a peripheral blocker is capable of binding to FKBP12 or variants thereof. In some embodiments, a peripheral blocker is capable of binding to one or more of the following proteins: FKBP12.6, FKBP13, FKBP25, FKBP52, FKBP51, FKBP36, FKBP23, FKBP38, FKBP60, FKBP65, FKBP19, FKBP22, FKBP133, FKBP16, and FKBP37. It should be understood that each of these protein names encompasses the human protein, and variants thereof, and also encompasses homologous proteins from other species, and variants thereof.

[0137] In some embodiments, a peripheral blocker exhibits one or more of the following characteristics: potent binding to FKBP12, minimal to no penetration of the blood-brain barrier, and oral bioavailability. In some embodiments, a peripheral blocker exhibits all of the following characteristics: potent binding to FKBP12, minimal to no penetration of the blood-brain barrier, and oral bioavailability.

[0138] Zhang et al. (2022) “Brain-restricted mTOR inhibition with binary pharmacology,” Nature, Sep;609(7928): 822-828, describes the development of a peripheral blocker capable of binding to FKBP12, referred to as “RapaBlock.” Surprisingly, as described in the Examples section herein, novel peripheral blockers were identified herein that demonstrate superior properties to RapaBlock (which is referred to herein as “C-001”). For example, many of the novel peripheral blockers identified herein demonstrated enhanced binding to recombinant FKBP12 protein and / or more potent engagement of FKBP12 in cells, relative to RapaBlock. In a cellular chimera displacement assay, many of the novel peripheral blockers identified herein showed improved chimera displacement and cellular rescue compared to RapaBlock. Importantly, many of the novel peripheral blockers identified herein showed dramatically improved peripheral blocking of everolimus activity in vivo when dosed orally to mice. RapaBlock shows very limited blocking activity when dosed orally in mice.

[0139] An “anti-CNS disease drug,” as used herein refers to a drug capable of inhibiting, reducing, or ameliorating at least one symptom of a CNS disease. As used herein, the term “anti- CNS disease drug” includes chimeric versions of an anti-CNS disease drug wherein the drug is linked to one or more additional components. In some embodiments, an anti-CNS drug is a component of a chimera. In other embodiments, anti-CNS drug is not a component of a chimera. Anti-CNS disease drugs compatible with aspects of the disclosure are able to cross the bloodbrain barrier. In some embodiments, an anti-CNS drug is capable of binding to one or more immunophilins and / or cyclophilins. In some embodiments, an anti-CNS drug is capable of binding to one or more FK506-binding proteins. In some embodiments, an anti-CNS drug is capable of binding to FKBP12 or variants thereof. In some embodiments, an anti-CNS drug is capable of binding to one or more of the following proteins: FKBP12.6, FKBP13, FKBP25, FKBP52, FKBP51, FKBP36, FKBP23, FKBP38, FKBP60, FKBP65, FKBP19, FKBP22, FKBP133, FKBP16, and FKBP37.

[0140] In some embodiments the anti-CNS disease drug itself binds to an FK506 binding protein, such as FKBP12. For example, the anti-CNS disease drug tacrolimus (also called “FK506”), and the anti-CNS disease drug everolimus, can each bind to FKBP12.

[0141] In some embodiments, the anti-CNS disease drug is tacrolimus. The present disclosure provides methods for CNS-selective activity of tacrolimus by administering tacrolimus with novel peripheral blocker compounds for use in Brain-Only™ pharmacology technology. Methods disclosed herein can be used to reduce peripheral side effects of tacrolimus. In some embodiments, a brain-impermeable peripheral blocker binds to and saturates FKBP12 in the periphery, while tacrolimus (which has FKBP12-binding ability) exhibits substantially reduced binding to FKBP12 in the periphery due to competition and so is in an inactive / closed conformation, which leads to no target engagement or reduced target engagement in the periphery. Tacrolimus, but not the peripheral blocker, is capable of crossing the blood-brain barrier (BBB). In the brain, tacrolimus binds to FKBP12, resulting in a conformational switch that exposes the functional part. Tacrolimus is retained in the brain cells due to its FKBP12 binding (intracellular pooling). Tacrolimus can engage with target protein in the brain.

[0142] In other embodiments, such as depicted in FIG. 1, the anti-CNS disease drug can be in a chimeric form where it is linked to an additional component that can bind to FKBP12. For example, Zhang et al. (2022) “Brain-restricted mTOR inhibition with binary pharmacology,” Nature, Sep;609(7928):822-828, describes the development of RapaLink-1, a brain permeable FKBP12-binding small molecule that can be used to generate chimeras with anti-CNS disease drugs. It should be appreciated that other FKBP12-binding small molecules with similar properties to RapaLink-1 could also be used to generate chimeras with anti-CNS disease drugs. As shown in FIG. 1, the brain-penetrant anti-CNS disease drug crosses the BBB and binds to both FKBP12 and a target protein within the CNS. The activity of the brain-penetrant anti-CNS disease drug is dependent on FKBP12 binding in the brain, causing localized intracellular accumulation and engagement with a target protein.

[0143] Peripheral blocker compounds

[0144] In one aspect, the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein the compounds are of Formula I:

[0145] wherein:

[0146] LAis optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted C2-12 alkylene, or C2-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-6 alkyl);

[0147] RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5- membered heteroaryl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, - ORA1, -SCN, -SRA1, -SSRA1, -N3, -NO, -N(RA1)2, -NO2, -N=S(=O)(RA1)2, - N=S(=O)(RA1)ORA1, -N=S(=O)(RA1)SRA1, -N=S(=O)(RA1)N(RA1)2, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -C(=O)N(RA1)S(=O)RA1, -C(=O)N(RA1)S(=O)ORA1, - C(=O)N(RA1)-S(=O)SRA1, -C(=O)N(RA1)S(=O)N(RA1)2, -C(=O)N(RA1)S(=O)2RA1, - C(=O)N(RA1)S(=O)2ORA1, -C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, - C(=NRA1)RA1, -C(=NRA1)ORA1, -C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, - S(=O)ORA1, -S(=O)SRA1, -S(=O)N(RA1)2, -S(=O)(=NRA1)RA1, -S(=O)(=NRA1)ORA1, - S(=O)(=NRA1)SRA1, -S(=O)(=NRA1)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, - S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, - S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)SRA1, -OC(=O)N(RA1)2, - OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, -OC(=NRA1)N(RA1)2, -OS(=O)RA1, - OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, - SC(=NRA1)RA1, -SC(=NRA1)ORA1, -SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, - NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, - NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, -NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, - NRA1S(=O)ORA1, -NRA1S(=O)SRA1, -NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, - NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, -NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, - Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, -OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, - B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, -P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, - OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; each instance of RA1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided that -LA-RAis not any one of-(CH2)3-(unsubstituted pyridinyl), -(CH2)3- (unsubstituted pyridine- 1 -oxide), -CH2CH=CH-(unsubstituted pyridinyl), -CH2CH=CH- (unsubstituted pyridine- 1 -oxide), -(CH2)3-C(=O)NH-(unsubstituted pyridinyl), -(CH2)3- C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3-hydroxy-oxetan-3-yl), and -(CH2)3-S-( substituted Ci-3alkyl);

[0148] ™RBis =O or -ORB1;

[0149] RB1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0150] Rcis -ORC1or hydrogen;

[0151] RC1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0152] RDis -ORD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -NO2, -N=S(=O)(RD1)2, - N=S(=O)(RD1)ORD1, -N=S(=O)(RD1)SRD1, -N=S(=O)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=O)N(RD1)2, -S(=O)(=NRD1)RD1, -S(=O)(=NRD1)ORD1, -S(=O)(=NRD1)SRD1, - S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, - NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, -OP(=O)(ORD1)2, -CN, halogen, or optionally substituted heteroaryl; each instance of RD1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;

[0153] = REis =0 or -0RE1; and

[0154] RE1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

[0155] When Formula I includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other. In certain embodiments, at least one instance is each instance.

[0156] In certain embodiments, RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5-membered heteroaryl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, -0RA1, -SCN, -SRA1, - SSRA1, -N3, -NO, -N(RA1)2, -N02, -N=S(=0)(RA1)2, -N=S(=0)(RA1)0RA1, - N=S(=O)(RA1)SRA1, -N=S(=0)(RA1)N(RA1)2, -C(=0)RA1, -C(=0)0RA1, -C(=O)SRA1, - C(=0)N(RA1)2, -C(=0)N(RA1)S(=0)RA1, -C(=0)N(RA1)S(=0)0RA1, -C(=0)N(RA1)- S(=O)SRA1, -C(=0)N(RA1)S(=0)N(RA1)2, -C(=0)N(RA1)S(=0)2RA1, - C(=0)N(RA1)S(=0)20RA1, -C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, - C(=NRA1)RA1, -C(=NRA1)0RA1, -C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, - S(=O)ORA1, -S(=O)SRA1, -S(=0)N(RA1)2, -S(=0)(=NRA1)RA1, -S(=0)(=NRA1)0RA1, - S(=O)(=NRA1)SRA1, -S(=0)(=NRA1)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, - S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, - S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)SRA1, -OC(=O)N(RA1)2, - OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, -OC(=NRA1)N(RA1)2, -OS(=O)RA1, - OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, - SC(=NRA1)RA1, -SC(=NRA1)ORA1, -SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, - NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, - NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, -NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, - NRA1S(=O)ORA1, -NRA1S(=O)SRA1, -NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, - NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, -NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, - Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, -OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, - B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, -P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, - OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; provided that -LA-RAis not any one of-(CH2)3-C(=O)NH-(unsubstituted pyridinyl), - (CH2)3-C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3 -hydroxy-ox etan- 3-yl), and -(CH2)3-S-( substituted Ci-3alkyl); and

[0157] RDis -ORD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -NO2, -N=S(=O)(RD1)2, - N=S(=O)(RD1)ORD1, -N=S(=O)(RD1)SRD1, -N=S(=O)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=O)N(RD1)2, -S(=O)(=NRD1)RD1, -S(=O)(=NRD1)ORD1, -S(=O)(=NRD1)SRD1, - S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, - NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, or -OP(=O)(ORD1)2.

[0158] In certain embodiments, LAis optionally substituted alkenylene. In certain embodiments, LAis optionally substituted C2-6 alkenylene. In certain embodiments, LAis unsubstituted C2-6 alkenylene. In certain embodiments, LAis optionally substituted C3-s alkenylene. In certain embodiments, LAis optionally substituted C7-9 alkenylene. In certain embodiments, LAis optionally substituted C10-12 alkenylene. In certain embodiments, the alkenylene described in this paragraph comprises only one CC double bond in the backbone. In certain embodiments, the alkenylene described in this paragraph comprises only two CC double bonds in the backbone. In certain embodiments, the alkenylene described in this paragraph comprises no CC triple bonds in the backbone. In certain embodiments, the alkenylene described in this paragraph is straight- chained. In certain embodiments, the alkenylene described in this paragraph is branched. In certain embodiments, the substituents on the alkenylene described in this paragraph are independently selected from the group consisting of halogen, -OH, and -©(optionally substituted C1-6 alkyl). In certain embodiments, the substituents on the alkenylene described in this paragraph are independently selected from the group consisting of -F, -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, — LAis — CH2CH=CH-, — CH2CH=CHCH2-, or — CH2CH=CH(CH2)2- In certain embodiments, LAis C2-6 alkenylene substituted with one or more -F. In certain embodiments, — LAis — CH2CH=CHCHF2-

[0159] In certain embodiments, LAis optionally substituted alkynylene. In certain embodiments, LAis optionally substituted C2-6 alkynylene. In certain embodiments, LAis unsubstituted C2-6 alkynylene. In certain embodiments, LAis optionally substituted C3-5 alkynylene. In certain embodiments, LAis optionally substituted C7-9 alkynylene. In certain embodiments, LAis optionally substituted C10-12 alkynylene. In certain embodiments, the alkynylene described in this paragraph comprises only one CC triple bond in the backbone. In certain embodiments, the alkynylene described in this paragraph comprises only two CC triple bonds in the backbone. In certain embodiments, the alkynylene described in this paragraph comprises no CC double bonds in the backbone. In certain embodiments, the alkynylene described in this paragraph is straight- chained. In certain embodiments, the alkynylene described in this paragraph is branched. In certain embodiments, the substituents on the alkynylene described in this paragraph are independently selected from the group consisting of halogen, -OH, and -©(optionally substituted C1-6 alkyl). In certain embodiments, the substituents on the alkynylene described in this paragraph are independently selected from the group consisting of -F, -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, — LAis — CH2C=C-, — CH2C=CCH2-, or — CH2C =C(CH2)2-. In certain embodiments, LAis C2-6 alkynylene substituted with one or more -F.

[0160] In certain embodiments, LAis unsubstituted C2-12 alkylene. In certain embodiments, LAis unsubstituted C2-6 alkylene. In certain embodiments, LAis unsubstituted C3-5 alkylene. In certain embodiments, LAis unsubstituted C7-9 alkylene. In certain embodiments, LAis unsubstituted C10- 12 alkylene. In certain embodiments, the alkylene described in this paragraph is straight-chained. In certain embodiments, the alkylene described in this paragraph is branched. In certain embodiments, LAis -(CH2)3- -(CH2)4- or -(CJb)?-.

[0161] In certain embodiments, LAis C2-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen (e.g., -F), -OH, and - O(unsubstituted C1-6 alkyl). In certain embodiments, LAis C2-6 alkylene substituted with one or more substituents independently selected from the group consisting of halogen (e.g., -F), -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, LAis C3-5 alkylene substituted with one or more substituents independently selected from the group consisting of halogen (e.g., -F), -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, LAis C7-9 alkylene substituted with one or more substituents independently selected from the group consisting of halogen (e.g., -F), -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, LAis C10-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen (e.g., -F), -OH, and -O(unsubstituted C1-6 alkyl). In certain embodiments, LAis C2-6 alkylene substituted with one or more -OH. In certain embodiments, LAis -CH2-CH(0H)- CH2-.

[0162] In certain embodiments, RAis -S(=O)2N(RA1)2. In certain embodiments, RAis - S(=O)2NH2, -S(=O)2NH(optionally substituted C1-6 alkyl), or -S(=O)2N(optionally substituted C1-6 alkyl)2. In certain embodiments, RAis -S(=0)2NHMe or -S(=O)2N(Me)2. In certain embodiments, RAis -S(=O)2NH-(CH2)i-3-P(=O)(optionally substituted C1-6 alkyl)2. In certain embodiments, RAis -S(=O)2NH-CH2-P(=O)(Me)2. In certain embodiments, RAis - S(=O)2NHC(=O)NH2, -S(=O)2NHC(=O)NH(optionally substituted C1-6 alkyl), - S(=O)2NHC(=O)N(optionally substituted C1-6 alkyl)2, -S(=O)2NH-(CH2)I-3-C(=O)OH, - S(=O)2NH-(CH2)i-3-C(=O)O(optionally substituted C1-6 alkyl), -S(=O)2NHC(=O)NH2, - S(=O)2NHC(=O)NH(optionally substituted C1-6 alkyl), or -S(=O)2NHC(=O)N(optionally substituted C1-6 alkyl)2. In certain embodiments, RAis -S(=O)2NHC(=O)N(Me)2, -S(=O)2NH- CH2-C(=0)0H, or -S(=O)2NHC(=O)N(Me)2. In certain embodiments, RAis - S(=0)2NHC(=0)NHMe. In certain embodiments, RAis -B(0RA1)2. In certain embodiments, RAis -B(0H)2. In certain embodiments, RAis -B(O(optionally substituted C1-6 alkyl))2. In certain embodiments, RAis -B(0RA1)2, wherein the two instances of RA1are joined together with the intervening atom to form an optionally substituted monocyclic heterocyclic ring. In certain embodiments, RAis -C(=0)N(RA1)2, -C(=O)ORA1, or -NRA1C(=0)N(RA1)2. In certain embodiments, RAis -C(=0)NH2. In certain embodiments, RAis -C(=O)NH(optionally substituted C1-6 alkyl) or -C(=O)N(optionally substituted C1-6 alkyl)2. In certain embodiments, RAis -C(=O)OH. In certain embodiments, RAis -C(=O)O(optionally substituted C1-6 alkyl). In certain embodiments, RAis -NHC(=0)N(RA1)2. In certain embodiments, RAis -NHC(=0)NH2. In certain embodiments, RAis -NHC(=O)NH(optionally substituted Ci-6 alkyl) or NHC(=O)N(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -NHC(=O)N(Me)- C(Me)2-C(=0)0H. In certain embodiments, RAis hydrogen. In certain embodiments, RAis optionally substituted monocyclic 5-membered heteroaryl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, or optionally substituted polycyclic heteroaryl. In certain embodiments, RAis optionally substituted pyridinyl. In certain embodiments, RAis optionally substituted, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl. In certain embodiments, RAis 3- hydroxy-pyridin-4-yl. In certain embodiments, RAis optionally substituted tetrazolyl. In certain embodiments, RAis optionally substituted 5-tetrazolyl. In certain embodiments, RAis optionally substituted isoxazolyl. In certain embodiments, RAis optionally substituted 5-isoxazolyl. In certain embodiments, RAis 3 -OH-5 -isoxazolyl. In certain embodiments, RAis optionally substituted pyrazolyl. In certain embodiments, RAis l-methyl-3-hydroxy-pyrazol-5-yl. In certain embodiments, RAis optionally substituted bicyclic 9- or 10-membered heteroaryl. In certain embodiments, the substituents on the heteroaryl described in this paragraph are independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, and - ©(optionally substituted Ci-6 alkyl). In certain embodiments, the substituents on the heteroaryl described in this paragraph are independently selected from the group consisting of-F, unsubstituted Ci-6 alkyl, -OH, and -O(unsubstituted Ci-6 alkyl).

