Synthesis of macrobicyclic thiolincosamines

Abstract

Provided herein are methods for preparing macrobicyclic thiolincosamines and associated synthetic intermediates. These routes allow access to lincosamide analogues, which are useful for the treatment and prevention of infectious diseases. The methods are scalable and provide access to multi-gram quantities of the aminooctose (northern) fragments of the lincosamide analogues.

Description

SYNTHESIS OF MACROBICYCLIC THIOLINCOSAMINES RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63 / 676,017, filed July 26, 2024, which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under AI168228 awarded by National Institutes of Health (NIH) and under 75A50122C00028 awarded by Biomedical Advanced Research and Development Authority (BARDA). The government has certain rights in this invention. BACKGROUND OF THE INVENTION

[0003] The lincosamide antibiotics inhibit bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome, near the peptidyl transferase center. The last lincosamide antibiotic to receive FDA approval was clindamycin, in 1970, but after more than 50 years of use in hospitals and the community, bacterial resistance to clindamycin is now widespread. For several years, research efforts have sought to explore and expand the lincosamides and other classes of antibiotics using convergent chemical synthesis. Recently, Applicant has reported the discovery of the potent, broad-spectrum antibiotics BT-33 and cresomycin (CRM), which contain the respective northern macrobicyclic fragments, 1 and 2. See International Application No. PCT / US2023 / 019059, filed April 19, 2023 (published as International Publication No. WO 2023 / 205206, published October 26, 2023), which is incorporated herein by reference in its entirety.

[0004] BT-33 and CRM comprise structurally distinct, conformationally restricted macrobicyclic northern halves, and share a common oxapanoprolinamide (OPP) southern scaffold, the latter emerging from the discovery of iboxamycin. See International Application No. PCT / US2018 / 046167, filed August 10, 2018 (published as International Publication No. WO 2019 / 032936, publishedH0824.70444WO00 1 / 236 #14234830v1February 14, 2019), which is incorporated herein by reference in its entirety. Like the macrobicyclic northern halves, the OPP southern fragment contains a new, fused ring that rigidifies the molecule with respect to natural or semi-synthetic lincosamides. In view of their promising in vitro and in vivo potencies, both BT-33 and CRM are advancing toward pre-clinical, investigational new drug (IND)– enabling studies, but these experiments require multi-gram quantities of each of the structurally distinct northern fragments (11- and 10-membered macrobicyclic thiolincosamines 1 and 2, respectively, Scheme 1).

[0005] Accordingly, the development of new scalable routes for the synthesis of macrobicyclic thiolincosamines represents a currently unmet need. SUMMARY OF THE INVENTION

[0006] The present disclosure stems from the recognition that macrobicyclic thiolincosamides, such as BT-33 and CRM, are potent, broad-spectrum antibiotics, but current synthetic routes may not allow for facile access to the multi-gram quantities needed for pre-clinical, investigational new drug (IND)–enabling studies or for later clinical studies.

[0007] Thus, disclosed are novel synthetic routes to access macrobicyclic thiolincosamines such as 1 and 2. These processes include novel carbon-carbon bond-forming reactions to create the adjoining stereocenters of the macrobicyclic thiolincosamines in a highly selective manner. These processes further include novel strategies for transannular macrocyclization, centered on C–S bond formation rather than C=C bond formation for ring closure. See, e.g., International Application No. PCT / US2023 / 019059, filed April 19, 2023 (published as International Publication No. WO 2023 / 205206, published October 26, 2023).

[0008] In one aspect, the present disclosure provides methods of preparing compounds of Formula (I):or pharmaceutically acceptable salts thereof, the methods comprising: deprotecting a compound of Formula (IV):H0824.70444WO00 2 / 236 #14234830v1or a salt thereof, under suitable conditions to provide a compound of Formula (II):, or a salt thereof; and coupling the compound of Formula (II), or salt thereof, with a compound of Formula (III):or a salt thereof, to provide the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; Z is a leaving group or −ORA; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; andH0824.70444WO00 3 / 236 #14234830v1each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0009] In another aspect, the present disclosure provides methods of preparing compounds of Formula (II):, or salts thereof, the methods comprising: deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogenH0824.70444WO00 4 / 236 #14234830v1atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0010] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IV):or salts thereof, the methods comprising: cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein:H0824.70444WO00 5 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.H0824.70444WO00 6 / 236 #14234830v1

[0011] In another aspect, the present disclosure provides methods of preparing compounds of Formula (IV-e):, or salts thereof, the methods comprising: reducing a compound of Formula (IV-d):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV-e), wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group;H0824.70444WO00 7 / 236 #14234830v1R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0012] In another aspect, the present disclosure provides methods of preparing compounds of Formula (V-g):or salts thereof, the methods comprising: reducing a compound of Formula (V-f):or a salt thereof, under suitable conditions to provide the compound of Formula (V-g), wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted orH0824.70444WO00 8 / 236 #14234830v1unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0013] In another aspect, the present disclosure provides methods of preparing compounds of Formula (V):or salts thereof, the methods comprising: coupling a compound of Formula (VI):H0824.70444WO00 9 / 236 #14234830v1or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; R15is halogen or -OR′; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting groupH0824.70444WO00 10 / 236 #14234830v1when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0014] In another aspect, the present disclosure provides methods of preparing compounds of Formula (VI):or salts thereof, the methods comprising: coupling a compound of Formula (VIII):or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; and R12is substituted or unsubstituted alkyl.

[0015] In another aspect, the present disclosure provides compounds of Formula (IV):and salts thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom;H0824.70444WO00 11 / 236 #14234830v1each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0016] In another aspect, the present disclosure provides compounds of Formula (V):and salts thereof, wherein:H0824.70444WO00 12 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0017] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.H0824.70444WO00 13 / 236 #14234830v1BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG.1 shows thermal ellipsoids from single-crystal X-ray diffraction for compound 4.

[0019] FIG.2 shows thermal ellipsoids from single-crystal X-ray diffraction for compound 20. DEFINITIONS

[0020] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0021] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0022] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified (e.g., cis or trans alkene), is absent or a single bond, and or is a single or double bond.

[0023] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more 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 of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.H0824.70444WO00 14 / 236 #14234830v1

[0024] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0025] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0026] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1- 8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n- hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i- Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., −CF3, Bn).

[0027] 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. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include −CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0028] 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 (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of theH0824.70444WO00 15 / 236 #14234830v1parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain 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 heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.

[0029] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (anH0824.70444WO00 16 / 236 #14234830v1“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3ormay be an (E)- or (Z)-double bond.

[0030] 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 (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 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 heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.

[0031] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”).H0824.70444WO00 17 / 236 #14234830v1The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), 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 C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0032] 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 (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). 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 heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0033] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7H0824.70444WO00 18 / 236 #14234830v1carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0034] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, theH0824.70444WO00 19 / 236 #14234830v1cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0035] “Carbocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl moiety.

[0036] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more 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.

[0037] In certain 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 certain 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 certain embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0038] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-memberedH0824.70444WO00 20 / 236 #14234830v1heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0039] “Heterocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety.

[0040] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon 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 C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.H0824.70444WO00 21 / 236 #14234830v1

[0041] “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.

[0042] 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 π 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 heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0043] In certain embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In certain 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 certain 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 certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain 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.H0824.70444WO00 22 / 236 #14234830v1

[0044] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0045] “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.

[0046] 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, heteroalkenylene 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.

[0047] 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 may be 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 permissibleH0824.70444WO00 23 / 236 #14234830v1substituent, 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 invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, 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 invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0048] Exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−,−N(ORcc)Rbb, −SH, −SRaa,−B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 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 =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 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,H0824.70444WO00 24 / 236 #14234830v1−SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)2N(Rcc)2, −P(=O)(NRcc)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 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, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−,−N(ORee)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)2Ree, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2- 6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 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 can be joined to form =O or =S; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10aryl 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; andH0824.70444WO00 25 / 236 #14234830v1each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6alkyl, −ON(C1-6alkyl)2, −N(C1-6alkyl)2, −N(C1-6alkyl)3+X−,−NH(C1-6alkyl)2+X−,−NH2(C1-6alkyl)+X−,−NH3+X−,−N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6 alkyl)2, −OC(=O)NH(C1-6 alkyl), −NHC(=O)( C1-6 alkyl), −N(C1-6 alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6alkyl), −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6 alkyl)2, −C(=NH)NH(C1-6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6 alkyl)2, −OC(NH)NH(C1-6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1-6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6 alkyl), −SO2N(C1-6 alkyl)2, −SO2NH(C1-6 alkyl), −SO2NH2, −SO2C1-6 alkyl, −SO2OC1-6 alkyl, −OSO2C1-6 alkyl, −SOC1-6 alkyl, −Si(C1-6 alkyl)3, −OSi(C1-6 alkyl)3 −C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, −C(=O)S(C1-6 alkyl), −C(=S)SC1-6 alkyl, −SC(=S)SC1-6 alkyl, −P(=O)2(C1-6 alkyl), −P(=O)(C1-6 alkyl)2, −OP(=O)(C1-6 alkyl)2, −OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1- 6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0049] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0050] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3, −OP(=O)2Raa, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −OP(=O)2N(Rbb)2, and −OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein.

[0051] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0052] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(NRbb)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0053] The term “disubstituted 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,H0824.70444WO00 26 / 236 #14234830v1−NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(NRbb)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.

[0054] The term “trisubstituted 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)3and −N(Rbb)3+X−,wherein Rbband X−are as defined herein.

[0055] The term “sulfonyl” refers to a group selected from −SO2N(Rbb)2, −SO2Raa, and −SO2ORaa, wherein Raaand Rbbare as defined herein.

[0056] The term “sulfinyl” refers to the group −S(=O)Raa, wherein Raais as defined herein.

[0057] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1,RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0058] The term “silyl” refers to the group −Si(Raa)3, wherein Raais as defined herein.

[0059] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0060] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa,H0824.70444WO00 27 / 236 #14234830v1−SO2Raa, −C(=NRbb)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, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)2N(Rcc)2, −P(=O)(NRcc)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom 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, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0061] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −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, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 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.

[0062] For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0063] Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),H0824.70444WO00 28 / 236 #14234830v11-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-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), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(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)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, 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-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0064] Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0065] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N-H0824.70444WO00 29 / 236 #14234830v1benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N- phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5- triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5- dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N- triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N- (N’,N’-dimethylaminomethylene)amine, N,N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N- salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-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).

[0066] 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, but are not limited to, −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, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)2N(Rbb)2, and −P(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0067] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), 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 S,S-dioxide, 1-[(2-H0824.70444WO00 30 / 236 #14234830v1chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1- ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4- (4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9- phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t- butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S- benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0068] In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa,H0824.70444WO00 31 / 236 #14234830v1−C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3, −P(=O)2Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)2N(Rbb)2, and −P(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0069] As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), −ORaa(when the O atom is attached to a carbonyl group, wherein Raais as defined herein), −O(C=O)RLG, or −O(SO)2RLG(e.g., tosyl, mesyl, besyl), wherein RLGis optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, the leaving group is a halogen. In certain embodiments, the leaving group is Cl.

[0070] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0071] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0072] The term “carbohydrate” or “saccharide” refers to an aldehydic or ketonic derivative of polyhydric alcohols. Carbohydrates include compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, and cellulose polysaccharides). The term “sugar” refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates. Most monosaccharides can be represented by the general formula CyH2yOy (e.g., C6H12O6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3. Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides. For example, deoxyribose is of the formula C5H10O4and is a monosaccharide. Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively. If the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose. Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively. Examples of aldotetrose sugars include erythrose and threose; and ketotetrose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, andH0824.70444WO00 32 / 236 #14234830v1idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. Each carbon atom of a monosaccharide bearing a hydroxyl group (−OH), with the exception of the first and last carbons, is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Because of this asymmetry, a number of isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula C6H12O6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e., 24) possible stereoisomers. The assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar. The aldehyde or ketone group of a straight-chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form. During the conversion from the straight-chain form to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring. The resulting possible pair of stereoisomers is called anomers. In an α anomer, the −OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the −CH2OH side branch. The alternative form, in which the −CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a β anomer. A carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g., a trisaccharide), respectively. The two or more monosaccharide units bound together by a covalent bond known as a glycosidic linkage formed via a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from another. Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose. Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.

[0073] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0074] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0075] 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. ForH0824.70444WO00 33 / 236 #14234830v1example, 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 invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivaloate, 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+(C1- 4 alkyl)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.

[0076] 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. The compounds described herein may be prepared, e.g., in crystalline form, and may be 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.

[0077] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1),H0824.70444WO00 34 / 236 #14234830v1lower 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)).

[0078] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.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.

[0079] 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”.

[0080] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-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 (i.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”.

[0081] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0082] 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 theH0824.70444WO00 35 / 236 #14234830v1parent 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. C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0083] The methods disclosed herein provide synthetic routes to macrobicyclic thiolincosamines and associated synthetic intermediates. These routes allow access to lincosamide analogues including those disclosed in International Application No. PCT / US2023 / 019059, filed April 19, 2023 (published as International Publication No. WO 2023 / 205206, published October 26, 2023), which is incorporated herein by reference in its entirety.

[0084] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

[0085] In one aspect, the present disclosure provides a method of preparing a compound of Formula (I):or a pharmaceutically acceptable salt thereof, the method comprising: deprotecting a compound of Formula (IV):or a salt thereof, under suitable conditions to provide a compound of Formula (II):H0824.70444WO00 36 / 236 #14234830v1or a salt thereof; and coupling the compound of Formula (II), or salt thereof, with a compound of Formula (III):or a salt thereof, to provide the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; Z is a leaving group or −ORA; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl,H0824.70444WO00 37 / 236 #14234830v1substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0086] In another aspect, the present disclosure provides methods of preparing compounds of Formula (I):or pharmaceutically acceptable salts thereof, the methods comprising: coupling a compound of Formula (II):, or a salt thereof, with a compound of Formula (III):or a salt thereof, to provide the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; Z is a leaving group or −ORA; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl,H0824.70444WO00 38 / 236 #14234830v1substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0087] In another aspect, the present disclosure provides a method of preparing a compound of Formula (II):, or a salt thereof, the method comprising: deprotecting a compound of Formula (IV):, or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein:H0824.70444WO00 39 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0088] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises: deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide a compound of Formula (IV′):H0824.70444WO00 40 / 236 #14234830v1or a salt thereof; and deprotecting the compound of Formula (IV′), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof.

