Central nervous system-selective activity of LXR agonists

Abstract

Aspects of the disclosure related to methods of administering LXR agonists with peripheral blocker compounds for use in reducing peripheral side effects.

Description

[0001] CENTRAL NERVOUS SYSTEM-SELECTIVE ACTIVITY OF LXR AGONISTS

[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 / 693,153, filed September 10, 2024, and U.S. Provisional Patent Application U.S.S.N. 63 / 807,488, 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 central nervous system-selective activity of LXR agonists by administering LXR agonists with novel peripheral blocker compounds using Brain- Only™ pharmacology technology. Methods and compositions disclosed herein can be used to reduce peripheral side effects of LXR agonists.

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

[0009] M1668.70004WQ00 1 / 511 (II- A) or (II-B), wherein:

[0010] L° is a linker, wherein the linker comprises in the backbone of the linker two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted;

[0011] R° is a radical of a liver X receptor (LXR) binder;

[0012] L1is optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted alkylene, or alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted Ci-6 alkyl);

[0013] R1is hydrogen, -S(=O)2N(R1A)2, 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, - OR1A, -SCN, -SR1A, -SSR1A, -N3, -NO, -N(R1A)2, -NO2, -N=S(=O)(R1A)2, - N=S(=O)(R1A)OR1A, -N=S(=O)(R1A)SR1A, -N=S(=O)(R1A)N(R1A)2, -C(=O)R1A, -C(=O)OR1A, -C(=O)SR1A, -C(=O)N(R1A)2, -C(=O)N(R1A)S(=O)R1A, -C(=O)N(R1A)S(=O)OR1A, - C(=O)N(R1A)-S(=O)SR1A, -C(=O)N(R1A)S(=O)N(R1A)2, -C(=O)N(R1A)S(=O)2R1A, - C(=O)N(R1A)S(=O)2OR1A, -C(=O)N(R1A)S(=O)2SR1A, -C(=O)N(R1A)S(=O)2N(R1A)2, - C(=NR1A)R1A, -C(=NR1A)OR1A, -C(=NR1A)SR1A, -C(=NR1A)N(R1A)2, -S(=O)R1A, - S(=O)OR1A, -S(=O)SR1A, -S(=O)N(R1A)2, -S(=O)(=NR1A)R1A, -S(=O)(=NR1A)OR1A, - S(=O)(=NR1A)SR1A, -S(=O)(=NR1A)N(R1A)2, -S(=O)2R1A, -S(=O)2OR1A, -S(=O)2SR1A, - S(=O)2N(R1A)C(=O)R1A, -S(=O)2N(R1A)C(=O)OR1A, -S(=O)2N(R1A)C(=O)SR1A, - S(=O)2N(R1A)C(=O)N(R1A)2, -OC(=O)R1A, -OC(=O)OR1A, -OC(=O)SR1A, -OC(=O)N(R1A)2, - OC(=NR1A)R1A, -OC(=NR1A)OR1A, -OC(=NR1A)SR1A, -OC(=NR1A)N(R1A)2, -OS(=O)R1A, - OS(=O)OR1A, -OS(=O)SR1A, -OS(=O)N(R1A)2, -OS(=O)2R1A, -OS(=O)2OR1A, -OS(=O)2SR1A, -OS(=O)2N(R1A)2, -ON(R1A)2, -SC(=O)R1A, -SC(=O)OR1A, -SC(=O)SR1A, -SC(=O)N(R1A)2, - SC(=NR1A)R1A, -SC(=NR1A)OR1A, -SC(=NR1A)SR1A, -SC(=NR1A)N(R1A)2, -NR1AC(=O)R1A, - NR1AC(=O)OR1A, -NR1AC(=O)SR1A, -NR1AC(=O)N(R1A)2, -NR1AC(=NR1A)R1A, - NR1AC(=NR1A)OR1A, -NR1AC(=NR1A)SR1A, -NR1AC(=NR1A)N(R1A)2, -NR1AS(=O)R1A, - NR1AS(=O)OR1A, -NR1AS(=O)SR1A, -NR1AS(=O)N(R1A)2, -NR1AS(=O)2R1A, - NR1AS(=O)2OR1A, -NR1AS(=O)2SR1A, -NR1AS(=O)2N(R1A)2, -Si(R1A)3, -Si(R1A)2OR1A, - Si(R1A)(OR1A)2, -Si(OR1A)3, -OSi(R1A)3, -OSi(R1A)2OR1A, -OSi(R1A)(OR1A)2, -OSi(OR1A)3, -

[0014] M1668.70004WQ00 2 / 511 B(OR1A)2, -OB(OR1A)2, -P(=O)(R1A)2, -P(=O)(R1A)OR1A, -P(=O)(OR1A)2, -OP(=O)(R1A)2, - OP(=O)(R1A)OR1A, or -OP(=O)(OR1A)2; each instance of R1Ais 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 RN1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;

[0015] = R2is =0 or -0R2A;

[0016] R2Ais 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;

[0017] R3is -0R3Aor hydrogen;

[0018] R3Ais 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] R4is -0R4A, -SCN, -SR4A, -SSR4A, -N3, -NO, -N(R4A)2, -N02, -N=S(=O)(R4A)2, - N=S(=O)(R4A)OR4A, -N=S(=O)(R4A)SR4A, -N=S(=O)(R4A)N(R4A)2, -S(=O)R4A, -S(=O)OR4A, - S(=O)SR4A, -S(=O)N(R4A)2, -S(=O)(=NR4A)R4A, -S(=O)(=NR4A)OR4A, -S(=O)(=NR4A)SR4A, - S(=O)(=NR4A)N(R4A)2, -S(=O)2R4A, -S(=O)2OR4A, -S(=O)2SR4A, -S(=O)2N(R4A)2, - S(=O)2N(R4A)C(=O)R4A, -S(=O)2N(R4A)C(=O)OR4A, -S(=O)2N(R4A)C(=O)SR4A, - S(=O)2N(R4A)C(=O)N(R4A)2, -0C(=0)R4A, -0C(=0)0R4A, -OC(=O)SR4A, -OC(=O)N(R4A)2, - OC(=NR4A)R4A, -OC(=NR4A)OR4A, -OC(=NR4A)SR4A, -OC(=NR4A)N(R4A)2, -OS(=O)R4A, - OS(=O)OR4A, -OS(=O)SR4A, -OS(=O)N(R4A)2, -OS(=O)2R4A, -OS(=O)2OR4A, -OS(=O)2SR4A, -OS(=O)2N(R4A)2, -ON(R4A)2, -SC(=O)R4A, -SC(=O)OR4A, -SC(=O)SR4A, -SC(=O)N(R4A)2, - SC(=NR4A)R4A, -SC(=NR4A)OR4A, -SC(=NR4A)SR4A, -SC(=NR4A)N(R4A)2, -NR4AC(=O)R4A, - NR4AC(=O)OR4A, -NR4AC(=O)SR4A, -NR4AC(=O)N(R4A)2, -NR4AC(=NR4A)R4A, - NR4AC(=NR4A)OR4A, -NR4AC(=NR4A)SR4A, -NR4AC(=NR4A)N(R4A)2, -NR4AS(=O)R4A, - NR4AS(=O)OR4A, -NR4AS(=O)SR4A, -NR4AS(=O)N(R4A)2, -NR4AS(=O)2R4A, - NR4AS(=O)2OR4A, -NR4AS(=O)2SR4A, -NR4AS(=O)2N(R4A)2, -OSi(R4A)3, -OSi(R4A)2OR4A, - OSi(R4A)(OR4A)2, -OSi(OR4A)3, -B(OR4A)2, -OB(OR4A)2, -P(=O)(R4A)2, -P(=O)(R4A)OR4A, - P(=O)(OR4A)2, -OP(=O)(R4A)2, -OP(=O)(R4A)OR4A, -OP(=O)(OR4A)2, -CN, halogen, or optionally substituted heteroaryl;

[0020] M1668.70004WQ00 3 / 511 each instance of R4Ais 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 R4Aattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;

[0021] = R5is =0 or -0R5A; and

[0022] R5Ais 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.

[0023] In another aspect, the present disclosure provides chimeras, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein the chimera is of the formula: wherein:

[0024] L° is a linker, wherein the linker comprises in the backbone of the linker two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted;

[0025] R° is a radical of a liver X receptor (LXR) binder;

[0026] L11Ais optionally substituted alkylene or a single bond;

[0027] L11Bis a single bond, -0-, -S-, -S-S-, -NR11B-, -C(=0)0-, -C(=NR11B)0-, -S(=0)0- -S(=0)20-, -C(=0)NR11B-, -C(=NR11B)NR11B-, -S(=0)NR11B-, -S(=0)2NR11B-, -0C(=0)-, - 0C(=NR11B)-, -0S(=0)-, -0S(=0)2-, -NR11BC(=0)-, -NR11BC(=NR11B)-, -NR11BS(=0)-, - NR11BS(=0)2-, -0C(=0)0-, -0C(=NR11B)0-, -0S(=0)0-, -0S(=0)20-, -NR11BC(=0)0-, - NR11BC(=NR11B)0-, -NR11BS(=0)0-, -NR11BS(=0)20-, -0C(=0)NR11B-, - 0C(=NR11B)NR11B-, -0S(=0)NR11B-, -0S(=0)2NR11B-, -NR11BC(=0)NR11B-, - NR11BC(=NR11B)NR11B-, -NR11BS(=0)NR11B-, -NR11BS(=0)2NR11B-, -C(=0)-, -C(=NR11B)-,

[0028] M1668.70004WQ00 4 / 511 -S(=0)-, -S(=0)2- -OP(=O)(OR11B)O- -SP(=O)(OR11B)O- -OP(=O)(OR11B)S- or - OP(=O)(SR11B)O-; each instance of R11Bis independently hydrogen, optionally substituted Ci-6 alkyl, 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 R11Battached to a nitrogen atom are joined with the nitrogen atom to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

[0029] R11is optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted alkyl, hydrogen, or halogen;

[0030] R12is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;

[0031] R13is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted alkyl, substituted alkenyl, or optionally substituted alkynyl;

[0032] L11Cis optionally substituted heterocyclyl ene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted arylene, or a single bond;

[0033] L13Bis optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted heteroalkenylene, optionally substituted alkenylene, optionally substituted heteroalkynylene, or optionally substituted alkynylene; and

[0034] L13Ais optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a single bond.

[0035] In another aspect, the present disclosure provides pharmaceutical compositions comprising: the chimera 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.

[0036] In another aspect, the present disclosure provides kits comprising: the chimera 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 chimera, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

[0037] M1668.70004WQ00 5 / 511 In another aspect, the present disclosure provides methods comprising administering to a subject:

[0038] (a) the chimera 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

[0039] (b) 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:

[0040] (I), wherein:

[0041] 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);

[0042] 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, -

[0043] M1668.70004WQ00 6 / 511 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), substituted Ci-3alkyl); =0 or -0RB1;

[0044] 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;

[0045] Rcis -ORC1or hydrogen;

[0046] 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;

[0047] M1668.70004WQ00 7 / 511 RDis -0RD1, -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;

[0048] = REis =0 or -0RE1; and

[0049] 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.

[0050] 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.

[0051] DEFINITIONS

[0052] 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

[0053] M1668.70004WO00 8 / 511 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.

[0054] 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.

[0055] 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.

[0056] In a formula, wedged bold ("^) and wedged hash bonds ( ') 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. If the stereochemistry of a chiral center indicated in a chemical formula is inconsistent with the stereochemistry of the chiral center stated in a chemical name, the stereochemistry of the chiral center stated in the chemical name controls.

[0057] M1668.70004WQ00 9 / 511 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.

[0058] 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.

[0059] 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.

[0060] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0061] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“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., ft-propyl, isopropyl), butyl (C4) (e.g., ft-butyl, tert-butyl, ec-butyl, isobutyl), pentyl (C5) (e.g., w-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., w-hexyl). Additional examples of alkyl groups include / / -heptyl (C7), ft-octyl (Cs), w-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

[0062] M1668.70004WO00 10 / 511 (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl ( / / -Bu), unsubstituted tert-butyl (tert-Bu or t- Bu), unsubstituted ec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-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)).

[0063] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“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.

[0064] 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 (“heteroC1-20 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

[0065] M1668.70004WQ00 11 / 511 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-8 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.

[0066] 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-

[0067] M1668.70004WO00 12 / 511 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 stereochemistry is not specified (e.g., -CEUCHCH3 or( )_ configuration.

[0068] 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 (“heteroC1-20 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

[0069] M1668.70004WQ00 13 / 511 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 heteroC1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1-20 alkenyl.

[0070] 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.

[0071] 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 (c.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 (“heteroC1-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having

[0072] M1668.70004WO00 14 / 511 from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-io 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

[0073] I 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 heteroC1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1-20 alkynyl.

[0074] 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

[0075] 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0076] 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0077] I I ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to

[0078] 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

[0079] M1668.70004WQ00 15 / 511 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- H- 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.

[0080] 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

[0081] M1668.70004WO00 16 / 511 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.

[0082] 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.

[0083] 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,

[0084] M1668.70004WQ00 17 / 511 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.

[0085] 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.

[0086] 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

[0087] M1668.70004WQ00 18 / 511 atoms (“C14 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.

[0088] “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.

[0089] 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 i 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.

[0090] 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

[0091] M1668.70004WQ00 19 / 511 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.

[0092] 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.

[0093] “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.

[0094] The term “unsaturated bond” refers to a double or triple bond.

[0095] M1668.70004WQ00 20 / 511 The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] M1668.70004WQ00 21 / 511 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 , -OP(ORCC)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, C1-20 alkenyl, C1-20 alkynyl, heteroC1-20 alkyl, heteroC1-20 alkenyl, heteroC1-20 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, C1-20 alkenyl, C1-20 alkynyl, heteroC1-20 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(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -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, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,

[0100] M1668.70004WQ00 22 / 511 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, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroC1-20 alkyl, heteroC1-20 alkenyl, heteroC1-20 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, “Ns, -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-io 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-io 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-io 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,

[0101] M1668.70004WQ00 23 / 511 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(=0)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), -0C(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI^ alkyl), -SO2N(Ci -6 alkyl)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.

[0102] 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(=0)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, -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(=0)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.,

[0103] M1668.70004WQ00 24 / 511 substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -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).

[0104] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0105] 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, -0N(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.

[0106] 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.

[0107] 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.

[0108] 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

[0109] M1668.70004WQ00 25 / 511 than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHC02Raa, -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.

[0110] 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.

[0111] 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.

[0112] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and - SO2ORaa, wherein Raaand Rbbare as defined herein.

[0113] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0114] 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.

[0115] 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.

[0116] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0117] 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, C1-20 alkenyl, C1-20 alkynyl, hetero C1-20 alkyl, hetero C1-20 alkenyl,

[0118] M1668.70004WQ00 26 / 511 hetero C1-20 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.

[0119] 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.

[0120] 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, C1-20 alkynyl, hetero C1-20 alkyl, hetero C1-20 alkenyl, hetero C1-20 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.

[0121] 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, N-benzoylphenylalanyl derivatives, benzamide, / ?-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (TV’ -

[0122] M1668.70004WQ00 27 / 511 dithiobenzyloxyacylamino)acetamide, 3-( / ?-hydroxyphenyl)propanamide, 3-(p- 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 .

[0123] 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(o-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-

[0124] M1668.70004WO00 28 / 511 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- methylcyclohexyl 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-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0125] 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 p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),

[0126] 2.3.5.6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs),

[0127] 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.

[0128] 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, 7V’- / ?-toluenesulfonylaminoacyl derivatives, TV ’-phenylaminothioacyl derivatives, 7V-benzoylphenylalanyl derivatives, 7V-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, 7V-phthalimide, 7V-dithiasuccinimide (Dts), TV-2, 3- diphenylmaleimide, 7V-2,5-dimethylpyrrole, 7V-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, 7V-methylamine, N- allylamine, 7V-[2-(trimethylsilyl)ethoxy]methylamine (SEM), TV-3 -acetoxypropylamine, 7V-(1- isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, / f-benzyl amine, N- di(4-methoxyphenyl)methylamine, 7V-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), 7V-9-phenylfluorenyl amine (PhF), TV-2, 7- dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), TV-2 -picolylamino N’-

[0129] M1668.70004WO00 29 / 511 oxide, TV- 1,1 -dimethylthiomethyleneamine, 7V-benzylideneamine, 7V-p- methoxybenzylideneamine, 7V-diphenylmethyleneamine, 7V-[(2-pyridyl)mesityl]methyleneamine, 7V-(7V’,7V’-dimethylaminomethylene)amine, 7V-p-nitrobenzylideneamine, 7V-salicylideneamine, N- 5-chlorosalicylideneamine, 7V-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, 7V-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, 7V-borane derivatives, N- diphenylborinic acid derivatives, 7V-[phenyl(pentaacylchromium- or tungsten)acyl]amine, TV- copper chelate, 7V-zinc chelate, 7V-nitroamine, 7V-nitrosoamine, amine 7V-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 TV, TV’ -isopropylidenediamine.

[0130] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0131] 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, -C02Raa, -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.

[0132] 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.

[0133] M1668.70004WQ00 30 / 511 Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0134] 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

[0135] M1668.70004WQ00 31 / 511 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, (E)-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).

[0136] 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.

[0137] 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.