[0163] In certain embodiments, RAis optionally substituted heterocyclyl. In certain embodiments, RAis optionally substituted monocyclic 4-membered heterocyclyl. In certain embodiments, RAis optionally substituted oxetanyl. In certain embodiments, RAis optionally substituted 3-oxetanyl. In certain embodiments, RAis 3 -Me-3 -oxetanyl or 3 -OH-3 -oxetanyl. In certain embodiments, RAis optionally substituted monocyclic 5-membered heterocyclyl. In certain embodiments, RAis monocyclic 5-membered heterocyclyl that comprises at least one nitrogen atom in the heterocyclic ring system and attached to LAand is substituted at least with O or optionally substituted Ci_6alkyl) oxo. In certain embodiments, RAis halogen or optionally substituted alkyl)0.4, optionally substituted C^g alkyl) O or optionally substituted C^g alkyl)

[0164] (halogen or optionally substituted alkyl)0-2O (halogen or optionally substituted Ci_6alkyl)0-2 (halogen or optionally substituted Ci_6alkyl)0-4 In certain embodiments, RAis

[0165] (halogen or optionally substituted Ci_6alkyl)0-4or

[0166] O

[0167] Q (halogen or optionally substituted Ci_6alkyl)0-2jn certain embodiments, RAis

[0168] (halogen or optionally substituted alkyl)0-6 or or optionally substituted Ci_6alkyl)

[0169] (halogen or optionally substituted C1.6 alkyl)o-4 incertain embodiments, RAis

[0170] O optionally substituted Ci.6alkyl) or optionally substituted Ci_6alkyl)

[0171] (halogen or optionally substituted alkyl)0-4(halogen or optionally substituted Ci.6alkyl)0-2

[0172] O or optionally substituted Ci_6alkyl)

[0173] O (halogen or optionally substituted alkyl)0-2 or(halngsn or optionally substituted Ci.6alkyl)0_4 . In certain embodiments, RAis

[0174] (halogen or optionally substituted Ci_6alkyl)o_4 oro o

[0175] O (halogen or optionally substituted Ci_6alkyl)0-2jn certain embodiments, RAis

[0176] (halogen or optionally substituted alkyl)0-6 or or optionally substituted Ci_6alkyl)

[0177] (halogen or optionally substituted alkyl)Q_4In certain embodiments, RAis

[0178] O. ,0 optionally substituted 0^6 alkyl)

[0179] O (halogen or optionally substituted C-|.6 alkyl)0-4 or optionally substituted Ci_6alkyl)

[0180] O (halogen or optionally substituted C-|.6 alkyl)0-2In certain embodiments, RAis embodiments, certain embodiments, . In certain

[0181] 0 ,0 £ X ■? N NH embodiments, RAis \ — ! In certain embodiments, RAis certain embodiments, RAis optionally substituted monocyclic 6-membered heterocyclyl. In certain embodiments, RAis optionally substituted bicyclic 7- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl described in this paragraph comprises no CC double bonds in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises only one CC double bond in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises no CC triple bonds in the backbone. In certain embodiments, the substituents on the heterocyclyl described in this paragraph are independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, -©(optionally substituted Ci-6 alkyl), and oxo. In certain embodiments, the substituents on the heterocyclyl described in this paragraph are independently selected from the group consisting of -F, unsubstituted Ci-6 alkyl, -OH, -O(unsubstituted Ci-6 alkyl), and oxo.

[0182] In certain embodiments, RAis -N=S(=O)(RA1)2. In certain embodiments, RAis - N=S(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -N=S(=0)(Me)2. In certain embodiments, RAis -ORA1. In certain embodiments, RAis -OH. In certain embodiments, RAis -©(optionally substituted Ci-6 alkyl). In certain embodiments, RAis -OMe. In certain embodiments, RAis -P(=O)(RA1)2 or -P(=O)(ORA1)2. In certain embodiments, RAis - P(=O)(optionally substituted Ci-6 alkyl)2 or -P(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, RAis -P(=0)(Me)2, -P(=O)(Et)2, -P(=O)(zz-Pr)2, -P(=O)(z-Pr)2, - P(=0)(0Me)2, -P(=O)(OEt)2, -P(=O)(O-w-Pr)2, or -P(=O)(O-z-Pr)2. In certain embodiments, RAis -C(=O)N(RA1)S(=O)2RA1, -NRA1S(=O)2RA1, -NRA1S(=O)2N(RA1)2, -S(=O)RA1, - S(=O)(=NRA1)RA1, -S(=O)2RA1, -S(=O)2N(RD1)2, or -S(=O)2N(RD1)C(=O)N(RD1)2. In certain embodiments, RAis -C(=O)NHS(=O)2RA1. In certain embodiments, RAis - C(=O)NHS(=O)2(optionally substituted Ci-6 alkyl). In certain embodiments, RAis - C(=0)NHS(=0)2Me. In certain embodiments, RAis -NRA1S(=O)2RA1. In certain embodiments, RAis -NHS(=0)2RA1. In certain embodiments, RAis -NHS(=O)2(optionally substituted Ci-6 alkyl). In certain embodiments, RAis -NHS(=0)2Me. In certain embodiments, RAis - NHS(=O)2-(CH2)I-3-C(=O)O(H or optionally substituted Ci-6 alkyl). In certain embodiments, RAis -NHS(=O)2-CH2-C(=O)OH. In certain embodiments, RAis -NHS(=O)2NH2, - NHS(=O)2NH(optionally substituted Ci-6 alkyl), or -NHS(=O)2N(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -NHS(=0)2NHMe or -NHS(=O)2N(Me)2. In certain embodiments, RAis -S(=O)RA1. In certain embodiments, RAis -S(=O)(optionally substituted Ci- 6 alkyl). In certain embodiments, RAis -S(=O)-(CH2)i-3-(optionally substituted heterocyclyl). In certain embodiments, RAis -S(=O)-(CH2)i-3-(optionally substituted 3- to 7-membered monocyclic heterocyclyl). In certain embodiments, RAis -S(=O)-(CH2)i-3-(optionally substituted oxetanyl). In certain embodiments, RAis -S(=O)-(CH2)i-3-(optionally substituted 3- oxetanyl). In certain embodiments, RAis -S(=O)(=NH)RA1. In certain embodiments, RAis - S(=O)(=NH)(optionally substituted Ci-6 alkyl). In certain embodiments, RAis - S(=O)(=NH)(Me), -S(=O)(=NH)(Et), -S(=O)(=NH)(zz-Pr), or -S(=O)(=NH)(z-Pr). In certain embodiments, RAis -S(=O)(=NH)(zz-Bu), -S(=O)(=NH)(z-Bu), -S(=O)(=NH)(.s-Bu), or - S(=O)(=NH)(t-Bu). In certain embodiments, RAis -S(=O)2RA1.

[0183] In certain embodiments, RAis -S(=O)2(optionally substituted Ci-6 alkyl) or - S(=O)2(optionally substituted heterocyclyl). In certain embodiments, RAis -S(=O)2Me. In certain embodiments, RAis -S(=O)2(optionally substituted 3- to 7-membered monocyclic heterocyclyl) or -S(=O)2(optionally substituted 7- to 12-membered bicyclic heterocyclyl). In certain embodiments, the heterocyclyl described in this paragraph comprises no CC double bonds in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises only one CC double bond in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises no CC triple bonds in the backbone. In certain embodiments, RAis - S(=O)2(optionally substituted imidazolidin-2-one). In certain embodiments, the substituents on the heterocyclyl described in this paragraph are independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, and -©(optionally substituted Ci-6 alkyl). In certain embodiments, the atom of the heterocyclyl described in this paragraph that is attached to the sulfur atom is a nitrogen atom. In certain embodiments, RAis

[0184] In certain embodiments, RAis -S(=O)2NH2, -S(=O)2NH(optionally substituted Ci-6 alkyl), or -S(=O)2N(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -

[0185] S(=O)2NH(Me) or -S(=O)2N(Me)2. In certain embodiments, RAis -S(=O)2NH-(CH2)I-3- C(=O)O(optionally substituted Ci-6 alkyl). In certain embodiments, RAis -S(=O)2NH-CH2- C(=O)OH. In certain embodiments, RAis -S(=O)2NH-(CH2)i-3-P(=O)(optionally substituted Ci- 6 alkyl)2. In certain embodiments, RAis -S(=O)2NH-CH2-P(=O)(Me)2. In certain embodiments, RAis -S(=O)2NHC(=O)N(RD1)2. In certain embodiments, RAis -S(=O)2NHC(=O)NH2, -

[0186] S(=O)2NHC(=O)NH(optionally substituted Ci-6 alkyl), or -S(=O)2NHC(=O)N(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -S(=O)2NHC(=O)N(Me)2.

[0187] In certain embodiments, at least one instance of RA1is hydrogen. In certain embodiments, each instance of RA1is hydrogen. In certain embodiments, at least one instance of RA1is not hydrogen. In certain embodiments, no instance of RA1is hydrogen. In certain embodiments, at least one instance of RA1is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, at least one instance of RA1is unsubstituted alkyl. In certain embodiments, at least one instance of RA1is unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of RA1is Me. In certain embodiments, at least one instance of RA1is Et, Pr, or Bu. In certain embodiments, at least one instance of RA1is substituted Ci-6 alkyl. In certain embodiments, at least one instance of RA1is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of RA1is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of RA1is optionally substituted alkenyl. In certain embodiments, at least one instance of RA1is optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, at least one instance of RA1is optionally substituted alkynyl. In certain embodiments, at least one instance of RA1is optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, at least one instance of RA1is optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of RA1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, at least one instance of RA1is saturated carbocyclyl. In certain embodiments, at least one instance of RA1is partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, at least one instance of RA1is optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of RA1is optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl. In certain embodiments, at least one instance of RA1is saturated heterocyclyl. In certain embodiments, at least one instance of RA1is partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, at least one instance of RA1is optionally substituted aryl. In certain embodiments, at least one instance of RA1is optionally substituted phenyl. In certain embodiments, at least one instance of RA1is unsubstituted phenyl. In certain embodiments, at least one instance of RA1is 2-mono-substituted phenyl. In certain embodiments, at least one instance of RA1is 3 -mono-substituted phenyl. In certain embodiments, at least one instance of RA1is 4-mono-substituted phenyl. In certain embodiments, RA1is di-substituted phenyl. In certain embodiments, at least one instance of RA1is optionally substituted naphthyl. In certain embodiments, at least one instance of RA1is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, at least one instance of RA1is optionally substituted heteroaryl. In certain embodiments, at least one instance of RA1is optionally substituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of RA1is optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, at least one instance of RA1is optionally substituted pyridinyl (e.g., 2-, 3-, or 4- pyridinyl). In certain embodiments, at least one instance of RA1is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, at least one instance of RA1is optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of RA1is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of RA1is 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. In certain embodiments, at least one instance of RA1is 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. In certain embodiments, two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form optionally substituted, monocyclic heterocyclyl (e.g., optionally substituted, 3- to 7- membered, monocyclic heterocyclyl). In certain embodiments, two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form optionally substituted, monocyclic heteroaryl (e.g., optionally substituted, 5- to 6-membered, monocyclic heteroaryl). In certain embodiments, at least one instance of RA1is hydrogen or optionally substituted Ci-6 alkyl. In certain embodiments, each instance of RA1is independently hydrogen or optionally substituted Ci-6 alkyl.

[0188] In certain embodiments, -LA-RAis not -(CH2)3-(optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not -(CH2)3-(unsubstituted 6- membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not -(CH2)3-(optionally substituted pyridinyl). In certain embodiments, -LA-RAis not -(CH2)3-(unsubstituted pyridinyl). In certain embodiments, -LA-RAis not -(CH2)3-(optionally substituted pyridine- 1 -oxide). In certain embodiments, -LA-RAis not -(CH2)3-(unsubstituted pyridine- 1 -oxide). In certain embodiments, -LA-RAis not -CH2CH=CH-(optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not -CH2CH=CH-(unsubstituted 6-membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not -CH2CH=CH-(optionally substituted pyridinyl). In certain embodiments, -LA-RAis not -CH2CH=CH-(unsubstituted pyridinyl). In certain embodiments, -LA-RAis not -CH2CH=CH-(optionally substituted pyridine- 1 -oxide). In certain embodiments, -LA-RAis not -CH2CH=CH-(unsubstituted pyridine- 1 -oxide). In certain embodiments, -LA-RAis not -(CH2)3-C(=O)NH-(unsubstituted 6-membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not -(CH2)3-C(=O)NH-(optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -LA-RAis not - (CH2)3-C(=O)NH-(optionally substituted monocyclic heteroaryl). In certain embodiments, -LA- RAis not -(CH2)2-4-C(=O)NH-(optionally substituted monocyclic heteroaryl). In certain embodiments, -LA-RAis not -(CH2)2-4-C(=O)OH. In certain embodiments, -LA-RAis not optionally substituted C2-4 alkenyl. In certain embodiments, -LA-RAis not -(unsubstituted C2-4 alkenylene)-C(=O)OH. In certain embodiments, -LA-RAis not -CH2CH=CH-(optionally substituted oxetanyl). In certain embodiments, -LA-RAis not -(unsubstituted C2-4 alkenylene)- (optionally substituted oxetanyl). In certain embodiments, -LA-RAis not -(unsubstituted C2-4 alkenylene)-(optionally substituted 4-membered monocyclic heterocyclyl). In certain embodiments, -LA-RAis not -(CH2)3-S-(optionally substituted C1-4 alkyl). In certain embodiments, -LA-RAis not -(CH2)2-4-S-(optionally substituted C1-4 alkyl).

[0189] In certain embodiments, -LA-RAis -(CH2)3-4-(optionally substituted oxetanyl), -(CH2)3- 4-(optionally substituted imidazolidin-2-one-l-yl), -(CH2)3-4-(optionally substituted imidazolidine-2, 4-di one-3 -yl), -(CH2)3-4-(optionally substituted oxazolidin-2-one-3-yl), -(CH2)3- 4-NHS(=O)2(optionally substituted C1-6 alkyl), -(CH2)3-4-S(=O)2NH2, -(CH2)3-4- S(=O)2NH(optionally substituted C1-6 alkyl), -(CH2)3-4-S(=O)2N(optionally substituted C1-6 alkyl)2, -CH2CH=CH(CH2)o-i-S(=0)2(optionally substituted C1-6 alkyl), -CH2CH=CH(CH2)O-I- S(=O)2NH(optionally substituted C1-6 alkyl), -CH2CH=CH(CH2)o-i-(optionally substituted limidazolidine-2, 4-di one-3 -yl), -CH2CH=CH(CH2)o-i-(optionally substituted oxazolidin-2-one- 3 -yl), -CH2CH=CH(CH2)o-i-(optionally substituted oxazolidine-2, 4-di one-3 -yl), - CH2CH=CH(CH2)o-i-(optionally substituted isothiazolidine-l,l-dioxide-2-yl), - CH2CH=CH(CH2)o-i-(optionally substituted oxetanyl), -CH2CH=CH(CH2)O-I-S(=0)-CH2- (optionally substituted oxetanyl), or -CH2CH=CH(CH2)o-i-S(=0)(optionally substituted C1-6 alkyl).

[0190] O

[0191] CH2CH=CH-(3 -OH-3 -oxetanyl), -CH2CH=CHCH2-(3 -OH-3 -oxetanyl), -CH2CH=CHCH2- S(=O)-CH2-(3-Me-3 -oxetanyl), or -CH2CH=CHCH2-S(=O)Me.

[0192] In certain embodiments, - RBis =0. In certain embodiments, - RBis -ORB1. In certain embodiments, =RBis -OH. In certain embodiments, =RBis -©(optionally substituted C1-6 alkyl). In certain embodiments, =RBis -OMe. In certain embodiments, the carbon atom to which RBis attached is of the S configuration. In certain embodiments, the carbon atom to which RBis attached is of the R configuration.

[0193] In certain embodiments, RB1is hydrogen. In certain embodiments, RB1is substituted alkyl

[0194] (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, RB1is unsubstituted alkyl. In certain embodiments, RB1is unsubstituted Ci-6 alkyl. In certain embodiments, RB1is Me. In certain embodiments, RB1is Et, Pr, or Bu. In certain embodiments, RB1is substituted Ci-6 alkyl. In certain embodiments, RB1is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, RB1is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, RB1is optionally substituted alkenyl. In certain embodiments, RB1is optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, RB1is optionally substituted alkynyl. In certain embodiments, RB1is optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, RB1is optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, RB1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, RB1is saturated carbocyclyl. In certain embodiments, RB1is partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, RB1is optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, RB1is optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl. In certain embodiments, RB1is saturated heterocyclyl. In certain embodiments, RB1is partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, RB1is optionally substituted aryl. In certain embodiments, RB1is optionally substituted phenyl. In certain embodiments, RB1is unsubstituted phenyl. In certain embodiments, RB1is 2-mono-substituted phenyl. In certain embodiments, RB1is 3 -mono-substituted phenyl. In certain embodiments, RB1is 4-mono-substituted phenyl. In certain embodiments, RB1is disubstituted phenyl. In certain embodiments, RB1is optionally substituted naphthyl. In certain embodiments, RB1is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, RB1is optionally substituted heteroaryl. In certain embodiments, RB1is optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, RB1is optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, RB1is optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, RB1is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, RB1is optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, RB1is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, RB1is hydrogen or optionally substituted Ci-6 alkyl.

[0195] In certain embodiments, Rcis -ORC1. In certain embodiments, Rcis -OH. In certain embodiments, Rcis -©(optionally substituted alkyl). In certain embodiments, Rcis - ©(optionally substituted Ci-6 alkyl). In certain embodiments, Rcis -OMe. In certain embodiments, Rcis hydrogen. In certain embodiments, the carbon atom to which Rcis attached is of the S configuration. In certain embodiments, the carbon atom to which Rcis attached is of the R configuration.

[0196] In certain embodiments, RC1is hydrogen. In certain embodiments, RC1is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (c.g, -F)). In certain embodiments, RC1is unsubstituted alkyl. In certain embodiments, RC1is unsubstituted Ci-6 alkyl. In certain embodiments, RC1is Me. In certain embodiments, RC1is Et, Pr, or Bu. In certain embodiments, RC1is substituted Ci-6 alkyl. In certain embodiments, RC1is substituted methyl (c.g, fluorinated methyl or Bn). In certain embodiments, RC1is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, RC1is optionally substituted alkenyl. In certain embodiments, RC1is optionally substituted, C2-6 alkenyl (c.g, optionally substituted vinyl or optionally substituted allyl). In certain embodiments, RC1is optionally substituted alkynyl. In certain embodiments, RC1is optionally substituted, C2-6 alkynyl (c.g, optionally substituted ethynyl). In certain embodiments, RC1is optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, RC1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, RC1is saturated carbocyclyl. In certain embodiments, RC1is partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, RC1is optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, RC1is optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl. In certain embodiments, RC1is saturated heterocyclyl. In certain embodiments, RC1is partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, RC1is optionally substituted aryl. In certain embodiments, RC1is optionally substituted phenyl. In certain embodiments, RC1is unsubstituted phenyl. In certain embodiments, RC1is 2-mono-substituted phenyl. In certain embodiments, RC1is 3 -mono-substituted phenyl. In certain embodiments, RC1is 4-mono-substituted phenyl. In certain embodiments, RC1is disubstituted phenyl. In certain embodiments, RC1is optionally substituted naphthyl. In certain embodiments, RC1is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, RC1is optionally substituted heteroaryl. In certain embodiments, RC1is optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, RC1is optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, RC1is optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, RC1is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, RC1is optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, RC1is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, RC1is hydrogen or optionally substituted Ci-6 alkyl.