[0089] In certain embodiments, the method further comprises cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein R13is a leaving group.

[0090] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises: cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide a compound of Formula (IV-d):or a salt thereof; and reducing the compound of Formula (IV-d), or pharmaceutially acceptable salt thereof, under suitable conditions to provide a compound of Formula (IV-e):or a salt thereof.H0824.70444WO00 41 / 236 #14234830v1

[0091] In certain embodiments, the method further comprises coupling a compound of Formula (VI):, or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein R15is halogen or – OR′.

[0092] In certain embodiments, the method further comprises coupling a compound of Formula (VIII):or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof.

[0093] In certain embodiments, the method further comprises oxidizing a compound of Formula (X):or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof.

[0094] In certain embodiments, the method further comprises reacting a compound of Formula (XI):or a salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof.

[0095] In certain embodiments, the method further comprises reacting a compound of Formula (XII):H0824.70444WO00 42 / 236 #14234830v1or a salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, wherein R16is a leaving group.

[0096] In another aspect, the present disclosure provides a method of preparing a compound of Formula (IV):or a salt thereof, the method comprising: cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –C(=O)RA, –H0824.70444WO00 43 / 236 #14234830v1–NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0097] In another aspect, the present disclosure provides a method of preparing a compound of Formula (IV-e):, or a salt thereof, the method comprising: reducing a compound of Formula (IV-d):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV-e), wherein:H0824.70444WO00 44 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.H0824.70444WO00 45 / 236 #14234830v1

[0098] In another aspect, the present disclosure provides a method of preparing a compound of Formula (V-g):, or a salt thereof, the method comprising: reducing a compound of Formula (V-f):, or a salt thereof, under suitable conditions to provide the compound of Formula (V-g), wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl;H0824.70444WO00 46 / 236 #14234830v1R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0099] In another aspect, the present disclosure provides a method of preparing a compound of Formula (V):or a salt thereof, the method comprising: coupling a compound of Formula (VI):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–;H0824.70444WO00 47 / 236 #14234830v1each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; R15is halogen or -OR′; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0100] In another aspect, the present disclosure provides a method of preparing a compound of Formula (VI):or a salt thereof, the method comprising: coupling a compound of Formula (VIII):H0824.70444WO00 48 / 236 #14234830v1or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; and R12is substituted or unsubstituted alkyl.

[0101] In another aspect, the present disclosure provides a compound of Formula (IV):or a salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted orH0824.70444WO00 49 / 236 #14234830v1unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0102] In another aspect, the present disclosure provides a compound of Formula (V):or a salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –C(=O)RA, –H0824.70444WO00 50 / 236 #14234830v1–NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring. Embodiments of Formula (I) and Preparation Thereof

[0103] As generally described herein, the compound of Formula (I):, or pharmaceutically acceptable salt thereof, is prepared by deprotecting a compound of Formula (IV):or a salt thereof, under suitable conditions to provide a compound of Formula (II):H0824.70444WO00 51 / 236 #14234830v1, or a salt thereof; and coupling the compound of Formula (II), or salt thereof, with a compound of Formula (III):or a salt thereof, to provide the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; Z is a leaving group or −ORA; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; andH0824.70444WO00 52 / 236 #14234830v1each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0104] In certain embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c):, or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the compound of Formula (I) is of Formula (I-a), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-b), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-c), or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is substituted or unsubstituted C1-3alkyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is –CH2F. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is halogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is fluoro. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl, and at least one R2is –CH2F. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl, and at least one R2is fluoro.

[0107] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R7is hydrogen.

[0108] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl, and R7is hydrogen. In certainH0824.70444WO00 53 / 236 #14234830v1embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl, at least one R2is –CH2F, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one R2is methyl, at least one R2is fluoro, and R7is hydrogen.

[0109] In certain embodiments of the compound of Formula (I) or (I-b), or pharmaceutically acceptable salt thereof, R1ais –S–.

[0110] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, and at least one R2is methyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, at least one R2is methyl, and at least one R2is –CH2F. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, at least one R2is methyl, and at least one R2is fluoro. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, and R7is hydrogen.

[0111] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, at least one R2is methyl, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, at least one R2is methyl, at least one R2is –CH2F, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, R1ais –S–, at least one R2is methyl, at least one R2is fluoro, and R7is hydrogen.

[0112] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen. In certain embodiments of the compound of Formula (I), (I- a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, at least one instance of R′ is benzyl.

[0113] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, and at least one R2is methyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, at least one R2is methyl, and at least one R2is –CH2F. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, at least one R2is methyl, and at least one R2is fluoro.H0824.70444WO00 54 / 236 #14234830v1

[0114] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, and R7is hydrogen.

[0115] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, at least one R2is methyl, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I- b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, at least one R2is methyl, at least one R2is –CH2F, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, at least one R2is methyl, at least one R2is fluoro, and R7is hydrogen.

[0116] In certain embodiments of the compound of Formula (I) or (I-b), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, and R1ais –S–.

[0117] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, and at least one R2is methyl. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, at least one R2is methyl, and at least one R2is –CH2F. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, at least one R2is methyl, and at least one R2is fluoro. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, and R7is hydrogen.

[0118] In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, at least one R2is methyl, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, at least one R2is methyl, at least one R2is –CH2F, and R7is hydrogen. In certain embodiments of the compound of Formula (I), (I-a), (I-b), or (I-c), or pharmaceutically acceptable salt thereof, each instance of R′ is independently hydrogen, R1ais –S–, at least one R2is methyl, at least one R2is fluoro, and R7is hydrogen.

[0119] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-d):H0824.70444WO00 55 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0120] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-d-1):or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-e):, or a pharmaceutically acceptable salt thereof.

[0122] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-f):, or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-f-1):H0824.70444WO00 56 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-f-2):, or a pharmaceutically acceptable salt thereof.

[0125] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g):, or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-1):or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-2):H0824.70444WO00 57 / 236 #14234830v1or a pharmaceutically acceptable salt thereof.

[0128] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-3):, or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-4):, or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-5):, or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-6):, or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-7):H0824.70444WO00 58 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g-8):, or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h):, or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-1):, or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-2):H0824.70444WO00 59 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-3):, or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-4):or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-5):or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h-6):H0824.70444WO00 60 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-i):, or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-i-1):, or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j):or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j-1):H0824.70444WO00 61 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j-2):, or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j-3):, or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound of Formula (I- j-3), R2is halogen. In certain embodiments of the compound of Formula (I-j-3), R2is fluoro.

[0147] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j-4):, or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound of Formula (I- j-4), R2is halogen. In certain embodiments of the compound of Formula (I-j-4), R2is fluoro.

[0148] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-j-5):H0824.70444WO00 62 / 236 #14234830v1or a pharmaceutically acceptable salt thereof. In certain embodiments of the compound of Formula (I- j-5), R2is halogen. In certain embodiments of the compound of Formula (I-j-5), R2is fluoro.

[0149] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k):, or a pharmaceutically acceptable salt thereof.

[0150] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k-1):or a pharmaceutically acceptable salt thereof.

[0151] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k-2):

[0152] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k-3):H0824.70444WO00 63 / 236 #14234830v1or a pharmaceutically acceptable salt thereof, wherein R9is as defined herein.

[0153] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k-4):, or a pharmaceutically acceptable salt thereof.or a pharmaceutically acceptable salt thereof.

[0155] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-l-1):H0824.70444WO00 64 / 236 #14234830v1, or a pharmaceutically acceptable salt thereof.

[0156] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-l-2):or a pharmaceutically acceptable salt thereof, wherein R9is as defined herein.

[0158] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-l-4):H0824.70444WO00 65 / 236 #14234830v1or a pharmaceutically acceptable salt thereof.

[0159] In certain embodiments, the compound of Formula (I) is:H0824.70444WO00 66 / 236 #14234830v1H0824.70444WO00 67 / 236 #14234830v1H0824.70444WO00 68 / 236 #14234830v1H0824.70444WO00 69 / 236 #14234830v1H0824.70444WO00 70 / 236 #14234830v1H0824.70444WO00 71 / 236 #14234830v1or pharmaceutically acceptable salt thereof.H0824.70444WO00 72 / 236 #14234830v1

[0160] In certain embodiments, the compound of Formula (I) is:, or pharmaceutically acceptable salt thereof.

[0161] In certain embodiments, the compound of Formula (I) is:, or pharmaceutically acceptable salt thereof.H0824.70444WO00 73 / 236 #14234830v1

[0162] In certain embodiments, the compound of Formula (I) is:, or pharmaceutically acceptable salt thereof.

[0163] In certain embodiments, the compound of Formula (I) is:, or pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, the compound of Formula (I) is:, or pharmaceutically acceptable salt thereof.

[0165] In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof.H0824.70444WO00 74 / 236 #14234830v1In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.00 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.05 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.10 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.15 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.20 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.25 molar equivalents of the compound of Formula (III), or salt thereof, relative to the compound of Formula (II), or salt thereof.

[0166] In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to a coupling reagent. In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.00, 1.05, 1.10, 1.15, 1.20, or 1.25 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.00 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.05 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.10 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.15 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.20 molar equivalents of the coupling reagent relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises exposure to 1.25 molar equivalents of the coupling reagent relative to theH0824.70444WO00 75 / 236 #14234830v1compound of Formula (II), or salt thereof. In certain embodiments, the coupling reagent is O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol- 1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)- N,N,N’,N’- tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]- N,N,N’N’-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), 1,3- dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), propanephosphonic acid anhydride (T3P), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7- azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-Cl), O-(N-succinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TPTU), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), or carbonyldiimidazole (CDI), or a combination thereof. In certain embodiments, the coupling reagent is O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU).

[0167] In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises addition of an amine base. In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises addition of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises addition of 1.0 molar equivalent of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises addition of 1.5 molar equivalents of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises addition of 2.0 molar equivalents of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises addition of 2.5 molar equivalents of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the method comprises addition of 3.0 molar equivalents of the amine base relative to the compound of Formula (II), or salt thereof. In certain embodiments, the amine base is N, N-diisopropylethylamine (DIPEA), triethylamine (TEA), tributylamine, or benzyldimethylamine. In certain embodiments, the amine base is N, N-diisopropylethylamine (DIPEA). In certain embodiments, the amine base is triethylamine (TEA). In certain embodiments, the amine base is tributylamine. In certain embodiments, the amine base is benzyldimethylamine.H0824.70444WO00 76 / 236 #14234830v1

[0168] In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises a polar aprotic solvent. In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate (EA), dimethylsulfoxide (DMSO), tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), or dimethylcarbonate (DMC). In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF). In certain embodiments, the solvent is or comprises N,N-dimethylacetamide (DMA). In certain embodiments, the solvent is or comprises dichloromethane (DCM). In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2- methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises ethyl acetate (EA). In certain embodiments, the solvent is or comprises dimethylsulfoxide (DMSO). In certain embodiments, the solvent is or comprises tert-butyl methyl ether (TBME). In certain embodiments, the solvent is or comprises cyclopentylmethyl ether (CPME). In certain embodiments, the solvent is or comprises dimethylcarbonate (DMC).

[0169] In certain embodiments, coupling the compound of Formula (II), or salt thereof, with the compound of Formula (III), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0170] In certain embodiments, the methods further comprise purifying the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, purifying the compound of Formula (I), or pharmaceutically acceptable salt thereof, comprises flash column chromatography. In certain embodiments, purifying the compound of Formula (I), or pharmaceutically acceptable salt thereof, comprises preparative HPLC.

[0171] In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is isolated as an oil. In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is isolated as a solid. In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is isolated as a foam.

[0172] In certain embodiments, the compound of Formula (I) is isolated as a pharmaceutically acceptable salt. In certain embodiments, the compound of Formula (I) is isolated as an acetate salt.

[0173] H0824.70444WO00 77 / 236 #14234830v1Embodiments of Formula (II) and Preparation Thereof

[0174] As generally described herein, the compound of Formula (II):, or salt thereof, is prepared by deprotecting a compound of Formula (IV):or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; andH0824.70444WO00 78 / 236 #14234830v1each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0175] In certain embodiments, the compound of Formula (II) is of Formula (II-a), (II-b), or (II-c):or a salt thereof.

[0176] In certain embodiments, the compound of Formula (II) is of Formula (II a), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-b), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-c), or a salt thereof.

[0177] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to an acid. In certain embodiments, the acid is an aqueous acid. In certain embodiments, the acid is HCl. In certain embodiments, the acid is an aqueous solution of HCl. In certain embodiments, the acid is HCl in methanol. In certain embodiments, the acid is HCl in methanol and 1,4-dioxane. In certain embodiments, the HCl in methanol is prepared by reacting trimethylsilyl chloride (TMSCl) and methanol. In certain embodiments, the HCl in methanol is prepared by reacting acetyl chloride and methanol.

[0178] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing a compound of Formula (IV′):or salt thereof, to an acid to provide a compound of Formula (II′):H0824.70444WO00 79 / 236 #14234830v1, or a salt thereof. In certain embodiments, the acid is an aqueous acid. In certain embodiments, the acid is HCl. In certain embodiments, the acid is an aqueous solution of HCl. In certain embodiments, the acid is HCl in methanol. In certain embodiments, the acid is HCl in methanol and 1,4-dioxane. In certain embodiments, the HCl in methanol is prepared by reacting trimethylsilyl chloride (TMSCl) and methanol. In certain embodiments, the HCl in methanol is prepared by reacting acetyl chloride and methanol.