[0138] 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(=0)(0RCC)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

[0139] M1668.70004WQ00 32 / 511 Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0140] 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.

[0141] 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.

[0142] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, c.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.

[0143] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0144] 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.

[0145] M1668.70004WO00 33 / 511 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.

[0146] 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,

[0147] M1668.70004WQ00 34 / 511 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.

[0148] 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.

[0149] 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)).

[0150] 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

[0151] M1668.70004WO00 35 / 511 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.

[0152] 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”.

[0153] 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”.

[0154] 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.

[0155] 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,

[0156] M1668.70004WQ00 36 / 511 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.

[0157] 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.

[0158] The terms “composition” and “formulation” are used interchangeably.

[0159] 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.

[0160] 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

[0161] M1668.70004WQ00 37 / 511 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.

[0162] 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.

[0163] 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.

[0164] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0165] 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.

[0166] 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.

[0167] 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

[0168] M1668.70004WQ00 38 / 511 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).

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] M1668.70004WQ00 39 / 511 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.

[0174] BRIEF DESCRIPTION OF THE DRAWINGS

[0175] In the figures, “11-001” refers to II-A-001; “11-007” refers to ILA-007; “11-004” refers to ILA-004; “11-010” refers to ILA-010; “11-003” refers to ILA-003; “11-006” refers to ILA-006; “11-011” refers to ILA-011; “11-002” refers to ILA-002; and “uM” refers to pM.

[0176] FIG. 1 depicts a schematic showing a representative embodiment of the Brain-Only™ pharmacology technology. The peripheral blocker (represented by the square) is not brain penetrant. The peripheral blocker binds to and saturates FKBP 12 in the periphery, whereas the chimera (represented by the arrow) exhibits substantially reduced binding to FKBP12 in the periphery due to competition. The right panel demonstrates that the chimera crosses the BBB. The chimera binds to FKBP 12 and causes intracellular accumulation. The FKBP-Chimera complex can engage with target protein in the brain.

[0177] FIGs. 2A and 2B show that chimera II-A-001 increased LXR mediated gene expression in a dose dependent manner, which could be blocked by the peripheral blocker RapaBlock.

[0178] FIGs. 3 A and 3B show results using the HepG2 reporter assay. FIG. 3 A provides a schematic of the assay. FIG. 3B shows that 125 nM of chimera II-A-001 increased LXR mediated gene expression by 1.7x, which can be blocked by the peripheral blocker RapaBlock. In previously reported preclinical models of AD, 1.5x fold increase in LXR gene expression was sufficient for beneficial effects.

[0179] FIGs. 4A to 4F show results using the INDIGO LXR reporter assay. These results were consistent with the HepG2 reporter assay. Chimera II-A-001 was able to agonize the LXRp reporter, but not LXRa, up to 10 pM. Further, chimera ILA-001 could be blocked by RapaBlock in this assay.

[0180] FIGs. 5 A and 5B show ApoE measurements. FIG. 5 A reflects ApoE measured inside cells. FIG. 5B reflects ApoE secreted outside of cells. As shown in FIG. 5 A, cellular ApoE was not increased in CCF-STTG1 cells that were treated with LXR agonists. FIG. 5B shows ApoE secreted to the media was increased by GW3965, chimera II-A-001, and T0901317 in CCF- STTG1.

[0181] M1668.70004WQ00 40 / 511 FIGs. 6A and 6B show that chimera II-A-001 is blocked by RapaBlock. In CCF-STTG1 cells, there was a dose responsive increase in ABCA1 protein levels with II-A-001 treatment. It was observed that 10 pM RapaBlock could block the increase significantly, whereas 10 pM RapaBlock was unable to block GW3965.

[0182] FIGs. 7Ato 7D show that chimera II-A-001 also increases SREBP-1 protein levels, which could be blocked by RapaBlock. GW3965 and chimera II-A-001 increased ABCA1 and SREBP- 1 in CCF-STTG1 cells after 48 hours of treatment. RapaBlock blocked the increase by II-A-001.

[0183] FIGs. 8 A to 8E show that chimera II-A-001 induced ApoE secretion, which was blocked by RapaBlock. The capture antibody was ApoE (pan) (D7I9N) Rabbit mAb, CST 10197SF. The detection antibody was ApoE (pan) (E8C2U) Mouse mAb, CST 31516SF. The secondary was Sulfo-Tag Gt anti-ms. GW3965 treatment increased ApoE secretion in a dose responsive manner at both 48 hour and 72 hour time points. Treatment with chimera II-A-001 treatment increased ApoE secretion, but not dose-dependently. For all doses tested, the increase in ApoE secretion was around 2-3x over DMSO treated cells. RapaBlock decreased ApoE secretion to DMSO level.

[0184] FIGs. 9A and 9B show results using the HepG2 LXR reporter assay. All chimeras increased LXR mediated gene expression. While GW3965 was the most potent, FK-(PEG) linkers were close in potency. Further, lOuM RapaBlock was able to block gene expression activation by chimera II-A-001 and FK-(PEG) linkers but did not block GW3965. “ND” means “not determined.”

[0185] FIGs. lOAto 10F show results using the HepG2 LXR reporter assay. “ND” means “not determined.”

[0186] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE PRESENT DISCLOSURE

[0187] The present disclosure provides methods and compositions for CNS-selective activity of LXR agonists by administering LXR agonists with novel peripheral blocker compounds for use in Brain-Only™ pharmacology technology. Compounds and methods disclosed herein can be used to reduce peripheral side effects of LXR agonists. 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.

[0188] Brain-Only™ pharmacology

[0189] 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

[0190] M1668.70004WQ00 41 / 511 “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.

[0191] 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 chimera, but not the peripheral blocker, is capable of crossing the blood-brain barrier (BBB). In the brain, the chimera binds to FKBP12, resulting in a conformational switch that exposes the functional part (indicated by an arrow) of the chimera. The chimera is retained in the brain cells due to its FKBP12 binding (intracellular pooling). The FKBP12-chimera complex can engage with a target protein in the brain, such as LXR. The anti-CNS disease drug (depicted as a chimera in FIG. 1) can be an LXR agonist.

[0192] 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.

[0193] 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

[0194] M1668.70004WQ00 42 / 511 characteristics: potent binding to FKBP12, minimal to no penetration of the blood-brain barrier, and oral bioavailability.

[0195] 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 the FKBP12-binder everolimus activity in vivo when dosed orally to mice. RapaBlock shows very limited blocking activity when dosed orally in mice.

[0196] 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. In some embodiments, the anti- CNS disease drug is an LXR agonist. 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. For example, as used herein, “LXR agonist” includes chimeric version of an LXR agonist whereby the LXR agonist is linked to one or more additional components. In some embodiments, one or more additional components of the chimera are capable of binding to FKBP12. 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 blood-brain barrier. In some embodiments, an anti-CNS drug (e.g., LXR agonist) is capable of binding to one or more immunophilins and / or cyclophilins. In some embodiments, an anti-CNS drug (e.g., LXR agonist) is capable of binding to one or more FK506-binding proteins. In some embodiments, an anti- CNS drug (e.g., LXR agonist) is capable of binding to FKBP12 or variants thereof. In some embodiments, an anti-CNS drug (e.g., LXR agonist) 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.

[0197] Some anti-CNS disease drugs, such as tacrolimus (also called “FK506”), and everolimus, can bind directly to FKBP12. In other embodiments of the Brain-Only™ pharmacology, such as depicted in FIG. 1, the anti-CNS disease drug can be linked to an additional component that can bind to FKBP12. For example, Zhang et al. (2022) “Brain-restricted mTOR inhibition with

[0198] M1668.70004WQ00 43 / 511 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 LXR agonist crosses the BBB and binds to both FKBP12 and a target protein within the CNS. The activity of the LXR agonist is dependent on FKBP12 binding in the brain, causing localized intracellular accumulation and engagement with a target protein.

[0199] Liver X Receptors

[0200] Liver X receptors (LXR) are ligand-activated transcription factors of the nuclear receptor (NR) superfamily. LXR isoforms comprise LXR-a (also known as NR1H3) and LXR-P (also known as NR1H2). While LXR-a is largely restricted to the spleen, liver, adipose tissue, intestines, kidney, and lungs, LXR-P is present in all tissues examined, including the brain, the most cholesterol-rich organ in the body. LXR binds with retinoid X receptor (RXR) to form an LXR-RXR heterodimer which interacts with LXR response elements (LXREs) to regulate gene expression at promoter regions. LXR-RXR is involved in the regulation of several genes associated with cholesterol and lipid metabolism. Mutations in LXR are associated with neurodegeneration, astrogliosis, myelin disorganization and impaired Ap production and clearance. Notably, LXR also directly regulates the expression of ApoE. Without wishing to be bound by any theory, it is believed that LXR increases levels and lipidation states of ApoE, allowing for reduction of Ap secretion and improvements in Ap clearance. Some findings further highlight a potential anti-inflammatory mechanism of LXR in Alzheimer’s disease (AD) pathology, which may provide a therapeutic benefit. LXR is a major therapeutic target for the treatment and prevention of AD.

[0201] LXR agonists

[0202] Agonists for LXR may be useful as therapies for the treatment of AD.

[0203] Aspects of the disclosure relate to selective activation of LXR binders in the CNS. As used herein, an “LXR binder” refers to any agent that is capable of binding to an LXR protein. It should be understood that the LXR protein name encompasses human proteins, and variants thereof, and also encompasses homologous proteins from other species, and variants thereof.

[0204] In certain embodiments, an LXR binder is an LXR agonist. The term “LXR agonist”, as used herein, refers to a molecule that is capable of binding and inducing transcriptional activity of LXR (e.g., enabling LXR-RXR heterodimerization), and encompasses both naturally

[0205] M1668.70004WQ00 44 / 511 occurring and synthetic molecules. Several naturally occurring LXR agonists have been identified, such as oxysterols and cholesterol biosynthetic intermediates. Exemplary oxysterols include 20(S)- hydroxycholesterol, 22(R)- hydroxycholesterol, 24(S)- hydroxycholesterol, 25- hydroxycholesterol, 27-hydroxycholesterol, 24(S),25-epoxycholesterol, and cholestenoic acid. Numerous synthetic LXR agonists are also known, such as acetyl-podocarpic dimer, hypocholamide, N,N-dimethyl-3P-hydroxy-cholenamide (DMHCA), GW3965, T0901317, LXR- 623, BMS-779788, BMS-852927, and VTP-38543.

[0206] In some embodiments, the LXR agonist is naturally occurring. In some embodiments, the LXR agonist is an oxysterol or a cholesterol biosynthetic intermediate. In some embodiments, the LXR agonist is one or more of 20(S)- hydroxycholesterol, 22(R)- hydroxycholesterol, 24(S)- hydroxycholesterol, 25- hydroxycholesterol, 27-hydroxycholesterol, 24(S),25-epoxycholesterol, or cholestenoic acid. In some embodiments, the LXR agonist is synthetic. In some embodiments, the LXR agonist is one or more of acetyl-podocarpic dimer, hypocholamide, N,N-dimethyl-3P- hydroxy-cholenamide (DMHCA), GW3965, T0901317, LXR-623, BMS-779788, BMS-852927, or VTP-38543.

[0207] In some embodiments, the LXR agonist is any LXR binder or chimera disclosed herein. In certain embodiments, the LXR agonist is of any one of the formulae shown in Table 1, or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof. In certain embodiments, the LXR agonist is of any one of chimeras II-A-001 to ILA-023 as disclosed herein.

[0208] Preclinical studies suggested that LXR agonists may have a therapeutic benefit for AD. However, several side effects have been associated with their systemic administration. Though LXR-P is the predominant LXR subtype in the brain, naturally occurring LXR agonists typically bind both LXR-P in the brain and LXR-a in the body (e.g., hepatic LXR-a), where increased LXR activity is associated with hypertriglyceridemia, elevated LDL-cholesterol, and hepatic steatosis, as well as an overall increase in risk of metabolic disease. A similar risk persists with certain synthetic LXR agonists designed to have high affinity for LXR-P over LXR-a, such as T0901317, which still binds other nuclear receptors in the body, thereby interfering in the function of LXR-independent pathways. Accordingly, means for administering LXR agonists primarily to the brain are highly desirable.

[0209] Described herein is a novel therapeutic strategy designed to achieve CNS-selective activation of LXR, thereby minimizing peripheral side effects and enhancing treatment efficacy. This targeted approach localizes therapeutic activity to the brain, the primary site of AD pathology, and avoids detrimental peripheral effects. The ability to selectively activate drugs in

[0210] M1668.70004WQ00 45 / 511 the CNS while minimizing peripheral side effects is a significant advancement, promising greater clinical benefits and improved patient outcomes.

[0211] Chimeras

[0212] In one aspect, the present disclosure provides chimeras, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein the chimeras are of Formula II-A or II-B:

[0213] L° is a linker, wherein the linker comprises in the backbone of the linker two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted;

[0214] R° is a radical of a liver X receptor (LXR) binder;

[0215] L1is optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted alkylene, or alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted Ci-6 alkyl);

[0216] R1is hydrogen, -S(=O)2N(R1A)2, 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, - OR1A, -SCN, -SR1A, -SSR1A, -N3, -NO, -N(R1A)2, -NO2, -N=S(=O)(R1A)2, - N=S(=O)(R1A)OR1A, -N=S(=O)(R1A)SR1A, -N=S(=O)(R1A)N(R1A)2, -C(=O)R1A, -C(=O)OR1A, -C(=O)SR1A, -C(=O)N(R1A)2, -C(=O)N(R1A)S(=O)R1A, -C(=O)N(R1A)S(=O)OR1A, -

[0217] M1668.70004WQ00 46 / 511 C(=O)N(R1A)-S(=O)SR1A, -C(=O)N(R1A)S(=O)N(R1A)2, -C(=O)N(R1A)S(=O)2R1A, - C(=O)N(R1A)S(=O)2OR1A, -C(=O)N(R1A)S(=O)2SR1A, -C(=O)N(R1A)S(=O)2N(R1A)2, - C(=NR1A)R1A, -C(=NR1A)OR1A, -C(=NR1A)SR1A, -C(=NR1A)N(R1A)2, -S(=O)R1A, - S(=O)OR1A, -S(=O)SR1A, -S(=O)N(R1A)2, -S(=O)(=NR1A)R1A, -S(=O)(=NR1A)OR1A, - S(=O)(=NR1A)SR1A, -S(=O)(=NR1A)N(R1A)2, -S(=O)2R1A, -S(=O)2OR1A, -S(=O)2SR1A, - S(=O)2N(R1A)C(=O)R1A, -S(=O)2N(R1A)C(=O)OR1A, -S(=O)2N(R1A)C(=O)SR1A, - S(=O)2N(R1A)C(=O)N(R1A)2, -OC(=O)R1A, -OC(=O)OR1A, -OC(=O)SR1A, -OC(=O)N(R1A)2, - OC(=NR1A)R1A, -OC(=NR1A)OR1A, -OC(=NR1A)SR1A, -OC(=NR1A)N(R1A)2, -OS(=O)R1A, - OS(=O)OR1A, -OS(=O)SR1A, -OS(=O)N(R1A)2, -OS(=O)2R1A, -OS(=O)2OR1A, -OS(=O)2SR1A, -OS(=O)2N(R1A)2, -ON(R1A)2, -SC(=O)R1A, -SC(=O)OR1A, -SC(=O)SR1A, -SC(=O)N(R1A)2, - SC(=NR1A)R1A, -SC(=NR1A)OR1A, -SC(=NR1A)SR1A, -SC(=NR1A)N(R1A)2, -NR1AC(=O)R1A, - NR1AC(=O)OR1A, -NR1AC(=O)SR1A, -NR1AC(=O)N(R1A)2, -NR1AC(=NR1A)R1A, - NR1AC(=NR1A)OR1A, -NR1AC(=NR1A)SR1A, -NR1AC(=NR1A)N(R1A)2, -NR1AS(=O)R1A, - NR1AS(=O)OR1A, -NR1AS(=O)SR1A, -NR1AS(=O)N(R1A)2, -NR1AS(=O)2R1A, - NR1AS(=O)2OR1A, -NR1AS(=O)2SR1A, -NR1AS(=O)2N(R1A)2, -Si(R1A)3, -Si(R1A)2OR1A, - Si(R1A)(OR1A)2, -Si(OR1A)3, -OSi(R1A)3, -OSi(R1A)2OR1A, -OSi(R1A)(OR1A)2, -OSi(OR1A)3, - B(OR1A)2, -OB(OR1A)2, -P(=O)(R1A)2, -P(=O)(R1A)OR1A, -P(=O)(OR1A)2, -OP(=O)(R1A)2, - OP(=O)(R1A)OR1A, or -OP(=O)(OR1A)2; each instance of R1Ais 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 RN1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;

[0218] = R2is =0 or -0R2A;

[0219] R2Ais 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;

[0220] R3is -0R3Aor hydrogen;

[0221] R3Ais 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;

[0222] R4is -0R4A, -SCN, -SR4A, -SSR4A, -N3, -NO, -N(R4A)2, -N02, -N=S(=O)(R4A)2, - N=S(=O)(R4A)OR4A, -N=S(=O)(R4A)SR4A, -N=S(=O)(R4A)N(R4A)2, -S(=O)R4A, -S(=O)OR4A, -