[0197] In certain embodiments, RDis -ORD1. In certain embodiments, RDis -O(optionally substituted alkyl) or -O(optionally substituted alkenyl). In certain embodiments, RDis - □(optionally substituted Ci-6 alkyl) or -O(optionally substituted C2-6 alkenyl). In certain embodiments, RDis -O-(CH2)I-6-OH, -O-(CH2)I-6-C(=O)OH, -O-(CH2)I.6-S(=O)2NH2, -O- (CH2)i-6-S(=O)2NH(optionally substituted C1-6 alkyl), -O-(CH2)i-6-S(=O)2N(optionally substituted C1-6 alkyl)2, -O-CH2-CH=CH-CH2-S(=O)2NH2, -O-CH2-CH=CH-CH2- S(=O)2NH(optionally substituted C1-6 alkyl), or -O-CH2-CH=CH-CH2-S(=O)2N(optionally substituted C1-6 alkyl)2. In certain embodiments, RDis -O-(CH2)i-6-OH or -O-CH2-CH=CH- CH2-S(=O)2NH(optionally substituted C1-6 alkyl). In certain embodiments, RDis -O-(CH2)2- OH, -O-CH2-CH(OH)-CH2OH, -O-CH2-C(=O)OH, -O-(CH2)2-C(=O)OH, or -O-CH2- CH=CH-CH2-S(=O)2NHMe. In certain embodiments, RDis -O-(CH2)i-6-C(=O)NH-(optionally substituted heteroaryl). In certain embodiments, RDis -O-(CH2)i-6-C(=O)NH-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, RDis -O-(CH2)i- 6-C(=O)NH-(optionally substituted pyridinyl). In certain embodiments, RDis -O-(CH2)I-6- (optionally substituted heterocyclyl). In certain embodiments, RDis -O-(CH2)i-6-(optionally substituted 3- to 7-membered monocyclic heterocyclyl). In certain embodiments, RDis -O- (CH2)i-6-(optionally substituted morpholinyl). In certain embodiments, RDis -O-(CH2)I-6- (optionally substituted heteroaryl). In certain embodiments, RDis -O-(CH2)i-6-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, RDis -O-(CH2)I- 6-(optionally substituted pyridinyl). In certain embodiments, RDis -©-(optionally substituted heteroaryl). In certain embodiments, RDis -©-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, RDis -©-(optionally substituted pyridinyl). In certain embodiments, RDis -©-(optionally substituted 9- or 10-membered bicyclic heteroaryl). In certain embodiments, RDis -©-(optionally substituted indolyl). In certain embodiments, RDis -©-(optionally substituted indol-5-yl). In certain embodiments, RDis -O-(unsubstituted indol-5- yl) or -O-(l-methylindol-5-yl). In certain embodiments, RDis -O-(CH2)3-C(=O)NH-(2- pyridinyl), -O-(CH2)3-(4-morpholinyl), or -O-(CH2)3-(2-pyridinyl). In certain embodiments, RDis -O(unsubstituted Ci-6 alkyl). In certain embodiments, RDis -OMe, -OEt, -O(w-Pr), or - O(z'-Pr). In certain embodiments, RDis -OMe. In certain embodiments, RDis -OH. In certain embodiments, the heterocyclyl described in this paragraph comprises no CC double bonds in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises only one CC double bond in the backbone. In certain embodiments, the heterocyclyl described in this paragraph comprises no CC triple bonds in the backbone. In certain embodiments, the substituents on the heterocyclyl described in this paragraph are independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, -©(optionally substituted Ci- 6 alkyl), and oxo. In certain embodiments, the substituents on the heteroaryl described in this paragraph are independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, and -©(optionally substituted Ci-6 alkyl). In certain embodiments, RDis - P(=O)(ORD1)2. In certain embodiments, RDis -P(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, RDis -P(=O)(OMe)2. In certain embodiments, RDis -P(=O)(RD1)2. In certain embodiments, RDis -P(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, RDis -P(=O)Me2. In certain embodiments, RDis -OP(=O)(ORD1)2. In certain embodiments, RDis -OP(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, RDis - OP(=O)(OMe)2. In certain embodiments, RDis -OP(=O)(RD1)2. In certain embodiments, RDis - OP(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, RDis -OP(=O)Me2. In certain embodiments, RDis -OC(=O)RD1. In certain embodiments, RDis -OC(=O)(substituted or unsubstituted alkyl). In certain embodiments, RDis -OC(=O)RD1. In certain embodiments, RDis -OC(=O)(Ci-6 alkyl substituted with at least one instance of hydroxy). In certain embodiments, RDis -OC(=O)C(CH3)(CH2OH)2. In certain embodiments, RDis -CN. In certain embodiments, RDis halogen. In certain embodiments, RDis -Cl. In certain embodiments, RDis optionally substituted heteroaryl. In certain embodiments, RDis optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, RDis optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, RDis optionally substituted tetrazolyl. In certain embodiments, RDis optionally substituted tetrazol- 1-yl or optionally substituted tetrazol-2-yl. In certain embodiments, RDis optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, RDis optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, RDis optionally substituted, 9- to 10-membered, bicyclic heteroaryl.

[0198] In certain embodiments, at least one instance of RD1is hydrogen. In certain embodiments, each instance of RD1is hydrogen. In certain embodiments, at least one instance of RD1is not hydrogen. In certain embodiments, no instance of RD1is hydrogen. In certain embodiments, at least one instance of RD1is optionally substituted alkyl or optionally substituted alkenyl. In certain embodiments, at least one instance of RD1is alkyl or alkenyl, each of which is optionally substituted with one or more carbon atom substituents. In certain embodiments, at least one instance of RD1is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, at least one instance of RD1is unsubstituted alkyl. In certain embodiments, at least one instance of RD1is unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of RD1is unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of RD1is Me. In certain embodiments, at least one instance of RD1is Et, Pr, or Bu. In certain embodiments, at least one instance of RD1is substituted C1-6 alkyl. In certain embodiments, at least one instance of RD1is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of RD1is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of RD1is optionally substituted alkenyl. In certain embodiments, at least one instance of RD1is optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, at least one instance of RD1is optionally substituted alkynyl. In certain embodiments, at least one instance of RD1is optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, at least one instance of RD1is optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of RD1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, at least one instance of RD1is saturated carbocyclyl. In certain embodiments, at least one instance of RD1is partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, at least one instance of RD1is optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7- membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of RD1is optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl. In certain embodiments, at least one instance of RD1is saturated heterocyclyl. In certain embodiments, at least one instance of RD1is partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, at least one instance of RD1is optionally substituted aryl. In certain embodiments, at least one instance of RD1is optionally substituted phenyl. In certain embodiments, at least one instance of RD1is unsubstituted phenyl. In certain embodiments, at least one instance of RD1is 2-mono- substituted phenyl. In certain embodiments, at least one instance of RD1is 3-mono-substituted phenyl. In certain embodiments, at least one instance of RD1is 4-mono-substituted phenyl. In certain embodiments, RD1is di -substituted phenyl. In certain embodiments, at least one instance of RD1is optionally substituted naphthyl. In certain embodiments, at least one instance of RD1is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, at least one instance of RD1is optionally substituted heteroaryl. In certain embodiments, at least one instance of RD1is optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of RD1is optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, at least one instance of RD1is optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of RD1is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, at least one instance of RD1is optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of RD1is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of RD1is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, TUP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of RD1is 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. In certain embodiments, two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form optionally substituted, monocyclic heterocyclyl (e.g, optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form optionally substituted, monocyclic heteroaryl (e.g., optionally substituted, 5- to 6-membered, monocyclic heteroaryl). In certain embodiments, each instance of RD1is independently hydrogen or optionally substituted Ci-6 alkyl.

[0199] In certain embodiments, - REis =0. In certain embodiments, - REis -0RE1. In certain embodiments, =REis -OH. In certain embodiments, =REis -©(optionally substituted Ci-6 alkyl). In certain embodiments, =REis -OMe. In certain embodiments, the carbon atom to which REis attached is of the R configuration. In certain embodiments, the carbon atom to which REis attached is of the S configuration.

[0200] In certain embodiments, RE1is hydrogen. In certain embodiments, RE1is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., - F)). In certain embodiments, RE1is unsubstituted alkyl. In certain embodiments, RE1is unsubstituted Ci-6 alkyl. In certain embodiments, RE1is Me. In certain embodiments, RE1is Et, Pr, or Bu. In certain embodiments, RE1is substituted Ci-6 alkyl. In certain embodiments, RE1is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, RE1is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, RE1is optionally substituted alkenyl. In certain embodiments, RE1is optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, RE1is optionally substituted alkynyl. In certain embodiments, RE1is optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, RE1is optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, RE1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, RE1is saturated carbocyclyl. In certain embodiments, RE1is partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, RE1is optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, RE1is optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl. In certain embodiments, RE1is saturated heterocyclyl. In certain embodiments, RE1is partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, RE1is optionally substituted aryl. In certain embodiments, RE1is optionally substituted phenyl. In certain embodiments, RE1is unsubstituted phenyl. In certain embodiments, RE1is 2-mono-substituted phenyl. In certain embodiments, RE1is 3-mono-substituted phenyl. In certain embodiments, RE1is 4-mono-substituted phenyl. In certain embodiments, RE1is disubstituted phenyl. In certain embodiments, RE1is optionally substituted naphthyl. In certain embodiments, RE1is optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, RE1is optionally substituted heteroaryl. In certain embodiments, RE1is optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, RE1is optionally substituted furanyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In certain embodiments, RE1is optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, RE1is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, RE1is optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, RE1is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, RE1is hydrogen or optionally substituted Ci-6 alkyl.

[0201] In certain embodiments, the compound is of a formula shown in Table 1 :

[0202] Table 1: Compounds associated with the disclosure

[0203]

[0204]

[0205]

[0206] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0207] In certain embodiments, the compound is of a formula shown in Table 1 A: Table 1A: Additional compounds associated with the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0208] In certain embodiments, the compound is of a formula shown in Table IB: Table IB: Additional compounds associated with the disclosure

[0209] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0210] In certain embodiments, the compound is of Formula 1-014, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is of Formula I- 045, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is of Formula 1-046, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is of Formula 1-056, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is of Formula I- 017, 1-025, 1-028, 1-029, 1-034, 1-036, 1-038, 1-042, 1-045, 1-046, 1-048, 1-049, 1-050, 1-052, 1-053, 1-054, 1-055, 1-056, 1-057, 1-061, 1-062, 1-063, 1-064, or 1-065, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0211] In certain embodiments, a provided compound (a compound provided herein, a compound described herein, or a compound of the present disclosure) is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0212] In certain embodiments, the molecular weight of a compound of Formula I is lower than 800, between 800 and 900, between 900 and 1000, between 1000 and 1100, between 1100 and 1200, between 1200 and 1300, between 1300 and 1400, or between 1400 and 1500, inclusive, g / mol.

[0213] In certain embodiments, the compounds provided herein are useful for being administered to a subject. In certain embodiments, the compounds provided herein are useful for being contacted with a cell, biological sample, or tissue. In certain embodiments, the compounds provided herein are useful for treating a disease in a subject in need thereof. In certain embodiments, the compounds provided herein are useful for preventing a disease in a subject in need thereof.

[0214] The compounds provided herein may be advantageous over known compounds (e.g., RapaBlock) at least in part because the compounds provided herein may be more potent, be more efficacious, have a better absorption profile (e.g., higher solubility, higher permeability, and / or less efflux), have a better distribution profile, have a better metabolism profile, have a better excretion profile, have higher bioavailability, be less toxic, have wider therapeutic window, be less resistance-prone, be easier administered, and / or show higher subject compliance.

[0215] Pharmaceutical Compositions, Kits, and Administration

[0216] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents.

[0217] 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 (z.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. In some embodiments, pharmaceutical compositions are 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.

[0218] Relative amounts of the active ingredient, the pharmaceutically acceptable 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 pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0219] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition.

[0220] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0221] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0222] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myij® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0223] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0224] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0225] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0226] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0227] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0228] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0229] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0230] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BEIT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0231] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0232] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0233] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0234] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0235] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, in some embodiments, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0236] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0237] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or di calcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0238] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0239] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0240] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0241] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0242] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0243] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0244] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0245] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0246] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0247] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0248] 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 pharmaceutical 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. 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 pharmaceutical 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.

[0249] In some embodiments, the compounds and compositions provided herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, 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). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0250] 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. In some embodiments, an effective amount is 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. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0251] In certain embodiments, an effective amount is an amount that is effective in binding FK506-binding protein 12 (FKBP12) or variants thereof. In certain embodiments, an effective amount is an amount that is effective in binding FKBP12. In certain embodiments, an effective amount is an amount that is effective in binding FK506-binding protein (FKBP) 12.6, FKBP13, FKBP25, FKBP52, FKBP51, FKBP36, FKBP23, FKBP38, FKBP60, FKBP65, FKBP19, FKBP22, FKBP133, FKBP16, and / or FKBP37.

[0252] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art. In some embodiments, the amount to be administered to, for example, a child or an adolescent is lower or the same as that administered to an adult.

[0253] In certain embodiments, the pharmaceutical compositions are useful for being administered to a subject. In certain embodiments, the pharmaceutical compositions are useful for being contacted with a cell, biological sample, or tissue. In certain embodiments, the pharmaceutical compositions are useful for treating a disease in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for preventing a disease in a subject in need thereof.

[0254] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs) comprising a compound or pharmaceutical composition provided herein; and instructions for using the compound or pharmaceutical composition provided herein. In some embodiments, the kit comprises 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 one unit dosage form. In certain embodiments, the kit includes a first container comprising a compound or pharmaceutical composition described herein.

[0255] In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof.

[0256] 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 and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing 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.

[0257] Methods of Use and Uses

[0258] Aspects of the disclosure relate to use of peripheral blocker compounds described herein in Brain-Only™ pharmacology for treatment of a disease or disorder of the CNS. In some embodiments, compounds disclosed herein are administered to a subject to treat, prevent, or slow the progression of one or more diseases or disorders of the CNS (e.g., a disease or disorder of the brain or spinal cord). In some embodiments, compounds disclosed herein are administered to a subject to treat, prevent, or slow the progression of one or more symptoms of a disease or disorder of the CNS.

[0259] Neurodegenerative Diseases

[0260] In some embodiments, the disease or disorder of the CNS is a neurodegenerative disease. As used herein, the term “neurodegenerative disease” refers to any disease or disorder characterized by progressive loss of neuronal cells, reduction in neuronal function and structure, and / or neuronal death in the CNS. In some embodiments, a subject has or is suspected of having a neurodegenerative disease. In some embodiments, a subject exhibits one or more symptoms associated with a neurodegenerative disease. In some embodiments, the one or more symptoms associated with neurodegenerative disease is selected from cognitive impairment (e.g., including mild cognitive impairment, severe cognitive impairment, memory loss, and / or short-term memory loss), ataxia, dementia, disinhibition, hypokinesia, hyperkinesia, or a combination thereof. In some embodiments, the neurodegenerative disease is associated with or believed to be caused, at least in part, by pathological aging. In some embodiments, the neurodegenerative disorder is associated with or believed to be caused, at least in part, by a brain injury, for example, as the result of a cerebrovascular accident (e.g., ischemic stroke or hemorrhagic stroke), brain tumor, or traumatic brain injury. In some embodiments, the neurodegenerative disorder is associated with or believed to be caused, at least in part, by reduced blood flow to the brain (e.g., myocardial ischemia). In some embodiments, the neurodegenerative disease is a disease selected from Alzheimer's disease (AD), preclinical Alzheimer's disease (PCAD), Parkinson's disease (PD), Huntington's disease (HD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS, e.g., familial ALS and sporadic ALS), multiple sclerosis (MS), vascular dementia (cerebral amyloid angiopathy and stroke), dementia with Lewy bodies, HIV dementia, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), Batten disease, Creutzfeldt- Jakob disease, and cognitive impairment no dementia (CIND).

[0261] Neuropsychiatric Disorders

[0262] In some embodiments, the disease or disorder of the CNS is a neuropsychiatric disorder. As used herein, the term “neuropsychiatric disorder” refers to disorders in which one or more of cognitive, affective, behavioral, or learning and / or memory functions are dysfunctional. In some embodiments, a subject has or is suspected of having a neuropsychiatric disorder. In some embodiments, a subject exhibits one or more symptoms of a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a disorder recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (e.g., DSM-IV, DSM-5). In some embodiments, the neuropsychiatric disorder is a disorder selected from anxiety disorder, attention deficit disorder, bipolar disorder, cognitive disorder, delirium, dementia, depression, dissociative disorders, eating disorders (e.g., anorexia nervosa), impulse-control disorders, mood disorders, mania, obsessive-compulsive disorders, personality disorders (e.g., borderline personality disorder), psychosis, psychotic disorders (e.g., schizophrenic disorders), post-traumatic stress disorders, sexual disorders, sleep disorders, somatoform disorders, and substance abuse disorders (e.g., alcoholism or drug addiction), or any combination thereof.

[0263] Neurodevelopmental Disorders

[0264] In some embodiments, the disease or disorder of the CNS is a neurodevelopmental disorder. As used herein, the term “neurodevelopmental disorder” refers to disorders in which the normal development of the nervous system is impaired. In some embodiments, a subject has or is suspected of having a neurodevelopmental disorder. In some embodiments, a subject exhibits one or more symptoms of a neurodevelopmental disorder. In some embodiments, the subject exhibits one or more of abnormalities in affect, learning ability, self-control, memory, attention, speech, behavior, epilepsy, or a combination thereof. In some embodiments, the neurodevelopmental disorder is a disorder selected from autism spectrum disorder (e.g., classic autism or Asperger syndrome), attention deficit disorder, Fragile X syndrome, Rett syndrome, pervasive developmental disorder not otherwise specified (PDD-N08), childhood disintegrative disorder (CDD), tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, and Smith-Lemli-Opitz syndrome, or any combination thereof.

[0265] Neuro-oncology

[0266] In some embodiments, the disease or disorder of the CNS is a disease associated with neuro-oncology. As used herein, “a disease associated with neuro-oncology” refers to a brain or spinal cord neoplasm. In some embodiments, a subject has or is suspected of having a disease associated with neuro-oncology. In some embodiments, a subject exhibits one or more symptoms of a disease associated with neuro-oncology. In some embodiments, the disease associated with neuro-oncology is selected from anaplastic astrocytoma, anaplastic mixed glioma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, astrocytic cancer, astrocytoma, brain metastases, brain stem glioma, central nervous system (CNS) tumors, colloid cyst, craniopharyngioma, ependymoma, ganglioglioma, ganglioglioneurocytoma, germ cell tumor, germinoma, glioblastoma multiforme (GBM), glioblastoma, glioma, mixed gliomas, hemangioblastoma, leptomeningeal disease (carcinomatous meningitis), low-grade glioma, lymphoma, medulloblastoma, meningioma, neurofibromatosis, neuromas, oligodendroglioma, pilocytic astrocytoma, pineal gland parenchymal tumor, pineal tumor, pineoblastoma, pituitary adenoma, primary brain tumor, chordoma, spinal cord tumors, vascular brain tumors, vestibular schwannomas, skull base tumors, and vestibular schwannomas, or any combination thereof.