[0179] In certain embodiments, the compound of Formula (II) or Formula (II′) is of Formula (II-a′), (II-b′), or (II-c′):or a salt thereof.

[0180] In certain embodiments, the compound of Formula (II) is of Formula (II-a′), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-b′), or a salt thereof. In certain embodiments, the compound of Formula (II) is of Formula (II-c′), or a salt thereof. In certain embodiments, the compound of Formula (II′) is of Formula (II-a′), or a salt thereof. In certain embodiments, the compound of Formula (II′) is of Formula (II-b′), or a salt thereof. In certain embodiments, the compound of Formula (II′) is of Formula (II-c′), or a salt thereof.

[0181] In certain embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II′), (II-a′), (II-b′), or (II-c′), or salt thereof, at least one R2is substituted or unsubstituted C1-3 alkyl. In certain embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II′), (II-a′), (II-b′), or (II-c′), or salt thereof, at least one R2is methyl.

[0182] In certain embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II′), (II-a′), (II-b′), or (II-c′), or salt thereof, R7is hydrogen.

[0183] In certain embodiments of the compound of Formula (II), (II-b), (II′), or (II-b′), or salt thereof, R1ais –S–.

[0184] In certain embodiments of the compound of Formula (II), (II-a), (II-b), or (II-c), or salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (II), (II-a), (II-b), or (II-c), or salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (II), (II-a), (II-b), or (II-c), or salt thereof, at least one instance of R′ is benzyl.H0824.70444WO00 80 / 236 #14234830v1

[0185] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0186] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0187] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0188] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0189] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.H0824.70444WO00 81 / 236 #14234830v1

[0190] In certain embodiments, the compound of Formula (II) is of formula:, or a salt thereof.

[0191] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:, or salt thereof.

[0192] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:, or salt thereof.

[0193] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:, or a salt thereof.

[0194] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:, or a salt thereof.

[0195] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:H0824.70444WO00 82 / 236 #14234830v1, or a salt thereof.

[0196] In certain embodiments, the compound of Formula (II) or Formula (II′) is of formula:, or a salt thereof.

[0197] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises a protic solvent. In certain embodiments, the solvent is or comprises water, methanol, ethanol, or octanol. In certain embodiments, the solvent is or comprises water. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises octanol. In certain embodiments, the solvent is or comprises 1,4-dioxane. In certain embodiments, the solvent is or comprises a protic solvent and 1,4-dioxane. In certain embodiments, the solvent is or comprises methanol and 1,4-dioxane.

[0198] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0199] In certain embodiments, the compound of Formula (II), or salt thereof, is isolated as a solid. In some embodiments, the solid is a crystalline solid. In certain embodiments, the compound of Formula (II) is isolated as a salt. In certain embodiments, the compound of Formula (II) is isolated as a hydrochloride salt.H0824.70444WO00 83 / 236 #14234830v1Embodiments of Formula (III)

[0200] As generally described herein, the compound of Formula (III):or salt thereof, is prepared by methods recognized by one of ordinary skill in the art, wherein: A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; and Z is a leaving group or −ORA.

[0201] In certain embodiments of the compound of Formula (III), or salt thereof, Z is halogen or −ORA. In certain embodiments of the compound of Formula (III), or salt thereof, Z is −OH. Embodiments of Formula (IV) and Preparation Thereof

[0202] As generally described herein, the compound of Formula (IV):or salt thereof, is prepared by cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted orH0824.70444WO00 84 / 236 #14234830v1unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0203] In certain embodiments, the compound of Formula (IV) is of Formula (IV-a), (IV-b), or (IV-c):or a salt thereof.

[0204] In certain embodiments, the compound of Formula (IV) is of Formula (IV-a), or a salt thereof. In certain embodiments, the compound of Formula (IV) is of Formula (IV-b), or a salt thereof. In certain embodiments, the compound of Formula (IV) is of Formula (IV-c), or a salt thereof.H0824.70444WO00 85 / 236 #14234830v1

[0205] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to a reductant.

[0206] In certain embodiments, exposing the compound of Formula (IV), or salt thereof, to a reductant provides a compound of Formula (IV′):or a salt thereof.

[0207] In certain embodiments, the compound of Formula (IV′) is of Formula (IV-a′), (IV-b′), or (IV-c′):or a salt thereof.

[0208] In certain embodiments, the compound of Formula (IV′) is of Formula (IV′′):or a salt thereof.

[0209] In certain embodiments, the compound of Formula (IV′′), or salt thereof, is of Formula (IV- a′′), (IV-b′′), or (IV-c′′):H0824.70444WO00 86 / 236 #14234830v1or a salt thereof.

[0210] In certain embodiments, the compound of Formula (IV′) is of Formula (IV′′′):or salt thereof.

[0211] In certain embodiments, the compound of Formula (IV′′′), or salt thereof, is of Formula (IV- a′′′), (IV-b′′′), or (IV-c′′′):or a salt thereof.

[0212] In certain embodiments, the compound of Formula (IV) is of Formula:H0824.70444WO00 87 / 236 #14234830v1or a salt thereof.

[0213] In certain embodiments, the compound of Formula (IV′) is of Formula:,H0824.70444WO00 88 / 236 #14234830v1, or a salt thereof.

[0214] In certain embodiments, the compound of Formula (IV′′′) is of Formula:or a salt thereof.

[0215] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 15 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 16 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 17 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 18 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 19 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 20 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certainH0824.70444WO00 89 / 236 #14234830v1embodiments, the method comprises exposure to 21 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 22 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 23 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 24 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof. In certain embodiments, the method comprises exposure to 25 molar equivalents of the reductant relative to the compound of Formula (IV), or salt thereof.

[0216] In certain embodiments, the reductant is lithium naphthalenide, lithium di-tert- butylbiphenylide (LiDBB), lithium 1-N,N-dimethylaminonaphthalenide (LDMAN), or hydrogen (H2) with a metal catalyst. In certain embodiments, the reductant is lithium naphthalenide or lithium di- tert-butylbiphenylide (LiDBB). In certain embodiments, the reductant is lithium naphthalenide. In certain embodiments, the reductant is lithium di-tert-butylbiphenylide (LiDBB). In certain embodiments, the reductant is lithium 1-N,N-dimethylaminonaphthalenide (LDMAN). In certain embodiments, the reductant is hydrogen (H2) with a metal catalyst. In certain embodiments, the metal catalyst is palladium on carbon (Pd / C).

[0217] In certain embodiments, an oxidant or Lewis acid may be used in place of the reductant. In certain embodiments, the oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In certain embodiments, the Lewis acid is anhydrous FeCl3, BCl3, or BBr3. In certain embodiments, the Lewis acid is BCl3 or BBr3. In certain embodiments, the Lewis acid is anhydrous FeCl3. In certain embodiments, the Lewis acid is 5 equivalents of anhydrous FeCl3.

[0218] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises a reaction temperature of between about -78 ℃ and about 25 ℃. In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises a reaction temperature of between about -78 ℃ and about 0 ℃. In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises a reaction temperature of between about 0 ℃ and about 25 ℃. In certain embodiments, the reaction temperature is about -78 ℃, about -75 ℃, about -70 ℃, about -65 ℃, about -60 ℃, about -55 ℃, about -50 ℃, about -45 ℃, about -40 ℃, about -35 ℃, about -30 ℃, about -25 ℃, about -20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about -78 ℃, about -75 ℃, about -70 ℃, about -65 ℃, about -60 ℃, about -55 ℃, about -50 ℃, about -45 ℃, about -40 ℃, about -35 ℃, about -30 ℃, about -25 ℃, about -20 ℃, about -15 ℃, about -10 ℃, about -5 ℃, or about 0 ℃. In certain embodiments, the reaction temperature is about -78 ℃ or about 0 ℃. In certain embodiments, the reaction temperature is about -H0824.70444WO00 90 / 236 #14234830v178 ℃. In certain embodiments, the reaction temperature is about 0 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0219] In certain embodiments, the reductant is lithium naphthalenide, and the reaction temperature is about 0 ℃. In certain embodiments, the reductant is lithium naphthalenide, and the reaction temperature is about 25 ℃. In certain embodiments, the reductant is lithium di-tert-butylbiphenylide (LiDBB), and the reaction temperature is about -78 ℃.

[0220] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises using 5 equivalents of anhydrous FeCl3 in dichloromethane and stirring for 30 minutes at room temperature.

[0221] In certain embodiments, deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises an ethereal solvent. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF), 2-methyltetrahydrofuran (2- MeTHF), diethyl ether, tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), or 1,4- dioxane. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises diethyl ether. In certain embodiments, the solvent is or comprises tert-butyl methyl ether (TBME). In certain embodiments, the solvent is or comprises cyclopentylmethyl ether (CPME). In certain embodiments, the solvent is or comprises 1,4-dioxane. In certain embodiments, the solvent is or comprises dichloromethane.

[0222] In certain embodiments, the methods further comprise cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein R13is a leaving group.

[0223] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, provides a compound of Formula (IV-d):H0824.70444WO00 91 / 236 #14234830v1, or a salt thereof.

[0224] In certain embodiments, the compound of Formula (IV-d), or salt thereof, is of Formula (IV- d-1), (IV-d-2), or (IV-d-3):or a salt thereof.

[0225] In certain embodiments, the compound of Formula (IV-d), or salt thereof, is of Formula (IV- d-1), or salt thereof. In certain embodiments, the compound of Formula (IV-d), or salt thereof, is of Formula (IV-d-2), or salt thereof. In certain embodiments, the compound of Formula (IV-d), or salt thereof, is of Formula (IV-d-3), or salt thereof.

[0226] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, provides a compound of Formula (IV-e):or a salt thereof.H0824.70444WO00 92 / 236 #14234830v1

[0227] In certain embodiments, the methods further comprise reducing the compound of Formula (IV-d), or salt thereof, to provide a compound of Formula (IV-e):, or salt thereof.

[0228] In certain embodiments, the compound of Formula (IV-e), or salt thereof, is of Formula (IV- e-1), (IV-e-2), or (IV-e-3):or a salt thereof.

[0229] In certain embodiments, the compound of Formula (IV-e), or salt thereof, is of Formula (IV- e-1), or salt thereof. In certain embodiments, the compound of Formula (IV-e), or salt thereof, is of Formula (IV-e-2), or salt thereof. In certain embodiments, the compound of Formula (IV-e), or salt thereof, is of Formula (IV-e-3), or salt thereof.

[0230] In certain embodiments of the compound of Formula (IV), (IV′), (IV′′), (IV′′′), (IV-a), (IV- b), (IV-c), (IV-a′), (IV-b′), (IV-c′), (IV-a′′), (IV-b′′), (IV-c′′), (IV-a′′′), (IV-b′′′), (IV-c′′′), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, at least one R2is substituted or unsubstituted C1-3alkyl. In certain embodiments of the compound of Formula (IV), (IV′), (IV′′), (IV′′′), (IV-a), (IV-b), (IV-c), (IV-a′), (IV-b′), (IV-c′), (IV-a′′), (IV-b′′), (IV-c′′), (IV- a′′′), (IV-b′′′), (IV-c′′′), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, at least one R2is methyl.

[0231] In certain embodiments of the compound of Formula (IV), (IV′), (IV′′), (IV′′′), (IV-a), (IV- b), (IV-c), (IV-a′), (IV-b′), (IV-c′), (IV-a′′), (IV-b′′), (IV-c′′), (IV-a′′′), (IV-b′′′), (IV-c′′′), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, R7is hydrogen.H0824.70444WO00 93 / 236 #14234830v1

[0232] In certain embodiments of the compound of Formula (IV), (IV′), (IV′′), (IV′′′), (IV-a), (IV- b), (IV-c), (IV-a′), (IV-b′), (IV-c′), (IV-a′′), (IV-b′′), (IV-c′′), (IV-a′′′), (IV-b′′′), (IV-c′′′), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, R12is unsubstituted C1-4alkyl. In certain embodiments of the compound of Formula (IV), (IV′), (IV′′), (IV′′′), (IV-a), (IV-b), (IV-c), (IV-a′), (IV-b′), (IV-c′), (IV-a′′), (IV-b′′), (IV-c′′), (IV-a′′′), (IV- b′′′), (IV-c′′′), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, R12is tert-butyl.

[0233] In certain embodiments of the compound of Formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), (IV-d-1), (IV-d-2), (IV-d-3), (IV-e), (IV-e-1), (IV-e-2), or (IV-e-3), or salt thereof, at least one instance of R′ is benzyl.

[0234] In certain embodiments, the compound of Formula (IV-d) is of formula:, or a salt thereof.

[0235] In certain embodiments, the compound of Formula (IV-e) is of formula:, or a salt thereof.

[0236] In certain embodiments, the compound of Formula (IV-e) is of Formula:H0824.70444WO00 94 / 236 #14234830v1or a salt thereof.

[0237] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to a nucleophilic base. In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.0 molar equivalent of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.1 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.2 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.3 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.4 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the method comprises exposure to 1.5 molar equivalents of the nucleophilic base relative to the compound of Formula (V), or salt thereof. In certain embodiments, the nucleophilic base is a hydroxide salt or an alkoxide salt. In certain embodiments, the nucleophilic base is a hydroxide salt. In certain embodiments, the hydroxide salt is sodium hydroxide or potassium hydroxide. In certain embodiments, the nucleophilic base is an alkoxide salt. In certain embodiments, the alkoxide salt is a methoxide salt, an ethoxide salt, or an isopropoxide salt. In certain embodiments, the alkoxide salt is a methoxide salt. In certainH0824.70444WO00 95 / 236 #14234830v1embodiments, the alkoxide salt is sodium methoxide. In certain embodiments, the alkoxide salt is an ethoxide salt. In certain embodiments, the alkoxide salt is an isopropoxide salt.