[0223] M1668.70004WQ00 47 / 511 S(=O)SR4A, -S(=O)N(R4A)2, -S(=O)(=NR4A)R4A, -S(=O)(=NR4A)OR4A, -S(=O)(=NR4A)SR4A, - S(=O)(=NR4A)N(R4A)2, -S(=O)2R4A, -S(=O)2OR4A, -S(=O)2SR4A, -S(=O)2N(R4A)2, - S(=O)2N(R4A)C(=O)R4A, -S(=O)2N(R4A)C(=O)OR4A, -S(=O)2N(R4A)C(=O)SR4A, - S(=O)2N(R4A)C(=O)N(R4A)2, -OC(=O)R4A, -OC(=O)OR4A, -OC(=O)SR4A, -OC(=O)N(R4A)2, - OC(=NR4A)R4A, -OC(=NR4A)OR4A, -OC(=NR4A)SR4A, -OC(=NR4A)N(R4A)2, -OS(=O)R4A, - OS(=O)OR4A, -OS(=O)SR4A, -OS(=O)N(R4A)2, -OS(=O)2R4A, -OS(=O)2OR4A, -OS(=O)2SR4A, -OS(=O)2N(R4A)2, -ON(R4A)2, -SC(=O)R4A, -SC(=O)OR4A, -SC(=O)SR4A, -SC(=O)N(R4A)2, - SC(=NR4A)R4A, -SC(=NR4A)OR4A, -SC(=NR4A)SR4A, -SC(=NR4A)N(R4A)2, -NR4AC(=O)R4A, - NR4AC(=O)OR4A, -NR4AC(=O)SR4A, -NR4AC(=O)N(R4A)2, -NR4AC(=NR4A)R4A, - NR4AC(=NR4A)OR4A, -NR4AC(=NR4A)SR4A, -NR4AC(=NR4A)N(R4A)2, -NR4AS(=O)R4A, - NR4AS(=O)OR4A, -NR4AS(=O)SR4A, -NR4AS(=O)N(R4A)2, -NR4AS(=O)2R4A, - NR4AS(=O)2OR4A, -NR4AS(=O)2SR4A, -NR4AS(=O)2N(R4A)2, -OSi(R4A)3, -OSi(R4A)2OR4A, - OSi(R4A)(OR4A)2, -OSi(OR4A)3, -B(OR4A)2, -OB(OR4A)2, -P(=O)(R4A)2, -P(=O)(R4A)OR4A, - P(=O)(OR4A)2, -OP(=O)(R4A)2, -OP(=O)(R4A)OR4A,-OP(=O)(OR4A)2, -CN, halogen, or optionally substituted heteroaryl; each instance of R4Ais 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 R4Aattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;

[0224] = R5is =0 or -0R5A; and

[0225] R5Ais 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.

[0226] When Formula II-A or II-B 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. When Formula IV-A, IV-B, or IV-C 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.

[0227] In certain embodiments, R1is hydrogen, -S(=O)2N(R1A)2, 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

[0228] M1668.70004WQ00 48 / 511 substituted tetrazinyl, optionally substituted polycyclic heteroaryl, -CN, -OR1A, -SCN, -SR1A, - SSR1A, -N3, -NO, -N(R1A)2, -NO2, -N=S(=O)(R1A)2, -N=S(=O)(R1A)OR1A, - N=S(=O)(R1A)SR1A, -N=S(=O)(R1A)N(R1A)2, -C(=O)R1A, -C(=O)OR1A, -C(=O)SR1A, - C(=O)N(R1A)2, -C(=O)N(R1A)S(=O)R1A, -C(=O)N(R1A)S(=O)OR1A, -C(=O)N(R1A)- S(=O)SR1A, -C(=O)N(R1A)S(=O)N(R1A)2, -C(=O)N(R1A)S(=O)2R1A, - C(=O)N(R1A)S(=O)2OR1A, -C(=O)N(R1A)S(=O)2SR1A, -C(=O)N(R1A)S(=O)2N(R1A)2, - C(=NR1A)R1A, -C(=NR1A)OR1A, -C(=NR1A)SR1A, -C(=NR1A)N(R1A)2, -S(=O)R1A, - S(=O)OR1A, -S(=O)SR1A, -S(=O)N(R1A)2, -S(=O)(=NR1A)R1A, -S(=O)(=NR1A)OR1A, - S(=O)(=NR1A)SR1A, -S(=O)(=NR1A)N(R1A)2, -S(=O)2R1A, -S(=O)2OR1A, -S(=O)2SR1A, - S(=O)2N(R1A)C(=O)R1A, -S(=O)2N(R1A)C(=O)OR1A, -S(=O)2N(R1A)C(=O)SR1A, - S(=O)2N(R1A)C(=O)N(R1A)2, -OC(=O)R1A, -OC(=O)OR1A, -OC(=O)SR1A, -OC(=O)N(R1A)2, - OC(=NR1A)R1A, -OC(=NR1A)OR1A, -OC(=NR1A)SR1A, -OC(=NR1A)N(R1A)2, -OS(=O)R1A, - OS(=O)OR1A, -OS(=O)SR1A, -OS(=O)N(R1A)2, -OS(=O)2R1A, -OS(=O)2OR1A, -OS(=O)2SR1A, -OS(=O)2N(R1A)2, -ON(R1A)2, -SC(=O)R1A, -SC(=O)OR1A, -SC(=O)SR1A, -SC(=O)N(R1A)2, - SC(=NR1A)R1A, -SC(=NR1A)OR1A, -SC(=NR1A)SR1A, -SC(=NR1A)N(R1A)2, -NR1AC(=O)R1A, - NR1AC(=O)OR1A, -NR1AC(=O)SR1A, -NR1AC(=O)N(R1A)2, -NR1AC(=NR1A)R1A, - NR1AC(=NR1A)OR1A, -NR1AC(=NR1A)SR1A, -NR1AC(=NR1A)N(R1A)2, -NR1AS(=O)R1A, - NR1AS(=O)OR1A, -NR1AS(=O)SR1A, -NR1AS(=O)N(R1A)2, -NR1AS(=O)2R1A, - NR1AS(=O)2OR1A, -NR1AS(=O)2SR1A, -NR1AS(=O)2N(R1A)2, -Si(R1A)3, -Si(R1A)2OR1A, - Si(R1A)(OR1A)2, -Si(OR1A)3, -OSi(R1A)3, -OSi(R1A)2OR1A, -OSi(R1A)(OR1A)2, -OSi(OR1A)3, - B(OR1A)2, -OB(OR1A)2, -P(=O)(R1A)2, -P(=O)(R1A)OR1A, -P(=O)(OR1A)2, -OP(=O)(R1A)2, - OP(=O)(R1A)OR1A, or -OP(=O)(OR1A)2; and

[0229] R4is -OR4A, -SCN, -SR4A, -SSR4A, -N3, -NO, -N(R4A)2, -NO2, -N=S(=O)(R4A)2, - N=S(=O)(R4A)OR4A, -N=S(=O)(R4A)SR4A, -N=S(=O)(R4A)N(R4A)2, -S(=O)R4A, -S(=O)OR4A, - S(=O)SR4A, -S(=O)N(R4A)2, -S(=O)(=NR4A)R4A, -S(=O)(=NR4A)OR4A, -S(=O)(=NR4A)SR4A, - S(=O)(=NR4A)N(R4A)2, -S(=O)2R4A, -S(=O)2OR4A, -S(=O)2SR4A, -S(=O)2N(R4A)2, - S(=O)2N(R4A)C(=O)R4A, -S(=O)2N(R4A)C(=O)OR4A, -S(=O)2N(R4A)C(=O)SR4A, - S(=O)2N(R4A)C(=O)N(R4A)2, -OC(=O)R4A, -OC(=O)OR4A, -OC(=O)SR4A, -OC(=O)N(R4A)2, - OC(=NR4A)R4A, -OC(=NR4A)OR4A, -OC(=NR4A)SR4A, -OC(=NR4A)N(R4A)2, -OS(=O)R4A, - OS(=O)OR4A, -OS(=O)SR4A, -OS(=O)N(R4A)2, -OS(=O)2R4A, -OS(=O)2OR4A, -OS(=O)2SR4A, -OS(=O)2N(R4A)2, -ON(R4A)2, -SC(=O)R4A, -SC(=O)OR4A, -SC(=O)SR4A, -SC(=O)N(R4A)2, - SC(=NR4A)R4A, -SC(=NR4A)OR4A, -SC(=NR4A)SR4A, -SC(=NR4A)N(R4A)2, -NR4AC(=O)R4A, - NR4AC(=O)OR4A, -NR4AC(=O)SR4A, -NR4AC(=O)N(R4A)2, -NR4AC(=NR4A)R4A, - NR4AC(=NR4A)OR4A, -NR4AC(=NR4A)SR4A, -NR4AC(=NR4A)N(R4A)2, -NR4AS(=O)R4A, - NR4AS(=O)OR4A, -NR4AS(=O)SR4A, -NR4AS(=O)N(R4A)2, -NR4AS(=O)2R4A, -

[0230] M1668.70004WQ00 49 / 511 NR4AS(=O)2OR4A, -NR4AS(=O)2SR4A, -NR4AS(=O)2N(R4A)2, -OSi(R4A)3, -OSi(R4A)2OR4A, - OSi(R4A)(OR4A)2, -OSi(OR4A)3, -B(OR4A)2, -OB(OR4A)2, -P(=O)(R4A)2, -P(=O)(R4A)OR4A, - P(=O)(OR4A)2, -OP(=O)(R4A)2, -OP(=O)(R4A)OR4A, or -OP(=O)(OR4A)2.

[0231] In certain embodiments, the chimera is a compound. In certain embodiments, the chimera is a small molecule. In certain embodiments, the chimera is a small molecule having a molecular weight between 1000 and 1200, between 1200 and 1400, between 1400 and 1700, between 1700 and 2000, between 2000 and 2300, between 2300 and 2600, or between 2600 and 3000, inclusive, g / mol.

[0232] In certain embodiments, L° is a linker, wherein the linker comprises in the backbone (parent chain) of the linker between 2 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 and 60, between 60 and 80, or between 80 and 100, inclusive, atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted.

[0233] In certain embodiments, L° is a linker, wherein the linker comprises in the backbone of the linker between 2 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 and 60, between 60 and 80, or between 80 and 100, inclusive, atoms independently selected from the group consisting of carbon, oxygen, and nitrogen, and the backbone of the linker is optionally substituted.

[0234] In certain embodiments, the backbone of the linker comprises no unsaturated bonds. In certain embodiments, the backbone of the linker comprises 1, 2, or 3 CC double bonds. In certain embodiments, the backbone of the linker comprises 1, 2, or 3 CC triple bonds.

[0235] In certain embodiments, the backbone of the linker comprises no cyclic moi eties. In certain embodiments, the backbone of the linker comprises 1, 2, or 3 cyclic moi eties independently selected from the group consisting of heterocyclylene, heteroarylene, arylene, and carbocyclylene. In certain embodiments, the backbone of the linker comprises 1 or 2 cyclic moi eties independently selected from the group consisting of heterocyclylene and heteroarylene. In certain embodiments, when the backbone of the linker comprises one or more cyclic moieties, the number of atoms in the backbone of the linker is the smallest number of atoms in the backbone of the linker.

[0236] In certain embodiments, the backbone of the linker is optionally substituted with one or more substituents independently selected from the group consisting of halogen, optionally substituted Ci-6 alkyl, -OH, -©(optionally substituted Ci-6 alkyl), -NH2, -NH(optionally substituted Ci-6 alkyl), -N(optionally substituted Ci-6 alkyl)2, and oxo, as valency permits. In certain embodiments, the backbone of the linker is optionally substituted with one or more substituents independently selected from the group consisting of-F, -CH3, -OH, -OCH3, -NH2,

[0237] M1668.70004WQ00 50 / 511 -NHCHs, -N(CHS)2, and oxo, as valency permits. In certain embodiments, the backbone of the linker is optionally substituted with one or more oxo, as valency permits.

[0238] In certain embodiments, L° is optionally substituted C2-100 alkylene, optionally substituted C2-100 alkenylene, optionally substituted C2-100 alkynylene, optionally substituted Ci-100 heteroalkylene, optionally substituted C2-100 heteroalkenylene, or optionally substituted C2-100 heteroalkynylene; optionally wherein one or more backbone atoms of the C2-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C 1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits.

[0239] In certain embodiments, L° is optionally substituted C2-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C1-10 heteroalkylene, optionally substituted C2-10 heteroalkenylene, or optionally substituted C2-10 heteroalkynylene; optionally wherein 1 or 2 backbone atoms of the C2-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, C1-10 heteroalkylene, C2-10 heteroalkenylene, or C2-10 heteroalkynylene are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits.

[0240] In certain embodiments, L° is optionally substituted C 10-30 alkylene, optionally substituted C 10-30 alkenylene, optionally substituted C10-30 alkynylene, optionally substituted C10-30 heteroalkylene, optionally substituted C10-30 heteroalkenylene, or optionally substituted C10-30 heteroalkynylene; optionally wherein 1, 2, or 3 backbone atoms of the C10-30 alkylene, C10-30 alkenylene, C10- 30 alkynylene, C 10-30 heteroalkylene, C10-30 heteroalkenylene, or C10-30 heteroalkynylene are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits.

[0241] In certain embodiments, L° is optionally substituted C30-60 alkylene, optionally substituted C30-60 alkenylene, optionally substituted C30-60 alkynylene, optionally substituted C30-60 heteroalkylene, optionally substituted C30-60 heteroalkenylene, or optionally substituted C30-60 heteroalkynylene; optionally wherein 1, 2, 3, or 4 backbone atoms of the C30-60 alkylene, C30-60 alkenylene, C30-60 alkynylene, C30-60 heteroalkylene, C30-60 heteroalkenylene, or C30-60 heteroalkynylene are

[0242] M1668.70004WQ00 51 / 511 independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits.

[0243] In certain embodiments, L° is optionally substituted Ceo-ioo alkylene, optionally substituted Ceo-ioo alkenylene, optionally substituted Ceo-ioo alkynylene, optionally substituted Ceo- ioo heteroalkylene, optionally substituted Ceo-ioo heteroalkenylene, or optionally substituted Ceo-ioo heteroalkynylene; optionally wherein 1, 2, 3, 4, or 5 backbone atoms of the Ceo-ioo alkylene, Ceo-ioo alkenylene, Ceo-ioo alkynylene, Ceo-ioo heteroalkylene, Ceo-ioo heteroalkenylene, or Ceo-ioo heteroalkynylene are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits.

[0244] In certain embodiments, L° is optionally substituted C2-60 alkylene, optionally substituted C2-60 alkenylene, optionally substituted C2-60 alkynylene, optionally substituted C2-60 heteroalkylene, optionally substituted C2-60 heteroalkenylene, or optionally substituted C2-60 heteroalky nyl ene .

[0245] In certain embodiments, L° is unsubstituted C2-6 alkylene. In certain embodiments, L° is unsubstituted Ce-io alkylene. In certain embodiments, L° is unsubstituted C10-20 alkylene. In certain embodiments, L° is unsubstituted C20-30 alkylene.

[0246] In certain embodiments, L° is optionally substituted C2-6 heteroalkylene. In certain embodiments, L° is optionally substituted Ce-io heteroalkylene. In certain embodiments, L° is optionally substituted C10-20 heteroalkylene. In certain embodiments, L° is optionally substituted C 20-40 heteroalkylene. In certain embodiments, L° is optionally substituted C40-60 heteroalkylene. In certain embodiments, L° is optionally substituted C2-60 heteroalkylene. In certain embodiments, L° is optionally substituted C2-60 alkylene or optionally substituted C2-60 heteroalkylene; and one or two backbone atoms of the C2-60 alkylene or C2-60 heteroalkylene are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, as valency permits. In certain embodiments, the optional substituents described in this paragraph are independently selected from the group consisting of halogen, optionally substituted C1-6 alkyl, -OH, - □(optionally substituted C1-6 alkyl), and oxo, as valency permits. In certain embodiments, the optional substituents described in this paragraph are independently selected from the group consisting of -F, -CH3, -OH, -OCH3, and oxo, as valency permits.

[0247] M1668.70004WO00 52 / 511 In certain embodiments, L° is of the formula: — ■L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-

[0248] L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0A10_L0B4_L0A11_L0A12_ pOC3_]J)A13_]J)A14_]J)B5_]J)A15_

[0249] JJ)A16. each of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8-, -L0A9-L0A10-, -LOAH

[0250] L0A12-, _LOAI3_]J)AI4_an(j _]j)Ai5_|j)Ai6_ jsjnciepenciently a single bond, -O-, -S-, -S-S-, -

[0251] NRa-, -C(=O)O-, -C(=NRa)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -

[0252] S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-, -OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -

[0253] NRaC(=NRa)-, -NRaS(=O)-, -NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -

[0254] OS(=O)2O-, -NRaC(=O)O-, -NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa- -OC(=NRa)NRa-, -OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, - NRaS(=O)NRa-, -NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2-, - OP(=O)(ORa)O-, -SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, optionally substituted Ci-6 alkyl, 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 Raattached to a nitrogen atom are joined with the nitrogen atom to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each of LOB1, L0B2, L0B3, L0B4, and L0B5is independently a single bond, optionally substituted Ci-100 alkylene, optionally substituted C2-ioo alkenylene, optionally substituted C2-ioo alkynylene, optionally substituted Ci-100 heteroalkylene, optionally substituted C2-ioo heteroalkenyl ene, or optionally substituted C2-ioo heteroalkynylene; and each of L0C1, L0C2, and L0C3is a single bond, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, or optionally substituted arylene; provided that the backbone of L° comprises two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, or boron.