[0267] Aspects of the disclosure relate to administering to a subject outside the CNS of the subject a peripheral blocker compound and an anti -CNS disease drug. In some embodiments, the peripheral blocker is administered concurrently with, prior to, or subsequent to the anti-CNS disease drug. In some embodiments, each of the peripheral blocker and anti-CNS disease drug is administered at a dose and / or on a time schedule determined for that pharmaceutical agent.

[0268] The peripheral blocker compound may be any peripheral blocker compound described herein. For example, the peripheral blocker compound may be a compound selected from the compounds provided in Table 1, Table 1A, or Table IB. In certain embodiments, the peripheral blocker compound is of Formula 1-014, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-045, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-046, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-056, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-017, 1-025, 1-028, 1-029, 1-034, 1-036, 1-038, 1-042, 1-045, 1- 046, 1-048, 1-049, 1-050, 1-052, 1-053, 1-054, 1-055, 1-056, 1-057, 1-061, 1-062, 1-063, 1-064, or I- 065, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0269] In some embodiments, the peripheral blocker compound (e.g., as described herein) is coadministered simultaneously with the anti-CNS disease drug. In some embodiments, the peripheral blocker compound (e.g., as described herein) and the anti-CNS disease drug are coadministered sequentially. In some embodiments, the peripheral blocker compound is co-administered after (e.g., after about 1, 5, 10, 15, 20, or about 30 minutes or after about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or about 24 hours, or more than 24 hours) the anti-CNS disease drug. In some embodiments, the anti-CNS drug is co-administered after (e.g., after about 1, 5, 10, 15, 20, or 30 minutes or after about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or about 24 hours, or more than 24 hours) the peripheral blocker compound. In some embodiments, subsequent to administration (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, or more than 24 hours following administration), the concentration of the peripheral blocker compound in circulating blood of the subject is greater than the concentration of the compound in the CNS of the subject. In some embodiments, subsequent to administration (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, or more than 24 hours following administration), the concentration of the compound in circulating blood of the subject is greater than the concentration of the compound in the CNS of the subject.

[0270] In some embodiments, the concentration of the peripheral blocker compound in circulating blood is greater than 3-fold (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-fold) the concentration of the peripheral blocker compound in the CNS. In some embodiments, the concentration of the peripheral blocker compound in circulating blood is greater than 20-fold the concentration of the peripheral blocker compound in the CNS. In some embodiments, the peripheral blocker compound, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is unable to cross the blood-brain barrier, whereas the anti-CNS disease drug is able to cross the blood-brain barrier. In some embodiments, the peripheral blocker compound is unable to cross the blood-brain barrier, whereas the anti-CNS disease drug is able to cross the blood-brain barrier.

[0271] In certain embodiments, the amount of the peripheral blocker and anti-CNS disease drug is effective in treating the disease or disorder of the CNS. In certain embodiments, the amount of the peripheral blocker and anti-CNS disease drug is effective in preventing the disease or disorder of the CNS.

[0272] Co-administration of Peripheral Blockers and Tacrolimus

[0273] Tacrolimus (CAS 104987-11-3) is a macrolide antibiotic produced by Streptomyces tsukubaensis. Tacrolimus is also known as FK-506, FR-900506, and Fujimycin.

[0274] Tacrolimus has the following chemical structure:

[0275]

[0276] Tacrolimus IUPAC Name:

[0277] ( 1 R,9S, 12S, 13R, 145, 17R, 18E, 215, 235,245, 255,275)- 1 , 14-dihydroxy- 12-[(E)- 1 - [(15,3 ,4 )-4-hydroxy-3-methoxycyclohexyl]prop-l-en-2-yl]-23,25-dimethoxy-l 3, 19,21,27- tetramethyl- 17-prop-2-enyl- 11 ,28-dioxa-4-azatricy clo[22.3.1.04,9]octacos- 18-ene-2,3 , 10,16- tetrone.

[0278] Tacrolimus is thought to exert an immunosuppressive effect by inhibiting the activity of calcineurin (CaN), a key mediatory of T-cell activation.

[0279] Tacrolimus acts by binding to FKBP12, a cytosolic enzyme which, in healthy cells, binds with FK506 to form an FK506-FKBP12 complex in response to increased intracellular calcium following stimulation of T cell receptors by antigens. The FK506-FKB12 complex is capable of binding CaN to block T-cell activation. In the absence of tacrolimus, CaN dephosphorylates and translocates nuclear factor of activated T cells (NF AT) proteins, which affect transcription of cytokine genes and, indirectly, T-cell activation, differentiation, and development. In the presence of tacrolimus, CaN forms part of a multi-protein complex of tacrolimus, FKBP12, calmodulin, CaN, and calcium, and is thereby made unavailable to initiate NFAT-mediated T-cell activation.

[0280] Tacrolimus, initially called FR000506, was first discovered in 1984. After its immunosuppressive effects were observed in vitro and in vivo, tacrolimus, then referred to as FK506, was further developed for use in prophylaxis of organ transplant rejection. It was approved for this use in Japan in 1993 and in the USA and UK in 1994. Relative to other calcineurin inhibitors (e.g., cyclosporine), tacrolimus is associated with significantly reduced incidence and severity of acute rejection in organ transplant patients, higher long-term rates of graft survival, and efficacy in refractory rejection rescue therapy. Tacrolimus is also used off- label for several indications related to dysregulated immune responses, such as Chron’s disease, graft-versus-host disease, myasthenia gravis, rheumatoid arthritis, and atopic dermatitis. Clinical observations and several pre-clinical studies have suggested tacrolimus may be useful for treatment of neurological disorders in which hyperactive calcineurin signaling has been implicated (e.g., neuroinflammatory diseases, pathological aging, AD). In the healthy brain, CaN is associated with several functions, including modulation of synaptic plasticity, modulation of neuroinflammation, regulation of glutamate, and formation of memory. Overexpression of CaN has been observed in both neuronal and glial cells of the hippocampus and cortex in human subjects exhibiting symptoms of cognitive decline. A potential protective effect of inhibition of CaN has been observed in solid organ transplant recipients treated with tacrolimus; these patients exhibit significantly reduced incidence of dementia relative to age-matched individuals of the general population. (Taglialatela et al. J Alzheimer s Dis. 2015;47(2):329-33).

[0281] In animal models of dementia, treatment with CaN inhibitors (e.g., tacrolimus) has been found to attenuate or rescue cognitive deficits and reduce the incidence of histopathological markers of neurodegeneration relative to controls, supporting the potential of CaN as a therapeutic target for treatment of dementia.

[0282] Tacrolimus is marketed under several trade names, including Prograf®, Advagraf®, Advagraf® XL, Graceptor®, Prograf® XL, Evarsus XR®, and Protopic®.

[0283] Tacrolimus is associated with several side effects common to calcineurin inhibitors (e.g., cyclosporine), such as: nephrotoxicity, neurotoxicity, hypertension (e.g., posttransplant hypertension), hyperlipidemia, disturbances in glucose metabolism, increased risk of infection, malignancies, gastrointestinal disturbances (e.g., diarrhea), alopecia, and neurotoxicity (e.g., headache, tremor, insomnia, paresthesia, seizures, delirium, cortical blindness, encephlaopathy).

[0284] Described herein is an innovative approach to enhance CNS-selective efficacy and mitigate peripheral toxicities associated with tacrolimus. By leveraging the Brain-Only™ pharmacology platform, this approach seeks to improve the safety and effectiveness of therapy, ultimately contributing to better health outcomes and quality of life for patients.

[0285] Aspects of the disclosure relate to use of peripheral blocker compounds described herein in Brain-Only™ pharmacology for CNS-selective activity of tacrolimus and treatment of a disease or disorder of the CNS, such as Alzheimer’s disease, an autoimmune response in the CNS, autoimmune encephalitis, or multiple sclerosis. In some embodiments, compounds disclosed herein are administered to a subject to treat, prevent, or slow the progression of one or more diseases or disorders of the CNS (e.g., Alzheimer’s disease, an autoimmune response in the CNS, autoimmune encephalitis, or multiple sclerosis). In some embodiments, compounds disclosed herein are administered to a subject to treat, prevent, or slow the progression of one or more symptoms of a disease or disorder of the CNS (e.g., Alzheimer’s disease, an autoimmune response in the CNS, autoimmune encephalitis, or multiple sclerosis).

[0286] In some embodiments, a subject has or is suspected of having Alzheimer’s disease. In some embodiments, a subject exhibits one or more symptoms associated with Alzheimer’s disease.

[0287] In some embodiments, a subject has or is suspected of having an autoimmune response in the CNS. In some embodiments, a subject exhibits one or more symptoms associated with an autoimmune response in the CNS.

[0288] In some embodiments, a subject has or is suspected of having autoimmune encephalitis. In some embodiments, a subject exhibits one or more symptoms associated with autoimmune encephalitis.

[0289] In some embodiments, a subject has or is suspected of having multiple sclerosis. In some embodiments, a subject exhibits one or more symptoms associated with multiple sclerosis.

[0290] Aspects of the disclosure relate to administering to a subject outside the CNS of the subject a peripheral blocker compound described herein and tacrolimus. In some embodiments, the peripheral blocker is administered concurrently with, prior to, or subsequent to tacrolimus. In some embodiments, each of the peripheral blocker and tacrolimus is administered at a dose and / or on a time schedule determined for that pharmaceutical agent.

[0291] The peripheral blocker compound may be any peripheral blocker compound described herein. For example, the peripheral blocker compound may be a compound selected from the compounds provided in Table 1, Table 1A, or Table IB. In certain embodiments, the peripheral blocker compound is of Formula 1-014, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-045, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-046, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-056, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the peripheral blocker compound is of Formula 1-017, 1-025, 1-028, 1-029, 1-034, 1-036, 1-038, 1-042, 1-045, 1- 046, 1-048, 1-049, 1-050, 1-052, 1-053, 1-054, 1-055, 1-056, 1-057, 1-061, 1-062, 1-063, 1-064, or I- 065, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0292] In certain embodiments, a peripheral blocker compound is a compound disclosed in International PCT Application Publication No. WO 2020 / 163594 or US Patent Publication No. 2023 / 0063768, which are incorporated herein by reference in their entireties. In certain embodiments, the compound is a compound disclosed in and incorporated by reference from any one of paragraphs 0386 and 0402 to 0454 and Tables 3 to 5 of International PCT Application Publication No. WO 2020 / 163594 and any one of paragraphs 0408 and 0424 to 0476 and Tables 3 to 5 of US Patent Publication No. 2023 / 0063768.

[0293] In some embodiments, the peripheral blocker compound is co-administered simultaneously with tacrolimus. In some embodiments, the peripheral blocker compound and tacrolimus are co-administered sequentially.

[0294] In some embodiments, the peripheral blocker compound is co-administered after (e.g., after about 1, 5, 10, 15, 20, or about 30 minutes or after about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or about 24 hours, or more than 24 hours) tacrolimus. In some embodiments, tacrolimus is coadministered after (e.g., after about 1, 5, 10, 15, 20, or 30 minutes or after about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or about 24 hours, or more than 24 hours) the peripheral blocker compound.

[0295] In some embodiments, subsequent to administration (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, or more than 24 hours following administration), the concentration of the peripheral blocker compound in circulating blood of the subject is greater than the concentration of the compound in the CNS of the subject. In some embodiments, subsequent to administration (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, or more than 24 hours following administration), the concentration of the compound in circulating blood of the subject is greater than the concentration of the compound in the CNS of the subject.

[0296] In some embodiments, the concentration of the peripheral blocker compound in circulating blood is greater than 3-fold (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-fold) the concentration of the peripheral blocker compound in the CNS. In some embodiments, the concentration of the peripheral blocker compound in circulating blood is greater than 20-fold the concentration of the peripheral blocker compound in the CNS. In some embodiments, the peripheral blocker compound, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is unable to cross the blood-brain barrier, whereas tacrolimus is able to cross the blood-brain barrier. In some embodiments, the peripheral blocker compound is unable to cross the blood-brain barrier, whereas tacrolimus is able to cross the blood-brain barrier.

[0297] In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one side effect associated with treatment of Alzheimer’s disease using tacrolimus. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one side effect associated with treatment of an autoimmune response in the CNS using tacrolimus. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one side effect associated with treatment of autoimmune encephalitis using tacrolimus. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one side effect of treatment of multiple sclerosis using tacrolimus. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one symptom associated with Alzheimer’s disease. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one symptom associated with an autoimmune response in the CNS. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one symptom associated with autoimmune encephalitis. In certain embodiments, wherein a peripheral blocker is administered with tacrolimus, an effective amount is an amount that is effective in reducing at least one symptom associated with multiple sclerosis.

[0298] In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in treating Alzheimer’s disease. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in preventing Alzheimer’s disease. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in treating an autoimmune response in the CNS. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in preventing an autoimmune response in the CNS. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in treating autoimmune encephalitis. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in preventing autoimmune encephalitis. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in treating multiple sclerosis. In certain embodiments, the amount of the peripheral blocker and tacrolimus is effective in preventing multiple sclerosis. EXAMPLES

[0299] The present disclosure is further illustrated by the following examples which should not be construed as limiting in any way. The contents of all cited references, including literature references, issued patents, and published patent applications, as cited throughout this application are hereby expressly incorporated herein by reference. It should further be understood that the contents of the figure and all the tables attached hereto are also expressly incorporated herein by reference.

[0300] Example 1: Methods

[0301] General Methods

[0302] All temperatures are in degrees Celsius (°C) and are uncorrected. Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification. The names of the products were determined using the naming software included in the Biovia electronic lab notebook. Silica gel chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO2 stationary phase columns with eluent flow-rate ranges of 15 to 200 mL / min, UV detection (254 and 280 nm). Reverse phase purification was carried out using C18 columns, UV detection (214 and 254 nm).

[0303] Walkup Methods (Agilent 1100 / 1200 series)

[0304] The analytical HPLC chromatograms were performed using an Agilent 1100 / 1200 series instrument with DAD detector (190 nm to 300 nm) and a thermostatted column compartment set to 35 °C. The mass spectra were recorded with a Waters SQD detector with the desolvation temperature set to 500 °C, the source temperature set to 150 °C and the desolvation gas flow set to 1000 L / hr. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive, or negative, ion mode and was set to scan between m / z 100-750 with a scan time of 0.2s. Products and intermediates were analyzed by HPLC / MS on the method A05. Method A05 is a 3.50-minute method using a Kinetex EVO C18 (5 pM, 4.6 x 50 mm) column, a flow rate of 2.20 mL / min, a buffer consisting of lOmM Ammonium Formate in water adjusted to pH 4 with Formic Acid, and Acetonitrile as the organic solvent. In this method, the %Acetonitrile is kept stable at 5% from 0.00-0.50 minutes and gradually increased to 100% from 0.50-2.50 minutes. From 2.50-3.50 minutes, the %Acetonitrile is kept stable at 100%.

[0305] Analytical QA / QC Methods

[0306] The analytical QA / QC chromatograms were performed using a Waters Acquity UHPLC instrument with DAD detector (200 nm to 320 nm) and a thermostatted column compartment. The mass spectra were recorded with a Waters SQD detector with the desolvation temperature set to 450 °C, the source temperature set to 150 °C, and the desolvation gas flow set to 1000 L / hr. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive, or negative, ion mode and was set to scan between m / z 100-2000 with a scan time of 0.2s. Products were analyzed by UHPLC / MS using one of the following methods: ACN_TFA_QC_10min_Vl_65C is a 10.00 minute method using an Acquity UHPLC BEH Cl 8 (1.7 pM, 2.1x50mm) column heated to 65 °C, a flow rate of 0.700 mL / min, a buffer consisting of 0.1% TFA in water, and Acetonitrile as the organic solvent. In this method, the %Acetonitrile is increased from 5% to 100% from 0.00-9.00 minutes and then kept stable at 100% from 9.00- 10.00 minutes.

[0307] ACN_AmForm_QC_10min_Vl_65C is a 10.00 minute method using an Acquity UHPLC BEH C18 (1.7 pM, 2.1x50mm) column heated to 65 °C, a flow rate of 0.700 mL / min, a buffer consisting of lOmM Ammonium Formate in water adjusted to pH 4 with Formic Acid, and Acetonitrile as the organic solvent. In this method, the %Acetonitrile is increased from 5% to 100% from 0.00-9.00 minutes and then kept stable at 100% from 9.00-10.00 minutes.

[0308] NMR Methods

[0309] The 1H NMR spectra were recorded on a Varian Mercury 300 MHz / 54 mm instrument, a Varian AS 400 MHz / 54 mm instrument, and a Bruker UltraShield 500 MHz / 54 mm instrument (BZH 43 / 500 / 70B, D221 / 54-3209). The chemical shifts are reported in parts-per-million and are referenced to solvent peaks, which in 1H NMR appear at 7.26 ppm for CDC13, 2.50 for DMSO- d6, and 3.31 ppm for CD3OD.

[0310] Analytical SFC Method

[0311] The SFC analyses were performed on an Agilent 1260 Infinity II SFC instrument with a DAD detector (190 to 400nm) and a thermostatted column compartment. The column compartment was set to 40 °C. The BPR Pressure was set to 120bar and the BPR temperature was set to 60 °C. All the columns used were 4.6mm x 250mm with a 5pM particle size. The columns available are: Chiralpak IBN-5, Lux Amylose-1, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, Lux Cellulose-4, Lux i-Amylose-1, Lux i-Amylose-3, Lux i-Cellulose-5. The modifiers available are: methanol, ethanol, isopropanol, lOmM ammonium formate in 1 : 1 ethanol / acetonitrile, lOmM ammonium formate in methanol, 0.5% formic acid in methanol, 0.1% ammonium hydroxide in isopropanol, 0.1% ammonium hydroxide in methanol and 0.1% ammonium hydroxide in 1 : 1 ethanol / acetonitrile. The analytical SFC method is a 7.00 minute method using one of the above columns and a flow rate of 3.00 mL / min. The %modifier is kept constant at 5% from 0.00-0.50 minutes then gradually increased to 60% from 0.50-3.50 minutes. Finally, the %modifier is kept constant at 60% from 3.50-7.00 minutes.