[0238] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to a reductant. In certain embodiments, the reductant is NaBH4, LiBH4, LiAl(OtBu)3H, LiEt3BH, or L-selectride. In certain embodiments, the reductant is NaBH4. In certain embodiments, the reductant is LiBH4. In certain embodiments, the reductant is LiAl(OtBu)3H. In certain embodiments, the reductant is LiEt3BH. In certain embodiments, the reductant is L-selectride.

[0239] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a reaction temperature of greater than ambient temperature, about 25 ℃ to about 80 ℃, or about 75 ℃. In certain embodiments, the reaction temperature is about 25 ℃ to about 80 ℃. In certain embodiments, the reaction temperature is about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, or about 80 ℃. In certain embodiments, the reaction temperature is about 75 ℃.

[0240] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises an alcohol. In certain embodiments, the solvent is or comprises methanol or ethanol. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises water, tetrahydrofuran (THF), or 2-methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises water. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2- methyltetrahydrofuran (2-MeTHF).

[0241] In certain embodiments, cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a reaction concentration of about 0.010 M to about 0.10 M, about 0.020 M to about 0.080 M, about 0.030 M to about 0.070 M, or about 0.040 M to about 0.060 M. In certain embodiments, the reaction concentration is about 0.010 M, about 0.015 M, about 0.020 M, about 0.025 M, about 0.030 M, about 0.035 M, about 0.040 M, about 0.045 M, about 0.050 M, about 0.055 M, or about 0.060 M. In certain embodiments, the reaction concentration is about 0.045 M. In certain embodiments, the reaction concentration is about 0.050 M.

[0242] In certain embodiments, the methods further comprise purifying the compound of Formula (X), or salt thereof. In certain embodiments, purifying the compound of Formula (X), or salt thereof, comprises flash column chromatography.H0824.70444WO00 96 / 236 #14234830v1

[0243] In certain embodiments, the compound of Formula (X), or salt thereof, is isolated as an oil. In certain embodiments, the compound of Formula (X), or salt thereof, is isolated as a solid. Embodiments of Formula (V) and Preparation Thereof

[0244] As generally described herein, the compound of Formula (V):or salt thereof, is prepared by coupling a compound of Formula (VI):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,H0824.70444WO00 97 / 236 #14234830v1–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; R15is halogen or –OR′; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0245] In certain embodiments, the compound of Formula (V) is of Formula (V-a):or a salt thereof.

[0246] In certain embodiments, the compound of Formula (V-a) is of Formula (V-a-1), (V-a-2), or (V-a-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

[0247] In certain embodiments, the compound of Formula (V-a) is of Formula (V-a-1), or a salt thereof. In certain embodiments, the compound of Formula (V-a) is of Formula (V-a-2), or a saltH0824.70444WO00 98 / 236 #14234830v1thereof. In certain embodiments, the compound of Formula (V-a) is of Formula (V-a-3), or a salt thereof.

[0248] In certain embodiments, the compound of Formula (V) is of Formula (V-b):or a salt thereof.

[0249] In certain embodiments of the compound of Formula (V) or (V-b), or salt thereof, R1ais –S–.

[0250] In certain embodiments, the compound of Formula (V) is of Formula (V-c):, or a salt thereof.

[0251] In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-1), (V-c-2), or (V-c-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

[0252] In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-1), or a salt thereof. In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-2), or a salt thereof. In certain embodiments, the compound of Formula (V-c) is of Formula (V-c-3), or a salt thereof.

[0253] In certain embodiments, the compound of Formula (V) is of Formula (V-d):H0824.70444WO00 99 / 236 #14234830v1, or a salt thereof.

[0254] In certain embodiments, the compound of Formula (V-d) is of Formula (V-d-1), (V-d-2), or (V-d-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

[0255] In certain embodiments, the compound of Formula (V-d) is of Formula (V-d-1), or a salt thereof. In certain embodiments, the compound of Formula (V-d) is of Formula (V-d-2), or a salt thereof. In certain embodiments, the compound of Formula (V-d) is of Formula (V-d-3), or a salt thereof.

[0256] In certain embodiments, the compound of Formula (V) is of Formula (V-e):, or a salt thereof.

[0257] In certain embodiments, the compound of Formula (V-e) is of Formula (V-e-1), (V-e-2), or (V-e-3):H0824.70444WO00 100 / 236 #14234830v1or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

[0258] In certain embodiments, the compound of Formula (V-e) is of Formula (V-e-1), or a salt thereof. In certain embodiments, the compound of Formula (V-e) is of Formula (V-e-2), or a salt thereof. In certain embodiments, the compound of Formula (V-e) is of Formula (V-e-3), or a salt thereof.

[0259] In certain embodiments, the compound of Formula (V) is of Formula (V-f):, or a salt thereof.

[0260] In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-1), (V-f-2), (V-f- 3), (V-f-4), (V-f-5), or (V-f-6):,H0824.70444WO00 101 / 236 #14234830v1, or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

[0261] In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-1), (V-f-2), or (V-f-3), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f- 1), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-2), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-3), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-4), (V-f-5), or (V-f-6), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f- 4), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-5), or a salt thereof. In certain embodiments, the compound of Formula (V-f) is of Formula (V-f-6), or a salt thereof.

[0262] In certain embodiments, the compound of Formula (V) is of Formula (V-g):or a salt thereof.

[0263] In certain embodiments, the methods further comprise reducing the compound of Formula (V- f), or salt thereof, to provide a compound of Formula (V-g):H0824.70444WO00 102 / 236 #14234830v1or a salt thereof.

[0264] In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-1), (V-g-2), (V- g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7):or a salt thereof.

[0265] In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-1), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-2), (V-g-3), or (V-g-4), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V- g-2), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-3), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-4), or aH0824.70444WO00 103 / 236 #14234830v1salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-5), (V-g-6), or (V-g-7), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-5), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V- g-6), or a salt thereof. In certain embodiments, the compound of Formula (V-g) is of Formula (V-g-7), or a salt thereof.

[0266] In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c-1), (V-c-2), (V-c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V- e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, R7is hydrogen.

[0267] In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c-1), (V-c-2), (V-c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V- e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V-f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g- 4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, R12is unsubstituted C1-4 alkyl. In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c-1), (V-c-2), (V- c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V-e-3), (V-f), (V-f-1), (V-f-2), (V-f- 3), (V-f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, R12is tert-butyl.

[0268] In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-b), (V-c), (V-c- 1), (V-d), (V-d-1), (V-e), (V-e-1), (V-f), (V-f-1), (V-g), (V-g-1), or (V-g-2), or salt thereof, R13is halogen. In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-b), (V-c), (V-c- 1), (V-d), (V-d-1), (V-e), (V-e-1), (V-f), (V-f-1), (V-g), (V-g-1), or (V-g-2), or salt thereof, R13is chloro.

[0269] In certain embodiments of the compound of Formula (V-a-1), (V-a-3), (V-c-1), (V-c-3), (V- d-1), (V-d-3), (V-e-1), (V-e-3), (V-f-1), (V-f-3), (V-g-2), or (V-g-4), or salt thereof, R14is tert-butyl.

[0270] In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c-1), (V-c-2), (V-c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V- e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V-f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g- 4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, each instance of R′ is independently hydrogen, benzyl, or pivaloyl. In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a- 3), (V-b), (V-c), (V-c-1), (V-c-2), (V-c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V-e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V-f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c- 1), (V-c-2), (V-c-3), (V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V-e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V-f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, at least one instance of R′ is benzyl. In certain embodiments of the compound of Formula (V), (V-a), (V-a-1), (V-a-2), (V-a-3), (V-b), (V-c), (V-c-1), (V-c-2), (V-c-3),H0824.70444WO00 104 / 236 #14234830v1(V-d), (V-d-1), (V-d-2), (V-d-3), (V-e), (V-e-1), (V-e-2), (V-e-3), (V-f), (V-f-1), (V-f-2), (V-f-3), (V- f-4), (V-f-5), (V-f-6), (V-g), (V-g-1), (V-g-2), (V-g-3), (V-g-4), (V-g-5), (V-g-6), or (V-g-7), or salt thereof, at least one instance of R′ is pivaloyl.

[0271] In certain embodiments, the compound of Formula (V) is of Formula:or a salt thereof.

[0272] In certain embodiments, the compound of Formula (V-f) is of Formula:or a salt thereof.H0824.70444WO00 105 / 236 #14234830v1

[0273] In certain embodiments, the compound of Formula (V-g) is of Formula:, or a salt thereof.

[0274] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to Zn and I2, to produce a reaction mixture.

[0275] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to 10, 15, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, or 50 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 28 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 29 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 30 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 31 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 32 molar equivalents of Zn relative to the compound of Formula (VI), or salt thereof.

[0276] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 3.0 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the method comprises exposure to 3.5 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof. In certain embodiments, the methodH0824.70444WO00 106 / 236 #14234830v1comprises exposure to 4.0 molar equivalents of I2relative to the compound of Formula (VI), or salt thereof.

[0277] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises a first reaction temperature of about 0 ℃ to about 25 ℃, about 0 ℃, about ambient temperature, about 18 ℃ to about 25 ℃, or about 23 ℃. In certain embodiments, the first reaction temperature is about 0 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the first reaction temperature is about 0 ℃ to about 25 ℃. In certain embodiments, the first reaction temperature is about 0 ℃. In certain embodiments, the first reaction temperature is about ambient temperature. In certain embodiments, the first reaction temperature is about 18 ℃ to about 25 ℃. In certain embodiments, the first reaction temperature is about 23 ℃.

[0278] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, further comprises addition of the compound of Formula (VII), or salt thereof, to the reaction mixture.

[0279] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises a second reaction temperature of greater than ambient temperature, about 25 ℃ to about 100 ℃, or about 90 ℃. In certain embodiments, the second reaction temperature is greater than ambient temperature. In certain embodiments, the second reaction temperature is about 25 ℃ to about 100 ℃. In certain embodiments, the second reaction temperature is about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, about 85 ℃, about 90 ℃, about 95 ℃, or about 100 ℃. In certain embodiments, the second reaction temperature is about 90 ℃.

[0280] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises N,N- dimethylformamide (DMF) or N,N-dimethylacetamide (DMA). In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF). In certain embodiments, the solvent is or comprises N,N-dimethylacetamide (DMA). In certain embodiments, the solvent is or comprises an ethereal solvent. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-MeTHF), or tert-butyl methyl ether (TBME). In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2- methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises tert-butyl methyl ether (TBME).

[0281] In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to palladium on carbon (Pd / C)H0824.70444WO00 107 / 236 #14234830v1and hydrogen (H2) or Lindlar’s catalyst and hydrogen (H2). In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to palladium on carbon (Pd / C) and hydrogen (H2). In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to Lindlar’s catalyst and hydrogen (H2). In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to a metal hydride. In some embodiments, the metal hydride is an aluminum hydride, a copper hydride, or a zirconium hydride. In some embodiments, the metal hydride is an aluminum hydride. In some embodiments, the metal hydride is a copper hydride. In some embodiments, the metal hydride is a zirconium hydride.

[0282] In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 molar equivalents of palladium on carbon (Pd / C) relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.1 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.2 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.3 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.4 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.5 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.1 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.6 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.7 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.8 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 0.9 molar equivalents of the Pd / C relative to the compound of Formula (V-f), or salt thereof. In certain embodiments, the method comprises exposure to 1 molar equivalent of the Pd / C relative to the compound of Formula (V-f), or salt thereof.

[0283] In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises an alcohol. In certain embodiments, the solvent is or comprises methanol or ethanol. In certain embodiments, the solvent is or comprises methanol. In certain embodiments, the solvent is or comprises ethanol. In certain embodiments, the solvent is or comprises methanol, ethanol, dichloromethane (DCM), ethyl acetate (EA), tetrahydrofuran (THF), orH0824.70444WO00 108 / 236 #14234830v12-methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises dichloromethane (DCM). In certain embodiments, the solvent is or comprises ethyl acetate (EA). In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran (2-MeTHF).

[0284] In certain embodiments, reducing the compound of Formula (V-f), or salt thereof, to provide the compound of Formula (V-g), or salt thereof, comprises a reaction temperature of ambient temperature, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is ambient temperature. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0285] In certain embodiments, reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, further comprises alkylating a compound of Formula (XIII-a) or (XIII-b):or a salt thereof, to provide the compound of Formula (VII-b), or salt thereof. Embodiments of Formula (VI) and Preparation Thereof

[0286] As generally described herein, the compound of Formula (VI):or salt thereof, is prepared by coupling a compound of Formula (VIII):or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof, wherein:H0824.70444WO00 109 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; R2is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA,R12is substituted or unsubstituted alkyl; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0287] In certain embodiments, the compound of Formula (VI) is of Formula (VI-a), (VI-b), or (VI-or a salt thereof.H0824.70444WO00 110 / 236 #14234830v1

[0288] In certain embodiments of the compound of Formula (VI) or (VI-b), or salt thereof, R1ais – S–.

[0289] In certain embodiments, the compound of Formula (VI) is of Formula (VI-a), or a salt thereof. In certain embodiments, the compound of Formula (VI) is of Formula (VI-b), or a salt thereof. In certain embodiments, the compound of Formula (VI) is of Formula (VI-c), or a salt thereof.

[0290] In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, R12is unsubstituted C1-4 alkyl. In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, R12is tert-butyl.

[0291] In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, each instance of R′ is independently hydrogen, benzyl, or pivaloyl. In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, at least one instance of R′ is benzyl. In certain embodiments of the compound of Formula (VI), (VI-a), (VI-b), or (VI-c), or salt thereof, at least one instance of R′ is pivaloyl.

[0292] In certain embodiments, the compound of Formula (VI) is of formula:, or a salt thereof.