[0255] In certain embodiments, L° is of the formula: — - L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-

[0256] L0A50A6_J^0B3_J^0A7_J^0A8_J^0C2_J^0A9_J^0A10_J^0B4_J^0A11_J^0A12_. each of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8-, -L0A9-L0A10-, and -L0A11- pO W is independently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O-, -

[0257] S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-, -

[0258] OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, -

[0259] NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, -

[0260] NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa-, -OC(=NRa)NRa-, -

[0261] M1668.70004WQ00 53 / 511 OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, - NRaS(=O)2NRa-, -C(=0)-, -C(=NRa)-, -S(=0)-, -S(=0)2- -OP(=O)(ORa)O- - SP(=O)(ORa)O- -OP(=O)(ORa)S- or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, optionally substituted Ci-6 alkyl, 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 Raattached to a nitrogen atom are joined with the nitrogen atom to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each of LOB1, L0B2, L0B3, and L0B4is independently a single bond, optionally substituted Ci-ioo alkylene, optionally substituted C2-ioo alkenylene, optionally substituted C2-ioo alkynylene, optionally substituted Ci-ioo heteroalkylene, optionally substituted C2-ioo heteroalkenylene, or optionally substituted C2-ioo heteroalkynylene; and each of L0C1and L0C2is a single bond, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, or optionally substituted arylene; provided that the backbone of L° comprises two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, or boron.

[0262] In certain embodiments, L° is of the formula: __«L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-ROA5_]^OA6_]^OB3_]^OA7_]^OA8_

[0263] In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-.

[0264] In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2-.

[0265] In certain embodiments, L° is of the formula: — L()AI-L()A2-L()B2-L0A3-L0A4-.

[0266] In certain embodiments, L° is of the formula: — O-L0B2-L0A3-L0A4-.

[0267] In certain embodiments, L0B1is optionally substituted Ci-io alkylene. In certain embodiments, L0B1is unsubstituted Ci-6 alkylene. In certain embodiments, L0B1is -CH2- In certain embodiments, L0B1is -(CH2)3- In certain embodiments, L0B1is -(CH2)2-, -(CH2)3- - (CH2)4-, or -(CH2)S-

[0268] In certain embodiments, L0B1is a single bond.

[0269] In certain embodiments, at least one of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-

[0270] C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, - NRaS(=O)2-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, -NRaS(=O)2NRa-, - C(=O)-, -C(=NRa)-, -S(=O)-, or -S(=O)2-

[0271] M1668.70004WQ00 54 / 511 In certain embodiments, at least one of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8_ _LOA9_LOA1O_,and_LOA11_LOA12_is_c(=O)NRa- or -NRaC(=O)-.

[0272] In certain embodiments, at least one of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8_ _LOA9_LOA1O_and_LOA11_LOA12_is_c(=O)NH- or -NHC(=O)-.

[0273] In certain embodiments, at least one of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7- L0A8-, _L0A9-L0A10-, and -LOA11-LOA12- is -C(=O)-.

[0274] In certain embodiments, at least one of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7- jn cer^ajnembodiments, at least one of -L0A1_L0A2_ L0A3_L0A4 _ L0A5-L°A6_ L0A7_L0A8_ ]J)A9_]J)A10_and_]J)A1 1_]J)A12_ | _

[0275] NH-.

[0276] In certain embodiments, at least one of-L0A1-L0A2- is -C(=O)NH- or -NHC(=O)-. In certain embodiments, at least one of-L0A1-L0A2- is -C(=O)-.

[0277] In certain embodiments, at least one of-L0A3-L0A4- is a single bond. In certain embodiments, at least one of-L0A3-L0A4- is -C(=O)-. In certain embodiments, at least one of- L0A3-L0A4- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of-L0A3-L0A4- is -C(=O)NH- or -NHC(=O)-. In certain embodiments, at least one of-L0A3-L0A4- is -NRa- In certain embodiments, at least one of-L0A3-L0A4- is -N(optionally substituted Ci-6 alkyl)- (e.g., - NMe-). In certain embodiments, at least one of-L0A3-L0A4- is -O-.

[0278] In certain embodiments, at least one of-L0A5-L0A6- is a single bond. In certain embodiments, at least one of-L0A5-L0A6- is -C(=O)-. In certain embodiments, at least one of- L0A5-L0A6- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of-L0A5-L0A6- is -C(=O)NH- or -NHC(=O)-. In certain embodiments, at least one of-L0A5-L0A6- is -O-. In certain embodiments, at least one of-L0A5-L0A6- is -S(=O)2-

[0279] In certain embodiments, at least one of-L0A7-L0A8- is a single bond. In certain embodiments, at least one of-L0A7-L0A8- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of-L0A7-L0A8- is -C(=O)NH- or -NHC(=O)-.

[0280] In certain embodiments, at least one of-L0A9-L0A10- is a single bond. In certain embodiments, at least one of-L0A9-L0A10- is -C(=O)-. In certain embodiments, at least one of- L0A9-L0A10- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of-L0A9- LOA1°- is -C(=O)NH- or -NHC(=O)-.

[0281] In certain embodiments, at least one of-L0A11-L0A12- is a single bond. In certain embodiments, at least one of-L0A11-L0A12- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of-L0A11-L0A12- is -C(=O)NH- or -NHC(=O)-.

[0282] In certain embodiments, at least one of-L0A13-L0A14- is -O-, -S-, -S-S-, -NRa-, - C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -NRaC(=O)-, -NRaC(=NRa)-, -

[0283] M1668.70004WQ00 55 / 511 NRaS(=O)-, -NRaS(=O)2- -NRaC(=O)NRa- -NRaC(=NRa)NRa- -NRaS(=O)NRa- - NRaS(=0)2NRa- -C(=0)-, -C(=NRa)-, -S(=0)-, or -S(=O)2- In certain embodiments, at least one of-L0A13-L0A14- is -C(=O)NRa- or -NRaC(=O)-. In certain embodiments, at least one of- L°AI3_LOAI4_ -C(=o)NH- or -NHC(=O)-. In certain embodiments, at least one of-L0A13- L°AI4_ is-C(=O)-. jncertain embodiments, at least one of-L0A13-L0A14- is -O- or -NRa- In certain embodiments, at least one of-L0A13-L0A14- is -NH-. In certain embodiments, at least one of — L°A13— L°A14~ is a single bond.

[0284] In certain embodiments, at least one of-L0A15-L0A16- is -O-, -S-, -S-S-, -NRa-, - C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -NRaC(=O)-, -NRaC(=NRa)-, - NRaS(=O)-, -NRaS(=O)2-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, - NRaS(=0)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, or -S(=O)2- In certain embodiments, at least one of-L0A15-L0A16- is a single bond.

[0285] In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted Ci-100 alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C2-30 alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C2-6 alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted Ce-io alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C10-20 alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C20-30 alkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted straightchain C2-15 alkylene.

[0286] In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted C1-10 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted C 10-20 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted C20-40 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted C40-60 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted Ceo -so heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted Cso-ioo heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is optionally substituted Ci-100 heteroalkylene. In certain embodiments, the optional substituents described in this paragraph are independently selected from the group consisting of halogen, optionally substituted C1-6 alkyl, -OH, - □(optionally substituted C1-6 alkyl), and oxo, as valency permits. In certain embodiments, the optional substituents described in this paragraph are independently selected from the group consisting of -F, -CH3, -OH, -OCH3, and oxo, as valency permits. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted Ci -10 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C 10-20 heteroalkylene. In certain embodiments, at

[0287] M1668.70004WQ00 56 / 511 least one of L0B2, L0B3, and L0B4is unsubstituted C20 -40 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C40 -60 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted Ceo -so heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted Cso -100 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted C2-50 heteroalkylene. In certain embodiments, at least one of L0B2, L0B3, and L0B4is unsubstituted straight-chain C2-30 heteroalkylene. In certain embodiments, at least one of the heteroalkylene comprises in the backbone at least one oxygen or nitrogen atom and no heteroatoms other than oxygen and nitrogen. In certain embodiments, at least one of the heteroalkylene comprises in the backbone at least one oxygen atom and no heteroatoms other than oxygen.

[0288] In certain embodiments, at least one of L0B2, L0B3, and L0B4comprises -(CH2CH2O)n3-, - (OCH2CH2)n3- , or - (CH2OCH2)n3- , wherein each instance of n3 is independently an integer between 1 and 20, inclusive.

[0289] In certain embodiments, at least one of L0B2, L0B3, and L0B4is -(CH2)ni-(O)n2- (CH2CH2O)n3- (CH2)n4- , wherein: each instance of nl is independently an integer between 0 and 6, inclusive. each instance of n2 is independently 0 or 1. each instance of n3 is independently an integer between 1 and 20, inclusive; and each instance of n4 is independently an integer between 1 and 6, inclusive.

[0290] In certain embodiments, at least one of L0B2, L0B3, and L0B4is -(CH2CH2O)n3-CH2CH2- wherein each instance of n3 is independently an integer between 1 and 15, inclusive.

[0291] In certain embodiments, at least one of L0B2is a single bond, -(CH2)i-i2-, or - (CH2CH2O)2-i2- CH2CH2- . In certain embodiments, at least one of L0B2is a single bond. In certain embodiments, at least one of L0B2is optionally substituted C1-20 alkylene. In certain embodiments, at least one of L0B2is optionally substituted C1-12 alkylene. In certain embodiments, at least one of L0B2is -CH2-. In certain embodiments, at least one of L0B2is - (CH2)2-4- In certain embodiments, at least one of L0B2is -(CH2)s-7-. In certain embodiments, at least one of L0B2is -(CH2)s-i2-. In certain embodiments, at least one of L0B2is -(CJbCJbO)^- CH2CH2-, wherein each instance of n3 is independently an integer between 1 and 15, inclusive. In certain embodiments, at least one of L0B2is -(CH2CH2O)2-i2-CH2CH2-

[0292] In certain embodiments, at least one of L0B3is a single bond, -(CH2)i-n-, or - (CH2CH2O)I -10-CH2CH2-. In certain embodiments, at least one of L0B3is a single bond. In certain embodiments, at least one of L0B3is optionally substituted C1-20 alkylene. In certain embodiments, at least one of L0B3is optionally substituted C1-11 alkylene. In certain embodiments, at least one of L0B3is -CH2-. In certain embodiments, at least one of L0B3is -

[0293] M1668.70004WQ00 57 / 511 (CH2)2-4- In certain embodiments, at least one of L0B3is -(CH2)s-7-. In certain embodiments, at least one of L0B3is -(CH2)s-n-. In certain embodiments, at least one of L0B3is -(CJbCJbO)^- CH2CH2-, wherein each instance of n3 is independently an integer between 1 and 15, inclusive. In certain embodiments, at least one of L0B3is -(CH2CH20)MO-CH2CH2-

[0294] In certain embodiments, at least one of L0B4is a single bond or -CH2-. In certain embodiments, at least one of L0B4is a single bond. In certain embodiments, at least one of L0B4is optionally substituted C1-6 alkylene. In certain embodiments, at least one of L0B4is -CH2-. In certain embodiments, at least one of L0B4is -(CH2)2-3-. In certain embodiments, at least one of L0B4is -(CH2)4-6-.

[0295] In certain embodiments, at least one of L0B5is optionally substituted C1-20 alkylene. In certain embodiments, at least one of L0B5is unsubstituted C1-5 alkylene. In certain embodiments, at least one L0B5is unsubstituted Ce-io alkylene. In certain embodiments, at least one of L0B5is unsubstituted Cn-20 alkylene. In certain embodiments, at least one of L0B5is a single bond.

[0296] In certain embodiments, at least one instance of nl is 0. In certain embodiments, at least one instance of nl is 1 or 2. In certain embodiments, at least one instance of nl is 3, 4, 5, or 6.

[0297] In certain embodiments, at least one instance of n3 is an integer between 1 and 6, inclusive. In certain embodiments, at least one instance of n3 is an integer between 7 and 12, inclusive. In certain embodiments, at least one instance of n3 is an integer between 13 and 20, inclusive.

[0298] In certain embodiments, at least one instance of n4 is 1 or 2. In certain embodiments, at least one instance of n4 is 3, 4, 5, or 6.

[0299] In certain embodiments, at least one of L0C1and L0C2is a single bond.

[0300] In certain embodiments, at least one of L0C1and L0C2is optionally substituted heterocyclylene or optionally substituted heteroarylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 4- to 7-membered monocyclic heterocyclylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are one or two nitrogen atoms. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are one or two oxygen atoms. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are nitrogen. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are oxygen. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 1,4-piperazinylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 1,4-piperidinylene. In certain embodiments, at least one of

[0301] M1668.70004WO00 58 / 511 L0C1and L0C2is optionally substituted 7- to 12-membered bicyclic heterocyclylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 7- to 12-membered bicyclic heterocyclylene wherein the ring heteroatoms are one or two nitrogen atoms. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 7- to 12-membered bicyclic heterocyclylene wherein the ring heteroatoms are one or two oxygen atoms. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 5- to 6-membered monocyclic heteroarylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 9- to 10-membered bicyclic heteroarylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 3- to 7-membered monocyclic carbocyclylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted 7- to 14-membered bicyclic carbocyclylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted phenylene (e.g., 1,4-phenylene). In certain embodiments, at least one of L0C1and L0C2is optionally substituted 9- to 11 -membered bicyclic arylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted arylene fused with optionally substituted 5- to 7- membered monocyclic heterocyclylene. In certain embodiments, at least one of L0C1and L0C2is optionally substituted arylene fused with optionally substituted 5- to 7-membered monocyclic carbocyclylene. In certain embodiments, at least one of L0C1and L0C2is a single bond, 4- to 7- membered monocyclic heterocyclylene, optionally substituted 7- to 12-membered bicyclic heterocyclylene, optionally substituted 5- to 6-membered monocyclic heteroarylene, optionally substituted 7- to 14-membered bicyclic carbocyclylene, optionally substituted phenylene, or optionally substituted 9- to 11 -membered bicyclic arylene.

[0302] In certain embodiments, the optionally substituted heteroarylene or optionally substituted heterocyclylene that replaces one of the backbone atoms is, or at least one of L0C1and L0C2is, of the formula:

[0303] M1668.70004WQ00 59 / 511

[0304] each of which is atached at either direction, wherein: k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); and

[0305] Rgis hydrogen, halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl). In certain embodiments, the optionally substituted heteroarylene that replaces one of the backbone atoms is, or at least one of L0C1and L0C2is, of the formula:

[0306] M1668.70004WQ00 60 / 511 each of which is atached at either direction.

[0307] In certain embodiments, the optionally substituted heteroarylene that replaces one of the backbone atoms is, or at least one of L0C1and L0C2is, of the formula: which is attached at either direction.

[0308] In certain embodiments, at least one of L0C3is a single bond. In certain embodiments, at least one of L0C3is optionally substituted heterocyclylene or optionally substituted heteroarylene. In certain embodiments, at least one of L0C3is optionally substituted 4- to 7-membered monocyclic heterocyclylene. In certain embodiments, at least one of L0C3is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are one or two nitrogen atoms. In certain embodiments, at least one of L0C3is optionally substituted 4- to 7- membered monocyclic heterocyclylene wherein the ring heteroatoms are one or two oxygen atoms. In certain embodiments, at least one of L0C3is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are nitrogen. In certain embodiments, at least one of L0C3is optionally substituted 4- to 7-membered monocyclic heterocyclylene wherein the ring heteroatoms are oxygen. In certain embodiments, at least one of L0C3is optionally substituted 1,4-piperazinylene. In certain embodiments, at least one of L0C3is optionally substituted 1,4-piperidinylene. In certain embodiments, at least one of L0C3is optionally substituted 7- to 12-membered bicyclic heterocyclylene. In certain embodiments, at least one of L0C3is optionally substituted 7- to 12-membered bicyclic heterocyclylene wherein the ring heteroatoms are one or two nitrogen atoms. In certain embodiments, at least one of L0C3is optionally substituted 7- to 12-membered bicyclic heterocyclylene wherein the ring heteroatoms are one or two oxygen atoms. In certain embodiments, at least one of L0C3is optionally substituted 5- to 6-membered monocyclic heteroarylene. In certain embodiments, at least one of L0C3is optionally substituted 9- to 10-membered bicyclic heteroarylene. In certain embodiments, at least one of L0C3is optionally substituted 3- to 7-membered monocyclic carbocyclylene. In certain embodiments, at least one of L0C3is optionally substituted 7- to 14- membered bicyclic carbocyclylene. In certain embodiments, at least one of L0C3is optionally

[0309] M1668.70004WQ00 61 / 511 substituted phenylene (e.g., 1,4-phenylene). In certain embodiments, at least one of L0C3is optionally substituted 9- to 11 -membered bicyclic arylene. In certain embodiments, at least one of L0C3is optionally substituted arylene fused with optionally substituted 5- to 7-membered monocyclic heterocyclylene. In certain embodiments, at least one of L0C3is optionally substituted each of which is attached at either direction, wherein: k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); k23 is an integer between 0 and 11, inclusive;

[0310] M1668.70004WQ00 62 / 511 each instance of Rf, if present, is independently halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl); and

[0311] Rgis hydrogen, halogen, optionally substituted Ci-6 alkyl, or -©-(optionally substituted Ci-6 alkyl).