[0312] Example 2: Preparation of the Compounds

[0313] 1-001

[0314] ( 1 / L9.SJ2.SJ3 / L14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-12-|(E)-2-|(l / ?.3 / ?.4 / ?)- 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-17-[(Z)-3-(3-hydroxyoxetan-3-yl)allyl]- 23, 25-dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- ene-2,3,10,16-tetrone

[0315] Hovey da-Grubbs II (39.0 mg, 62.0 mmol) was added to a mixture of tacrolimus (500 mg, 0.620 mol) and 1-ethenylcyclobutan-l-ol (436 mg, 4.35 mol) in DCE (6.20 mL) in a 10.0 mL microwave vial. The reaction mixture was irradiated at 150 °C under N2 for 5 minutes. The mixture was concentrated under reduced pressure, and the residue was purified via silica gel column chromatography using a gradient of MeOH in DCM (5%) to provide the title compound as a solid (100 mg, 18.4%). 1H NMR (400 MHz, CD3OD) 5 5.84 - 5.62 (m, 2H), 5.44 - 5.07 (m, 1H), 5.06 - 4.83 (m, 1H), 4.60 (s, 1H), 4.58 - 4.42 (m, 4H), 4.33 (d, J = 6.5 Hz, 1H), 4.11 - 3.71 (m, 1H), 3.65 - 3.50 (m, 2H), 3.46 (d, J = 9.7 Hz, 1H), 3.39 - 3.26 (m, 9H), 3.03 - 2.84 (m, 1H), 2.69 (s, 1H), 2.61 - 2.49 (m, 1H), 2.49 - 2.40 (m, 1H), 2.36 (dd, J = 11.7, 5.2 Hz, 1H), 2.31 - 2.16 (m, 3H), 2.13 - 2.00 (m, 4H), 1.92 - 1.12 (m, 23H), 1.07 - 0.65 (m, 11H). 4 protons not observed, m / z (ES+) [M+NH4]+ = 893.4.

[0316] 1-002

[0317] (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-[(E)-3-diethoxyphosphorylallyl]- l,14-dihydroxy-12-[(E)-2-[(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]- 23, 25-dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- ene-2,3,10,16-tetrone

[0318] Hovey da-Grubbs Catalyst® M720 (12.5 mg, 0.0199 mmol) was added to a degassed mixture of tacrolimus (200 mg, 0.249 mmol) and 1- [ethoxy (vinyl)phosphoryl] oxy ethane (0.191 mL, 1.24 mmol) in DCE (2.40 mL) at 22 °C under nitrogen. The mixture was stirred at 85 °C for 1 h and concentrated. The residue was purified by silica gel column chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and MeOH in EtOAc (0-10%) to provide the title compound as a solid (164 mg, 70%). *HNMR (400 MHz, CDC13) 8 6.77 - 6.52 (m, 1H), 5.76 - 5.59 (m, 1H), 5.42 - 5.16 (m, 1H), 5.11 - 4.96 (m, 2H), 4.73 - 4.55 (m, 1H), 4.43 (d, J= 13.6 Hz, 1H), 4.05 (td, J= 7.2, 3.6 Hz, 4H), 3.88 (t, J= 10.2 Hz, 1H), 3.69 (d, J= 8.6 Hz, 1H), 3.59 (d, J= 8.5 Hz, 1H), 3.56 - 3.47 (m, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 3.34 - 3.27 (m, 3H), 3.11 - 2.92 (m, 2H), 2.84 - 2.56 (m, 2H), 2.37 - 2.26 (m, 3H), 2.15 (dd, J = 11.0, 4.5 Hz, 3H), 2.11 - 1.95 (m, 5H), 1.93 - 1.71 (m, 5H), 1.66 (d, J= 7.8 Hz, 6H), 1.59 (s, 3H), 1.56 - 1.34 (m, 5H), 1.33 - 1.28 (m, 6H), 1.20 - 1.02 (m, 2H), 1.02 - 0.95 (m, 3H), 0.95 - 0.90 (m, 3H), 0.88 - 0.81 (m, 3H). Three protons not observed, m / z (ES+) [M+NH4]+= 957.4; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 5.41 min.

[0319] 1-004 (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-(3-diethoxyphosphorylpropyl)-l,14- dihydroxy-12-[(7i)-2-[(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18-ene-

[0320] 2,3,10,16-tetrone

[0321] ( 1 R,9S, 125, 137?, 145, 177?, 18E, 215, 235, 247?, 255, 277?)- 17-[(£)-3 -diethoxyphosphorylallyl]- 1,14- dihydroxy-12-[(7y)-2-[(17?,37?,47?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy- 13,19,21 ,27-tetram ethyl- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene-

[0322] 2,3,10,16-tetrone (150 mg, 0.160 mmol) was added to a mixture of Pd / C (10.0 wt.%, 13.6 mg, 0.0128 mmol) in EtOAc (3.80 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 2 h under H2. The mixture was filtered through Celite, washed with EtOAc (5.00 mL) and concentrated to provide the title compound as a solid (132 mg, 88%). 'H NMR (400 MHz, CDCI3) 6 5.38 - 5.17 (m, 1H), 5.15 - 4.96 (m, 2H), 4.61 (d, .7 = 4.1 Hz, 1H), 4.43 (d, J= 12.3 Hz, 1H), 4.15 - 4.00 (m, 4H), 3.89 (s, 1H), 3.71 (d, .7 = 9.7 Hz, 1H), 3.59 (d, .7 = 9.2 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 3.34 - 3.28 (m, 3H), 3.00 (t, J= 10.3 Hz, 2H), 2.83 - 2.65 (m, 1H), 2.39 - 2.20 (m, 3H), 2.19 - 2.08 (m, 3H), 2.07 - 1.85 (m, 5H), 1.84 - 1.68 (m, 6H), 1.67 - 1.57 (m, 8H), 1.56 (s, 3H), 1.55 - 1.33 (m, 7H), 1.33 - 1.24 (m, 6H), 1.12 - 1.02 (m, 2H), 1.02 - 0.95 (m, 3H), 0.94 - 0.89 (m, 3H), 0.89 - 0.79 (m, 3H). Three protons not observed, m / z (ES+) [M+Na]+= 964.3; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 5.43 min.

[0323] 1-003

[0324] ( 1 / ?.95.125.13 / ?.145.17 / ?.18E.215.235.24 / ?.255.27 / ?)-1.14-dihydroxy-12-|(E)-2-|(l / ?.3 / ?.4 / ?)- 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-17-[(7i)-pent-2-enyl]-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-

[0325] 2,3,10,16-tetrone

[0326] Hovey da-Grubbs Catalyst® M720 (7.95 mg, 0.0127 mmol) was added to a degassed mixture of tacrolimus (150 mg, 0.187 mmol) and (7y)-hex-3-ene (0.232 mL, 1.87 mmol) in DCE (1.80 mL) at 22 °C. The mixture was stirred at 22 °C for 30 min and concentrated. The residue was purified by silica gel column chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0- 100%) to provide the title compound as a solid (108 mg, 70%). 'H NMR (400 MHz, CDCh) 8 5.53 - 5.37 (m, 1H), 5.35 - 5.17 (m, 2H), 5.12 - 4.96 (m, 2H), 4.84 - 4.55 (m, 1H), 4.47 - 4.20 (m, 1H), 3.98 - 3.84 (m, 1H), 3.79 - 3.62 (m, 1H), 3.62 - 3.51 (m, 1H), 3.51 - 3.21 (m, 12H), 3.07 - 2.94 (m, 2H), 2.82 - 2.67 (m, 2H), 2.48 - 1.23 (m, 33H), 1.14 - 0.76 (m, 14H). m / z (ES+) [M+NH4]+= 849.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 6.58 min.

[0327] 1-005

[0328] Step 1: (l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-12-|(E)-2- [(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-[(Zi)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]-ll,28- dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0329] Hovey da-Grubbs Catalyst® M720 (60.0 mg, 0.0958 mmol) was added to a degassed mixture of tacrolimus (500 mg, 0.622 mmol) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.00 mL, 5.90 mmol) in DCE (5.00 mL) at 22 °C. The mixture was stirred at 85 °C for 2 h and concentrated. The residue was purified by silica gel column chromatography (25 g cartridge) using a gradient of EtOAcZEtOH (3: 1) in hexanes (0-80%) to provide the title compound as a solid (450 mg, 78%). m / z (ES’) [M-H]’ = 928.6; HPLC (A05) tR= 1.90 min.

[0330] Step 2: |(E)-3-|( l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-12-|(E)- 2-[(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0331] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]prop-l-enyl]boronic acid

[0332] NaIO4(310 mg, 1.45 mmol) and NH4OAc (112 mg, 1.45 mmol) were added to a mixture of (lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-l,14-dihydroxy-12-[(E)-2-[(lA,3A,4A)-4- hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17- [(£)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]-l l,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (450 mg, 0.484 mmol) in acetone (3.00 ml) and water (1.00 mL) at 22 °C. The mixture was stirred at 22 °C for 16 h and concentrated. The mixture was diluted with EtOAc (15.0 mL) and water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 15.0 mL), and the combined organic extracts were washed with brine (20.0 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 60 g cartridge) using a gradient of water [10 mM (NH4 HCO2)] and MeCN (10-80%) to provide the title compound as a solid (250 mg, 61%).JH NMR (400 MHz, CD3OD) 5 6.50 - 6.36 (m, 1H), 5.64 - 5.53 (m, 1H), 5.27 - 5.07 (m, 2H), 4.94 - 4.87 (m, 1H), 4.62 (s, 1H), 4.35 (d, J= 13.5 Hz, 1H), 4.10 - 3.93 (m, 1H), 3.77 - 3.44 (m, 4H), 3.43 - 3.33 (m, 11H), 3.09 - 2.96 (m, 2H), 2.92 - 2.74 (m, 1H), 2.58 - 2.43 (m, 1H), 2.41 - 2.07 (m, 6H), 2.06 - 1.85 (m, 5H), 1.85 - 1.54 (m, 12H), 1.54 - 1.23 (m, 5H), 1.20 - 1.05 (m, 2H), 1.02 - 0.83 (m, 10H). Three protons not observed, m / z (ES+) [M+NH4] = 865.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR = 4.80 min.

[0333] 1-006

[0334] ( 1 / L9.SJ2.S 3 / L14.S.17 / ?.18E.21.S.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-12-|(E)-2-|(l / ?.3 / ?.4 / ?)- 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-17-pentyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16- tetrone

[0335] (lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-l,14-dihydroxy-12-[(E)-2-[(lA,3A,4A)-4- hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17- [(E)-pent-2-enyl]-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (36.0 mg, 0.0433 mmol) was added to a mixture of Pd / C (10.0 wt.%, 3.68 mg, 0.00346 mmol) in EtOAc (1.04 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washed with DCM (20.0 mL) and concentrated to provide the title compound as a solid (30.0 mg, 83%).1H NMR (400 MHz, CDCI3) 5 5.35 - 5.17 (m, 1H), 5.12 - 4.95 (m, 2H), 4.85 - 4.56 (m, 1H), 4.49 - 4.21 (m, 1H), 3.99 - 3.85 (m, 1H), 3.77 - 3.55 (m, 2H), 3.54 - 3.14 (m, 12H), 3.08 - 2.94 (m, 2H), 2.82 - 2.61 (m, 2H), 2.37 - 1.14 (m, 37H), 1.12 - 0.76 (m, 14H). m / z (ES+) [M+NH4]+= 851.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR = 6.81 min.

[0336] 1-007 3-|(l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.21.S.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-12-|(E)-2- [(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0337] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]propylboronic acid

[0338] [(E)-3-[(17?,95,125,137?,145,177?,18E',215,235,247?,255,277?)-l,14-dihydroxy-12-[(E)-2-

[0339] [(1 A,3A,47?)-4-hydroxy-3 -methoxy-cyclohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27- tetramethyl-2,3 , 10,16-tetraoxo- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-en- 17-yl]prop- l-enyl]boronic acid (200 mg, 0.236 mmol) was added to a mixture of Pd / C (10.0 wt.%, 50.0 mg, 0.0470 mmol) in EtOAc (10.0 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washed with EtOAc (5.00 mL) and concentrated to provide the title compound as a solid (83.0 mg, 41%).JH NMR (400 MHz, CD3OD) 5 5.28 - 5.07 (m, 2H), 4.94 - 4.87 (m, 1H), 4.68 - 4.58 (m, 1H), 4.38 - 4.30 (m, 1H), 4.14 - 3.90 (m, 1H), 3.77 - 3.44 (m, 3H), 3.44 - 3.33 (m, 11H), 3.10 - 2.97 (m, 2H), 2.91 - 2.72 (m, 1H), 2.52 - 2.27 (m, 2H), 2.27 - 2.08 (m, 3H), 2.08 - 1.86 (m, 5H), 1.86 - 1.53 (m, 12H), 1.53 - 1.06 (m, 11H), 1.02 - 0.82 (m, 10H), 0.80 - 0.72 (m, 1H). Five protons not observed, m / z (ES+) [M+Na]+= 872.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.79 min.

[0340] 1-008

[0341] Step 1: (E)-4-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2- [(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0342] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]but-2-enoic acid

[0343] Hovey da-Grubbs Catalyst® M720 (331 mg, 0.529 mmol) was added to a degassed mixture of tacrolimus (6.25 g, 7.77 mmol) and acrylic acid (10.1 mL, 148 mmol) in DCE (75.0 mL) at 22 °C. The mixture was stirred at 85 °C for 90 min and concentrated. The residue was purified by silica gel column chromatography (220 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (4.51 g, 68%). 'H NMR (400 MHz, CDCh) 8 6.99 - 6.79 (m, 1H), 5.83 (d, J= 15.4 Hz, 1H), 5.34 - 5.16 (m, 1H), 5.08 (t, J= 9.7 Hz, 1H), 5.03 - 4.94 (m, 1H), 4.74 - 4.54 (m, 1H), 4.52 - 4.41 (m, 1H), 4.41 - 4.22 (m, 1H), 3.94 - 3.84 (m, 1H), 3.76 - 3.67 (m, 1H), 3.64 - 3.56 (m, 1H), 3.56 - 3.44 (m, 2H), 3.44 - 3.40 (m, 3H), 3.40 - 3.35 (m, 3H), 3.35 - 3.24 (m, 3H), 3.07 - 2.95 (m, 2H), 2.83 - 2.72 (m, 1H), 2.72 - 2.59 (m, 2H), 2.47 - 1.28 (m, 28H), 1.15 - 0.68 (m, 11H). Three protons not observed, m / z (ES‘) [M-H]’= 846.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR = 4.68 min.

[0344] Step 2: 4-[(l / ?, 9S, 13 / ?, 145, HR, 18 / 2215.235, 24 / ?, 255, 27 / ?)-l, 14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0345] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]butanoic acid

[0346] (£)-4-[(l / ?,95,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(£)-2-[(l / ?,3 / ?,4 / ?)-4- hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 2,3,10,16-tetraoxo-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-17-yl]but-2-enoic acid (1.57 g, 1.85 mmol) was added to a mixture of Pd / C (10.0 wt.%, 158 mg, 0.148 mmol) in EtOAc (44.6 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h under H2. The mixture was filtered through Celite, washed with DCM (200 mL), and concentrated. The residue was purified by silica gel chromatography (50 g cartridge) using a gradient of MeOH in DCM (0- 10%) to provide the title compound as a solid (1.28 g, 81%). 'HNMR (400 MHz, CDCI3) 6 5.35 - 5.17 (m, 1H), 5.12 - 4.95 (m, 2H), 4.86 - 4.58 (m, 1H), 4.47 - 4.29 (m, 2H), 3.99 - 3.84 (m, 1H), 3.76 - 3.65 (m, 1H), 3.62 - 3.53 (m, 1H), 3.45 - 3.25 (m, 12H), 3.07 - 2.58 (m, 5H), 2.47 - 1.29 (m, 33H), 1.13 - 1.01 (m, 2H), 1.01 - 0.95 (m, 3H), 0.95 - 0.90 (m, 3H), 0.90 - 0.78 (m, 3H). One proton not observed, m / z (ES‘) [M-H]' = 848.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR = 4.78 min.

[0347] Step 3: 4-[(l / ?, 9S, 125, 13 / ?, 145, HR, 18E,215, 235.24 / ?, 255.27 / ?)-l,14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0348] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]-7V-methylsulfonyl-butanamide

[0349] DMAP (43.1 mg, 0.353 mmol) was added to a mixture of 4- [(l / ?,95,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2-[(l / ?,3 / ?,4 / ?)-4- hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 2,3,10,16-tetraoxo-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-17-yl]butanoic acid (250 mg, 0.294 mmol) and methanesulfonamide (56.0 mg, 0.588 mmol) in dry DMF (2.50 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 5 min and EDC.HC1 (67.7 mg, 0.353 mmol) was added at 0 °C. The mixture was stirred at 22 °C for 16 h and concentrated. The residue was diluted with water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 5.00 mL) and the combined organic extracts were dried (MgSCh), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0- 20%) to provide the title compound as a solid (34 mg, 13%).JH NMR (400 MHz, CDCh) 8 8.95 - 8.48 (m, 1H), 5.42 - 5.16 (m, 1H), 5.11 - 4.99 (m, 2H), 5.01 - 4.57 (m, 1H), 4.43 (d, J= 13.6 Hz, 1H), 4.07 - 3.89 (m, 1H), 3.88 - 3.63 (m, 1H), 3.63 - 3.53 (m, 1H), 3.46 - 3.28 (m, 15H), 3.00 (td, J= 12.5, 6.8 Hz, 2H), 2.83 - 2.57 (m, 1H), 2.37 - 2.28 (m, 3H), 2.22 - 2.08 (m, 4H), 2.07 - 1.90 (m, 6H), 1.82 - 1.73 (m, 3H), 1.71 - 1.64 (m, 6H), 1.60 (d, J= 7.0 Hz, 3H), 1.57 - 1.24 (m, 8H), 1.12 - 1.01 (m, 2H), 1.00 - 0.95 (m, 3H), 0.94 - 0.90 (m, 3H), 0.89 - 0.82 (m, 3H). Three protons not observed, m / z (ES+) [M+NH4] = 943.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.85 min.