[0293] In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to a Lewis acid. In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.0 molar equivalent of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.1 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.2 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprisesH0824.70444WO00 111 / 236 #14234830v1exposure to 1.3 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.4 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.5 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.6 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.7 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.8 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.9 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the Lewis acid relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the Lewis acid is CuSO4 or titanium (IV) ethoxide. In certain embodiments, the Lewis acid is CuSO4. In certain embodiments, the Lewis acid is anhydrous CuSO4. In certain embodiments, the Lewis acid is titanium (IV) ethoxide.

[0294] In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposure to 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposure to 1.0, 1.5, 2.0, 2.5, or 3.0 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof.

[0295] In certain embodiments, the method comprises exposure to 1.0 molar equivalent of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 1.5 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof. In certain embodiments, the method comprises exposure to 3.0 molar equivalents of the compound of Formula (IX), or salt thereof, relative to the compound of Formula (VIII), or salt thereof.

[0296] In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises dichloromethane (DCM), toluene, tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-MeTHF), or 1,2-dichloroethane (DCE). In certain embodiments, the solventH0824.70444WO00 112 / 236 #14234830v1is or comprises dichloromethane (DCM) or toluene. In certain embodiments, the solvent is or comprises dichloromethane (DCM). In certain embodiments, the solvent is or comprises toluene. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran (2-MeTHF). In certain embodiments, the solvent is or comprises 1,2-dichloroethane (DCE).

[0297] In certain embodiments, coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 50 ℃.

[0298] In certain embodiments, the methods further comprise purifying the compound of Formula (VI), or salt thereof. In certain embodiments, purifying the compound of Formula (VI), or salt thereof, comprises flash column chromatography.

[0299] In certain embodiments, the compound of Formula (VI), or salt thereof, is isolated as a foam. Embodiments of Formula (VII) and Preparation Thereof

[0300] As generally described herein, the compound of Formula (VII):or salt thereof, is prepared by methods disclosed herein, wherein: each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R13is a leaving group;H0824.70444WO00 113 / 236 #14234830v1R15is halogen or –OR′; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0301] In certain embodiments, the compound of Formula (VII) is of Formula (VII-a):or a salt thereof, wherein R15is halogen.

[0302] In certain embodiments, the compound of Formula (VII) is of Formula (VII-b):or a salt thereof, wherein R15is halogen.

[0303] In certain embodiments, the compound of Formula (VII-b) is of Formula (VII-b-1), (VII-b-2), or (VII-b-3):or a salt thereof.

[0304] In certain embodiments, the compound of Formula (VII-b), or salt thereof, is prepared by alkylating a compound of Formula (XIII-a) or (XIII-b): (XIII-a) or (XIII-b), or a salt thereof.H0824.70444WO00 114 / 236 #14234830v1

[0305] In certain embodiments, the compound of Formula (VII-b), or salt thereof, is prepared by alkylating a compound of Formula (XIII-a), or a salt thereof. In certain embodiments, the compound of Formula (VII-b), or salt thereof, is prepared by alkylating a compound of Formula (XIII-b), or a salt thereof.

[0306] In certain embodiments of the compound of Formula (VII-a), (VII-b), or (VII-b-1), R2is substituted or unsubstituted C1-3alkyl. In certain embodiments of the compound of Formula (VII-a), (VII-b), or (VII-b-1), R2is methyl.

[0307] In certain embodiments of the compound of Formula (VII-a), (VII-b), (VII-b-1), (VII-b-2), or (VII-b-3), R13is halogen. In certain embodiments of the compound of Formula (VII-a), (VII-b), (VII-b-1), (VII-b-2), or (VII-b-3), R13is chloro.

[0308] In certain embodiments of the compound of Formula (VII-a), (VII-b), or (VII-b-2), R15is halogen. In certain embodiments of the compound of Formula (VII-a), (VII-b), or (VII-b-2), R15is bromo.

[0309] In certain embodiments, the compound of Formula (VII) is of Formula:, or a salt thereof. Embodiments of Formula (VIII) and Preparation Thereof

[0310] As generally described herein, the compound of Formula (VIII):or salt thereof, is prepared by oxidizing a compound of Formula (X):or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, wherein:H0824.70444WO00 115 / 236 #14234830v1each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; R2is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA,each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0311] In certain embodiments, the compound of Formula (VIII) is of Formula (VIII-a):, or a salt thereof.

[0312] In certain embodiments of the compound of Formula (VIII) or (VIII-a), or salt thereof, R1ais –S–.

[0313] In certain embodiments, the compound of Formula (VIII) is of Formula (VIII-b):or a salt thereof.

[0314] In certain embodiments of the compound of Formula (VIII), (VIII-a), or (VIII-b), or salt thereof, each instance of R′ is independently hydrogen, benzyl, or pivaloyl. In certain embodiments ofH0824.70444WO00 116 / 236 #14234830v1the compound of Formula (VIII), (VIII-a), or (VIII-b), or salt thereof, at least one instance of R′ is hydrogen. In certain embodiments of the compound of Formula (VIII), (VIII-a), or (VIII-b), or salt thereof, at least one instance of R′ is benzyl. In certain embodiments of the compound of Formula (VIII), (VIII-a), or (VIII-b), or salt thereof, at least one instance of R′ is pivaloyl.

[0315] In certain embodiments, the compound of Formula (VIII) is of formula:, or a salt thereof.

[0316] In certain embodiments, oxidizing the compound of Formula (X), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (X), or salt thereof, to an oxidant. In certain embodiments, oxidizing the compound of Formula (X), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (X), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.0 molar equivalent of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.1 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.2 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.3 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.4 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.5 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.6 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.7 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.8 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 1.9 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the oxidant relative to the compound of Formula (X), or salt thereof.H0824.70444WO00 117 / 236 #14234830v1

[0317] In certain embodiments, the oxidant is a hypervalent iodine oxidant. In certain embodiments, the hypervalent iodine oxidant is Dess-Martin periodinane (DMP), hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, or iodobenzene dichloride. In certain embodiments, the hypervalent iodine oxidant is Dess-Martin periodinane (DMP). In certain embodiments, the oxidant is dimethyl sulfoxide (DMSO), oxalyl chloride, and an amine base (Swern oxidation); dimethyl sulfoxide (DMSO), SO3•pyridine, and an amine base (Parikh-Doering oxidation); tetrapropylammonium perruthenate (Ley oxidation); or a copper (I) salt, nitroxyl radical, N-methyl imidazole, and oxygen (O2) (Stahl oxidation). In certain embodiments, the oxidant is dimethyl sulfoxide (DMSO), oxalyl chloride, and an amine base (Swern oxidation). In certain embodiments, the oxidant dimethyl sulfoxide (DMSO), SO3•pyridine, and an amine base (Parikh-Doering oxidation). In certain embodiments, the oxidant is tetrapropylammonium perruthenate (Ley oxidation). In certain embodiments, the oxidant is a copper (I) salt, nitroxyl radical, N-methyl imidazole, and oxygen (O2) (Stahl oxidation).

[0318] In certain embodiments, oxidizing the compound of Formula (X), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises dichloromethane (DCM), chloroform, dimethylsulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), or 2-methyltetrahydrofuran (2- MeTHF). In certain embodiments, the solvent is or comprises dichloromethane. In certain embodiments, the solvent is or comprises chloroform. In certain embodiments, the solvent is or comprises dimethylsulfoxide (DMSO). In certain embodiments, the solvent is or comprises acetonitrile. In certain embodiments, the solvent is or comprises tetrahydrofuran (THF). In certain embodiments, the solvent is or comprises 2-methyltetrahydrofuran (2-MeTHF).

[0319] In certain embodiments, oxidizing the compound of Formula (X), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, or about 25 ℃. In certain embodiments, the reaction temperature is about 20 ℃. In certain embodiments, the reaction temperature is about 21 ℃. In certain embodiments, the reaction temperature is about 22 ℃. In certain embodiments, the reaction temperature is about 23 ℃. In certain embodiments, the reaction temperature is about 24 ℃. In certain embodiments, the reaction temperature is about 25 ℃.

[0320] In certain embodiments, the compound of Formula (VIII), or salt thereof, is obtained as an oil. Embodiments of Formula (IX)

[0321] As generally described herein, the compound of Formula (IX):H0824.70444WO00 118 / 236 #14234830v1(IX), or salt thereof, is prepared by methods recognized by one of ordinary skill in the art, wherein R12is substituted or unsubstituted alkyl.

[0322] In certain embodiments of the compound of Formula (IX), or salt thereof, R12is unsubstituted C1-6alkyl. In certain embodiments of the compound of Formula (IX), or salt thereof, R12is unsubstituted C1-4alkyl. In certain embodiments of the compound of Formula (IX), or salt thereof, R12is tert-butyl.

[0323] In certain embodiments, the compound of Formula (IX) is of formula:, or a salt thereof. Embodiments of Formula (X) and Preparation Thereof

[0324] As generally described herein, the compound of Formula (X):or salt thereof, is prepared by reacting a compound of Formula (XI):or a salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; R2is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA,H0824.70444WO00 119 / 236 #14234830v1each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0325] In certain embodiments, the compound of Formula (X) is of Formula (X-a):or a salt thereof.

[0326] In certain embodiments of the compound of Formula (X) or (X-a), or salt thereof, R1ais –S–.

[0327] In certain embodiments, the compound of Formula (X) is of Formula (X-b):or a salt thereof.

[0328] In certain embodiments of the compound of Formula (X), (X-a), or (X-b), or salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (X), (X-a), or (X-b), or salt thereof, each instance of R′ is independently hydrogen. In certain embodiments of the compound of Formula (X), (X-a), or (X-b), or salt thereof, each instance of R′ is benzyl.

[0329] In certain embodiments, the compound of Formula (X) is of formula:, or a salt thereof.

[0330] In certain embodiments, the compound of Formula (X) is of formula:H0824.70444WO00 120 / 236 #14234830v1, or a salt thereof.

[0331] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a nucleophile. In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.0 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.1 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.2 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.3 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.4 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 2.5 molar equivalents of the nucleophile relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the nucleophile is bis(trimethylsilyl)sulfide.

[0332] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a Lewis acid. In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 0.4 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 0.5 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 0.6 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 0.7 molar equivalentsH0824.70444WO00 121 / 236 #14234830v1of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises exposure to 0.8 molar equivalents of the Lewis acid relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the Lewis acid is trimethylsilyl triflate.

[0333] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises dichloromethane or chloroform. In certain embodiments, the solvent is or comprises dichloromethane. In certain embodiments, the solvent is or comprises chloroform.

[0334] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, is performed in a pressurized vessel.

[0335] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 80 ℃.

[0336] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises addition of pivaloyl chloride. In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises addition of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of pivaloyl chloride relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises addition of 1.0 molar equivalent of pivaloyl chloride relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises addition of 1.5 molar equivalents of pivaloyl chloride relative to the compound of Formula (XI), or salt thereof.

[0337] In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises addition of an amine base. In certain embodiments, reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises addition of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents of the amine base. In certain embodiments, the method comprises addition of 1.0 molar equivalent of the amine base relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises addition of 1.5 molar equivalents of the amine base relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the method comprises addition of 2.0 molar equivalents of the amine base relative to the compound of Formula (XI), or salt thereof. In certain embodiments, the amine base is triethylamine, tributylamine, benzyldimethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-eneH0824.70444WO00 122 / 236 #14234830v1(DBU), or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In certain embodiments, the amine base is triethylamine. In certain embodiments, the amine base is tributylamine. In certain embodiments, the amine base is benzyldimethylamine. In certain embodiments, the amine base is pyridine. In certain embodiments, the amine base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In certain embodiments, the amine base is 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0338] In certain embodiments, the methods further comprise purifying the compound of Formula (X), or salt thereof. In certain embodiments, purifying the compound of Formula (X), or salt thereof, comprises flash column chromatography.

[0339] In certain embodiments, the compound of Formula (X), or salt thereof, is isolated as an oil. Embodiments of Formula (XI) and Preparation Thereof

[0340] As generally described herein, the compound of Formula (XI):or salt thereof, is prepared by reacting a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; and R16is a leaving group.

[0341] In certain embodiments, the compound of Formula (XI) is of Formula (XI-a):, or a salt thereof.

[0342] In certain embodiments of the compound of Formula (XI) or (XI-a), or salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (XI) or (XI-a), or salt thereof, each instance of R′ is independently hydrogen. In certain embodiments of the compound of Formula (XI) or (XI-a), or salt thereof, each instance of R′ is benzyl.H0824.70444WO00 123 / 236 #14234830v1

[0343] In certain embodiments, the compound of Formula (XI) is of formula:, or a salt thereof.

[0344] In certain embodiments, reacting the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, comprises exposure to a Lewis acid. In certain embodiments, reacting the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, comprises exposure to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 molar equivalents of the Lewis acid relative to the compound of Formula (XII), or salt thereof. In certain embodiments, reacting the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, comprises exposure to 0.4 molar equivalents of the Lewis acid relative to the compoundof Formula (XII), or salt thereof. In certain embodiments, the Lewis acid is FeCl3 or Fe(ClO4)2 · xH2O(iron (II) perchlorate hexahydrate). In certain embodiments, the Lewis acid is FeCl3. In certainembodiments, the Lewis acid is Fe(ClO4)2 · xH2O (iron (II) perchlorate hexahydrate).

[0345] In certain embodiments, reacting the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, comprises exposure to a solvent. In certain embodiments, the solvent is or comprises acetonitrile.

[0346] In certain embodiments, reacting the compound of Formula (XII), or salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, comprises a reaction temperature of about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃. In certain embodiments, the reaction temperature is about 80 ℃. In certain embodiments, the reaction temperature is about 81 ℃. In certain embodiments, the reaction temperature is about 82 ℃.

[0347] In certain embodiments, the methods further comprise purifying the compound of Formula (XI), or salt thereof. In certain embodiments, purifying the compound of Formula (XI), or salt thereof, comprises flash column chromatography.