[0312] In certain embodiments, at least one of L0C3is of the formula: each of which is attached at either direction.

[0313] In certain embodiments, at least one of L0C3is of the formula: which is attached at either direction.

[0314] In some embodiments, L° is of the formula: — (CH2)n5-C(=O)NH-(CH2)n6-NHC(=O)-, - (CH2)n6-NHC(=O)-, - (CH2)n5-C(=O)NH-(CH2CH2O)n7-CH2CH2-NHC(=O)-, or - (CH2)n5-C(=O)NH-(CH2CH2O)n7-CH2CH2-C(=O)NH-, - (CH2)n5-NHC(=O)-

[0315] (CH2CH2O)n7-CH2CH2-NHC(=O)-, or - (CH2)n5-NHC(=O)-(CH2CH2©)n7-CH2CH2-

[0316] C(=O)NH-; n5 is an integer between 1 and 6, inclusive; n6 is an integer between 1 and 20, inclusive; and n7 is an integer between 1 and 20, inclusive.

[0317] M1668.70004WQ00 63 / 511 In certain embodiments, n5 is 1 or 2. In certain embodiments, n5 is 3, 4, 5, or 6.

[0318] In certain embodiments, n6 is an integer between 1 and 6, inclusive. In certain embodiments, n6 is an integer between 7 and 12, inclusive. In certain embodiments, n6 is an integer between 13 and 20, inclusive.

[0319] In certain embodiments, n7 is an integer between 1 and 6, inclusive. In certain embodiments, n7 is an integer between 7 and 12, inclusive. In certain embodiments, n7 is an integer between 13 and 20, inclusive.

[0320] In some embodiments, at least one instance of Rais -H. In some embodiments, at least one instance of Rais optionally substituted Ci-6 alkyl (e.g., -CH3). In some embodiments, each instance of Rais independently -H or optionally substituted Ci-6 alkyl. In certain embodiments, each instance of Rais independently -H or unsubstituted Ci-6 alkyl.

[0321] In certain embodiments, L° is of the formula: — - L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-

[0322] L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0A10_L0B4_L0A11_L0A12_ p0C3_b0An_b0A14_b0B5_b0ALS_

[0323] LOA16; and 1, 2, or 3 of -L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8-, -L0A9-L0A10-, - L0A11-L0A12_ ]^o \13_]^o \14 _ ]jni 5_]jl\16_ J^OBI ]J)B2 j^0B3 ]J)B4 jJ)B5 ]J)C1 ]J)C2anc[ L°c3are asingle bond. In certain embodiments, L° is of the formula: __« L0B 1-L0A1-L0A2-L0B2-L0A3-L0A4- J^0cl_J^0A5_j^0A6_j^0B3_j^0A7_j^0A8_j^0c2_j^0A9_j^0A10_j^0B4_j^0A11_j^0A12_ ]A)C3_]jnB3_]jni4_]j:)B5_L0A15_L0A16.and4, 5,orgof_L0Al_L0A2_ _L0A3_L0A4_ _L0A5_L0A6_ _L0A7_L0A8_ _L0A9_ JJIAIO _ L<)A11_JJ)A12 _ LOA13_LOA14 _ ]jni 5_]jl\16_ ]J) Bl ]J)B2 j^0B3 ]J)B4 j^0B5 ]J)C1 ]J)C2anj

[0324] L0C3are a single bond. In certain embodiments, L° is of the formula: — L()BI-L()AI-L0A2-L0B2- J^0A3_j^0A4_j^0cl_j^0A5_j^0A6_j^0B3_j^0A7_j^0A8_j^0c2_j^0A9_j^0A10_j^0B4_j^0A1]J)C3_]J) U 3_

[0325] L0A14_L0B5_L0A15_L0A16.an(j7,8 Qr9of_L0A1_L0A2_ _L0A3_L0A4_ _L0A5_L0A6_ _L0A7_L0A8_ _ L0A9_L0A10_ L°A11_JA)A12 _ J^0A13_J^0A14 _ ]jn LS_]jn 16_ ]J) Bl ]J)B2 jJ)B3 ^0B4 j^0B5 j^OCl

[0326] L0C2, and L0C3are a single bond.

[0327] In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0Ai0_L0B4_L0Ai i_L0Ai2_.and Or 3 of -L0A1-L0A2-, - L0A3-L0A4_ L0A5-L°A6_ L0A7_L0A8 _ ]jn9_]j:ni o _ jJJAl 1_JJ)A12_ J^OBI ]J)B2 ]J)B3 ^0B4 jJ)Cl and L0C2are a single bond. In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2- J^0B2_J^0A3_J^0A4_J^0C1_J^0A5_J^0A6_J^0B3_J^0A7_J^0A8_J^0C2_J^0A9_J^0A10_J^0B4_J^0A11_J^0A12_.anj 4 5 or 6 of -L0A1-L0A2_ L0A3-L0A4_ L0A5-L0A6_ ^OA7_^OA8 _ ]j)A9_|j)Aio _ ]jni i_]jni 2_ jjiBi

[0328] L0B2, pOB3^ pOB4^ ^001,andj^oc2are a s£ngiebond in certain embodiments, L° is of the formula: L0B1_L0A1_L0A2_L0B2_L0A3_L0A4_L0C1_L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0A10_L0B4_L0All_L0A12_.and or 9 of_L0Al_L0A2_ _L0A3_L0A4_5_L0A5_L0A6_ _L0A7_L0A8_ _L0A9_L0A10_ _L0Al l_L0A12_LOB1,L0B2,L0B3,L0B4,LOC1,an(JL0C2are a single bond

[0329] M1668.70004WO00 64 / 511 In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-

[0330] L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0A10_L0B4_L0A1 1_L0A12_- L0B1_L0A1_L0A2_ L0B2-L0A3_

[0331] L0A4_ L0C1_L0A5_L0A6_ L0B3_L0A7_L0A8_ L0C2_J^OA9_J^OAIO_ ^OB4an(j _L0A1 1_L0A12_ARE ASshown in the table below; and optionally the chimera is of Formula II-A:

[0332] M1668.70004WQ00 65 / 511

[0333] In certain embodiments, L° is of the formula: — L0B1-L0A1-L0A2-L0B2-L0A3-L0A4-L0C1-

[0334] L0A5_L0A6_L0B3_L0A7_L0A8_L0C2_L0A9_L0A10_L0B4_L0Al l_L0A12_. JJ)B1 _^OA 1 _]^OA2_ ^0B2 _J^0A3_

[0335] L0A4_ L0C 1_L0A5_L0A6_ L0B3_L0A7_L0A8_ L0C2_J^OA9_J^OAIO_ ^OIUanj _L0A1 1_L0A12_ARE ASshown in the table below; and optionally the chimera is of Formula IV-A:

[0336] M1668.70004WQ00 66 / 511

[0337] M1668.70004WQ00 67 / 511

[0338]

[0339] M1668.70004WQ00 68 / 511

[0340] M1668.70004WQ00 69 / 511

[0341] (continued)

[0342] M1668.70004WQ00 70 / 511

[0343] M1668.70004WQ00 71 / 511

[0344] M1668.70004WQ00 72 / 511

[0345] In certain embodiments, the LXR binder is a compound. In certain embodiments, the

[0346] LXR binder is a small molecule having a molecular weight not more than 1000 g / mol. In certain embodiments, the LXR binder is a small molecule having a molecular weight between 200 and 300, between 300 and 400, between 400 and 600, between 600 and 800, or between 800 and 1000, inclusive, g / mol. In certain embodiments, the LXR binder is a peptide or protein. In certain embodiments, the LXR binder is an oligonucleotide or polynucleotide. In certain embodiments, the LXR binder has a Ki value of not more than 25 pM in an in vitro LXR binding assay. In certain embodiments, the LXR binder has a value of not more than 10 pM in an in vitro LXR binding assay. In certain embodiments, the LXR binder has a value of not more than 5 pM in an in vitro LXR binding assay.

[0347] In certain embodiments, the LXR binder is of any one of the formulae shown in Table 1 :

[0348] Table 1. LXR binders associated with the disclosure

[0349] M1668.70004WQ00 73 / 511

[0350] M1668.70004WQ00 74 / 511

[0351] M1668.70004WQ00 75 / 511

[0352] M1668.70004WQ00 76 / 511

[0353] M1668.70004WQ00 77 / 511

[0354] or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof.

[0355] In certain embodiments, the LXR binder is of the formula:

[0356] (GW3965) (RGX-104), or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof. or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof.

[0357] In certain embodiments, the LXR binder is of the formula:

[0358] M1668.70004WQ00 78 / 511

[0359] (T0901317), or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof.

[0360] In some embodiments, any of the LXR binders described herein is an LXR agonist. In certain embodiments, the analog is obtained by replacing a moiety with an isostere thereof. In certain embodiments, the analog is obtained by replacing -OH with optionally substituted 1-piperazinyl, replacing -O- with -NH-, or replacing optionally substituted alkyl with optionally substituted alkylene-NH2. In certain embodiments, the analog is obtained by replacing one moiety with another moiety. In certain embodiments, the analog is obtained by replacing one atom with another atom or with two, three, or more atoms, as valency permits.

[0361] In certain embodiments, the radical is a monovalent moiety obtained by removing one monovalent single-atom moiety (e.g., -H, -F, -Cl, -Br, or -I) from the LXR binder. In certain embodiments, the radical is a monovalent moiety obtained by removing one monovalent reactive moiety (e.g., -NH2, -NH(nitrogen atom substituent), -OH, -SH, or -C(=O)OH) from the LXR binder. In certain embodiments, the radical is a monovalent moiety obtained by changing an oxygen atom in a heterocyclic ring system of the LXR binder to a nitrogen atom.

[0362] In certain embodiments, R° is of the formula:

[0363] In certain embodiments, R° is of the formula:

[0364] M1668.70004WQ00 79 / 511

[0365] In certain embodiments, L1is optionally substituted alkenylene. In certain embodiments, L1is optionally substituted C2-6 alkenylene. In certain embodiments, L1is unsubstituted C2-6 alkenylene. In certain embodiments, L1is optionally substituted C3-5 alkenylene. In certain embodiments, L1is optionally substituted C7-9 alkenylene. In certain embodiments, L1is 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, — L1is — CH2CH=CH-, — CH2CH=CHCH2-, or — CH2CH=CH(CH2)2- In certain embodiments, L1is C2-6 alkenylene substituted with one or more -F. In certain embodiments, — L1is — CH2CH=CHCHF2-

[0366] In certain embodiments, L1is optionally substituted alkynylene. In certain embodiments, L1is optionally substituted C2-6 alkynylene. In certain embodiments, L1is unsubstituted C2-6 alkynylene. In certain embodiments, L1is optionally substituted C3-5 alkynylene. In certain embodiments, L1is optionally substituted C7-9 alkynylene. In certain embodiments, L1is 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

[0367] M1668.70004WQ00 80 / 511 Ci-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 Ci-6 alkyl). In certain embodiments, — L1is — CH2C=C-, — CH2C=CCH2-, or —

[0368] CH2C =C(CH2)2-. In certain embodiments, L1is C2-6 alkynylene substituted with one or more -F.

[0369] In certain embodiments, L1is unsubstituted methylene. In certain embodiments, L1is unsubstituted C2-12 alkylene. In certain embodiments, L1is unsubstituted C2-6 alkylene. In certain embodiments, L1is unsubstituted C3-5 alkylene. In certain embodiments, L1is unsubstituted C7-9 alkylene. In certain embodiments, L1is unsubstituted C 10-12 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, L1is -(CH2)3-, -(CH2)4- or - (CH2)5-.

[0370] In certain embodiments, L1is 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, L1is 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, L1is 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, L1is 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, L1is 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, L1is C2-6 alkylene substituted with one or more -OH. In certain embodiments, L1is -CH2-CH(OH)-CH2-

[0371] In certain embodiments, R1is -S(=O)2N(R1A)2. In certain embodiments, R1is - S(=O)2NH2, -S(=O)2NH(optionally substituted C1-6 alkyl), or -S(=O)2N(optionally substituted C1-6 alkyl)2. In certain embodiments, R1is -S(=0)2NHMe or -S(=O)2N(Me)2. In certain embodiments, R1is -S(=O)2NH-(CH2)i-3-P(=O)(optionally substituted C1-6 alkyl)2. In certain embodiments, R1is -S(=O)2NH-CH2-P(=O)(Me)2. In certain embodiments, R1is - 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, R1is -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, R1is - S(=0)2NHC(=0)NHMe. In certain embodiments, R1is -B(0R1A)2. In certain embodiments, R1is

[0372] M1668.70004WO00 81 / 511 -B(0H)2. In certain embodiments, R1is -B(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, R1is -B(OR1A)2, wherein the two instances of R1Aare joined together with the intervening atom to form an optionally substituted monocyclic heterocyclic ring. In certain embodiments, R1is -C(=0)N(R1A)2, -C(=O)OR1A, or -NR1AC(=0)N(R1A)2. In certain embodiments, R1is -C(=0)NH2. In certain embodiments, R1is -C(=O)NH(optionally substituted Ci-6 alkyl) or -C(=O)N(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is - C(=O)OH. In certain embodiments, R1is -C(=O)O(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -NHC(=0)N(R1A)2. In certain embodiments, R1is -NHC(=0)NH2. In certain embodiments, R1is -NHC(=O)NH(optionally substituted Ci-6 alkyl) or NHC(=O)N(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is -NHC(=0)N(Me)-C(Me)2-C(=0)0H. In certain embodiments, R1is hydrogen. In certain embodiments, R1is 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, R1is optionally substituted pyridinyl. In certain embodiments, R1is optionally substituted, 2- pyridinyl, 3-pyridinyl, or 4-pyridinyl. In certain embodiments, R1is 3-hydroxy-pyridin-4-yl. In certain embodiments, R1is optionally substituted tetrazolyl. In certain embodiments, R1is optionally substituted 5-tetrazolyl. In certain embodiments, R1is optionally substituted isoxazolyl. In certain embodiments, R1is optionally substituted 5-isoxazolyl. In certain embodiments, R1is 3 -OH-5 -isoxazolyl. In certain embodiments, R1is optionally substituted pyrazolyl. In certain embodiments, R1is l-methyl-3-hydroxy-pyrazol-5-yl. In certain embodiments, R1is 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).

[0373] In certain embodiments, R1is optionally substituted heterocyclyl. In certain embodiments, R1is optionally substituted monocyclic 4-membered heterocyclyl. In certain embodiments, R1is optionally substituted oxetanyl. In certain embodiments, R1is optionally substituted 3-oxetanyl. In certain embodiments, R1is 3 -Me-3 -oxetanyl or 3 -OH-3 -oxetanyl. In certain embodiments, R1is optionally substituted monocyclic 5-membered heterocyclyl. In certain embodiments, R1is monocyclic 5-membered heterocyclyl that comprises at least one nitrogen atom in the heterocyclic ring system and attached to L1and is substituted at least with

[0374] M1668.70004WQ00 82 / 511N^(H or optionally substituted C1_6alkyl) oxo. In certain embodiments, R1is (halogen or optionally substituted Ci.6alkyl)0^ optionally substituted C^.g alkyl)

[0375] (halogen or optionally substituted C-|.g alkyl)0-2

[0376] O

[0377] ^N'ZS'N'^Hor°Ptional|y substituted C^g alkyl)

[0378] O (halogen or optionally substituted alkyl)0-2 or(halngen or optionally substituted C^g alkyl)0.4. In certain embodiments, R1is

[0379] (halogen or optionally substituted C^g alkyl)0-4or

[0380] O

[0381] O (halogen or optionally substituted alkyl)0-2 In certainembodiments, R1is

[0382] (halogen or optionally substituted C^g alkyl)0-6 or or optionally substituted C^g alkyl)

[0383] (halogen or optionally substituted C-|_6 alkyl)o-4 jncertain embodiments, R1is

[0384] O or optionally substituted Ci.6alkyl)

[0385] (halogen or optionally substituted C1_6alkyl)0-4optionally substituted C1_6alkyl)

[0386] (halogen or optionally substituted C1_6alkyl)0-2

[0387] M1668.70004WQ00 83 / 511 O

[0388] '"N'ZS'N"^oropt'OHslly substituted C1_6alkyl)

[0389] O (halogen or optionally substituted alkyl)o_2 or(halngpn or optionally substituted alkyl)0-4. In certain embodiments, R1is

[0390] (halogen or optionally substituted alkyl)o_4 oro o (halogen or optionally substituted alkyl)0-2 In certainembodiments, R1is

[0391] (halogen or optionally substituted C1_6alkyl)0.6 oror optionally substitutedC1_6alkyl)

[0392] (halogen or optionally substituted alkyl)0.4 . incertain embodiments, R1is

[0393] O. P r optionally substituted alkyl)

[0394] O (halogen or optionally substituted alkyl)0- or optionally substituted alkyl) 9 y\J / ^N NH

[0395] 0 (halogen or optionally substituted alkyl)^In certainembodiments, R1is

[0396] M1668.70004WQ00 84 / 511

[0397] o embodiments, R1is . In certain embodiments, certain certain embodiments, R1is . In certain embodiments,

[0398] M1668.70004WQ00 85 / 511

[0399] substituted monocyclic 6-membered heterocyclyl. In certain embodiments, R1is 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.