[0350] 1-009 (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-[(E)-3-dimethylphosphorylallyl]- l,14-dihydroxy-12-[(£')-2-[(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]- 23, 25-dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- ene-2,3,10,16-tetrone

[0351] Grubbs Catalyst® M204 (302 mg, 0.356 mmol) was added to a degassed mixture of tacrolimus (715 mg, 0.889 mmol), Cui (0.169 g, 0.889 mmol) and 1 -dimethylphosphorylethylene (278 mg, 2.67 mmol) in DCE (8.58 mL) at 22 °C under nitrogen. The mixture was stirred at 85 °C for 45 min and concentrated. The residue was purified by silica gel column chromatography (14 g cartridge) using a gradient of EtOAc in hexanes (50-100%) and MeOH in DCM (0-10%) to provide the title compound as a solid (114 mg, 15%). 'H NMR (400 MHz, CDCh) 8 6.68 - 6.46 (m, 1H), 5.94 - 5.76 (m, 1H), 5.39 - 5.30 (m, 1H), 5.22 - 4.93 (m, 2H), 4.67 - 4.32 (m, 2H), 4.00 - 3.80 (m, 1H), 3.76 - 3.53 (m, 2H), 3.52 - 3.18 (m, 12H), 3.09 - 2.55 (m, 4H), 2.46 - 1.13 (m, 37H), 1.08 - 0.80 (m, 11H). m / z (ES+) [M+H]+= 880.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.56 min.

[0352] 1-010

[0353] (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-(3-dimethylphosphorylpropyl)-l,14- dihydroxy-12-[(£')-2-[(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18-ene- 2,3,10,16-tetrone

[0354] (17?,95,125,137?,145,177?,18E,215,235,247?,255,277?)-17-[(£)-3-dimethylphosphorylallyl]-l,14- dihydroxy-12-[(7y)-2-[(17?,37?,47?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy- 13,19,21 ,27-tetram ethyl- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene- 2,3,10,16-tetrone (67.0 mg, 0.0761 mmol) was added to a mixture of Pd / C (10.0 wt.%, 13.0 mg, 0.0122 mmol) in EtOAc (1.83 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated to provide the title compound as a solid (51.0 mg, 76%). *HNMR (400 MHz, CDCh) 6 5.40 - 5.33 (m, 1H), 5.31 - 5.18 (m, 1H), 5.09 - 4.95 (m, 1H), 4.75 - 4.54 (m, 1H), 4.42 (d, J= 13.6 Hz, 1H), 3.99 - 3.84 (m, 1H), 3.73 (d, J= 9.6 Hz, 1H), 3.69 - 3.44 (m, 3H), 3.44 - 3.18 (m, 11H), 3.04 - 2.61 (m, 4H), 2.41 - 1.20 (m, 40H), 1.08 - 0.79 (m, 11H). m / z (ES+) [M+H]+= 882.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.53 min.

[0355] 1-011

[0356] ( 1 / ?.95.125.13 / ?.145.17 / ?.18E.215.235.24 / ?.255.27 / ?)-1.14-dihydroxy-12-|(E)-2-|(l / ?.3 / ?.4 / ?)- 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23, 25-dimethoxy-13, 19, 21,27- tetramethyl-17-[(E)-3-( FH-tetrazol-5-yl)allyl]-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene-2,3,10,16-tetrone

[0357] Hovey da-Grubbs Catalyst® M720 (93.5 mg, 0.149 mmol) was added to a degassed mixture of tacrolimus (600 mg, 0.746 mmol), Cui (42.6 mg, 0.224 mmol) and 5-vinyl-17 / -tetrazole (400 mg, 4.16 mmol) in Me-THF (10.0 mL) at 22 °C. The mixture was stirred at 60 °C for 1 h. A mixture of Hovey da-Grubbs Catalyst® M720 (93.5 mg, 0.149 mmol) and Cui (42.6 mg, 0.224 mmol) in Me-THF (1.00 mL) was added. The mixture was stirred at 60 °C for 2 h and concentrated. The residue was purified by silica gel column chromatography (25 g cartridge) using a gradient of EtOAc / EtOH (3: 1) (+5% formic acid) in hexanes (0-80%) to provide the title compound as a solid (170 mg, 26%). 'H NMR (400 MHz, CD30D) 5 6.87 - 6.72 (m, 1H), 6.64 - 6.45 (m, 1H), 5.29 - 5.09 (m, 2H), 5.06 - 4.95 (m, 1H), 4.62 - 4.57 (m, 1H), 4.42 - 4.28 (m, 1H), 4.17 - 3.95 (m, 1H), 3.82 - 3.47 (m, 4H), 3.43 - 3.32 (m, 11H), 3.07 - 2.96 (m, 1H), 2.88 - 2.67 (m, 1H), 2.47 - 2.25 (m, 3H), 2.24 - 1.86 (m, 9H), 1.85 - 1.52 (m, 13H), 1.49 - 1.05 (m, 8H), 1.02 - 0.85 (m, 9H), 0.83 - 0.74 (m, 1H). One proton not observed, m / z (ES+) [M+H]+= 872.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.76 min.

[0358] 1-012

[0359] Step 1: tert-butyl 2-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-

[0360] [(1 / ?, 9S, 125, 13 / ?, 145, 17 / ?, 18E,215, 235, 24R, 255, 27 / ?)-l,14-dihydroxy-23,25-dimethoxy- 13, 19,21 ,27-tetramethyl-2,3, 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa-4- azatricyclo [22.3.1.04,9] octacos-18-en- 12-yl] prop- 1-enyl] -2-methoxy-cyclohexoxy] acetate

[0361] A mixture of tert-butyl diazoacetate (0.0699 mL, 0.480 mmol) in dry DCM (0.100 mL) was added dropwise to a mixture of (l / ?,95,125,13 / ?,145,17 / ?,18E',215,235,24 / ?,255,27 / ?)-l,14- dihydroxy-12-[(E)-2-[(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-17-pentyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18- ene-2,3,10,16-tetrone (200 mg, 0.240 mmol) in DCM (1.20 mL) at 39 °C under nitrogen. The mixture was stirred at 39 °C for 1 h. A mixture of tert-butyl diazoacetate (0.0699 mL, 0.480 mmol) in dry DCM (0.100 mL) was added dropwise at 39 °C. The mixture was stirred at 39 °C for 1 h and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-50%) to provide the title compound as a solid (69.0 mg, 30%). m / z (ES+) [M+NH4]+= 965.6; HPLC (A05) tR= 2.29 min.

[0362] Step 2: 2-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14- dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-17-pentyl-ll,28- dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy- cyclohexoxy] acetic acid

[0363] TFA (0.100 mL, 1.35 mmol) was added to a mixture of tert-butyl 2-[(17?,27?,47?)-4-[(E)-2- [(17?,95,125,137?,145,177?,18E,215,235,247?,255,277?)-l,14-dihydroxy-23,25-dimethoxy- 13,19,21 ,27-tetramethyl-2,3 , 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy-cyclohexoxy]acetate (68.0 mg, 0.0717 mmol) in DCM (0.900 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (55-65%) to provide the title compound as a solid (25.0 mg, 39%). 'HNMR (400 MHz, CDCI3) 8 5.36 - 5.15 (m, 1H), 5.10 - 4.95 (m, 2H), 4.91 - 4.57 (m, 1H), 4.43 (d, .7 = 14.1 Hz, 1H), 4.29 (dd, J= 17.5, 1.6 Hz, 1H), 3.98 (dd, J= 17.6, 2.2 Hz, 1H), 3.90 (td, J= 9.2, 2.6 Hz, 1H), 3.66 (d, J= 9.6 Hz, 1H), 3.57 (d, J= 7.9 Hz, 1H), 3.49 (d, J= 0.7 Hz, 3H), 3.38 (d, J= 3.3 Hz, 3H), 3.36 - 3.22 (m, 6H), 3.16 - 2.91 (m, 2H), 2.84 - 2.66 (m, 1H), 2.41 - 1.07 (m, 37H), 1.04 - 0.84 (m, 14H). One proton not observed, m / z (ES+) [M+NH4]+= 909.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 6.84 min.

[0364] 1-014

[0365] Step 1: A-methylprop-2-ene-l-sulfonamide

[0366] DIPEA (1.53 mL, 8.96 mmol) and methanamine (2.00 M in THF, 4.69 mL, 9.39 mmol) were added to a mixture of prop-2-ene-l -sulfonyl chloride (0.814 mL, 8.54 mmol) in THF (26.0 mL) at 0 °C under nitrogen. The mixture was stirred at 22 °C for 90 min and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as an oil (558 mg, 48%). 'HNMR (300 MHz, CDCI3) 6 6.04 - 5.80 (m, 1H), 5.52 - 5.32 (m, 2H), 4.27 (s, 1H), 3.87 - 3.66 (m, 2H), 2.95 - 2.66 (m, 3H).

[0367] Step 2: ( )-4-(l / ?, 9S, 125.13 / ?, 145.17 / ?. ISE.215.235, 24 / ?, 255, 27 / ?)- l,14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?) 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0368] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl |-\-methyl-but-2-ene-l -sulfonamide

[0369] Nitro-Grela catalyst (66.8 mg, 0.0995 mmol) was added to a degassed mixture of tacrolimus (800 mg, 0.995 mmol) and A-methylprop-2-ene-l -sulfonamide (558 mg, 4.13 mmol) in toluene (9.14 mL) at 22 °C. The mixture was stirred at 60 °C for 1 h and concentrated. The residue was purified by silica gel column chromatography (25 g cartridge) using a gradient of MeOH in DCM (0-10%) followed by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (50-60%) to provide the title compound as a solid (317 mg, 35%). 'H NMR (400 MHz, CDCI3) 8 5.83 - 5.69 (m, 1H), 5.60 - 5.44 (m, 1H), 5.35 - 5.15 (m, 1H), 5.14 - 4.86 (m, 3H), 4.64 - 4.24 (m, 2H), 4.00 - 3.88 (m, 1H), 3.85 - 3.51 (m, 4H), 3.50 - 3.24 (m, 12H), 3.12 - 2.42 (m, 8H), 2.37 - 1.23 (m, 28H), 1.13 - 0.77 (m, 11H). Two protons not observed, m / z (ES+) [M+NH4]+= 928.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 5.21 min.

[0370] 1-013

[0371] (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2-[(l / ?,3 / ?,4 / ?)- 4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-2,3,10,16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-17-yl]- \-methyl-butane-l -sulfonamide

[0372] (E)-4-(l / ?,95,125,13 / ?,145,17 / ?,18.E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2-

[0373] [(l / ?,3 / ?,4 / ?)-4-hydroxy-3 -methoxy-cyclohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27- tetramethyl-2,3 , 10,16-tetraoxo- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-en- 17-y 1]-7V- methyl-but-2-ene-l -sulfonamide (100 mg, 0.110 mmol) was added to a mixture of Pd / C (10.0 wt.%, 11.7 mg, 0.0110 mmol) in EtOAc (2.64 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated to provide the title compound as a solid (88.0 mg, 88%).1H NMR (400 MHz, CDCI3) 6 5.36 - 5.17 (m, 1H), 5.12 - 4.95 (m, 2H), 4.72 - 4.59 (m, 1H), 4.47 - 4.09 (m, 2H), 4.00 - 3.83 (m, 1H), 3.75 - 3.52 (m, 2H), 3.50 - 3.21 (m, 12H), 3.12 - 2.63 (m, 8H), 2.39 - 1.24 (m, 32H), 1.11 - 0.78 (m, 11H). Four protons not observed, m / z (ES+) [M+NH4]+= 930.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 5.17 min.

[0374] 1-015

[0375] Step 1: tert-butyl 3-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-

[0376] [(1 / ?, 9S, 125, 13 / ?, 145, 17 / ?, 18E,215, 235, 24R, 255, 27 / ?)-l,14-dihydroxy-23,25-dimethoxy- 13, 19,21 ,27-tetramethyl-2, 3, 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy- cyclohexoxy] propanoate

[0377]

[0378] 2,6-Ditert-butylpyridine (0.485 mL, 2.16 mmol) was added to a mixture of

[0379] ( 17?, 95, 125, 13R, 145, 17R, 18E,215, 235, 247?, 255, 277?)- 1 , 14-dihydroxy- 12-[(E)-2-[( lR,3R,4R)-4- hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17- pentyl-1 l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (300 mg, 0.360 mmol) and tert-butyl 3 -(trifluoromethyl sulfonyloxy)propanoate (300 mg, 1.08 mmol) in dry DCM (3.00 mL) at 0 °C under nitrogen. The mixture was stirred at 22 °C for 56 h and diluted with H2O (15.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (30.0 mL), dried (MgSCh), filtered, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-50%) to provide the title compound as a solid (146 mg, 42%). m / z (ES’) [M-H]- = 960.7; HPLC (A05) tR= 2.31 min.

[0380] Step 2: 3-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14- dihydroxy-23,25-dimethoxy-13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-17-pentyl-l 1,28- dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy- cyclohexoxy] propanoic acid

[0381] TFA (0.282 mL, 3.79 mmol) was added to a mixture of tert-butyl 3-[(17?,27?,47?)-4-[(E)-2- [(17?,95,125,137?,145,177?,18E,215,235,247?,255,277?)-l,14-dihydroxy-23,25-dimethoxy- 13,19,21 ,27-tetramethyl-2,3 , 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy-cyclohexoxy]propanoate (140 mg, 0.145 mmol) in DCM (1.60 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (80-90%) to provide the title compound as a solid (43.0 mg, 33%). 'H NMR (400 MHz, CDCI3) 8 5.36 - 5.17 (m, 1H), 5.12 - 4.98 (m, 2H), 4.60 (d, J= 4.7 Hz, 1H), 4.49 - 4.22 (m, 1H), 3.98 - 3.86 (m, 2H), 3.79 - 3.65 (m, 2H), 3.62 - 3.55 (m, 1H), 3.46 - 3.24 (m, 12H), 3.19 - 2.96 (m, 2H), 2.81 - 2.58 (m, 3H), 2.34 - 1.22 (m, 37H), 1.07 - 0.98 (m, 4H), 0.96 - 0.81 (m, 10H). One proton not observed, m / z (ES+) [M+NH4]+= 923.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 6.79 min.

[0382] 1-016

[0383] Step 1: (l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.21.S.23.S.24 / ?.25.S.27 / ?)-12-|(E)-2-|(l / ?.3 / ?.4 / ?)-4- allyloxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-l,14-dihydroxy-23,25-dimethoxy- 13,19,21,27-tetramethyl-17-pentyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene- 2,3,10,16-tetrone

[0384] A mixture of prop-2-en-l-ol (127 pL, 1.87 mmol) and 2,4,6-tri-tert-butylpyridine (463 mg, 1.87 mmol) in DCM (6.00 mL) was added to a mixture of TfzO (315 pL, 1.87 mmol) in dry DCM (6.00 mL) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 30 min, and a mixture of (lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-l,14-dihydroxy-12-[(E)-2-[(lA,3A,4A)- 4-hydroxy-3 -methoxy-cy clohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27-tetramethyl- 17-pentyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (1.20 g, 1.44 mmol) and 2,4,6-tri-tert-butylpyridine (463 mg, 1.87 mmol) in DCM (12.0 mL) was added at -78 °C. The mixture was stirred at 0 °C for 1 h and diluted with H2O (20.0 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (100 g cartridge) using a gradient of EtOAc in hexanes (20-30%) to provide the title compound as a solid (450 mg, 36%). 'H NMR (400 MHz, CDCI3) 8 6.01 - 5.88 (m, 1H), 5.35 - 5.18 (m, 2H), 5.15 (dq, J= 10.3, 1.7 Hz, 1H), 5.09 - 4.96 (m, 2H), 4.89 - 4.55 (m, 1H), 4.48 - 4.20 (m, 1H), 4.14 (dt, J= 5.6, 1.5 Hz, 2H), 3.96 - 3.84 (m, 1H), 3.78 - 3.63 (m, 1H), 3.57 (d, J= 7.1 Hz, 1H), 3.50 - 3.35 (m, 7H), 3.35 - 3.28 (m, 3H), 3.28 - 3.09 (m, 3H), 3.02 (t, J= 11.7 Hz, 1H), 2.75 (td, J= 16.1, 2.5 Hz, 1H), 2.33 - 1.22 (m, 37H), 1.09 - 0.82 (m, 14H). m / z (ES’) [M-H]’ = 872.6; HPLC (A05) tR= 2.21 min.

[0385] Step 2: (E)-4-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-

[0386] I,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-17-pentyl-

[0387] II,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy- cyclohexoxy] but-2-enoic acid

[0388] Hovey da-Grubbs Catalyst® M720 (11.0 mg, 0.0175 mmol) was added to a degassed mixture of (17?,95,125,137?,145,177?,18E,215,235,247?,255,277?)-12-[(E)-2-[(17?,37?,47?)-4-allyloxy-3- methoxy-cyclohexyl]-l-methyl-vinyl]-l,14-dihydroxy-23,25-dimethoxy-13,19,21,27- tetramethyl-17-pentyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (225 mg, 0.257 mmol) in toluene (2.48 mL) at 22 °C. The mixture was stirred at 80 °C for 20 min and concentrated. The residue was purified by silica gel column chromatography (14 g cartridge) using a gradient of MeOH in DCM (0-10%) to provide the title compound as a solid (115 mg, 49%).XH NMR (400 MHz, CDC13) 5 7.12 - 6.36 (m, 1H), 6.20 - 5.81 (m, 1H), 5.37 - 5.08 (m, 1H), 5.07 - 4.58 (m, 2H), 4.46 - 4.22 (m, 3H), 3.99 - 3.81 (m, 1H), 3.62 (m, 3H), 3.49 - 3.15 (m, 12H), 3.08 - 2.65 (m, 3H), 2.34 - 1.25 (m, 37H), 1.18 - 0.74 (m, 14H). One proton not observed. m / z (ES+) [M+NH4]+= 935.6; (A05) tR= 1.95 min.

[0389] Step 3: 4-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14- dihydroxy-23,25-dimethoxy-13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-17-pentyl-l 1,28- dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy- cyclohexoxy] butanoic acid

[0390]

[0391] (£)-4-[(l / ?,2 / ?,4 / ?)-4-[(E)-2-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14- dihydroxy -23 ,25-dimethoxy- 13,19,21 ,27-tetramethyl-2,3 , 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa- 4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy-cyclohexoxy]but-2-enoic acid (115 mg, 0.125 mmol) was added to a mixture of Pd / C (10.0 wt.%, 13.3 mg, 0.0125 mmol) in EtOAc (3.02 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated to provide the title compound as a solid (115 mg, 100%). m / z (ES+) [M+NH4]+= 937.5; HPLC (A05) tR = 1.98 min.