[0348] In certain embodiments, the compound of Formula (XI), or salt thereof, is isolated as an oil. Embodiments of Formula (XII)

[0349] As generally described herein, the compound of Formula (XII):H0824.70444WO00 124 / 236 #14234830v1or salt thereof, is prepared by methods recognized by one of ordinary skill in the art, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; and R16is a leaving group.

[0350] In certain embodiments, the compound of Formula (XII) is of Formula (XII-a):or a salt thereof.

[0351] In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, each instance of R′ is independently hydrogen or benzyl. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, each instance of R′ is independently hydrogen. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, each instance of R′ is benzyl.

[0352] In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, R16is −ORA. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, R16is −ORA, wherein RAis hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, R16is −OH. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, R16is −ORA, wherein RAis substituted or unsubstituted C1-3alkyl. In certain embodiments of the compound of Formula (XII) or (XII-a), or salt thereof, R16is −OCH3.

[0353] In certain embodiments, the compound of Formula (XII) is of formula:, or a salt thereof.H0824.70444WO00 125 / 236 #14234830v1Group R′

[0354] As generally described herein, each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom.

[0355] In certain embodiments, at least one occurrence of R′ is hydrogen.

[0356] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group selected from −RO1, −C(=O)RO2, and –Si(RO1)3, wherein: each occurrence of RO1is, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; and RO2is −ORO1, −N(RO1)2, −SRO1, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0357] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −RO1, and wherein RO1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −RO1, and wherein RO1is substituted or unsubstituted alkyl.

[0358] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein: each occurrence of RO1is, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; and RO2is −ORO1, −N(RO1)2, −SRO1, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl,H0824.70444WO00 126 / 236 #14234830v1substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0359] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted or unsubstituted C1-4 alkyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted or unsubstituted aryl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted or unsubstituted phenyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is substituted phenyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −C(=O)RO2, and wherein RO2is phenyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is benzoyl (Bz).

[0360] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −Si(RO1)3, and wherein: each occurrence of RO1is, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl. In certain embodiments, at least one occurrence of R′ is an oxygen protecting group, wherein the oxygen protecting group is −Si(RO1)3, and wherein: each occurrence of RO1is, independently, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

[0361] In certain embodiments, at least one occurrence of R′ is an oxygen protecting group selected from methoxymethyl (MOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), benzyl (Bn), p-methoxybenzyl, 3,4- dimethoxybenzyl, benzoate (Bz), p-methoxybenzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoateH0824.70444WO00 127 / 236 #14234830v1(mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, pentafluorobenzoate, p-nitrobenzoate, 2- iodobenzoate, o-(dibromomethyl)benzoate, 2-(methylthiomethoxymethyl)benzoate, o- (methoxyacyl)benzoate, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, 4- (methylthiomethoxy)butyrate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3- tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, α-naphthoate, methyl carbonate, 9- fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t- butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 4- ethoxy-1-napththyl carbonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), methanesulfonate (mesylate), benzylsulfonate, 2-formylbenzenesulfonate, and tosylate (Ts).

[0362] In certain embodiments, at least one occurrence of R′ is a nitrogen protecting group when attached to a nitrogen atom.

[0363] In certain embodiments, at least one occurrence of R′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group selected from −RS1, −C(=O)RS2, and –Si(RS1)3, wherein: each occurrence of RS1is, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; and RS2is −ORS1, −N(RS1)2, −SRS1, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0364] In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −RS1, and wherein RS1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedH0824.70444WO00 128 / 236 #14234830v1aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −RS1, and wherein RS1is substituted or unsubstituted alkyl.

[0365] In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein: RS1is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; and RS2is −ORS1, −N(RS1)2, −SRS1, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0366] In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is substituted or unsubstituted alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is substituted alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is unsubstituted alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is substituted or unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is unsubstituted methyl, isopropyl, or t-butyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is −C(=O)RS2, and wherein RS2is t-butyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is pivaloyl.

[0367] In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is –Si(RS1)3, and wherein each occurrence of RS1is, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted orH0824.70444WO00 129 / 236 #14234830v1unsubstituted heteroaralkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is –Si(RS1)3, and wherein each occurrence of RS1is, independently, substituted or unsubstituted alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is –Si(RS1)3, and wherein each occurrence of RS1is, independently, unsubstituted alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is –Si(RS1)3, and wherein each occurrence of RS1is, independently, unsubstituted C1-6alkyl. In certain embodiments, at least one occurrence of R′ is a sulfur protecting group, wherein the sulfur protecting group is –Si(CH3)3, Groups A, B, R8, R9, and p

[0368] As generally described herein, A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0369] In certain embodiments, A is substituted or unsubstituted heteroaliphatic.

[0370] In certain embodiments, A is substituted or unsubstituted heterocyclyl.

[0371] In certain embodiments, A is substituted or unsubstituted 4-8 membered monocyclic heterocyclyl, or substituted or unsubstituted fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 4-8 membered monocyclic heterocyclyl, or substituted or unsubstituted 8- 12 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5- 8 membered monocyclic heterocyclyl, or substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-8 membered monocyclic heterocyclyl, or substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or substituted or unsubstituted 9-10 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or substituted or unsubstituted 10-membered fused bicyclic heterocyclyl.

[0372] In certain embodiments, A is substituted or unsubstituted 4-8 membered monocyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-8 membered monocyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-7 membered monocyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-membered monocyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 6-membered monocyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 7-membered monocyclic heterocyclyl.H0824.70444WO00 130 / 236 #14234830v1

[0373] In certain embodiments, A is of formula:, wherein: n is 1, 2, or 3; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; Each occurrence of R9is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN,p is 0-4.

[0374] In certain embodiments, A is of formula:, , rtain embodiments, A is of formula:. certain rmula:. certain embodiments, A is of formula:.H0824.70444WO00 131 / 236 #14234830v1

[0375] In certain embodiments, A is of formula:. certain embodiments, A is of formula:. certain embodiments,

[0376] In certain embodiments, A is substituted or unsubstituted fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 9-10 membered fused bicyclic heterocyclyl. In certain embodiments, A is substituted or unsubstituted 10-membered fused bicyclic heterocyclyl.

[0377] In certain embodiments, A is of formula:B is carbocyclyl or heterocyclyl; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each occurrence of R9is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups areH0824.70444WO00 132 / 236 #14234830v1joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; and p is 0-4.

[0378] In certain embodiments, B is cycloalkyl, cycloalkenyl, or heterocyclyl. In certain embodiments, B is heterocyclyl. In certain embodiments, B is a 5-8 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 5-8 membered heterocyclyl ring. In certain embodiments, B is a 5-7 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 5-7 membered heterocyclyl ring. In certain embodiments, B is a 6-7 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 6-7 membered heterocyclyl ring. In certain embodiments, B is a 6-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 6-membered heterocyclyl ring. In certain embodiments, B is a 7-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 7-membered heterocyclyl ring.

[0379] In certain embodiments, A is of formula:, wherein: X is O, S, NR9or C(R9)2; Y is O, S, N, NR9, C(R9)2, CR9, CH2, or CH; n is 0 or 1; p is 0-4; and represents a single or double bond.

[0380] In certain embodiments, X is O, S, NR9or C(R9)2. In certain embodiments, X is O, S, or NR9. In certain embodiments, X is O or S. In certain embodiments, X is O.

[0381] In certain embodiments, Y is O, S, NR9, C(R9)2, CR9, CHR9, CH2, or CH. In certain embodiments, Y is O, NR9, C(R9)2, CR9, CHR9, CH2, or CH. In certain embodiments, Y is NR9, C(R9)2, CR9, CHR9, CH2, or CH. In certain embodiments, Y is C(R9)2, CR9, CHR9, CH2, or CH. In certain embodiments, Y is C(R9)2, CR9, CHR9, CH2, or CH. In certain embodiments, Y is C(R9)2, CHR9, or CH2. In certain embodiments, Y is C(R9)2. In certain embodiments, Y is CHR9. In certain embodiments, Y is CH2. In certain embodiments, Y is CR9or CH. In certain embodiments, Y is CR9. In certain embodiments, Y is CH.

[0382] In certain embodiments, n is 0. In certain embodiments, n is 1.

[0383] In certain embodiments, p is 0-3. In certain embodiments, p is 0-2. In certain embodiments, p is 0-1. In certain embodiments, p is 1-2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.H0824.70444WO00 133 / 236 #14234830v1

[0384] In certain embodiments, X is O; Y is NR9, C(R9)2, CR9, CHR9, CH2, or CH; n is 1; and p is 0- 2. In certain embodiments, X is O; Y is C(R9)2, CR9, CHR9, CH2, or CH; n is 1; and p is 0-2. In certain embodiments, X is O; Y is CR9or CH; n is 1; and p is 1. In certain embodiments, X is O; Y is C(R9)2, CHR9, or CH2; n is 1; and p is 0-2.

[0385] In certain embodiments, A is of formula:.

[0386] In certain embodiments, A is of formula:.

[0387] In certain embodiments, A is of formula:.

[0388] In certain embodiments, A is of formula:.

[0389] In certain embodiments, A is of formula:.

[0390] In certain embodiments, A is of formula:.

[0391] In certain embodiments,.H0824.70444WO00 134 / 236 #14234830v1

[0392] In certain embodiments, A is of formula:.

[0393] In certain embodiments, A is of formula:.

[0394] In certain embodiments, A is of formula:.

[0395] In certain embodiments, A is of formula:.

[0396] In certain embodiments, A is of formula:.

[0397] In certain embodiments, A is of formula:.H0824.70444WO00 135 / 236 #14234830v1

[0398] In certain embodiments, A is of formula:.

[0399] In certain embodiments, A is of formula:.

[0400] In certain embodiments, A is of formula:.

[0401] In certain embodiments, A is of formula:.

[0402] In certain embodiments, A is of formula:.

[0403] In certain embodiments,.H0824.70444WO00 136 / 236 #14234830v1unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group.

[0407] In certain embodiments, R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or –C(=O)RA. In certain embodiments, R8is hydrogen, substituted or unsubstituted alkyl, or –C(=O)RA. In certain embodiments, R8is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R8is hydrogen or unsubstituted alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-6alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-4alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-3alkyl. In certain embodiments, R8is hydrogen or unsubstituted C1-2alkyl. In certain embodiments, R8is hydrogen or ethyl. In certain embodiments, R8is hydrogen or methyl. In certain embodiments, R8is hydrogen.

[0408] In certain embodiments, R8is unsubstituted C1-6alkyl. In certain embodiments, R8is unsubstituted C1-4alkyl. In certain embodiments, R8is unsubstituted C1-3alkyl. In certain embodiments, R8is unsubstituted C1-2alkyl. In certain embodiments, R8is ethyl. In certain embodiments, R8is methyl.

[0409] As generally described herein, each occurrence of R9is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA,H0824.70444WO00 137 / 236 #14234830v1–NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring. In certain embodiments, the R9substituent is the (S) stereocenter (i.e., the carbon to which it is attached is of the (S) configuration). In certain embodiments, the R9substituent is the (R) stereocenter (i.e., the carbon to which it is attached is of the (R) configuration).

[0410] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, –ORA, or –N(RA)2; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0411] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, –C(=O)ORA, –C(=O)N(RA)2, –C(=NRA)N(RA)2, –ORA, or –N(RA)2; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0412] In certain embodiments, at least one instance of R9is halogen, substituted or unsubstituted alkenyl, substituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or two R9groups are joined to form a substituted or unsubstituted carbocyclyl ring.

[0413] In certain embodiments, at least one instance of R9is halogen, unsubstituted ethenyl, substituted or unsubstituted phenethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl; or two R9groups are joined to form an unsubstituted cycloalkyl ring.

[0414] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted aryl or substituted or unsubstituted aralkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted phenyl or substituted or unsubstituted phenethyl.

[0415] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or unsubstituted heteroalkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocyclyl.H0824.70444WO00 138 / 236 #14234830v1

[0416] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R9is unsubstituted alkenyl. In certain embodiments, at least one instance of R9is –CH=CH2.

[0417] In certain embodiments, at least one instance of R9is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R9is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R9is unsubstituted C3-6cycloalkyl. In certain embodiments, at least one instance of R9is unsubstituted C5-6cycloalkyl. In certain embodiments, at least one instance of R9is unsubstituted cyclopentyl. In certain embodiments, at least one instance of R9is unsubstituted cyclohexyl.

[0418] In certain embodiments, at least one instance of R9is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R9is substituted or unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R9is substituted C1-6 alkyl. In certain embodiments, at least one instance of R9is C1-6 alkyl substituted with halogen, alkenyl, C3-6 cycloalkyl, or –ORA. In certain embodiments, at least one instance of R9is C1-6 alkyl substituted with halogen, alkenyl, C3-6 cycloalkyl, heterocyclyl, –N(RA)2, –SO2RA, or –ORA. In certain embodiments, at least one instance of R9is –CH2CH=CH2. In certain embodiments, at least one instance of R9is –CH2CH2F. In certain embodiments, at least one instance of R9is –CH2CHF2. In certain embodiments, at least one instance of R9is –CH2CH2CH2F. In certain embodiments, at least one instance of R9is –CH2CH2CF2H. In certain embodiments, at least one instance of R9is –CH2CH2CH2Cl. In certain embodiments, at least one instance of R9is. In certain embodiments, at least one instance of R9is –CH2CH2CH2OCH3. In certain embodiments, at least one instance of R9is –CH2CH2CH2OH. In certain embodiments, at least one instance of R9is –CH2CH2CH2SO2CH3. In certain embodiments, at least one instance of R9is. In certain embodiments, at least one instance of R9is –CH2CH2CH2NH2. In certain embodiments, at least one instance of R9is –CH2CH2CH2N(CH3)2. In certain embodiments, at least one instance of R9is –CH2C(CH3)2OH. In certain embodiments, at least one instance of R9is –CH2CF2CH3. In certain embodiments, at least one instance of R9is.H0824.70444WO00 139 / 236 #14234830v1

[0419] In certain embodiments, at least one instance of R9is unsubstituted C1-6alkyl. In certain embodiments, at least one instance of R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, or –C(CH3)3. In certain embodiments, at least one instance of R9is –CH3, –CH2CH3, –CH2CH2CH3, –CH2CH2CH2CH3, –CH(CH3)2, –CH2CH(CH3)2, –CH2C(CH3)3, or –C(CH3)3. In certain embodiments, at least one instance of R9is –CH3. In certain embodiments, at least one instance of R9is –CH2CH3. In certain embodiments, at least one instance of R9is –CH2CH2CH3. In certain embodiments, at least one instance of R9is –CH(CH3)2. In certain embodiments, at least one instance of R9is –C(CH3)3. In certain embodiments, at least one instance of R9is –CH2CH(CH3)2. Group Z

[0420] As generally described herein, Z is a leaving group or −ORA. In certain embodiments, Z is halogen or −ORA.