[0400] In certain embodiments, R1is -N=S(=O)(R1A)2. In certain embodiments, R1is - N=S(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is -N=S(=0)(Me)2. In certain embodiments, R1is -OR1A. In certain embodiments, R1is -OH. In certain embodiments, R1is -©(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -OMe. In certain embodiments, R1is -P(=O)(R1A)2 or -P(=O)(OR1A)2. In certain embodiments, R1is - P(=O)(optionally substituted Ci-6 alkyl)2 or -P(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, R1is -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, R1is -C(=O)N(R1A)S(=O)2R1A, -NR1AS(=O)2R1A, -NR1AS(=O)2N(R1A)2, -S(=O)R1A, - S(=O)(=NR1A)R1A, -S(=O)2R1A, -S(=O)2N(R4A)2, or -S(=O)2N(R4A)C(=O)N(R4A)2. In certain embodiments, R1is -C(=O)NHS(=O)2R1A. In certain embodiments, R1is - C(=O)NHS(=O)2(optionally substituted Ci-6 alkyl). In certain embodiments, R1is - C(=0)NHS(=0)2Me. In certain embodiments, R1is -NHS(=O)2(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -NHS(=0)2Me. In certain embodiments, R1is -NHS(=O)2- (CH2)I-3-C(=O)O(H or optionally substituted Ci-6 alkyl). In certain embodiments, R1is -

[0401] M1668.70004WQ00 86 / 511 NHS(=O)2-CH2-C(=O)OH. In certain embodiments, R1is -NHS(=O)2NH2, - NHS(=O)2NH(optionally substituted Ci-6 alkyl), or -NHS(=O)2N(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is -NHS(=0)2NHMe or -NHS(=O)2N(Me)2. In certain embodiments, R1is -S(=O)R1A. In certain embodiments, R1is -S(=O)(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -S(=O)-(CH2)i-3-(optionally substituted heterocyclyl). In certain embodiments, R1is -S(=O)-(CH2)i-3-(optionally substituted 3- to 7-membered monocyclic heterocyclyl). In certain embodiments, R1is -S(=O)-(CH2)i-3-(optionally substituted oxetanyl). In certain embodiments, R1is -S(=O)-(CH2)i-3-(optionally substituted 3-oxetanyl). In certain embodiments, R1is -S(=O)(=NH)R1A. In certain embodiments, R1is - S(=O)(=NH)(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -S(=O)(=NH)(Me), -S(=O)(=NH)(Et), -S(=O)(=NH)(zz-Pr), or -S(=O)(=NH)(z-Pr). In certain embodiments, R1is - S(=O)(=NH)(zz-Bu), -S(=O)(=NH)(z-Bu), -S(=O)(=NH)( -Bu), or -S(=0)(=NH)(7-Bu). In certain embodiments, R1is -S(=O)2R1A.

[0402] In certain embodiments, R1is -S(=O)2(optionally substituted Ci-6 alkyl) or - S(=O)2(optionally substituted heterocyclyl). In certain embodiments, R1is -S(=O)2Me. In certain embodiments, R1is -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, R1is - 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, R1is .

[0403] In certain embodiments, R1is -S(=O)2NH2, -S(=O)2NH(optionally substituted Ci-6 alkyl), or -S(=O)2N(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is - S(=0)2NH(Me) or -S(=O)2N(Me)2. In certain embodiments, R1is -S(=O)2NH-(CH2)I-3- C(=O)O(optionally substituted Ci-6 alkyl). In certain embodiments, R1is -S(=O)2NH-CH2- C(=O)OH. In certain embodiments, R1is -S(=O)2NH-(CH2)i-3-P(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, R1is -S(=O)2NH-CH2-P(=O)(Me)2. In certain embodiments, R1is -S(=O)2NHC(=O)N(R4A)2. In certain embodiments, R1is -S(=O)2NHC(=O)NH2, - 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, R1is -S(=O)2NHC(=O)N(Me)2.

[0404] M1668.70004WQ00 87 / 511 In certain embodiments, at least one instance of R1Ais hydrogen. In certain embodiments, each instance of R1Ais hydrogen. In certain embodiments, at least one instance of R1Ais not hydrogen. In certain embodiments, no instance of R1Ais hydrogen. In certain embodiments, at least one instance of R1Ais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, at least one instance of R1Ais unsubstituted alkyl. In certain embodiments, at least one instance of R1Ais unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of R1Ais Me. In certain embodiments, at least one instance of R1Ais Et, Pr, or Bu. In certain embodiments, at least one instance of R1Ais substituted Ci-6 alkyl. In certain embodiments, at least one instance of R1Ais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R1Ais substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R1Ais optionally substituted alkenyl. In certain embodiments, at least one instance of R1Ais optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, at least one instance of R1Ais optionally substituted alkynyl. In certain embodiments, at least one instance of R1Ais optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, at least one instance of R1Ais optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R1Ais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, at least one instance of R1Ais saturated carbocyclyl. In certain embodiments, at least one instance of R1Ais partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, at least one instance of R1Ais optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R1Ais 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 R1Ais saturated heterocyclyl. In certain embodiments, at least one instance of R1Ais partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, at least one instance of R1Ais optionally substituted aryl. In certain embodiments, at least one instance of R1Ais optionally substituted phenyl. In certain embodiments, at least one instance of R1Ais unsubstituted phenyl. In certain embodiments, at least one instance of R1Ais 2-mono-substituted phenyl. In certain embodiments, at least one instance of R1Ais 3 -mono-substituted phenyl. In certain embodiments, at least one

[0405] M1668.70004WQ00 88 / 511 instance of R1Ais 4-mono-substituted phenyl. In certain embodiments, R1Ais di-substituted phenyl. In certain embodiments, at least one instance of R1Ais optionally substituted naphthyl. In certain embodiments, at least one instance of R1Ais optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, at least one instance of R1Ais optionally substituted heteroaryl. In certain embodiments, at least one instance of R1Ais optionally substituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R1Ais 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 R1Ais optionally substituted pyridinyl (e.g., 2-, 3-, or 4- pyridinyl). In certain embodiments, at least one instance of R1Ais optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, at least one instance of R1Ais optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R1Ais 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 R1Ais 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 R1Ais 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 R1Aattached 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 R1Aattached 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 R1Ais hydrogen or optionally substituted Ci-6 alkyl. In certain embodiments, each instance of R1Ais independently hydrogen or optionally substituted Ci-6 alkyl.

[0406] In certain embodiments, -L'-R1is 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-ox etan- 3-yl), and -(CH2)3-S-( substituted C1-3 alkyl). In certain embodiments, -L'-R1is not -(CEhjs- (optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -L'-R1is not -(CH2)3-(unsubstituted 6-membered monocyclic heteroaryl). In certain embodiments, -L1-

[0407] M1668.70004WQ00 89 / 511 R1is not -(CH2)3-(optionally substituted pyridinyl). In certain embodiments, -L'-R1is not - (CH2)3-(unsubstituted pyridinyl). In certain embodiments, -L'-R1is not -(CH2)3-(optionally substituted pyridine- 1 -oxide). In certain embodiments, -L'-R1is not -(CH2)3-(unsubstituted pyridine- 1 -oxide). In certain embodiments, -L'-R1is not -CH2CH=CH-(optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -L'-R1is not -CH2CH=CH- (unsubstituted 6-membered monocyclic heteroaryl). In certain embodiments, -L'-R1is not - CH2CH=CH-(optionally substituted pyridinyl). In certain embodiments, -L'-R1is not - CH2CH=CH-(unsubstituted pyridinyl). In certain embodiments, -L'-R1is not -CH2CH=CH- (optionally substituted pyridine- 1 -oxide). In certain embodiments, -L'-R1is not -CH2CH=CH- (unsubstituted pyridine- 1 -oxide). In certain embodiments, -L'-R1is not -(CH2)3-C(=O)NH- (unsubstituted 6-membered monocyclic heteroaryl). In certain embodiments, -L'-R1is not - (CH2)3-C(=O)NH-(optionally substituted 6-membered monocyclic heteroaryl). In certain embodiments, -L'-R1is not -(CH2)3-C(=O)NH-(optionally substituted monocyclic heteroaryl). In certain embodiments, -L'-R1is not -(CH2)2-4-C(=O)NH-(optionally substituted monocyclic heteroaryl). In certain embodiments, -L'-R1is not -(CH2)2-4-C(=O)OH. In certain embodiments, -L'-R1is not optionally substituted C2-4 alkenyl. In certain embodiments, -L'-R1is not - (unsubstituted C2-4 alkenylene)-C(=O)OH. In certain embodiments, -L'-R1is not -CH2CH=CH- (optionally substituted oxetanyl). In certain embodiments, -L'-R1is not -(unsubstituted C2-4 alkenylene)-(optionally substituted oxetanyl). In certain embodiments, -L'-R1is not - (unsubstituted C2-4 alkenylene)-(optionally substituted 4-membered monocyclic heterocyclyl). In certain embodiments, -L'-R1is not -(CH2)3-S-(optionally substituted C1-4 alkyl). In certain embodiments, -L'-R1is not -(CH2)2-4-S-(optionally substituted C1-4 alkyl).

[0408] In certain embodiments, -L'-R1is -(CH2)3-4-(optionally substituted oxetanyl), -(CH2)3-4- (optionally substituted imidazolidin-2-one-l-yl), -(CH2)3-4-(optionally substituted imidazolidine- 2,4-dione-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).

[0409] M1668.70004WQ00 90 / 511 o

[0410] < ^N NH

[0411] In certain embodiments, -L'-R1is -(CH2)3-(3-OH-3-oxetanyl), -(CH2)4-( ), -

[0412] 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.

[0413] In certain embodiments, -L'-R1is optionally substituted C1-6 alkyl. In certain embodiments, -L'-R1is unsubstituted C1-6 alkyl (e.g., -CH3). In certain embodiments, -L'-R1is optionally substituted C2-6 alkenyl. In certain embodiments, -L'-R1is unsubstituted C2-6 alkenyl (e g., -CH2CH=CH2).

[0414] In certain embodiments, =R2is =0. In certain embodiments, =R2is -0R2A. In certain embodiments, =R2is -OH. In certain embodiments, =R2is -©(optionally substituted C1-6 alkyl). In certain embodiments, =R2is -OMe. In certain embodiments, the carbon atom to which R2is attached is of the S configuration. In certain embodiments, the carbon atom to which R2is attached is of the R configuration.

[0415] In certain embodiments, R2Ais hydrogen. In certain embodiments, R2Ais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, R2Ais unsubstituted alkyl. In certain embodiments, R2Ais unsubstituted C1-6 alkyl. In certain embodiments, R2Ais Me. In certain embodiments, R2Ais Et, Pr, or Bu. In certain embodiments, R2Ais substituted C1-6 alkyl. In certain embodiments, R2Ais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R2Ais substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R2Ais optionally substituted alkenyl. In certain embodiments, R2Ais optionally substituted, C2-6 alkenyl (e.g, optionally substituted vinyl or optionally substituted allyl). In certain embodiments, R2Ais optionally substituted alkynyl. In certain embodiments, R2Ais optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, R2Ais optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic,

[0416] M1668.70004WQ00 91 / 511 3- to 7-membered carbocyclyl). In certain embodiments, R2Ais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, R2Ais saturated carbocyclyl. In certain embodiments, R2Ais partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, R2Ais optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R2Ais 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, R2Ais saturated heterocyclyl. In certain embodiments, R2Ais partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, R2Ais optionally substituted aryl. In certain embodiments, R2Ais optionally substituted phenyl. In certain embodiments, R2Ais unsubstituted phenyl. In certain embodiments, R2Ais 2-mono-substituted phenyl. In certain embodiments, R2Ais 3 -mono-substituted phenyl. In certain embodiments, R2Ais 4-mono-substituted phenyl. In certain embodiments, R2Ais disubstituted phenyl. In certain embodiments, R2Ais optionally substituted naphthyl. In certain embodiments, R2Ais optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R2Ais optionally substituted heteroaryl. In certain embodiments, R2Ais optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R2Ais 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, R2Ais optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R2Ais optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, R2Ais optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R2Ais 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, R2Ais hydrogen or optionally substituted Ci-6 alkyl.

[0417] In certain embodiments, R3is -OR3A. In certain embodiments, R3is -OH. In certain embodiments, R3is -©(optionally substituted alkyl). In certain embodiments, R3is -©(optionally substituted Ci-6 alkyl). In certain embodiments, R3is -OMe. In certain embodiments, R3is hydrogen. In certain embodiments, the carbon atom to which R3is attached is of the S configuration. In certain embodiments, the carbon atom to which R3is attached is of the R configuration.

[0418] M1668.70004WQ00 92 / 511 In certain embodiments, R3Ais hydrogen. In certain embodiments, R3Ais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, R3Ais unsubstituted alkyl. In certain embodiments, R3Ais unsubstituted Ci-6 alkyl. In certain embodiments, R3Ais Me. In certain embodiments, R3Ais Et, Pr, or Bu. In certain embodiments, R3Ais substituted Ci-6 alkyl. In certain embodiments, R3Ais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R3Ais substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R3Ais optionally substituted alkenyl. In certain embodiments, R3Ais optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, R3Ais optionally substituted alkynyl. In certain embodiments, R3Ais optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, R3Ais optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R3Ais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, R3Ais saturated carbocyclyl. In certain embodiments, R3Ais partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, R3Ais optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R3Ais 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, R3Ais saturated heterocyclyl. In certain embodiments, R3Ais partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, R3Ais optionally substituted aryl. In certain embodiments, R3Ais optionally substituted phenyl. In certain embodiments, R3Ais unsubstituted phenyl. In certain embodiments, R3Ais 2-mono-substituted phenyl. In certain embodiments, R3Ais 3 -mono-substituted phenyl. In certain embodiments, R3Ais 4-mono-substituted phenyl. In certain embodiments, R3Ais disubstituted phenyl. In certain embodiments, R3Ais optionally substituted naphthyl. In certain embodiments, R3Ais optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R3Ais optionally substituted heteroaryl. In certain embodiments, R3Ais optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R3Ais 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, R3Ais optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R3A

[0419] M1668.70004WQ00 93 / 511 is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, R3Ais optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R3Ais 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, R3Ais hydrogen or optionally substituted Ci-6 alkyl.

[0420] In certain embodiments, R4is -OR4A. In certain embodiments, R4is -O(optionally substituted alkyl) or -O(optionally substituted alkenyl). In certain embodiments, R4is - □(optionally substituted Ci-6 alkyl) or -O(optionally substituted C2-6 alkenyl). In certain embodiments, R4is -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, R4is -O-(CH2)i-6-OH or -O-CH2-CH=CH- CH2-S(=O)2NH(optionally substituted C1-6 alkyl). In certain embodiments, R4is -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, R4is -O-(CH2)i-6-C(=O)NH-(optionally substituted heteroaryl). In certain embodiments, R4is -O-(CH2)i-6-C(=O)NH-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, R4is -O-(CH2)I- 6-C(=O)NH-(optionally substituted pyridinyl). In certain embodiments, R4is -O-(CH2)I-6- (optionally substituted heterocyclyl). In certain embodiments, R4is -O-(CH2)i-6-(optionally substituted 3- to 7-membered monocyclic heterocyclyl). In certain embodiments, R4is -O- (CH2)i-6-(optionally substituted morpholinyl). In certain embodiments, R4is -O-(CH2)I-6- (optionally substituted heteroaryl). In certain embodiments, R4is -O-(CH2)i-6-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, R4is -O-(CH2)I- 6-(optionally substituted pyridinyl). In certain embodiments, R4is -O-(optionally substituted heteroaryl). In certain embodiments, R4is -O-(optionally substituted 5- or 6-membered monocyclic heteroaryl). In certain embodiments, R4is -O-(optionally substituted pyridinyl). In certain embodiments, R4is -O-(optionally substituted 9- or 10-membered bicyclic heteroaryl). In certain embodiments, R4is -O-(optionally substituted indolyl). In certain embodiments, R4is - O-(CH2)3-C(=O)NH-(2-pyridinyl), -O-(CH2)3-(4-morpholinyl), or -O-(CH2)3-(2 -pyridinyl). In certain embodiments, R4is -O(unsubstituted C1-6 alkyl). In certain embodiments, R4is -OMe, - OEt, -O(«-Pr), or -O(z-Pr). In certain embodiments, R4is -OMe. In certain embodiments, R4is - 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

[0421] M1668.70004WQ00 94 / 511 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, R4is -P(=O)(OR4A)2. In certain embodiments, R4is -P(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, R4is -P(=0)(0Me)2. In certain embodiments, R4is -P(=O)(R41)2. In certain embodiments, R4is -P(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, R4is -P(=0)Me2. In certain embodiments, R4is -OP(=O)(OR41)2. In certain embodiments, R4is -OP(=O)(O(optionally substituted Ci-6 alkyl))2. In certain embodiments, R4is -0P(=0)(0Me)2. In certain embodiments, R4is -OP(=O)(R41)2. In certain embodiments, R4is -OP(=O)(optionally substituted Ci-6 alkyl)2. In certain embodiments, R4is - 0P(=0)Me2. In certain embodiments, R4is -OC(=O)R41. In certain embodiments, R4is - OC(=O)(substituted or unsubstituted alkyl). In certain embodiments, R4is -OC(=O)R41. In certain embodiments, R4is -OC(=O)(Ci-6 alkyl substituted with at least one instance of hydroxy). In certain embodiments, R4is -CN. In certain embodiments, R4is halogen. In certain embodiments, R4is -Cl. In certain embodiments, R4is optionally substituted heteroaryl. In certain embodiments, R4is optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R4is 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, R4is optionally substituted tetrazolyl. In certain embodiments, R4is optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R4is optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, R4is optionally substituted, 9- to 10- membered, bicyclic heteroaryl.