[0392] Step 4: 4-[(l / ?, 2R, 4 / ?)-4-[(E)-2- [(! / ?, 9S, 125.13 / ?, 145, HR, 18E.2LS.235, 24 / ?, 255, 27 / ?)-l, 14- dihydroxy-23,25-dimethoxy-13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-17-pentyl-l 1,28- dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy-cyclohexoxy]-V-(2-pyridyl)butanamide

[0393] HATU (52.3 mg, 0.137 mmol) was added to a mixture of 4-[(l / ?,2 / ?,4 / ?)-4-[(E)-2- [(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-23,25-dimethoxy- 13,19,21 ,27-tetramethyl-2,3 , 10,16-tetraoxo- 17-pentyl- 11 ,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-l-enyl]-2-methoxy-cyclohexoxy]butanoic acid (115 mg, 0.125 mmol), DIPEA (0.0535 mL, 0.312 mmol) and pyridin-2-amine (23.5 mg, 0.250 mmol) in dry DMF (0.565 mL) at 0 °C. The mixture was stirred at 22 °C for 20 h, and pyridin-2- amine (11.8 mg, 0.125 mmol) and HATU (52.3 mg, 0.137 mmol) were added at 22 °C. The mixture was stirred at 22 °C for 72 h and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (80-90%) to provide the title compound as a solid (60.0 mg, 48%). 'HNMR (400 MHz, CDCI3) 8 8.47 - 8.35 (m, 1H), 8.29 - 8.23 (m, 1H), 8.20 (d, J= 8.4 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.01 (dd, J= 7.3, 5.0 Hz, 1H), 5.35 - 5.16 (m, 1H), 5.11 - 4.95 (m, 2H), 4.88 - 4.55 (m, 1H), 4.46 - 4.20 (m, 1H), 3.98 - 3.84 (m, 1H), 3.75 - 3.51 (m, 4H), 3.49 - 3.22 (m, 11H), 3.22 - 2.96 (m, 3H), 2.83 - 2.47 (m, 3H), 2.39 - 1.13 (m, 39H), 1.11 - 0.78 (m, 14H). m / z (ES+) [M+H]+= 996.4; UHPLC (ACN_AmForm_QC_10min_Vl_65C) 1R = 7.49 min.

[0394] 1-040

[0395] 4-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2- [(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0396] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]but-2-ene-l-sulfonamide

[0397] Hovey da-Grubbs Catalyst® M720 (31.2 mg, 0.0498 mmol) was added to a degassed mixture of tacrolimus (400 mg, 0.498 mmol) and prop-2-ene-l -sulfonamide (250 mg, 2.06 mmol) in toluene (4.57 mL) at 22 °C. The mixture was stirred at 80 °C for 1 h, filtered, washed with EtOAc (3.00 mL), and the filtrate was concentrated. The residue was purified by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (45-55%) to provide the title compound as a solid (129 mg, 29%). 'H NMR (400 MHz, CDCI3) 8 5.89 - 5.70 (m, 1H), 5.70 - 5.52 (m, 1H), 5.39 - 5.21 (m, 2H), 5.13 - 4.77 (m, 3H), 4.62 - 4.11 (m, 1H), 4.06 - 3.82 (m, 1H), 3.77 - 3.66 (m, 2H), 3.66 - 3.45 (m, 3H), 3.45 - 3.17 (m, 12H), 3.09 - 2.40 (m, 5H), 2.39 - 1.12 (m, 29H), 1.11 - 0.82 (m, 11H). One proton not observed, m / z (ES+) [MHSEU]4= 914.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 4.94 min.

[0398] 1-017

[0399] 4-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2- [(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0400] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]butane-l-sulfonamide

[0401] 4-[(lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-l,14-dihydroxy-12-[(E)-2-[(lA,3A,4A)- 4-hydroxy-3 -methoxy-cy clohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27-tetramethyl- 2,3,10,16-tetraoxo-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-17-yl]but-2-ene-l- sulfonamide (175 mg, 0.195 mmol) was added to a mixture of Pd / C (10.0 wt.%, 20.8 mg, 0.0195 mmol) in EtOAc (4.70 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 1 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated. The residue was purified by silica gel chromatography (5 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (95.0 mg, 54%). 'H NMR (400 MHz, CDCI3) 6 5.38 - 5.17 (m, 1H), 5.15 - 4.95 (m, 3H), 4.70 - 4.39 (m, 2H), 4.30 - 4.08 (m, 1H), 4.04 - 3.87 (m, 1H), 3.77 - 3.64 (m, 1H), 3.64 - 3.48 (m, 2H), 3.46 - 3.17 (m, 12H), 3.16 - 2.91 (m, 4H), 2.82 - 2.54 (m, 2H), 2.46 - 1.13 (m, 34H), 1.12 - 0.77 (m, 11H). m / z (ES+) [M+NH4]+= 916.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 4.89 min.

[0402] 1-018

[0403] Step 1: (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-[(E)-4-(2,4- dioxoimidazolidin- l-yl)but-2-enyl] -1 , 14-dihydroxy- 12- [(E)-2- [(ll?,37?,41?)-4-hydroxy-3- methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-

[0404] 4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0405] Hovey da-Grubbs Catalyst® M720 (66.8 mg, 0.107 mmol) was added to a degassed mixture of tacrolimus (857 mg, 1.07 mmol) and l-allylimidazolidine-2, 4-dione (310 mg, 2.21 mmol) in DCE (9.80 mL) at 22 °C. The mixture was stirred at 80 °C for 15 min, and a mixture of 1- allylimidazolidine-2, 4-dione (310 mg, 2.21 mmol) in DCE (4.00 mL) was added at 80 °C. The mixture was stirred at 80 °C for 15 min and concentrated. The residue was purified by reverse phase chromatography (C18, 30 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (45- 55%) to provide the title compound as a solid (149 mg, 15%). m / z (ES+) [M+NH4]+= 933.6; HPLC (A05) tR= 1.60 min.

[0406] Step 2: (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-[4-(2,4-dioxoimidazolidin-l- yl)butyl]-l,14-dihydroxy-12-[(£)-2-[(ll?,37?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl- vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0407] ( 17?, 95, 125, 137?, 145, 177?, 18E, 215, 235, 247?, 255, 277?)- 17-[(E)-4-(2,4-dioxoimidazolidin- 1 -yl)but- 2-enyl]-l,14-dihydroxy-12-[(E)-2-[(17?, 37?, 47?)-4-hydroxy-3-methoxy-cy cl ohexyl]-l -methyl- vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene-2,3,10,16-tetrone (149 mg, 0.163 mmol) was added to a mixture of Pd / C (10.0 wt.%, 17.3 mg, 0.0163 mmol) in EtOAc (3.92 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated to provide the title compound as a solid (110 mg, 74%).JH NMR (400 MHz, CDCI3) 8 7.70 - 7.60 (m, 1H), 5.36 - 5.17 (m, 1H), 5.11 - 4.95 (m, 2H), 4.78 - 4.56 (m, 1H), 4.46 - 4.29 (m, 1H), 4.01 - 3.82 (m, 3H), 3.76 - 3.63 (m, 1H), 3.62 - 3.52 (m, 1H), 3.52 - 3.17 (m, 14H), 3.12 - 2.92 (m, 2H), 2.83 - 2.61 (m, 2H), 2.39 - 1.18 (m, 33H), 1.14 - 0.75 (m, 11H). Two protons not observed, m / z (ES+) fM+NEU]* = 935.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR = 4.92 min.

[0408] 1-019

[0409] Step 1: ( )-4-[(l / ?, 9S, 125, 13 / ?, 145, HR, 18E,215, 235, 24 / ?, 255, 27 / ?)-l,14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18- en-17-yl]but-2-enamide

[0410] Hovey da-Grubbs Catalyst® M720 (26.5 mg, 0.0423 mmol) was added to a degassed mixture of tacrolimus (500 mg, 0.622 mmol) and prop-2-enamide (840 mg, 11.8 mmol) in DCE (6.00 mL) at 22 °C. The mixture was stirred at 80 °C for 1 h and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (40-50%) to provide the title compound as a solid (92.0 mg, 18%). m / z (ES+) [M+H]+= 847.7; HPLC (A05) tR= 1.60 min.

[0411] Step 2: 4-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0412] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en-17-yl]butanamide

[0413] (E)-4-[(l A, 95, 125, 13R, 145, 17 / ?, 18E, 215, 235,247?, 255,27 / ?)- 1 , 14-dihydroxy- 12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3 -methoxy-cyclohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27- tetramethyl-2,3 , 10,16-tetraoxo- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-en- 17-yl]but-2- enamide (92.0 mg, 0.109 mmol) was added to a mixture of Pd / C (10.0 wt.%, 11.6 mg, 0.0109 mmol) in EtOAc (2.62 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washing with EtOAc (40.0 mL) and concentrated. The residue was purified by silica gel chromatography (5 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (54.0 mg, 59%).JH NMR (400 MHz, CDCI3) 8 5.65 - 5.45 (m, 1H), 5.39 - 5.17 (m, 2H), 5.14 - 4.96 (m, 2H), 4.78 - 4.58 (m, 1H), 4.54 - 4.38 (m, 1H), 4.02 - 3.82 (m, 1H), 3.74 - 3.54 (m, 2H), 3.44 - 3.24 (m, 12H), 3.23 - 2.63 (m, 4H), 2.33 - 1.25 (m, 34H), 1.19 - 0.76 (m, 11H). One proton not observed. m / z (ES+) [M+NH4]+= 866.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 4.66 min.

[0414] 1-020

[0415] Step 1: (l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / 0-1.14-dihydroxy-23.25- dimethoxy-12-[(£)-2-[(ll?,3^,41?)-3-methoxy-4-[(£')-3-(2-pyridyl)allyloxy]cyclohexyl]-l- methyl-vinyl]-13,19,21,27-tetramethyl-17-pentyl-ll,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0416] Hovey da-Grubbs Catalyst® M720 (16.1 mg, 0.0257 mmol) was added to a degassed mixture of (lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-12-[(E)-2-[(lA,3A,4A)-4-allyloxy-3- methoxy-cyclohexyl]-l-methyl-vinyl]-l,14-dihydroxy-23,25-dimethoxy-13,19,21,27- tetramethyl-17-pentyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (150 mg, 0.172 mmol) and 2-vinylpyridine (0.0203 mL, 0.189 mmol) in DCE (1.66 mL) at 22 °C. The mixture was stirred at 100 °C in a microwave reactor for 30 min and concentrated. The residue was purified by silica gel column chromatography (14 g cartridge) using a gradient of EtOAc in hexanes (40-100%) to provide the title compound as a solid (62.0 mg, 38%). m / z (ES+) [M+H]+= 951.8; (A05) tR= 2.18 min.

[0417] Step 2: (l / ?.9.S.12.S.13 / ?.14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / ?)-1.14-dihydroxy-23.25- dimethoxy-12-[(£)-2-[(ll?,31?,41?)-3-methoxy-4-[3-(2-pyridyl)propoxy]cyclohexyl]-l-methyl- vinyl]-13, 19,21, 27-tetramethyl-17-pentyl-ll, 28-dioxa-4-azatricy clo[22.3.1.04, 9]octacos-18- ene-2,3,10,16-tetrone

[0418] (lA,95,125,13A,145,17A,18E,215,235,24A,255,27A)-l,14-dihydroxy-23,25-dimethoxy-12-[(E)- 2-[(lA,3A,4A)-3-methoxy-4-[(£)-3-(2-pyridyl)allyloxy]cyclohexyl]-l-methyl-vinyl]-13,19,21,27- tetramethyl-17-pentyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone (110 mg, 0.116 mmol) was added to a mixture of Pd / C (10.0 wt.%, 12.3 mg, 0.0116 mmol) in EtOAc (2.78 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 2 h under EE. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NELXEICO?)] and MeCN (85-95%) to provide the title compound as a solid (54.5 mg, 49%).JH NMR (400 MHz, CDCI3) 6 8.54 - 8.49 (m, 1H), 7.61 - 7.54 (m, 1H), 7.20 - 7.13 (m, 1H), 7.12 - 7.05 (m, 1H), 5.35 - 5.15 (m, 1H), 5.08 - 4.95 (m, 2H), 4.88 - 4.54 (m, 1H), 4.47 - 4.16 (m, 1H), 3.89 (m, 1H), 3.77 - 3.52 (m, 4H), 3.52 - 3.17 (m, 11H), 3.15 - 2.97 (m, 3H), 2.91 - 2.68 (m, 3H), 2.39 - 1.13 (m, 37H), 1.11 - 0.76 (m, 14H). Two protons not observed, m / z (ES+) [M+H]+= 953.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 7.78 min.

[0419] 1-030

[0420] Step 1: 3-allylimidazolidine-2, 4-dione

[0421] A mixture of KOH (1.87 g, 30.0 mmol) and hydantoin (3.00 g, 30.0 mmol) in EtOH (250 mL) was stirred at 70 °C for 2 h. 3 -Bromoprop- 1-ene (3.37 mL, 39.0 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The mixture was filtered, concentrated, and diluted with water (150 mL) and DCM (150 mL). The aqueous phase was extracted with DCM / MeOH (9: 1, 3 x 100 mL), and the combined organic extracts were washed with brine (150 mL), dried (Na2SO4), filtered, and concentrated to provide the title compound as a solid (2.60 g, 62%).1H NMR (400 MHz, DMSO-ifc) 6 8.06 (s, 1H), 5.86 - 5.69 (m, 1H), 5.16 - 5.02 (m, 2H), 3.96 - 3.92 (m, 4H). Step 2: (lR,9S,12S,13R,14S,nR,18E,21S,23S,24R,25S,21R)-n-[(E)-4-(2,5- dioxoimidazolidin- l-yl)but-2-enyl] -1 , 14-dihydroxy- 12- [(E)-2- [(ll?,37?,41?)-4-hydroxy-3- methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa- 4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0422] Hovey da-Grubbs Catalyst® M720 (117 mg, 0.187 mmol) was added to a degassed mixture of tacrolimus (1.00 g, 1.24 mmol) and 3 -allylimidazolidine-2, 4-dione (1.04 g, 7.46 mmol) in DCE (10.0 mL) at 22 °C. The mixture was stirred at 80 °C for 1 h and concentrated. The residue was purified by reverse phase chromatography (C18, 30 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (10-100%) to provide the title compound as a solid (203 mg, 18%). 'H NMR (400 MHz, CD3OD) 5 5.64 - 5.38 (m, 2H), 5.28 - 5.05 (m, 2H), 4.92 - 4.86 (m, 1H), 4.61 (s, 1H), 4.34 (d, J= 13.8 Hz, 1H), 4.14 - 3.88 (m, 5H), 3.79 - 3.69 (m, 1H), 3.67 - 3.43 (m, 3H), 3.42 - 3.33 (m, 10H), 3.08 - 2.94 (m, 2H), 2.90 - 2.70 (m, 1H), 2.47 - 1.85 (m, 12H), 1.85 - 1.04 (m, 18H), 1.05 - 0.83 (m, 10H). Four protons not observed, m / z (ES+) [M+NH4]+= 933.5; UHPLC (ACN_TFA_QC_10min_Vl_65C) tR= 4.80 min.

[0423] 1-021

[0424] (l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-17-[4-(2,5-dioxoimidazolidin-l- yl)butyl]-l,14-dihydroxy-12-[(£)-2-[(ll?,37?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl- vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

[0425] ( 17?, 95, 125, 137?, 145, 177?, 18E, 215, 235, 247?, 255, 277?)- 17-[(E)-4-(2,5-dioxoimidazolidin- 1 -yl)but-

[0426] 2-enyl]-l,14-dihydroxy-12-[(E)-2-[(17?, 37?, 47?)-4-hydroxy-3-methoxy-cy cl ohexyl]-l -methyl- vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-l l,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene-2,3,10,16-tetrone (225 mg, 0.246 mmol) was added to a mixture of Pd / C (10.0 wt.%, 26.1 mg, 0.0246 mmol) in EtOAc (5.00 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated to provide the title compound as a solid (182 mg, 81%). 'H NMR (400 MHz, CDC13) 8 5.41 (S, 1H), 5.35 - 5.17 (m, 1H), 5.14 - 4.95 (m, 2H), 4.59 (d, J= 5.3 Hz, 1H), 4.42 (d, J= 13.7 Hz, 1H), 3.99 - 3.82 (m, 3H), 3.75 - 3.64 (m, 1H), 3.62 - 3.53 (m, 1H), 3.53 - 3.46 (m, 2H), 3.42 - 3.24 (m, 11H), 3.08 - 2.91 (m, 2H), 2.81 - 2.64 (m, 1H), 2.33 - 1.85 (m, 12H), 1.84 - 1.69 (m, 4H), 1.69 - 1.57 (m, 10H), 1.57 - 1.23 (m, 8H), 1.10 - 0.77 (m, 11H). Three protons not observed, m / z (ES+) [M+NH4] = 935.5; UHPLC (ACN_AmForm_QC_10min_Vl_65C) tR= 4.86 min.

[0427] 1-022 Step 1: ( 1 / L9.S.12.S.13 / L14.S.17 / ?.18E.2LS.23.S.24 / ?.25.S.27 / ?)-l 7-|(E)-4-aminobiit-2-enyl|- 1 J4-dihydroxy-12-|( / :)-2-|( l / ?.3 / ?.4 / ?)-4-hydroxy-3-methoxy-cyclohexyl|-l-methyl-vinyl|- 23, 25-dimethoxy-13, 19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- ene-2,3,10,16-tetrone

[0428] Trifluoromethanesulfonic acid (8.23 mL, 93.3 mmol) was added dropwise to a mixture of prop-2 - en-l-amine (6.98 mL, 93.3 mmol) in EtOAc (60.0 mL) at 0 °C. Tacrolimus (5.00 g, 6.22 mmol) was added at 22 °C, the mixture was degassed with N2, and Hovey da-Grubbs Catalyst® M720 (265 mg, 0.423 mmol) was added at 22 °C. The mixture was stirred at 80 °C for 30 min, and Hovey da-Grubbs Catalyst® M720 (265 mg, 0.423 mmol) was added at 80 °C. The mixture was stirred at 80 °C for 30 min, cooled to 22 °C, washed with NaHCCL (0.500 M in water, 80.0 mL), and the organic phase was concentrated. The residue was purified by reverse phase chromatography (Cl 8, 51 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (30-40%) and concentrated. The residue was diluted with EtOAc (80.0 mL), washed with sat. aq. NaHCOs (80.0 mL) and concentrated to provide the title compound as a solid (1.15 g, 22%). m / z (ES+) [M+H]+= 833.6; HPLC (A05) tR= 1.49 min.

[0429] Step 2: [(E)-4-[(l / ?,95,125,13 / ?,145,17 / ?,18E,215,235,24 / ?,255,27 / ?)-l,14-dihydroxy-12-[(E)- 2-[(ll?,31?,41?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy-

[0430] 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en- 17-yl] but-2-enyl] urea

[0431] DIPEA (77.1 pL, 0.450 mmol) was added to a mixture of

[0432] ( 17?, 95, 125, 137?, 145, 177?, 18E, 215, 235, 247?, 255, 277?)- 17-[(E)-4-aminobut-2-enyl]- 1,14- dihydroxy-12-[(7f)-2-[(17?,37?,47?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25- dimethoxy- 13,19,21 ,27-tetram ethyl- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene- 2,3,10,16-tetrone (250 mg, 0.300 mmol), phenyl carbamate (45.3 mg, 0.330 mmol), and DMAP (2.72 mg, 0.0222 mmol) in dry THF (2.17 mL) at 22 °C. The mixture was stirred at 45 °C for 12 h and concentrated. The residue was purified by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (35-45%) to provide the title compound as a solid (101 mg, 38%). m / z (ES+) [M+H]+= 876.7; HPLC (A05) tR= 1.62 min.