[0421] In certain embodiments, Z is halogen. In certain embodiments, Z is fluoro, chloro, bromo, or iodo. In certain embodiments, Z is chloro, bromo, or iodo. In certain embodiments, Z is fluoro. In certain embodiments, Z is chloro. In certain embodiments, Z is bromo. In certain embodiments, Z is iodo.

[0422] In certain embodiments, Z is −ORA. In certain embodiments, Z is −ORA, wherein RAis hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or an oxygen protecting group. In certain embodiments, Z is −ORA, wherein RAis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, Z is −OH. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted alkyl. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted C1-6 alkyl. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted C1-3 alkyl. In certain embodiments, Z is −ORA, wherein RAis substituted C1-3alkyl. In certain embodiments, Z is −ORA, wherein RAis C1-3alkyl substituted with at least one fluoro. In certain embodiments, Z is −ORA, wherein RAis methyl, ethyl, n-propyl, or isopropyl.

[0423] In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted heterocyclyl. In certain embodiments, Z is −ORA, wherein RAis substituted 5-6 membered heterocyclyl. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted aryl. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted heteroaryl. In certain embodiments, Z is −ORA, wherein RAis substituted or unsubstituted 5-10 membered heteroaryl. In certain embodiments, Z isH0824.70444WO00 140 / 236 #14234830v1Groups R1and q

[0424] As generally described herein, each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–.

[0425] As generally described herein, q is 3, 4, 5, or 6. In certain embodiments, q is 3, 4, or 5. In certain embodiments, q is 4 or 5. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6.

[0426] In certain embodiments, at least one occurrence of R1is –CR2R2–. In certain embodiments, at least one occurrence of R1is =CR2– or –CR2=. In certain embodiments, at least one occurrence of R1is =CR2–. In certain embodiments, at least one occurrence of R1is –CR2=. In certain embodiments, at least one occurrence of R1is ≡C– or –C≡. In certain embodiments, at least one occurrence of R1is ≡C–. In certain embodiments, at least one occurrence of R1is –C≡. In certain embodiments, at least one occurrence of R1is =N– or –N=. In certain embodiments, at least one occurrence of R1is =N–. In certain embodiments, at least one occurrence of R1is –N=. In certain embodiments, at least one occurrence of R1is –NR2–. In certain embodiments, at least one occurrence of R1is –O–. In certain embodiments, at least one occurrence of R1is –S–.

[0427] In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, or –O–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, =N–, –N=, –NR2–, or –O–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, or –NR2–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, =N–, –N=, or –NR2–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, or –O–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, or –O–. In certain embodiments, each R1is independently –CR2R2–, ≡C–, –C≡, or –O–. In certain embodiments, each R1is independently –CR2R2–, =CR2–, –CR2=, ≡C–, or –C≡. In certain embodiments, each R1is independently –CR2R2–, =CR2–, or –CR2=. In certain embodiments, each R1is independently –CR2R2–, =CR2–, or –CR2=; and q is 3. In certain embodiments, each R1is independently –CR2R2–, =CR2–, or –CR2=; and q is 4. In certain embodiments, each R1is independently –CR2R2–, =CR2–, or –CR2=; and q is 5. In certain embodiments, each R1is independently –CR2R2–, =CR2–, or –CR2=; and q is 6. In certain embodiments, each R1is independently –CR2R2–, ≡C–, or –C≡. In certain embodiments, each R1isH0824.70444WO00 141 / 236 #14234830v1independently –CR2R2–, ≡C–, or –C≡; and q is 3. In certain embodiments, each R1is independently –CR2R2–, ≡C–, or –C≡; and q is 4. In certain embodiments, each R1is independently –CR2R2–, ≡C–, or –C≡; and q is 5. In certain embodiments, each R1is independently –CR2R2–, ≡C–, or –C≡; and q is 6. Group R1a

[0428] As generally described herein, R1ais –NR2–, –O–, or –S–.

[0429] In certain embodiments, R1ais –NR2–. In certain embodiments, R1ais –NH–. In certain embodiments, R1ais –O–. In certain embodiments, R1ais –S–. Group R2

[0430] As generally described herein, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0431] In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, or –CN; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0432] In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORA, –N(RA)2, –SRA, or –CN; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0433] In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, –ORA, –N(RA)2, or –SRA; or two R2groups are joined to form aH0824.70444WO00 142 / 236 #14234830v1substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

[0434] In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, or –ORA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

[0435] In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R2is, independently, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl.

[0436] In certain embodiments, at least one occurrence, wherein R20is hydrogen, halogen, substituted or unsubstituted alkyl, –CN, –ORA, –N(RA)2, or –SRA; X is N or CH; and R10is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0437] In certain embodiments, at least one occurrence, wherein R20is hydrogen, halogen, substituted or unsubstituted alkyl, –CN, –ORA, –N(RA)2, or –SRA; X is N or.H0824.70444WO00 143 / 236 #14234830v1

[0438] In certain embodiments, each occurrence of R2is, independently, hydrogen, fluoro, fluoromethyl, difluoromethyl, methyl, –OH, –CH2NH2, –CH2OH, –CH2OAc, –C≡CH,hydrogen, halogen, substituted or unsubstituted alkyl, –CN, –ORA, –N(RA)2, or –SRA; X is N or CH;.

[0439] In certain embodiments, each occurrence of R2is, independently, hydrogen, –OH,fluoromethyl, difluoromethyl, or methyl.

[0440] In certain embodiments, at least one occurrence of R2is hydrogen. In certain embodiments, at least one occurrence of R2is –OH. In certain embodiments, at least one occurrence of R2is –CH2NH2. In certain embodiments, at least one occurrence of R2is –CH2OH. In certain embodiments, at least one occurrence of R2is –CH2OAc. In certain embodiments, at least one occurrence of R2is –C≡CH.H0824.70444WO00 144 / 236 #14234830v1In certain embodiments, at least one occurrence. certain embodiments, at least one occurrence of R2is. In certain embodiments, at least one occurrence of R2is. In certain embodiments, at least one occurrence of R2is . In certain embodiments, at least one occurrence. certain embodiments, at least one. , . embodiments, at least one occurrence. certain embodiments, at least one occurrence of R2is fluoro. In certain embodiments, at least one occurrence of R2is fluoromethyl. In certain embodiments, at least one occurrence of R2is difluoromethyl. In certain embodiments, at least one occurrence of R2is methyl.

[0441] In certain embodiments, at least one occurrence of R2is fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, haloalkyl, unsubstituted alkyl, orH0824.70444WO00 145 / 236 #14234830v1substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, C1-6haloalkyl, unsubstituted C1-6alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, C1-4haloalkyl, unsubstituted C1-4alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, C1-3 haloalkyl, unsubstituted C1-3 alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, C1-2haloalkyl, unsubstituted C1-2alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, at least one occurrence of R2is fluoro, fluoromethyl, methyl, or substituted or unsubstituted triazolyl. In certain embodiments, at least one occurrence of R2is fluoro, fluoromethyl, methyl, or substituted triazolyl. In certain embodiments, at least one occurrence of R2is fluoro, fluoromethyl, methyl,.

[0442] In certain embodiments, at least one occurrence of R2is fluoro or methyl. In certain embodiments, at least one occurrence of R2is fluoromethyl or methyl. In certain embodiments, at least one occurrence of R2is substituted or unsubstituted triazolyl or methyl. In certain embodiments, at least one occurrence of R2is substituted triazolyl or methyl. In certain embodiments, at least one occurrence of R2is methyl o.

[0443] In certain embodiments, at least one occurrence of R2is halogen, substituted or unsubstituted alkyl, or –ORA. In certain embodiments, at least one occurrence of R2is fluoro, substituted or unsubstituted alkyl, or –ORA. In certain embodiments, at least one occurrence of R2is fluoro, substituted or unsubstituted alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, unsubstituted alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, unsubstituted C1-6 alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, unsubstituted C1-4 alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, unsubstituted C1-3 alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, unsubstituted C1-2 alkyl, or –OH. In certain embodiments, at least one occurrence of R2is fluoro, methyl, or –OH.

[0444] In certain embodiments, at least one occurr...

Claims

CLAIMS What is claimed is:

1. A method of preparing a compound of Formula (I):or a pharmaceutically acceptable salt thereof, the method comprising: deprotecting a compound of Formula (IV):or a salt thereof, under suitable conditions to provide a compound of Formula (II):or salt thereof; and coupling the compound of Formula (II), or salt thereof, with a compound of Formula (III):or a salt thereof, to provide the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; A is substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; Z is a leaving group or −ORA; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–;H0824.70444WO00 191 / 236 #14234830v1R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

2. A method of preparing a compound of Formula (II):, or a salt thereof, the method comprising: deprotecting a compound of Formula (IV):H0824.70444WO00 192 / 236 #14234830v1or a salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting groupH0824.70444WO00 193 / 236 #14234830v1when attached to a sulfur atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

3. The method of claim 1 or 2, wherein: the compound of Formula (II) is of Formula (II-a):, or a salt thereof; and the compound of Formula (IV) is of Formula (IV-a):or a salt thereof.

4. The method of claim 1 or 2, wherein: the compound of Formula (II) is of Formula (II-b):or a salt thereof; and the compound of Formula (IV) is of Formula (IV-b):, or a salt thereof.

5. The method of claim 1 or 2, wherein: the compound of Formula (II) is of Formula (II-c):H0824.70444WO00 194 / 236 #14234830v1or a salt thereof; and the compound of Formula (IV) is of Formula (IV-c):or a salt thereof.

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

7. The method of any one of claims 1, 2, and 4, wherein the compound of Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1, 2, and 5, wherein the compound of Formula (I) is of Formula (I-c):H0824.70444WO00 195 / 236 #14234830v1or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to a reductant.

10. The method of claim 9, wherein exposing the compound of Formula (IV), or salt thereof, to the reductant provides a compound of Formula (IV′):or a salt thereof.

11. The method of claim 10, wherein the compound of Formula (IV′) is of Formula (IV-a′), (IV- b′), or (IV-c′):or a salt thereof.

12. The method of claim 10 or 11, wherein the compound of Formula (IV′) is of Formula (IV′′):or a salt thereof.H0824.70444WO00 196 / 236 #14234830v113. The method of claim 12, wherein the compound of Formula (IV′′), or salt thereof, is of Formula (IV-a′′), (IV-b′′), or (IV-c′′):or a salt thereof.

14. The method of claim 10 or 11, wherein the compound of Formula (IV′) is of Formula (IV′′′):or salt thereof.

15. The method of claim 14, wherein the compound of Formula (IV′′′), or salt thereof, is of Formula (IV-a′′′), (IV-b′′′), or (IV-c′′′):or a salt thereof.H0824.70444WO00 197 / 236 #14234830v116. The method of any one of claims 9-15, wherein the reductant is lithium naphthalenide or lithium di-tert-butylbiphenylide (LiDBB).

17. The method of any one of claims 9-16, wherein the reductant is lithium naphthalenide.

18. The method of any one of claims 9-16, wherein the reductant is lithium di-tert- butylbiphenylide (LiDBB).

19. The method of any one of claims 1-18, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises a reaction temperature of between about -78 ℃ and about 0 ℃.

20. The method of any one of claims 1-19, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV), or salt thereof, to an acid.

21. The method of any one of claims 10-19, wherein deprotecting the compound of Formula (IV), or salt thereof, under suitable conditions to provide the compound of Formula (II), or salt thereof, comprises exposing the compound of Formula (IV′), or salt thereof, to an acid to provide a compound of Formula (II′):or a salt thereof.

22. The method of any one of claims 1-21, wherein the compound of Formula (II) or Formula (II′) is of Formula (II-a′), (II-b′), or (II-c′):, or a salt thereof.

23. The method of any one of claims 20-22, wherein the acid is HCl.H0824.70444WO00 198 / 236 #14234830v124. A method of preparing a compound of Formula (IV):or a salt thereof, the method comprising: cyclizing a compound of Formula (V):, or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group;H0824.70444WO00 199 / 236 #14234830v1R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

25. The method of any one of claims 1-23 further comprising cyclizing a compound of Formula (V):or a salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, wherein R13is a leaving group.

26. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-a):or a salt thereof.H0824.70444WO00 200 / 236 #14234830v127. The method of claim 26, wherein the compound of Formula (V-a) is of Formula (V-a-1), (V- a-2), or (V-a-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

28. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-b):or a salt thereof.

29. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-c):or a salt thereof.H0824.70444WO00 201 / 236 #14234830v130. The method of claim 29, wherein the compound of Formula (V-c) is of Formula (V-c-1), (V- c-2), or (V-c-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

31. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-d):or a salt thereof.

32. The method of claim 31, wherein the compound of Formula (V-d) is of Formula (V-d-1), (V- d-2), or (V-d-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.H0824.70444WO00 202 / 236 #14234830v133. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-e):or a salt thereof.