[0422] In certain embodiments, at least one instance of R4Ais hydrogen. In certain embodiments, each instance of R4Ais hydrogen. In certain embodiments, at least one instance of R4Ais not hydrogen. In certain embodiments, no instance of R4Ais hydrogen. In certain embodiments, at least one instance of R4Ais optionally substituted alkyl or optionally substituted alkenyl. In certain embodiments, at least one instance of R4Ais alkyl or alkenyl, each of which is optionally substituted with one or more carbon atom substituents. In certain embodiments, at least one instance of R4Ais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., -F)). In certain embodiments, at least one instance of R4Ais unsubstituted alkyl. In certain

[0423] M1668.70004WQ00 95 / 511 embodiments, at least one instance of R4Ais unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of R4Ais unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of R4Ais Me. In certain embodiments, at least one instance of R4Ais Et, Pr, or Bu. In certain embodiments, at least one instance of R4Ais substituted C1-6 alkyl. In certain embodiments, at least one instance of R4Ais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R4Ais substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R4Ais optionally substituted alkenyl. In certain embodiments, at least one instance of R4Ais optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted allyl). In certain embodiments, at least one instance of R4Ais optionally substituted alkynyl. In certain embodiments, at least one instance of R4Ais optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, at least one instance of R4Ais optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R4Ais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, at least one instance of R4Ais saturated carbocyclyl. In certain embodiments, at least one instance of R4Ais partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, at least one instance of R4Ais optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7- membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R4Ais 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 R4Ais saturated heterocyclyl. In certain embodiments, at least one instance of R4Ais partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, at least one instance of R4Ais optionally substituted aryl. In certain embodiments, at least one instance of R4Ais optionally substituted phenyl. In certain embodiments, at least one instance of R4Ais unsubstituted phenyl. In certain embodiments, at least one instance of R4Ais 2-mono- substituted phenyl. In certain embodiments, at least one instance of R4Ais 3-mono-substituted phenyl. In certain embodiments, at least one instance of R4Ais 4-mono-substituted phenyl. In certain embodiments, R4Ais di-substituted phenyl. In certain embodiments, at least one instance of R4Ais optionally substituted naphthyl. In certain embodiments, at least one instance of R4Ais optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, at least one instance of R4Ais optionally substituted heteroaryl. In certain embodiments, at least one instance

[0424] M1668.70004WQ00 96 / 511 of R4Ais optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R4Ais 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 R4Ais optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of R4Ais optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, at least one instance of R4Ais optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R4Ais 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 R4Ais an oxygen protecting group e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, at least one instance of R4Ais 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 R4Aattached 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 R4Aattached 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 R4Ais independently hydrogen or optionally substituted Ci-6 alkyl.

[0425] In certain embodiments, = R5is =0. In certain embodiments, = R5is -0R5A. In certain embodiments, =R5is -OH. In certain embodiments, =R5is -©(optionally substituted Ci-6 alkyl). In certain embodiments, =R5is -OMe. In certain embodiments, the carbon atom to which R5is attached is of the R configuration. In certain embodiments, the carbon atom to which R5is attached is of the S configuration.

[0426] In certain embodiments, R5Ais hydrogen. In certain embodiments, R5Ais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., - F)). In certain embodiments, R5Ais unsubstituted alkyl. In certain embodiments, R5Ais unsubstituted Ci-6 alkyl. In certain embodiments, R5Ais Me. In certain embodiments, R5Ais Et, Pr, or Bu. In certain embodiments, R5Ais substituted Ci-6 alkyl. In certain embodiments, R5Ais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R5Ais substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R5Ais optionally substituted alkenyl. In certain embodiments, R5Ais optionally substituted, C2-6 alkenyl (e.g., optionally substituted vinyl or optionally substituted

[0427] M1668.70004WQ00 97 / 511 allyl). In certain embodiments, R5Ais optionally substituted alkynyl. In certain embodiments, R5Ais optionally substituted, C2-6 alkynyl (e.g., optionally substituted ethynyl). In certain embodiments, R5Ais optionally substituted carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, R5Ais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. In certain embodiments, R5Ais saturated carbocyclyl. In certain embodiments, R5Ais partially unsaturated carbocyclyl (e.g., comprising only one CC double bond in the carbocyclic ring system). In certain embodiments, R5Ais optionally substituted heterocyclyl (e.g., optionally substituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R5Ais 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, R5Ais saturated heterocyclyl. In certain embodiments, R5Ais partially unsaturated heterocyclyl (e.g., comprising only one CC double bond in the heterocyclic ring system). In certain embodiments, R5Ais optionally substituted aryl. In certain embodiments, R5Ais optionally substituted phenyl. In certain embodiments, R5Ais unsubstituted phenyl. In certain embodiments, R5Ais 2-mono-substituted phenyl. In certain embodiments, R5Ais 3 -mono-substituted phenyl. In certain embodiments, R5Ais 4-mono-substituted phenyl. In certain embodiments, R5Ais disubstituted phenyl. In certain embodiments, R5Ais optionally substituted naphthyl. In certain embodiments, R5Ais optionally substituted alkyl or optionally substituted phenyl. In certain embodiments, R5Ais optionally substituted heteroaryl. In certain embodiments, R5Ais optionally substituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R5Ais 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, R5Ais optionally substituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R5Ais optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, R5Ais optionally substituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R5Ais 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, R5Ais hydrogen or optionally substituted C1-6 alkyl.

[0428] In certain embodiments, the chimera is of any one of the formulae shown in Table 1 A: Table 1 A. Exemplary chimeras associated with the disclosure

[0429] M1668.70004WQ00 98 / 511

[0430]

[0431] M1668.70004WQ00 99 / 511

[0432]

[0433] M1668.70004WQ00 100 / 511

[0434] M1668.70004WQ00 101 / 511

[0435] M1668.70004WQ00 102 / 511

[0436]

[0437] M1668.70004WQ00 103 / 511

[0438]

[0439] M1668.70004WQ00 104 / 511

[0440] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0441] In certain embodiments, the chimera is of any one of the formulae shown in Table IB:

[0442] Table IB. Additional exemplary chimeras associated with the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0443] M1668.70004WQ00 105 / 511

[0444]

[0445] In certain embodiments, R11is optionally substituted alkynyl.

[0446] In certain embodiments, R11is optionally substituted C2-6 alkynyl.

[0447] In certain embodiments, R11is -C=CH.

[0448] In certain embodiments, R11is optionally substituted carbocyclyl.

[0449] In certain embodiments, R11is optionally substituted heterocyclyl.

[0450] In certain embodiments, R11is optionally substituted 3- to 7-membered monocyclic heterocyclyl or optionally substituted 7- to 12-membered bicyclic heterocyclyl.

[0451] In certain embodiments, R11is optionally substituted heterocyclyl comprising at least one ring nitrogen atom that is attached to L11B.

[0452] In certain embodiments, R11is optionally substituted heteroaryl.

[0453] In certain embodiments, R11is optionally substituted, 5- to 6-membered, monocyclic heteroaryl.

[0454] In certain embodiments, R11is optionally substituted pyridinyl.

[0455] In certain embodiments, R11is optionally substituted 1,2,3-triazolyl.

[0456] In certain embodiments, R13is optionally substituted phenyl.

[0457] In certain embodiments, R13is 3, 5 -di substituted phenyl.

[0458] M1668.70004WQ00 106 / 511 In certain embodiments, R13is 3,5-dichloro phenyl.

[0459] In certain embodiments, R13is optionally substituted alkyl.

[0460] In certain embodiments, R13is unsubstituted Ci-6 alkyl.

[0461] In certain embodiments, R13is optionally substituted heteroaryl.

[0462] In certain embodiments, R13is optionally substituted, 5- to 6-membered, monocyclic heteroaryl.

[0463] In certain embodiments, R13is optionally substituted pyridinyl or optionally substituted pyrazolyl.

[0464] In certain embodiments, Ll lcis a single bond.

[0465] In certain embodiments, L13Bis optionally substituted heterocyclylene.

[0466] In certain embodiments, L13Bis C3-10 heterocyclylene optionally substituted with one or more substituents independently selected from the group consisting of halogen, substituted or unsubstituted C1-6 alkyl, and oxo.

[0467] In certain embodiments, L13Bis unsubstituted unbranched C3-10 heterocyclylene comprising 1, 2, or 3 oxygen atoms as the only backbone heteroatoms, as valency permits.

[0468] In certain embodiments, L13Bis -(CH2)4-7-O-, wherein the -O- thereof is attached to L13A.

[0469] In certain embodiments, L13Ais optionally substituted phenylene.

[0470] In certain embodiments, L13Ais optionally substituted 1,3 -phenylene.

[0471] In certain embodiments, L13Ais 5-chloro-l,3-phenylene.

[0472] In certain embodiments, L11Ais optionally substituted, C1-6 alkylene.

[0473] In certain embodiments, L11Ais optionally substituted methylene.

[0474] In certain embodiments, L11Ais -CH2-.

[0475] In certain embodiments, L11Ais -CH(CH3)-, optionally wherein the CH3 thereof is of the S configuration.

[0476] In certain embodiments, L11Ais a single bond.

[0477] In certain embodiments, L11Bis a single bond.

[0478] In certain embodiments, L11Bis -C(=O)-.

[0479] In certain embodiments, L11Bis -C(=O)NR11B-, wherein the -C thereof is attached to

[0480] L11A.

[0481] In certain embodiments, each instance of R11Bis independently hydrogen or optionally substituted C1-6 alkyl.

[0482] In certain embodiments, L11Bis -C(=O)NH- or -C(=0)N(CH3)-, wherein the -C thereof is attached to L11A.

[0483] In certain embodiments, R12is optionally substituted alkyl.

[0484] M1668.70004WO00 107 / 511 In certain embodiments, R12is substituted Ci-6 alkyl.

[0485] In certain embodiments, R12is C1-2 alkyl substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -ORaa, -NH2, -NHRbb, - N(Rbb)2, and -NRbbC(=O)Raa; each instance of Raais, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroC1-20 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, C1-20 alkyl, Ci-2o perhaloalkyl, Ci-2o 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, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroC1-20 alkyl, heteroC1-20 alkenyl, heteroC1-20 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(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=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,

[0486] M1668.70004WO00 108 / 511 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, 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 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, 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 -6 alkyl)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.

[0487] M1668.70004WQ00 109 / 511 In certain embodiments, R12is C1-2 alkyl substituted with one or more substituents independently selected from the group consisting of-F, -Cl, -OH, -OCH3, -OC2H5, -NH2, - NHCH3, -NHC2H5, -N(CH3)2, and -NHC(=O)CH3.

[0488] In certain embodiments, R12is -CH2-OH or -CH2-OCH3.

[0489] In certain embodiments, R12is optionally substituted alkenyl.

[0490] In certain embodiments, R12is -CH=CH2.

[0491] In certain embodiments, the chimera is of the formula shown in Table 1C:

[0492] Table 1C. Additional exemplary chimera associated with the disclosure or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0493] In certain embodiments, the chimera is of any one of the formulae shown in Table ID: Table ID. Additional exemplary chimeras associated with the disclosure

[0494] M1668.70004WQ00 110 / 511

[0495] M1668.70004WQ00 111 / 511

[0496] M1668.70004WQ00 112 / 511

[0497] M1668.70004WQ00 113 / 511

[0498] M1668.70004WQ00 114 / 511

[0499]

[0500] M1668.70004WQ00 115 / 511

[0501] M1668.70004WQ00 116 / 511

[0502] M1668.70004WQ00 117 / 511

[0503]

[0504] M1668.70004WQ00 118 / 511

[0505]

[0506] M1668.70004WQ00 119 / 511

[0507]

[0508] M1668.70004WQ00 120 / 511

[0509] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0510] In certain embodiments, a provided chimera (a chimera provided herein, a chimera described herein, or a chimera of the present disclosure) is a chimera of Formula II-A or II-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided chimera is a chimera of Formula II-A or II-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided chimera is a chimera of Formula II-A or II-B, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided chimera is a chimera of Formula II-A or II-B, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided chimera is a chimera of Formula II-A or II-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided chimera (a chimera provided herein, a chimera described herein, or a chimera of the present disclosure) is a chimera of Formula IV-A, IV-B, or IV-C, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided chimera is a chimera of Formula IV-A, IV-B, or IV-C, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided chimera is a chimera of Formula IV-A, IV-B, or IV-C, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided chimera is a chimera of Formula IV-A, IV-B, or IV-C, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided chimera is a chimera of Formula IV-A, IV-B, or IV-C, or a pharmaceutically acceptable salt thereof.

[0511] In certain embodiments, the chimeras provided herein are useful for being administered to a subject. In certain embodiments, the chimeras provided herein are useful for being contacted

[0512] M1668.70004WQ00 121 / 511 with a cell, biological sample, or tissue. In certain embodiments, the chimeras provided herein are useful for treating a disease in a subject in need thereof. In certain embodiments, the chimeras provided herein are useful for preventing a disease in a subject in need thereof.

[0513] In certain embodiments, the chimera, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is able to cross the blood-brain barrier.

[0514] Pharmaceutical Compositions, Kits, and Administration

[0515] In another aspect, the present disclosure provides pharmaceutical compositions comprising a chimera or compound (e.g., peripheral blocker) disclosed herein and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents.

[0516] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the chimera or 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.

[0517] 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.

[0518] 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.

[0519] 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.

[0520] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose,

[0521] M1668.70004WQ00 122 / 511 sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0522] 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.

[0523] 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.

[0524] 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,

[0525] M1668.70004WQ00 123 / 511 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.

[0526] 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.

[0527] 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.

[0528] 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.

[0529] 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.

[0530] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0531] 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.

[0532] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium

[0533] M1668.70004WQ00 124 / 511 metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0534] 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.

[0535] 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.

[0536] 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.

[0537] 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,

[0538] M1668.70004WQ00 125 / 511 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.

[0539] 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.

[0540] 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.

[0541] 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.

[0542] 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.

[0543] 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

[0544] M1668.70004WQ00 126 / 511 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.

[0545] 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.

[0546] 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.

[0547] Dosage forms for topical and / or transdermal administration of a chimera or 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

[0548] M1668.70004WQ00 127 / 511 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.

[0549] 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.

[0550] 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.

[0551] 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

[0552] M1668.70004WQ00 128 / 511 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.

[0553] 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).

[0554] 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.

[0555] 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.

[0556] 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.

[0557] M1668.70004WQ00 129 / 511 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.

[0558] 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.

[0559] Chimeras or 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.

[0560] In some embodiments, the chimeras, compounds, or 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

[0561] M1668.70004WQ00 130 / 511 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 chimera, compound, or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0562] The exact amount of a chimera or 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 chimera or 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 chimera or 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 chimera or compound described herein. In

[0563] M1668.70004WQ00 131 / 511 certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a chimera or compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a chimera or compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a chimera or compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a chimera or compound described herein.

[0564] In certain embodiments, an effective amount is an amount that is effective in reducing at least one side effect associated with treatment of AD by an LXR agonist. In certain embodiments, an effective amount is an amount that is effective in reducing at least one symptom of AD.

[0565] 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.

[0566] 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.

[0567] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs) comprising a chimera or compound or pharmaceutical composition provided herein; and instructions for using the chimera or compound or pharmaceutical composition provided herein. In some embodiments, the kit comprises a pharmaceutical composition or chimera 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 chimera or compound described herein. In some embodiments, the pharmaceutical composition or chimera 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 chimera or compound or pharmaceutical composition described herein.

[0568] M1668.70004WQ00 132 / 511 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.

[0569] 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.

[0570] In certain embodiments, the kits comprise a chimera provided herein or a pharmaceutical composition comprising the chimera; a compound provided herein or a pharmaceutical composition comprising the compound; and instructions for using the chimera or pharmaceutical composition comprising the chimera, and the compound or pharmaceutical composition comprising the compound. In some embodiments, the kit further comprises a first container and a second container. In certain embodiments, the first container comprises the instructions. In certain embodiments, the second container comprises the chimera or pharmaceutical composition comprising the chimera, and the compound or pharmaceutical composition comprising the compound. In some embodiments, the kit further comprises a third container. In certain embodiments, the second container comprises the chimera or pharmaceutical composition comprising the chimera, and the third container comprises the compound or pharmaceutical composition comprising the compound. In some embodiments, the kit further comprises a fourth container comprising a pharmaceutical excipient for dilution or suspension of: the chimera or pharmaceutical composition comprising the chimera, and / or the compound or pharmaceutical composition comprising the compound. In certain embodiments, the first container is a box, bag, vial, or bottle. In certain embodiments, each of the second to fourth containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler. In certain embodiments, “comprises” associated with the kits described herein refers to “encloses.”