[0433] Step 3: 4-[(17?, 95, 125, 13 / ?, 145, 17 / ?.18E,215,235, 24 / ?, 255, 277?)-!, 14-dihydroxy-12-[(E)-2- [(l / ?,3 / ?,4 / ?)-4-hydroxy-3-methoxy-cyclohexyl]-l-methyl-vinyl]-23,25-dimethoxy- 13, 19,21, 27-tetramethyl-2, 3,10, 16-tetraoxo-ll,28-dioxa-4-azatricyclo[22.3.1.04, 9]octacos-18- en- 17-yl] butylurea [(E)-4-[(17?,95,125,137?,145,177?,18E,215,235,247?,255,277?)-l,14-dihydroxy-12-[(E)-2- [(17?,37?,47?)-4-hydroxy-3 -methoxy-cyclohexyl]- 1 -methyl-vinyl]-23 ,25-dimethoxy- 13,19,21 ,27- tetramethyl-2,3 , 10,16-tetraoxo- 11 ,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-en- 17-yl]but-2- enyl]urea (123 mg, 0.140 mmol) was added to a mixture of Pd / C (10.0 wt.%, 29.9 mg, 0.0281 mmol) in EtOAc (3.38 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 3 h under H2. The mixture was filtered through Celite, washed with EtOAc (40.0 mL) and concentrated. The residue was purified by silica gel chromatography (5 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a soli...

Claims

CLAIMSWhat is claimed is:

1. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I:wherein:LAis optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted C2-12 alkylene, or C2-12 alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-6 alkyl);RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5- membered heteroaryl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, - ORA1, -SCN, -SRA1, -SSRA1, -N3, -NO, -N(RA1)2, -NO2, -N=S(=O)(RA1)2, - N=S(=O)(RA1)ORA1, -N=S(=O)(RA1)SRA1, -N=S(=O)(RA1)N(RA1)2, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -C(=O)N(RA1)S(=O)RA1, -C(=O)N(RA1)S(=O)ORA1, - C(=O)N(RA1)-S(=O)SRA1, -C(=O)N(RA1)S(=O)N(RA1)2, -C(=O)N(RA1)S(=O)2RA1, - C(=O)N(RA1)S(=O)2ORA1, -C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, - C(=NRA1)RA1, -C(=NRA1)ORA1, -C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, - S(=O)ORA1, -S(=O)SRA1, -S(=O)N(RA1)2, -S(=O)(=NRA1)RA1, -S(=O)(=NRA1)ORA1, - S(=O)(=NRA1)SRA1, -S(=O)(=NRA1)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, - S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, -263S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)SRA1, -OC(=O)N(RA1)2, - OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, -OC(=NRA1)N(RA1)2, -OS(=O)RA1, - OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, - SC(=NRA1)RA1, -SC(=NRA1)ORA1, -SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, - NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, - NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, -NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, - NRA1S(=O)ORA1, -NRA1S(=O)SRA1, -NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, - NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, -NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, - Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, -OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, - B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, -P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, - OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; each instance of RA1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RA1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; provided that -LA-RAis not any one of-(CH2)3-(unsubstituted pyridinyl), -(CH2)3- (unsubstituted pyridine- 1 -oxide), -CH2CH=CH-(unsubstituted pyridinyl), -CH2CH=CH- (unsubstituted pyridine- 1 -oxide), -(CH2)3-C(=O)NH-(unsubstituted pyridinyl), -(CH2)3- C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3-hydroxy-oxetan-3-yl), and -(CH2)3-S-( substituted Ci-3alkyl);~ RBis =0 or -0RB1;RB1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;Rcis -ORC1or hydrogen;RC1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;RDis -0RD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -N02, -N=S(=0)(RD1)2, - N=S(=0)(RD1)0RD1, -N=S(=O)(RD1)SRD1, -N=S(=0)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=0)N(RD1)2, -S(=0)(=NRD1)RD1, -S(=0)(=NRD1)0RD1, -S(=O)(=NRD1)SRD1, -S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, - NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, -OP(=O)(ORD1)2, -CN, halogen, or optionally substituted heteroaryl; each instance of RD1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RD1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;REis =0 or -0RE1; andRE1is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:RAis -S(=O)2N(RA1)2, hydrogen, halogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted monocyclic 5- membered heteroaryl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, -0RA1, -SCN, -SRA1, -SSRA1, -N3, -NO, - N(RA1)2, -N02, -N=S(=0)(RA1)2, -N=S(=0)(RA1)0RA1, -N=S(=O)(RA1)SRA1, -N=S(=O)(RA1)N(RA1)2, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, - C(=O)N(RA1)S(=O)RA1, -C(=O)N(RA1)S(=O)ORA1, -C(=O)N(RA1)-S(=O)SRA1, - C(=O)N(RA1)S(=O)N(RA1)2, -C(=O)N(RA1)S(=O)2RA1, -C(=O)N(RA1)S(=O)2ORA1, - C(=O)N(RA1)S(=O)2SRA1, -C(=O)N(RA1)S(=O)2N(RA1)2, -C(=NRA1)RA1, -C(=NRA1)ORA1, - C(=NRA1)SRA1, -C(=NRA1)N(RA1)2, -S(=O)RA1, -S(=O)ORA1, -S(=O)SRA1, -S(=O)N(RA1)2, - S(=O)(=NRA1)RA1, -S(=O)(=NRA1)ORA1, -S(=O)(=NRA1)SRA1, -S(=O)(=NRA1)N(RA1)2, - S(=O)2RA1, -S(=O)2ORA1, -S(=O)2SRA1, -S(=O)2N(RA1)C(=O)RA1, -S(=O)2N(RA1)C(=O)ORA1, -S(=O)2N(RA1)C(=O)SRA1, -S(=O)2N(RA1)C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, - OC(=O)SRA1, -OC(=O)N(RA1)2, -OC(=NRA1)RA1, -OC(=NRA1)ORA1, -OC(=NRA1)SRA1, - OC(=NRA1)N(RA1)2, -OS(=O)RA1, -OS(=O)ORA1, -OS(=O)SRA1, -OS(=O)N(RA1)2, - OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2SRA1, -OS(=O)2N(RA1)2, -ON(RA1)2, -SC(=O)RA1, - SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, -SC(=NRA1)RA1, -SC(=NRA1)ORA1, - SC(=NRA1)SRA1, -SC(=NRA1)N(RA1)2, -NRA1C(=O)RA1, -NRA1C(=O)ORA1, -NRA1C(=O)SRA1, -NRA1C(=O)N(RA1)2, -NRA1C(=NRA1)RA1, -NRA1C(=NRA1)ORA1, -NRA1C(=NRA1)SRA1, - NRA1C(=NRA1)N(RA1)2, -NRA1S(=O)RA1, -NRA1S(=O)ORA1, -NRA1S(=O)SRA1, - NRA1S(=O)N(RA1)2, -NRA1S(=O)2RA1, -NRA1S(=O)2ORA1, -NRA1S(=O)2SRA1, - NRA1S(=O)2N(RA1)2, -Si(RA1)3, -Si(RA1)2ORA1, -Si(RA1)(ORA1)2, -Si(ORA1)3, -OSi(RA1)3, - OSi(RA1)2ORA1, -OSi(RA1)(ORA1)2, -OSi(ORA1)3, -B(ORA1)2, -OB(ORA1)2, -P(=O)(RA1)2, - P(=O)(RA1)ORA1, -P(=O)(ORA1)2, -OP(=O)(RA1)2, -OP(=O)(RA1)ORA1, or -OP(=O)(ORA1)2; provided that -LA-RAis not any one of-(CH2)3-C(=O)NH-(unsubstituted pyridinyl), - (CH2)3-C(=O)OH, -CH2CH=CH2, -CH2CH=CH-C(=O)OH, -CH2CH=CH-(3 -hydroxy-ox etan- 3-yl), and -(CH2)3-S-( substituted Ci-3alkyl); andRDis -ORD1, -SCN, -SRD1, -SSRD1, -N3, -NO, -N(RD1)2, -NO2, -N=S(=O)(RD1)2, - N=S(=O)(RD1)ORD1, -N=S(=O)(RD1)SRD1, -N=S(=O)(RD1)N(RD1)2, -S(=O)RD1, -S(=O)ORD1, - S(=O)SRD1, -S(=O)N(RD1)2, -S(=O)(=NRD1)RD1, -S(=O)(=NRD1)ORD1, -S(=O)(=NRD1)SRD1, - S(=O)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=O)2N(RD1)C(=O)RD1, -S(=O)2N(RD1)C(=O)ORD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -OC(=O)RD1, -OC(=O)ORD1, -OC(=O)SRD1, -OC(=O)N(RD1)2, - OC(=NRD1)RD1, -OC(=NRD1)ORD1, -OC(=NRD1)SRD1, -OC(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -OS(=O)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -ON(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=O)N(RD1)2, - SC(=NRD1)RD1, -SC(=NRD1)ORD1, -SC(=NRD1)SRD1, -SC(=NRD1)N(RD1)2, -NRD1C(=O)RD1, - NRD1C(=O)ORD1, -NRD1C(=O)SRD1, -NRD1C(=O)N(RD1)2, -NRD1C(=NRD1)RD1, - NRD1C(=NRD1)ORD1, -NRD1C(=NRD1)SRD1, -NRD1C(=NRD1)N(RD1)2, -NRD1S(=O)RD1, - NRD1S(=O)ORD1, -NRD1S(=O)SRD1, -NRD1S(=O)N(RD1)2, -NRD1S(=O)2RD1, -266NRD1S(=O)2ORD1, -NRD1S(=O)2SRD1, -NRD1S(=O)2N(RD1)2, -OSi(RD1)3, -OSi(RD1)2ORD1, - OSi(RD1)(ORD1)2, -OSi(ORD1)3, -B(ORD1)2, -OB(ORD1)2, -P(=O)(RD1)2, -P(=O)(RD1)ORD1, - P(=O)(ORD1)2, -OP(=O)(RD1)2, -OP(=O)(RD1)ORD1, or -OP(=O)(ORD1)2.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein LAis unsubstituted C2-6 alkylene.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein LAis -(CH2)3-, -(CH2)4- or -(CH2)s-5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein LAis C2-6 alkylene substituted with one or more -OH.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein LAis unsubstituted C2-6 alkenylene.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein — LAis — CH2CH=CH-, — CH2CH=CHCH2-, or — CH2CH=CH(CH2)2-8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein LAis C2-6 alkenylene substituted with one or more -F.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -S(=O)2N(RA1)2.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or267prodrug thereof, wherein RAis -S(=O)2NH2, -S(=O)2NH(optionally substituted Ci-6 alkyl), or - S(=O)2N(optionally substituted Ci-6 alkyl)2.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -B(0RA1)2.

12. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -C(=0)N(RA1)2, -C(=O)ORA1, or -NRA1C(=0)N(RA1)2.

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis hydrogen.

14. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis optionally substituted monocyclic 5-membered heteroaryl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, or optionally substituted polycyclic heteroaryl.

15. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis optionally substituted pyridinyl.

16. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis optionally substituted heterocyclyl.

17. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis monocyclic 5-membered heterocyclyl that comprises at least one nitrogen atom in the heterocyclic ring system and attached to LAand is substituted at least with oxo.

18. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or0or optionally substituted C^g alkyl) prodrug thereof, wherein RAis halogen or optionally substitutedalkyl)0.40 0 or optionally substituted C^g alkyl) / ""N^O0 (halogen or optionally substitutedalkyl)0.2(halogen or optionally substituted C^g alkyl)0-40 -0 (halogen or optionally substituted C^g alkyl)0-2 or(halogen or optionally substituted C^g alkyl)0-619. The compound of any one of claims 1-8, a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis optionally substituted oxetanyl.

20. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -N=S(=O)(RA1)2.

21. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -ORA1.

22. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -P(=O)(RA1)2 or -P(=O)(ORA1)2.

23. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -C(=0)N(RA1)S(=0)2RA1, -NRA1S(=0)2RA1, - NRA1S(=O)2N(RA1)2, -S(=O)RA1, -S(=O)(=NRA1)RA1, -S(=O)2RA1, -S(=O)2N(RD1)2, or - S(=O)2N(RD1)C(=O)N(RD1)2.

24. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -NRA1S(=0)2RA1.

25. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -NHS(=O)2(optionally substituted Ci-6 alkyl).

26. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RAis -S(=O)(optionally substituted Ci-6 alkyl) or -S(=O)-(CH2)I-3- (optionally substituted 3- to 7-membered monocyclic heterocyclyl).

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of RA1is independently hydrogen or optionally substituted Ci-6 alkyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein = RBis =0.

29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein = RBis -OH.

30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the carbon atom to which RBis attached is of the S configuration.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RB1is hydrogen or optionally substituted Ci-6 alkyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rcis -OH.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rcis -©(optionally substituted alkyl).

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the carbon atom to which Rcis attached is of the S configuration.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RC1is hydrogen or optionally substituted Ci-6 alkyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -ORD1.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of RD1is optionally substituted alkyl or optionally substituted alkenyl.

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: at least one instance of RD1is alkyl or alkenyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of -ORaa,271-C(=O)ORaa, -C(=0)N(Rbb)2, -S(=O)2N(Rbb)2, 3-14 membered heterocyclyl, and 5-14 membered heteroaryl; each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, Ci-20 alkenyl, C1-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X , -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -0C(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi-ioalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,272heteroalkenyl, 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; each instance of Reeis, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, Ci-io alkenyl, Ci-io alkynyl, heteroCi-io alkyl, heteroCi-io alkenyl, heteroCi-io alkynyl, 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, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, 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-6 alkyl)2, -N(CI-6 alkyl ) X , -NH(Ci6alkyl )2X , -NH2(CI-6 alkyl) X , -NH3X , -N(OCI-6 alkyl)(Ci-6 alkyl), -N(OH)(CI-6 alkyl), -NH(OH), -SH, -SC ; alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci 6 alkyl), -OC(=O)(C1 6 alkyl), -OCO2(Ci6alkyl), -C(=O)NH2, -C(=O)N(Ci6alkyl)2, -OC(=O)NH(Ci6alkyl), -NHC(=O)( Ci^ alkyl), -N(CI-6 alkyl)C(=O)( Ci^ alkyl), -NHCO2(CI 6 alkyl), -NHC(=O)N(Ci6alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=0)NH2, -C(=NH)O(Ci^ alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCi6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(Ci6alkyl), -C(=NH)NH2, -OC(=NH)N(CI6alkyl)2, -OC(NH)NH(Ci6alkyl), -0C(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI^ alkyl), -SO2N(CI 6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2C1 6 alkyl, -SO2OC16alkyl, -OSO2C1 6 alkyl, -SOCi6alkyl, -Si(Ci-6 alkyl)3, -OSi(Ci6alkyl)3-C(=S)N(CI-6 alkyl)2, C(=S)NH(Ci6alkyl), C(=S)NH2, -C(=O)S(CI-6 alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6 alkyl)2, -P(=O)(Ci^ alkyl)2, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OCi6alkyl)2, C1-10 alkyl, Ci-io perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents are joined to form =0 or =S; and each X is a counterion.27339. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RD1is unsubstituted C1-3 alkyl.

40. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -OH.

41. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -©(optionally substituted C1-6 alkyl) or -©(optionally substituted C2-6 alkenyl).

42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -OMe, -OEt, -O(w-Pr), or -O(z-Pr).

43. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -O-(CH2)I-6-OH or -O-CH2-CH=CH-CH2- S(=O)2NH(optionally substituted C1-6 alkyl).

44. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -P(=O)(ORD1)2.

45. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -OC(=O)RD1or -OP(=O)(RD1)2.

46. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -O-(CH2)i-6-(optionally substituted heterocyclyl) or -O- (optionally substituted heteroaryl).27447. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis -CN or halogen.

48. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis optionally substituted heteroaryl.

49. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein RDis optionally substituted tetrazolyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein = REis =0.

51. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein = REis -OH.

52. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein = REis -©(optionally substituted Ci-6 alkyl).

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the carbon atom to which REis attached is of the R configuration.

54. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 1, Table 1 A, and Table IB.27555. The compound of claim 54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula 1-014.

56. The compound of claim 54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula 1-046.

57. The compound of claim 54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula 1-017, 1-025, 1-028, 1-029, 1-034, 1-036, 1-038, 1- 042, 1-045, 1-046, 1-048, 1-049, 1-050, 1-052, 1-053, 1-054, 1-055, 1-056, 1-057, 1-061, 1-062, 1-063, 1-064, or 1-065.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is unable to cross the blood-brain barrier.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof.

60. A pharmaceutical composition comprising: the compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.

61. A kit comprising: the compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 60; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.27662. A method comprising administering to a subject the compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 60.

63. The method of claim 62, further comprising administering to the subject an anti-CNS disease drug.

64. The method of claim 62 or 63, wherein the subject has, is suspected of having, or is at risk of having a disease of the central nervous system.

65. The method of claim 64, wherein the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or pharmaceutical composition, and the amount of the anti-CNS disease drug, are effective in treating the disease of the central nervous system.

66. The method of any one of claims 62-65, wherein the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition, is administered by intravenous administration.

67. The method of any one of claims 62-66, wherein the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition, is administered by oral administration.

68. The method of any one of claims 62-67, wherein the anti-CNS disease drug is able to cross the blood-brain barrier.

69. The method of any one of claims 62-68, wherein the subject is a human.

70. A method comprising contacting a cell, tissue, or biological sample with the compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 60.27771. The method of claim 70, wherein the cell, tissue, or biological sample is in vitro.

72. The method of claim 70, wherein the cell, tissue, or biological sample is in vivo.

73. The method of any one of claims 70-72, further comprising contacting the cell, tissue, or biological sample with an anti-CNS disease drug.

74. The method of any one of claims 70-73, wherein the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition is effective in binding FK506-binding protein 12 (FKBP12).

75. The method of any one of claims 70-74, wherein the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition is effective in binding FK506-binding protein (FKBP) 12.6, FKBP13, FKBP25, FKBP52, FKBP51, FKBP36, FKBP23, FKBP38, FKBP60, FKBP65, FKBP19, FKBP22, FKBP133, FKBP16, and / or FKBP37.278

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