34. The method of claim 33, wherein the compound of Formula (V-e) is of Formula (V-e-1), (V- e-2), or (V-e-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

35. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-f):, or a salt thereof.H0824.70444WO00 203 / 236 #14234830v136. The method of claim 35, wherein the compound of Formula (V-f) is of Formula (V-f-1), (V-f- 2), or (V-f-3):or a salt thereof, wherein R14is substituted or unsubstituted alkyl.

37. The method of 35 or 36, wherein the compound of Formula (V-f) is of Formula (V-f-4), (V-f- 5), or (V-f-6):or a salt thereof.

38. The method of any one of claims 24-37, wherein cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, provides a compound of Formula (IV-d):H0824.70444WO00 204 / 236 #14234830v1or a salt thereof.

39. The method of claim 38, wherein the compound of Formula (IV-d), or salt thereof, is of Formula (IV-d-1), (IV-d-2), or (IV-d-3):or a salt thereof.

40. The method of any one of claims 24-37, wherein cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, provides a compound of Formula (IV-e):, or a salt thereof.

41. A method of preparing a compound of Formula (IV-e):H0824.70444WO00 205 / 236 #14234830v1or a salt thereof, the method comprising: reducing a compound of Formula (IV-d):or a salt thereof, under suitable conditions to provide the compound of Formula (IV-e), wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; andH0824.70444WO00 206 / 236 #14234830v1each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

42. The method of claim 38 or 39 further comprising reducing the compound of Formula (IV-d), or salt thereof, to provide a compound of Formula (IV-e):or salt thereof.

43. The method of any one of claims 40-42, wherein the compound of Formula (IV-e), or salt thereof, is of Formula (IV-e-1), (IV-e-2), or (IV-e-3):or a salt thereof.

44. The method of claim 24 or 25, wherein the compound of Formula (V) is of Formula (V-g):H0824.70444WO00 207 / 236 #14234830v1or a salt thereof.

45. A method of preparing a compound of Formula (V-g):or a salt thereof, the method comprising reducing a compound of Formula (V-f):or a salt thereof, under suitable conditions to provide the compound of Formula (V-g), wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted orH0824.70444WO00 208 / 236 #14234830v1unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

46. The method of any one of claims 35-37 further comprising reducing the compound of Formula (V-f), or salt thereof, to provide a compound of Formula (V-g):, or a salt thereof.

47. The method of any one of claims 44-46, wherein the compound of Formula (V-g) is of Formula (V-g-1)or a salt thereof.H0824.70444WO00 209 / 236 #14234830v148. The method of any one of claims 44-47, wherein the compound of Formula (V-g) is of Formula (V-g-2), (V-g-3), or (V-g-4):or a salt thereof.

49. The method of any one of claims 44-48, wherein the compound of Formula (V-g) is of Formula (V-g-5), (V-g-6), or (V-g-7):or a salt thereof.

50. The method of any one of claims 24-44 and 46-49, wherein cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises exposing the compound of Formula (V), or salt thereof, to a nucleophilic base.

51. The method of claim 50, wherein the nucleophilic base is an alkoxide salt.H0824.70444WO00 210 / 236 #14234830v152. The method of claim 51, wherein the alkoxide salt is sodium methoxide.

53. The method of any one of claims 24-44 and 46-52, wherein cyclizing the compound of Formula (V), or salt thereof, under suitable conditions to provide the compound of Formula (IV), or salt thereof, comprises a reaction temperature of greater than ambient temperature, about 25 ℃ to about 80 ℃, or about 75 ℃.

54. A method of preparing a compound of Formula (V):or a salt thereof, the method comprising: coupling a compound of Formula (VI):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl,H0824.70444WO00 211 / 236 #14234830v1substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; R15is halogen or -OR′; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

55. The method of any one of claims 24-53 further comprising coupling a compound of Formula (VI):or a salt thereof, with a compound of Formula (VII):or a salt thereof, to provide the compound of Formula (V), or salt thereof, wherein R15is halogen or - OR′.H0824.70444WO00 212 / 236 #14234830v156. The method of claim 54 or 55, wherein the compound of Formula (VI) is of Formula (VI-a):or a salt thereof.

57. The method of claim 54 or 55, wherein the compound of Formula (VI) is of Formula (VI-b):or a salt thereof.

58. The method of claim 54 or 55, wherein the compound of Formula (VI) is of Formula (VI-c):or a salt thereof.

59. The method of any one of claims 54-58, wherein the compound of Formula (VII) is of Formula (VII-a):or a salt thereof, wherein R15is halogen.

60. The method of any one of claims 54-58, wherein the compound of Formula (VII) is of Formula (VII-b):H0824.70444WO00 213 / 236 #14234830v1, or a salt thereof, wherein R15is halogen.

61. The method of claim 60, wherein the compound of Formula (VII-b) is of Formula (VII-b-1), (VII-b-2), or (VII-b-3):or a salt thereof.

62. The method of any one of claims 54-61, wherein reacting the compound of Formula (VI), or salt thereof, with the compound of Formula (VII), or salt thereof, to provide the compound of Formula (V), or salt thereof, comprises exposing the compound of Formula (VI), or salt thereof, to Zn and I2, to produce a reaction mixture.

63. The method of claim 62, comprising a first reaction temperature of about ambient temperature, about 18 ℃ to about 25 ℃, or about 23 ℃.

64. The method of claim 62 or 63 further comprising addition of the compound of Formula (VII), or salt thereof, to the reaction mixture.

65. The method of claim 64, comprising a first reaction temperature of greater than ambient temperature, about 25 ℃ to about 100 ℃, or about 90 ℃.

66. The method of any one of claims 60-65 further comprising alkylating a compound of Formula (XIII-a) or (XIII-b): (XIII-, or a salt thereof, to provide the compound of Formula (VII-b), or salt thereof.

67. A method of preparing a compound of Formula (VI)H0824.70444WO00 214 / 236 #14234830v1, or a salt thereof, the method comprising: coupling a compound of Formula (VIII):or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; R1ais –NR2–, –O–, or –S–; and R12is substituted or unsubstituted alkyl.

68. The method of any one of claims 54-66 further comprising coupling a compound of Formula (VIII):or a salt thereof, with a compound of Formula (IX): (IX), or a salt thereof, to provide the compound of Formula (VI), or salt thereof.

69. The method of claim 67 or 68, wherein the compound of Formula (VIII) is of Formula (VIII- a):H0824.70444WO00 215 / 236 #14234830v1or a salt thereof.

70. The method of any one of claims 67-69, wherein the compound of Formula (VIII) is of Formula (VIII-a):or a salt thereof.

71. The method of any one of claims 67-70, wherein coupling the compound of Formula (VIII), or salt thereof, with the compound of Formula (IX), or salt thereof, comprises exposing the compound of Formula (VIII), or salt thereof, to a Lewis acid.

72. The method of claim 71, wherein the Lewis acid is CuSO4.

73. The method of any one of claims 67-72 further comprising oxidizing a compound of Formula (X):or a salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof.

74. The method of claim 73, wherein the compound of Formula (X) is of Formula (X-a):or a salt thereof.

75. The method of claim 73 or 74, wherein the compound of Formula (X) is of Formula (X-a):H0824.70444WO00 216 / 236 #14234830v1or a salt thereof.

76. The method of any one of claims 73-75, wherein oxidizing the compound of Formula (X), or salt thereof, under suitable conditions to provide the compound of Formula (VIII), or salt thereof, comprises exposing the compound of Formula (X), or salt thereof, to an oxidant.

77. The method of claim 76, wherein the oxidant is Dess-Martin periodinane (DMP).

78. The method of any one of claims 73-77 further comprising reacting a compound of Formula (XI):or a salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof.

79. The method of claim 78, wherein the compound of Formula (XI) is of Formula (XI-a):, or a salt thereof.

80. The method of claim 78 or 79, wherein reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a nucleophile.

81. The method of claim 80, wherein the nucleophile is bis(trimethylsilyl)sulfide.

82. The method of any one of claims 78-81, wherein reacting the compound of Formula (XI), or salt thereof, under suitable conditions to provide the compound of Formula (X), or salt thereof, comprises exposing the compound of Formula (XI), or salt thereof, to a Lewis acid.

83. The method of claim 82, wherein the Lewis acid is trimethylsilyl triflate.H0824.70444WO00 217 / 236 #14234830v184. The method of any one of claims 78-83, further comprising reacting a compound of Formula (XII):or a salt thereof, under suitable conditions to provide the compound of Formula (XI), or salt thereof, wherein R16is a leaving group.

85. The method of claim 84, wherein the compound of Formula (XII) is of Formula (XII-a):, or a salt thereof.

86. The method of any one of claims 1-85, wherein A is substituted or unsubstituted heterocyclyl.

87. The method of any one of claims 1-86, wherein A is substituted or unsubstituted 4-8 membered monocyclic heterocyclyl, or substituted or unsubstituted fused bicyclic heterocyclyl.

88. The method of any one of claims 1-87, wherein A is substituted or unsubstituted 4-8 membered monocyclic heterocyclyl.

89. The method of any one of claims 1-88, wherein A is of formula:, wherein: n is 1, 2, or 3; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; Each occurrence of R9is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted orH0824.70444WO00 218 / 236 #14234830v1unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN,.

91. The method of any one of claims 1-87, wherein A is substituted or unsubstituted fused bicyclic heterocyclyl.

92. The method of any one of claims 1-87 and 91, wherein A is of formula:, wherein: B is carbocyclyl or heterocyclyl; R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –S(O)2RA, or a nitrogen protecting group; each occurrence of R9is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN,H0824.70444WO00 219 / 236 #14234830v1–C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, -OS(O)2RA, or -S(O)2RA; or two R9groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; and p is 0-4.

93. The method of claim 92, wherein A is of formula:, wherein: X is O, S, NR9or C(R9)2; Y is O, S, N, NR9, C(R9)2, CR9, CH2, or CH; n is 0 or 1; p is 0-4; and represents a single or double bond.

94. The method of claim 93, wherein: Ais of formula:.. The method of claim 93 or 94, wherein: A is of formula:.

96. The method of any one of claims 93-95, wherein: A is of formula:.H0824.70444WO00 220 / 236 #14234830v197. The method of any one of claims 92-96, wherein: A is of formula:.

98. The method of any one of claims 92-97, wherein: A is of formula:.

99. The method of any one of claims 92-98, wherein: A is of formula:.

100. The method of any one of claims 92-99, wherein:.

101. The method of any one of claims 92-100, wherein:H0824.70444WO00 221 / 236 #14234830v1A is of formula:.

102. The method of any one of claims 92-101, wherein: A is of formula:.

103. The method of any one of claims 1-102, wherein R7is hydrogen.

104. The method of any one of claims 89, 90, and 92-103, wherein R8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or –C(=O)RA.

105. The method of any one of claims 92-104, wherein R8is hydrogen or substituted or unsubstituted alkyl.

106. The method of any one of claims 92-105, wherein R8is hydrogen or methyl.

107. The method of any one of claims 92-106, wherein R8is hydrogen.

108. The method of any one of claims 92-106, wherein R8is methyl.

109. The method of any one of claims 92-108, wherein at least one instance of R9is independently substituted or unsubstituted alkyl.

110. The method of any one of claims 92-109, wherein at least one instance of R9is independently substituted or unsubstituted C1-6 alkyl.H0824.70444WO00 222 / 236 #14234830v1111. The method of any one of claims 92-110, wherein at least one instance of R9is independently –CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or -CH(CH3)3.

112. The method of any one of claims 92-111, wherein at least one instance of R9is independently -CH2CH(CH3)2.

113. The method of any one of claims 1-112, wherein each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

114. The method of any one of claims 1-113, wherein each occurrence of R2is, independently, hydrogen, halogen, or substituted or unsubstituted alkyl.

115. The method of claim 1, wherein the compound of Formula (I) is:H0824.70444WO00 223 / 236 #14234830v1H0824.70444WO00 224 / 236 #14234830v1H0824.70444WO00 225 / 236 #14234830v1H0824.70444WO00 226 / 236 #14234830v1H0824.70444WO00 227 / 236 #14234830v1H0824.70444WO00 228 / 236 #14234830v1or pharmaceutically acceptable salt thereof.H0824.70444WO00 229 / 236 #14234830v1116. The method of claim 1 or 2, wherein the compound of Formula (II) is:, or salt thereof.

117. The method of claim 1 or 2, wherein the compound of Formula (IV) is: ,, , ,H0824.70444WO00 230 / 236 #14234830v1, or a salt thereof.

118. The method of claim 24 or 25, wherein the compound of Formula (V) is:, or a salt thereof.

119. The method of claim 54 or 55, wherein the compound of Formula (VI) is:, or a salt thereof.

120. The method of claim 54 or 55, wherein the compound of Formula (VII) is:H0824.70444WO00 231 / 236 #14234830v1or a salt thereof.

121. A compound of Formula (IV):or a salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, –NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, –OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group;H0824.70444WO00 232 / 236 #14234830v1R12is substituted or unsubstituted alkyl; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

122. The compound of claim 121, wherein the compound is: ,H0824.70444WO00 233 / 236 #14234830v1or a salt thereof.

123. A compound of Formula (V):or a salt thereof, wherein: each occurrence of R′ is independently hydrogen, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom; each R1is independently a bond, –CR2R2–, =CR2–, –CR2=, ≡C–, –C≡, =N–, –N=, –NR2–, –O–, or –S–; R1ais –NR2–, –O–, or –S–; each occurrence of R2is, independently, hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, –ORA, –N(RA)2, –SRA, –CN, –SCN, –C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2,–NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; or two R2groups are joined to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; R7is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or nitrogen protecting group; R12is substituted or unsubstituted alkyl; R13is a leaving group; q is 3, 4, 5, or 6; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted orH0824.70444WO00 234 / 236 #14234830v1unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, 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 RAgroups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

124. The compound of claim 123, wherein the compound is:, or a salt thereof.H0824.70444WO00 235 / 236 #14234830v1

Images