[0571] Methods of Use and Uses

[0572] Aspects of the disclosure relate to use of chimeras and peripheral blocker compounds described herein in Brain-Only™ pharmacology for CNS-selective activity of LXR agonists and treatment of a disease or disorder of the CNS, such as AD. In some embodiments, chimeras and

[0573] M1668.70004WQ00 133 / 511 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., AD). In some embodiments, chimeras and 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., AD).

[0574] In another aspect, the present disclosure provides methods of administering to a subject:

[0575] (a) any chimera described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition described herein; and

[0576] (b) any peripheral blocker compound (“compound”) described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, optionally wherein the compound is of Formula I: wherein:

[0577] 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);

[0578] 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,

[0579] M1668.70004WQ00 134 / 511 -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), substituted Ci-3alkyl); =0 or -0RB1;

[0580] 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;

[0581] M1668.70004WQ00 135 / 511 Rcis -ORC1or hydrogen;

[0582] 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;

[0583] 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;

[0584] = REis =0 or -0RE1; and

[0585] 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.

[0586] 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.

[0587] M1668.70004WQ00 136 / 511 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, -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; 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

[0588] 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, -

[0589] M1668.70004WQ00 137 / 511 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.

[0590] 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-

[0591] 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-s 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

[0592] M1668.70004WQ00 138 / 511 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 Ci-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 Ci-6 alkyl). In certain embodiments, — LAis — CHbC^C-, — CH2C=CCH2-, or — CH2C =C(CH2)2-. In certain embodiments, LAis C2-6 alkynylene substituted with one or more -F.

[0593] 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 -(CH2)s-

[0594] 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-.

[0595] 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, -

[0596] M1668.70004WQ00 139 / 511 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, -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 Ci-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 Ci-6 alkyl) or -C(=O)N(optionally substituted Ci-6 alkyl)2. In certain embodiments, RAis -C(=O)OH. In certain embodiments, RAis -C(=O)O(optionally substituted Ci-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 opti...

Claims

CLAIMSWhat is claimed is:

1. A chimera, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the chimera is of Formula I A or II-B:L° is a linker, wherein the linker comprises in the backbone of the linker two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted;R° is a radical of a liver X receptor (LXR) binder;L1is optionally substituted alkenylene, optionally substituted alkynylene, unsubstituted alkylene, or alkylene substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted Ci-6 alkyl);R1is hydrogen, -S(=O)2N(R1A)2, 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, - OR1A, -SCN, -SR1A, -SSR1A, -N3, -NO, -N(R1A)2, -NO2, -N=S(=O)(R1A)2, - N=S(=O)(R1A)OR1A, -N=S(=O)(R1A)SR1A, -N=S(=O)(R1A)N(R1A)2, -C(=O)R1A, -C(=O)OR1A, -C(=O)SR1A, -C(=O)N(R1A)2, -C(=O)N(R1A)S(=O)R1A, -C(=O)N(R1A)S(=O)OR1A, - C(=O)N(R1A)-S(=O)SR1A, -C(=O)N(R1A)S(=O)N(R1A)2, -C(=O)N(R1A)S(=O)2R1A, -M1668.70004WQ00 500 / 511C(=O)N(R1A)S(=O)2OR1A, -C(=O)N(R1A)S(=O)2SR1A, -C(=O)N(R1A)S(=O)2N(R1A)2, - C(=NR1A)R1A, -C(=NR1A)OR1A, -C(=NR1A)SR1A, -C(=NR1A)N(R1A)2, -S(=O)R1A, - S(=O)OR1A, -S(=O)SR1A, -S(=O)N(R1A)2, -S(=O)(=NR1A)R1A, -S(=O)(=NR1A)OR1A, - S(=O)(=NR1A)SR1A, -S(=O)(=NR1A)N(R1A)2, -S(=O)2R1A, -S(=O)2OR1A, -S(=O)2SR1A, - S(=O)2N(R1A)C(=O)R1A, -S(=O)2N(R1A)C(=O)OR1A, -S(=O)2N(R1A)C(=O)SR1A, - S(=O)2N(R1A)C(=O)N(R1A)2, -OC(=O)R1A, -OC(=O)OR1A, -OC(=O)SR1A, -OC(=O)N(R1A)2, - OC(=NR1A)R1A, -OC(=NR1A)OR1A, -OC(=NR1A)SR1A, -OC(=NR1A)N(R1A)2, -OS(=O)R1A, - OS(=O)OR1A, -OS(=O)SR1A, -OS(=O)N(R1A)2, -OS(=O)2R1A, -OS(=O)2OR1A, -OS(=O)2SR1A, -OS(=O)2N(R1A)2, -ON(R1A)2, -SC(=O)R1A, -SC(=O)OR1A, -SC(=O)SR1A, -SC(=O)N(R1A)2, - SC(=NR1A)R1A, -SC(=NR1A)OR1A, -SC(=NR1A)SR1A, -SC(=NR1A)N(R1A)2, -NR1AC(=O)R1A, - NR1AC(=O)OR1A, -NR1AC(=O)SR1A, -NR1AC(=O)N(R1A)2, -NR1AC(=NR1A)R1A, - NR1AC(=NR1A)OR1A, -NR1AC(=NR1A)SR1A, -NR1AC(=NR1A)N(R1A)2, -NR1AS(=O)R1A, - NR1AS(=O)OR1A, -NR1AS(=O)SR1A, -NR1AS(=O)N(R1A)2, -NR1AS(=O)2R1A, - NR1AS(=O)2OR1A, -NR1AS(=O)2SR1A, -NR1AS(=O)2N(R1A)2, -Si(R1A)3, -Si(R1A)2OR1A, - Si(R1A)(OR1A)2, -Si(OR1A)3, -OSi(R1A)3, -OSi(R1A)2OR1A, -OSi(R1A)(OR1A)2, -OSi(OR1A)3, - B(OR1A)2, -OB(OR1A)2, -P(=O)(R1A)2, -P(=O)(R1A)OR1A, -P(=O)(OR1A)2, -OP(=O)(R1A)2, - OP(=O)(R1A)OR1A, or -OP(=O)(OR1A)2; each instance of R1Ais 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 RN1attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;= R2is =0 or -0R2A;R2Ais 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;R3is -0R3Aor hydrogen;R3Ais 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;R4is -0R4A, -SCN, -SR4A, -SSR4A, -N3, -NO, -N(R4A)2, -N02, -N=S(=O)(R4A)2, - N=S(=O)(R4A)OR4A, -N=S(=O)(R4A)SR4A, -N=S(=O)(R4A)N(R4A)2, -S(=O)R4A, -S(=O)OR4A, - S(=O)SR4A, -S(=O)N(R4A)2, -S(=O)(=NR4A)R4A, -S(=O)(=NR4A)OR4A, -S(=O)(=NR4A)SR4A, -M1668.70004WQ00 501 / 511S(=O)(=NR4A)N(R4A)2, -S(=O)2R4A, -S(=O)2OR4A, -S(=O)2SR4A, -S(=O)2N(R4A)2, - S(=O)2N(R4A)C(=O)R4A, -S(=O)2N(R4A)C(=O)OR4A, -S(=O)2N(R4A)C(=O)SR4A, - S(=O)2N(R4A)C(=O)N(R4A)2, -OC(=O)R4A, -OC(=O)OR4A, -OC(=O)SR4A, -OC(=O)N(R4A)2, - OC(=NR4A)R4A, -OC(=NR4A)OR4A, -OC(=NR4A)SR4A, -OC(=NR4A)N(R4A)2, -OS(=O)R4A, - OS(=O)OR4A, -OS(=O)SR4A, -OS(=O)N(R4A)2, -OS(=O)2R4A, -OS(=O)2OR4A, -OS(=O)2SR4A, -OS(=O)2N(R4A)2, -ON(R4A)2, -SC(=O)R4A, -SC(=O)OR4A, -SC(=O)SR4A, -SC(=O)N(R4A)2, - SC(=NR4A)R4A, -SC(=NR4A)OR4A, -SC(=NR4A)SR4A, -SC(=NR4A)N(R4A)2, -NR4AC(=O)R4A, - NR4AC(=O)OR4A, -NR4AC(=O)SR4A, -NR4AC(=O)N(R4A)2, -NR4AC(=NR4A)R4A, - NR4AC(=NR4A)OR4A, -NR4AC(=NR4A)SR4A, -NR4AC(=NR4A)N(R4A)2, -NR4AS(=O)R4A, - NR4AS(=O)OR4A, -NR4AS(=O)SR4A, -NR4AS(=O)N(R4A)2, -NR4AS(=O)2R4A, - NR4AS(=O)2OR4A, -NR4AS(=O)2SR4A, -NR4AS(=O)2N(R4A)2, -OSi(R4A)3, -OSi(R4A)2OR4A, - OSi(R4A)(OR4A)2, -OSi(OR4A)3, -B(OR4A)2, -OB(OR4A)2, -P(=O)(R4A)2, -P(=O)(R4A)OR4A, - P(=O)(OR4A)2, -OP(=O)(R4A)2, -OP(=O)(R4A)OR4A, -OP(=O)(OR4A)2, -CN, halogen, or optionally substituted heteroaryl; each instance of R4Ais 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 R4Aattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted monocyclic, heterocyclic or heteroaryl ring;= R5is =0 or -0R5A; andR5Ais 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 chimera of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein =R2is =0.

3. The chimera of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3is -OH.M1668.70004WQ00 502 / 5114. The chimera of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R4is -OH.

5. The chimera of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein =R5is =0.

6. A chimera, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the chimera is of the formula:(IV-A), (IV-B), or (IV-C), wherein:L° is a linker, wherein the linker comprises in the backbone of the linker two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, and boron, and the backbone of the linker is optionally substituted;R° is a radical of a liver X receptor (LXR) binder;L11Ais optionally substituted alkylene or a single bond;L11Bis a single bond, -O-, -S-, -S-S-, -NR11B-, -C(=O)O-, -C(=NR11B)O-, -S(=O)O- -S(=O)2O-, -C(=O)NR11B-, -C(=NR11B)NR11B-, -S(=O)NR11B-, -S(=O)2NR11B-, -OC(=O)-, - OC(=NR11B)-, -OS(=O)-, -OS(=O)2-, -NR11BC(=O)-, -NR11BC(=NR11B)-, -NR11BS(=O)-, - NR11BS(=O)2-, -OC(=O)O-, -OC(=NR11B)O-, -OS(=O)O-, -OS(=O)2O-, -NR11BC(=O)O-, - NR11BC(=NR11B)O-, -NR11BS(=O)O-, -NR11BS(=O)2O-, -OC(=O)NR11B-, - OC(=NR11B)NR11B-, -OS(=O)NR11B-, -OS(=O)2NR11B-, -NR11BC(=O)NR11B-, - NR11BC(=NR11B)NR11B-, -NR11BS(=O)NR11B-, -NR11BS(=O)2NR11B-, -C(=O)-, -C(=NR11B)-, -S(=O)-, -S(=O)2-, -OP(=O)(OR11B)O-, -SP(=O)(OR11B)O-, -OP(=O)(OR11B)S-, or - OP(=O)(SR11B)O-; each instance of R11Bis independently hydrogen, optionally substituted Ci-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when M1668.70004WQ00 503 / 511attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R11Battached to a nitrogen atom are joined with the nitrogen atom to form optionally substituted heterocyclyl or optionally substituted heteroaryl;R11is optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted alkyl, hydrogen, or halogen;R12is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;R13is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted alkyl, substituted alkenyl, or optionally substituted alkynyl;L11Cis optionally substituted heterocyclyl ene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted arylene, or a single bond;L13Bis optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted heteroalkenylene, optionally substituted alkenylene, optionally substituted heteroalkynylene, or optionally substituted alkynylene; andL13Ais optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclyl ene, or a single bond.

7. The chimera of claim 6, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug8. The chimera of any one of claims 6-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R13is 3,5-dichloro phenyl.M1668.70004WQ00 504 / 5119. The chimera of any one of claims 6-8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R12is -CH2-OH or -CH2-OCH3.

10. The chimera of any one of claims 6-9, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:L° is of the formula: -LOBI_LOAI_LOA2_LOB2_LOA3_LOA4_LOCI_LOA5_LOA6_LOB3_LOA7_L0A8_L0C2_L0A9_L0A10_L0B4_L0A11_L0A12_- each of-L0A1-L0A2-, -L0A3-L0A4-, -L0A5-L0A6-, -L0A7-L0A8-, -L0A9-L0A10-, and -L0A11- L°A12_ jsindependently a single bond, -O-, -S-, -S-S-, -NRa-, -C(=O)O-, -C(=NRa)O-, - S(=O)O-, -S(=O)2O-, -C(=O)NRa-, -C(=NRa)NRa-, -S(=O)NRa-, -S(=O)2NRa-, -OC(=O)-, - OC(=NRa)-, -OS(=O)-, -OS(=O)2-, -NRaC(=O)-, -NRaC(=NRa)-, -NRaS(=O)-, - NRaS(=O)2-, -OC(=O)O-, -OC(=NRa)O-, -OS(=O)O-, -OS(=O)2O-, -NRaC(=O)O-, - NRaC(=NRa)O-, -NRaS(=O)O-, -NRaS(=O)2O-, -OC(=O)NRa-, -OC(=NRa)NRa-, - OS(=O)NRa-, -OS(=O)2NRa-, -NRaC(=O)NRa-, -NRaC(=NRa)NRa-, -NRaS(=O)NRa-, - NRaS(=O)2NRa-, -C(=O)-, -C(=NRa)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORa)O-, - SP(=O)(ORa)O-, -OP(=O)(ORa)S-, or -OP(=O)(SRa)O-; each instance of Rais independently hydrogen, optionally substituted C1-6 alkyl, 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 Raattached to a nitrogen atom are joined with the nitrogen atom to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each of LOB1, L0B2, L0B3, and L0B4is independently a single bond, optionally substituted Ci-100 alkylene, optionally substituted C2-100 alkenylene, optionally substituted C2-100 alkynylene, optionally substituted Ci-100 heteroalkylene, optionally substituted C2-100 heteroalkenylene, or optionally substituted C2-100 heteroalkynylene; and each of L0C1and L0C2is a single bond, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, or optionally substituted arylene; provided that the backbone of L° comprises two or more atoms independently selected from the group consisting of carbon, oxygen, sulfur, selenium, nitrogen, phosphorous, silicon, or boron.M1668.70004WQ00 505 / 51111. The chimera of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the LXR binder is of any one of the formulae shown in Table 1, or a tautomer, stereoisomer, isotopically labeled compound, prodrug, or analog thereof.

12. The chimera of claim 1 or 6, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the chimera is of any one of the formulae shown in Tables 1 A, IB, 1C, and ID.

13. The chimera of any one of claims 1-12 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the chimera, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is able to cross the blood-brain barrier.

14. A pharmaceutical composition comprising: the chimera of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.

15. A kit comprising: the chimera of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 14; and instructions for using the chimera, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

16. A method comprising administering to a subject:(a) the chimera of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 14; and(b) 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:M1668.70004WQ00 506 / 511wherein: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, - 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, -M1668.70004WQ00 507 / 511NRA1C(=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), substituted Ci-3alkyl);=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(=0)(=NRD1)N(RD1)2, -S(=O)2RD1, -S(=O)2ORD1, -S(=O)2SRD1, -S(=O)2N(RD1)2, - S(=0)2N(RD1)C(=0)RD1, -S(=0)2N(RD1)C(=0)0RD1, -S(=O)2N(RD1)C(=O)SRD1, - S(=O)2N(RD1)C(=O)N(RD1)2, -0C(=0)RD1, -0C(=0)0RD1, -OC(=O)SRD1, -0C(=0)N(RD1)2, - 0C(=NRD1)RD1, -0C(=NRD1)0RD1, -0C(=NRD1)SRD1, -0C(=NRD1)N(RD1)2, -OS(=O)RD1, - OS(=O)ORD1, -OS(=O)SRD1, -0S(=0)N(RD1)2, -OS(=O)2RD1, -OS(=O)2ORD1, -OS(=O)2SRD1, -OS(=O)2N(RD1)2, -0N(RD1)2, -SC(=O)RD1, -SC(=O)ORD1, -SC(=O)SRD1, -SC(=0)N(RD1)2, -M1668.70004WQ00 508 / 511SC(=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.

17. The method of claim 16, wherein LAis -(CH2)3-, -(CH2)4- or -(CH2)s-18. The method of any one of claims 16-17, wherein RAis -S(=O)2N(RA1)2or - NHS(=0)2RA1.

19. The method of any one of claims 16-18, wherein =RBis =0.

20. The method of any one of claims 16-19, wherein Rcis -OH.

21. The method of any one of claims 16-20, wherein RDis -OH.

22. The method of any one of claims 16-21, wherein =REis =0.

23. The method of claim 16, wherein the compound is any one of the formulae shown in Table 2, Table 2 A, and Table 2B.M1668.70004WO00 509 / 51124. The method of any one of claims 16-23, wherein the compound, or the tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is unable to cross the bloodbrain barrier.

25. The method of any one of claims 16-24, wherein the subject has, is suspected of having, or is at risk of having Alzheimer’s disease.M1668.70004WQ00 510 / 511

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